KontRASt-06: An Open-label Phase II Trial Evaluating the Activity and Safety of JDQ443 Single-agent as First-line Treatment for Patients With Locally Advanced or Metastatic KRAS G12C-mutated Non-small Cell Lung Cancer With a PD-L1 Expression < 1% or a PD-L1 Expression ≥ 1% and an STK11 Co-mutation.
Phase: PHASE2
Conditions: Locally Advanced or Metastatic KRAS G12C-mutated NSCLC With a PD-L1 Expression <1% or a PD-L1 Expression ≥ 1% and an STK11 Co-mutation
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
JDQ443 
Clinical Trial Protocol CJDQ443B12201 
KontRASt-06: An open-label phase II trial evaluating the 
activity and safety of JDQ443 single-agent as first-line 
treatment for patients with locally advanced or metastatic 
KRAS G12C-mutated non-small cell lung cancer with a PD-
L1 expression < 1% or a PD-L1 expression ≥ 1% and an 
STK11 co-mutation. 
Document type: 
Amended Protocol Version 
Regulatory Agency Identifier 
Number(s): 
EudraCT: 2022-001088-29 and US IND: 
152,296 
Version number: 
01 (Clean) 
Clinical Trial Phase: 
II 
Release date: 
06-Jun-2023 (content final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 5.0 dated 14-Jan-2022 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 8 
Amendment 01 (06-June-2023) ........................................................................................... 9 
1 
Protocol summary .............................................................................................................. 13 
1.1 
Summary ................................................................................................................ 13 
1.2 
Schema ................................................................................................................... 17 
1.3 
Schedule of activities (SoA) .................................................................................. 17 
2 
Introduction ....................................................................................................................... 29 
2.1 
Study rationale ....................................................................................................... 29 
2.2 
Background ............................................................................................................ 29 
2.2.1 
Overview of non-small cell lung cancer (NSCLC) pathogenesis, 
epidemiology and treatment .................................................................. 29 
2.2.2 
KRAS mutation in NSCLC ................................................................... 30 
2.2.3 
KRAS mutation as a therapeutic target in NSCLC ............................... 31 
2.2.4 
Rationale to evaluate JDQ443 as first-line treatment for selected 
patients with NSCLC ............................................................................ 38 
2.3 
Benefit/Risk assessment ........................................................................................ 39 
3 
Objectives, endpoints, and estimands ................................................................................ 39 
3.1 
Primary estimands ................................................................................................. 41 
3.2 
Secondary estimands ............................................................................................. 42 
4 
Study design ...................................................................................................................... 44 
4.1 
Overall design ........................................................................................................ 44 
4.2 
Scientific rationale for study design ...................................................................... 45 
4.3 
Justification for dose .............................................................................................. 46 
4.4 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 46 
4.5 
Rationale for public health emergency mitigation procedures .............................. 46 
4.6 
Purpose and timing of interim analyses/design adaptations .................................. 46 
4.7 
End of study definition .......................................................................................... 47 
5 
Study population ................................................................................................................ 47 
5.1 
Inclusion criteria .................................................................................................... 47 
5.2 
Exclusion criteria ................................................................................................... 48 
5.3 
Screen failures ....................................................................................................... 51 
5.3.1 
Participant numbering ........................................................................... 52 
6 
Study treatment(s) and concomitant therapy ..................................................................... 53 

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6.1 
Study treatment(s) .................................................................................................. 53 
6.1.1 
Additional study treatments .................................................................. 53 
6.1.2 
Treatment arms/group ........................................................................... 53 
6.1.3 
Guidelines for continuation of treatment .............................................. 53 
6.1.4 
Treatment duration ................................................................................ 54 
6.2 
Preparation, handling, storage, and accountability ................................................ 55 
6.2.1 
Handling of study treatment .................................................................. 55 
6.2.2 
Handling of other treatment .................................................................. 56 
6.2.3 
Instruction for prescribing and taking study treatment ......................... 56 
6.3 
Measures to minimize bias: randomization and blinding ...................................... 57 
6.3.1 
Treatment assignment, randomization .................................................. 57 
6.3.2 
Treatment blinding ................................................................................ 57 
6.3.3 
Emergency breaking of assigned treatment code .................................. 57 
6.4 
Study treatment compliance .................................................................................. 57 
6.5 
Dose modification .................................................................................................. 58 
6.5.1 
Dose modification guidelines ................................................................ 58 
6.5.2 
Definitions of dose limiting toxicities (DLTs) ...................................... 66 
6.5.3 
Follow-up for toxicities ......................................................................... 66 
6.6 
Continued access to study treatment after the end of the study ............................. 69 
6.6.1 
Post-trial access ..................................................................................... 69 
6.7 
Treatment of overdose ........................................................................................... 69 
6.7.1 
Reporting of study treatment errors including misuse/abuse ................ 69 
6.8 
Concomitant and other therapy .............................................................................. 70 
6.8.1 
Concomitant therapy ............................................................................. 70 
6.8.2 
Prohibited medication ........................................................................... 71 
7 
Discontinuation of study treatment and participant discontinuation/withdrawal .............. 72 
7.1 
Discontinuation of study treatment ........................................................................ 72 
7.1.1 
Follow-up for safety evaluations ........................................................... 73 
7.1.2 
Follow-up for efficacy evaluations and PROs ...................................... 73 
7.1.3 
Overall Survival .................................................................................... 73 
7.2 
Participant discontinuation from the study ............................................................ 74 
7.3 
Withdrawal of informed consent and exercise of participants’ data privacy 
rights ...................................................................................................................... 74 
7.4 
Lost to follow-up ................................................................................................... 75 
7.5 
Early study termination by the Sponsor ................................................................. 75 
8 
Study Assessments and Procedures ................................................................................... 75 

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8.1 
Molecular pre-screening ........................................................................................ 76 
8.2 
Screening ............................................................................................................... 79 
8.2.1 
Eligibility screening .............................................................................. 79 
8.3 
Participant demographics/other baseline characteristics ....................................... 79 
8.4 
Efficacy assessments ............................................................................................. 80 
8.4.1 
Tumor assessment ................................................................................. 80 
8.4.2 
Appropriateness of efficacy assessments .............................................. 85 
8.5 
Safety assessments ................................................................................................. 85 
8.5.1 
Physical examinations ........................................................................... 86 
8.5.2 
Vital signs.............................................................................................. 86 
8.5.3 
Electrocardiograms ............................................................................... 86 
8.5.4 
Clinical safety laboratory tests .............................................................. 87 
8.5.5 
Pregnancy testing .................................................................................. 89 
8.5.6 
Appropriateness of safety measurements .............................................. 90 
8.6 
Additional assessments .......................................................................................... 90 
8.6.1 
Clinical Outcome Assessments (COAs) ............................................... 90 
8.7 
Adverse events (AEs), serious adverse events (SAEs), and other safety 
reporting ................................................................................................................. 93 
8.7.1 
Adverse events ...................................................................................... 93 
8.7.2 
Serious adverse events .......................................................................... 95 
8.7.3 
SAE reporting........................................................................................ 96 
8.7.4 
Pregnancy .............................................................................................. 97 
8.7.5 
Disease-related events and/or disease related outcomes not 
qualifying as AEs or SAEs .................................................................... 98 
8.8 
Pharmacokinetics ................................................................................................... 98 
8.8.1 
Pharmacokinetic blood collection and handling ................................... 99 
8.8.2 
Analytical method ............................................................................... 100 
8.9 
Biomarkers ........................................................................................................... 100 
8.9.1 
Use of residual biological samples ...................................................... 104 
8.10 
 assessments ............................................................................... 104 
9 
Statistical considerations ................................................................................................. 104 
9.1 
Analysis sets ........................................................................................................ 105 
9.2 
Statistical analyses ............................................................................................... 105 
9.2.1 
General considerations ........................................................................ 105 
9.2.2 
Participant demographics and other baseline characteristics .............. 106 
9.2.3 
Treatments ........................................................................................... 106 
9.3 
Primary endpoint(s)/estimand(s) analysis ............................................................ 106 
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9.3.1 
Definition of primary endpoint(s) ....................................................... 106 
9.3.2 
Statistical model, hypothesis, and method of analysis ........................ 106 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) .. 107 
9.3.4 
Handling of missing values not related to intercurrent event ............. 107 
9.3.5 
Multiplicity adjustment (if applicable) ................................................ 107 
9.3.6 
Sensitivity analyses ............................................................................. 107 
9.3.7 
Supplementary analysis ....................................................................... 107 
9.4 
Secondary endpoint(s)/estimand(s) analysis ........................................................ 108 
9.4.1 
Efficacy and/or pharmacodynamic endpoint(s) .................................. 108 
9.4.2 
Safety endpoints .................................................................................. 109 
9.4.3 
Pharmacokinetics ................................................................................ 111 
9.4.4 
Patient-reported outcomes ................................................................... 112 
9.5 
Exploratory endpoint(s)/estimand(s) analysis ..................................................... 113 
9.5.1 
Biomarkers .......................................................................................... 113 
9.5.2 
Pharmacokinetics ................................................................................ 114 
9.6 
(Other) Safety analyses ........................................................................................ 114 
9.7 
Other analyses ...................................................................................................... 114 
9.8 
Interim analysis .................................................................................................... 114 
9.8.1 
Primary endpoint: ORR in cohort A ................................................... 115 
9.8.2 
Key secondary endpoint: ORR in cohort B......................................... 115 
9.9 
Sample size determination ................................................................................... 116 
9.9.1 
Primary endpoint(s) ............................................................................. 116 
9.9.2 
Secondary endpoint(s) ......................................................................... 117 
10 Supporting documentation and operational considerations ............................................. 119 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations ................. 119 
10.1.1 
Regulatory and ethical considerations ................................................ 119 
10.1.2 
Informed consent process .................................................................... 120 
10.1.3 
Data protection .................................................................................... 121 
10.1.4 
Committees structure .......................................................................... 122 
10.1.5 
Data quality assurance ......................................................................... 122 
10.1.6 
Source documents ............................................................................... 123 
10.1.7 
Publication policy................................................................................ 124 
10.1.8 
Protocol adherence and protocol amendments .................................... 124 
10.2 
Appendix 2: Abbreviations and definitions ......................................................... 125 
10.2.1 
List of abbreviations ............................................................................ 125 
10.2.2 
Definitions ........................................................................................... 127 

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10.3 
Appendix 3: Clinical laboratory tests .................................................................. 129 
10.3.1 
Clinically notable laboratory values and vital signs ........................... 129 
10.4 
Appendix 4: Participant Engagement .................................................................. 129 
10.5 
Appendix 5: Liver safety monitoring .................................................................. 129 
10.6 
Appendix 6: Renal safety monitoring .................................................................. 133 
10.7 
Appendix 7: Drugs that are prohibited or to be used with caution while on 
JDQ443 treatment ................................................................................................ 135 
10.8 
Appendix 8: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival, and Overall Survival (based on RECIST 1.1) 137 
10.8.1 
Introduction ......................................................................................... 137 
10.8.2 
Efficacy assessments ........................................................................... 138 
10.8.3 
Efficacy definitions ............................................................................. 147 
10.8.4 
Data handling and programming rules ................................................ 156 
10.8.5 
References (available upon request) ................................................... 160 
11 References ....................................................................................................................... 161 
 
List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 13 
Table 1-2 
Allowable window for participant assessments .................................... 19 
Table 1-3 
Assessment Schedule ............................................................................ 20 
Table 3-1 
Objectives and related endpoints .......................................................... 40 
Table 4-1 
Rationale for study design ..................................................................... 45 
Table 6-1 
Investigational drug ............................................................................... 53 
Table 6-2 
Dose and treatment schedule ................................................................. 56 
Table 6-3 
Criteria for dose reduction / interruption and re-initiation of 
JDQ443 treatment for adverse drug reactions. ...................................... 59 
Table 6-4 
Dose reduction steps for JDQ443 ......................................................... 66 
Table 6-5 
Follow-up evaluations for selected toxicities ........................................ 67 
Table 6-6 
Guidance on specific clinical and diagnostic assessments .................... 68 
Table 8-1 
Imaging Assessment Collection Plan .................................................... 81 
Table 8-2 
Physical Assessments ............................................................................ 85 
Table 8-3 
ECOG Performance Status .................................................................... 86 
Table 8-4 
Central ECG collection plan ................................................................. 86 
Table 8-5 
Clinical laboratory parameters collection plan ..................................... 88 
Table 8-6 
PRO completion schedule if study treatment is delayed/rescheduled .. 93 

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Table 8-7 
PK blood collection log for JDQ443 treatment (intensive sampling; 
for approximately 10 participants in Cohort A and approximately 
10 participants in Cohort B) .................................................................. 99 
Table 8-8 
PK blood collection log for JDQ443 treatment (standard sampling; 
remaining participants in Cohort A and Cohort B) ............................. 100 
Table 8-9 
Biomarker sample collection plan ....................................................... 101 
Table 9-1 
JDQ443 plasma pharmacokinetic parameters - non-compartmental 
analysis ................................................................................................ 112 
Table 9-2 
PPoS at the primary analysis based on various numbers of 
responders observed at the IA ............................................................. 115 
Table 9-3 
PPoS at the final analysis based on various numbers of responders 
observed .............................................................................................. 116 
Table 9-4 
Exact binomial 95 percent confidence intervals for various sample 
sizes and observed ORRs (cohort A) .................................................. 117 
Table 9-5 
Operating Characteristics (cohort A) .................................................. 117 
Table 9-6 
Exact binomial 95 percent confidence intervals for various sample 
sizes and observed ORRs (cohort B) .................................................. 118 
Table 9-7 
Operating characteristics (cohort B) ................................................... 118 
Table 10-1 
Liver event and laboratory trigger definitions .................................... 130 
Table 10-2 
Follow-up requirements for liver laboratory triggers - ALT, AST, 
bilirubin ............................................................................................... 130 
Table 10-3 
Follow-up requirements for liver laboratory triggers - isolated 
hyperbilirubinemia .............................................................................. 131 
Table 10-4 
Specific renal alert criteria and actions ............................................... 133 
Table 10-5 
Renal event follow-up ......................................................................... 134 
Table 10-6 
Drugs to be prohibited while on treatment with JDQ443 ................... 135 
Table 10-7 
Drugs to be used with caution while on treatment with JDQ443 ....... 135 
Table 10-8 
Response criteria for target lesion ....................................................... 143 
Table 10-9 
Response criteria for non-target lesions .............................................. 145 
Table 10-10 
Overall response lesion to each assessment ........................................ 146 
Table 10-11 
Overall lesion response at each assessment: participants with non-
target disease only ............................................................................... 154 
Table 10-12 
Options for event dates used in PFS, TTP, duration of response ........ 155 
 

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List of figures 
Figure 1-1 
Study design .......................................................................................... 17 
Figure 2-1 
PK/PD Relationship of JDQ443 in MIA PaCa-2 and NCI-H2122 
tumor-bearing nude mice after a single oral treatment. ........................ 33 
Figure 2-2 
Anti-tumor activity after repeated treatments of MIA PaCa-2 and 
NCI-H2122 tumor-bearing nude mice. ................................................. 34 
Figure 7-1 
Study Flow ............................................................................................ 74 
 

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Amendment 01 (06-June-2023) 
Amendment rationale 
At the time of release of this amendment, the study has enrolled 
 participants.  
The primary purpose of this amendment is summarized as follows: 
• To update the inclusion criterion #8 to reduce the eligibility threshold for creatinine 
clearance from ≥60 mL/min to ≥45 mL/min by calculation using the Cockcroft-Gault 
equation. This is based on results from CJDQ443B12101 (hADME) study which showed 
that total radiolabeled drug/metabolites were almost exclusively excreted via feces (on 
average 
%). JDQ443 excretion in urine was 
 (
%). Upon analysis of AEs 
reported under the AESI of ‘renal toxicity’ from the FIH study CJDQ443A12101 (data cut 
off: 28-Oct-2022), the renal safety profile appears acceptable for this patient population 
based on the currently available data. 
• To modify the exclusion criteria #4 for CNS disease to allow more flexibility for 
eligibility of patients with stable brain metastasis following recent FDA guidance on 
eligibility criteria for brain metastasis [Cancer Clinical Trial Eligibility Criteria_Brain 
Metastases Guidance for Industry]) and for further clarity. As a consequence, criteria 
based on number of lesions and dimension is eliminated, and more details are given for 
definition of stable metastasis and allowed treatment. 
• To increase flexibility regarding material to be submitted for biomarker analyses at pre-
screening and C1D1. If a tumor block (preferred option) cannot be submitted at pre-
screening, tumor sections can be provided. The fixed number of 20 tumor sections to be 
sent to the central laboratory has been updated to a range of 16-20 tumor sections, 
allowing more flexibility. Similar flexibility has been implemented at C1D1, switching 
from fixed 10 tumor sections to a range of 6-10 tumor sections.  
• To specify that patient enrollment in China must be based on local results from tissue or 
blood in regards to PD-L1 expression, KRAS G12C status and STK11 mutation status 
(cohort B only) for the following reasons: (i) the central laboratory for these biomarker 
tests does not have facilities in China, (ii) samples cannot be exported outside China, (iii) 
and a China-based central assay with appropriate validation will not be ready until late 
stage of the study and will be dedicated to retrospective (post-enrollment) biomarker 
testing.  
Changes to the protocol  
• Table 1-1: FACT-GP5 endpoint moved from secondary to exploratory objective. FACT-
GP5 is included as exploratory to inform internal decision-making regarding development 
and tolerability. 
• Section 1.1: wording added to clarify that Steering committee’s members can include 
individuals who collectively have experience and expertise in leading the conduct of 
clinical studies within the disease area. 
• Figure 1-1: Added footnote to clarify that for Chinese patients, only local biomarker 
results can be used for enrollment. 
• Table 1-2: Added visit window for C1D15 as it was missed in original protocol. 
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• Table 1-3: 
• Added footnote #1 to clarify PD-L1 expression, KRAS G12C status and STK11 
mutation status (cohort B only) must be determined by local assessment in China. 
• Added footnote #4 with reference to specific sections and appendixes for the ad hoc 
hematological and/or biochemistry sampling required in case of toxicities. 
• Updated footnote #19 to define intensive PK sampling scheme and standard PK 
sampling scheme. 
• Removed “x” from EOT for Food consumption as it was inserted in error.  
• Section 3.2: Removed duplicate text 
• Section 4.5: updated as per new Clinical Trial Protocol template 
• Section 5.1:  
• Inclusion criteria #4 modified by removing information on non-validated assay 
regarding local results. Nevertheless, these specifications remain available in the 
biomarker section as mandatory requirements. 
• Inclusion criteria # 5 modified to clarify PD-L1 expression, KRAS G12C status and 
STK11 mutation status (cohort B only) status must be determined by local assessment 
in China  
• Inclusion criteria #5 “Mandatory provision of a formalin-fixed paraffin-embedded 
(FFPE) tumor tissue sample with at least 20% tumor content for the central 
assessment of KRAS G12C, PD-L1 and STK11 mutation status for all participants, 
including those who have biomarker status based on local tests.” has been removed. 
Nevertheless, these specifications remain available in the biomarker section as 
mandatory requirements.  
• Modified inclusion criteria #10 reducing the creatinine clearance limit for eligibility 
to the study from 60 mL/min to 45 mL/min, as discussed in the protocol amendment 
rationale section 
• Section 5.2: Modified exclusion criteria #4 for CNS disease as discussed in the protocol 
amendment rational section.  
• Section 6.2: added wording to clarify when pre-dose PK samples are collected  
• Table 6-3:  
• Dose modification guidance on ‘LVEF decreased’ was updated to include guidance 
when the ‘LVEF is 40% to ≤45% and decrease is <10% points from baseline’. Also, 
further updates made to clarify the next steps when there is no improvement in 
ejection fraction even after 3 weeks of interruption of study medication. 
• Grade 1 and 2 instructions added for ECG QTc interval prolonged and vascular 
disorders adverse drug reactions. 
• Wording updated for rash
 to indicate to treat participants per 
institutional practice. 
• Section 8.1:  
• Added text to clarify the patient enrollment in China will be based on local 
assessments only 
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• Added text to clarify rules for enrollment based on local biomarker results and sample 
collection for subsequent central analysis 
• Updated header from “Tissue requirements (all participants)” to “Sample 
requirements (all participants)”  
• Added wording to further detail the STK11 mutation status 
• Section 8.6.1: 
• Added text to define clinical outcome assessment (COAs), patient centricity and 
patient reported outcomes  
• Added text to clarify back-up options allowed for ePRO collections (web and 
interviewer modes). 
• Sections 8.7.1 and 8.7.3: Adjusted wording to fulfill Indian HA new regulations on SAE 
reporting 
• Section 8.7.5: Added following wording to fulfill Indian HA new regulations on SAE 
reporting ‘If more stringent, local regulations regarding reporting criteria and timelines 
prevail.’ 
• Section 8.8.1:  
• Added text to clarify PK blood collection log for participants in China vs outside of 
China.  
• Changed number of participants to be recruited for intensive PK to approximately 10 
participants per cohort (was 10 participants prior). 
• Table 8-7 and Table 8-8: Tables modified to have the same sample number and 
reference ids for both cohorts A and B 
• Section 8.9: Added text to clarify PD-L1 expression, KRAS G12C status and STK11 
mutation status (cohort B only) must be determined by local assessment for China. 
• Section 8.9.1: Language changes to allow more flexibility on additional research. 
• Table 8-9: Removal of fresh tissue biopsy submission at pre-screening; implementation of 
a range of tumor sections to be submitted at pre-screening and C1D1 allowing more 
flexibility; as well as highlighting “Where available” at C1D1 for tissue submission. 
• Section 9.4.4. Editorial changes made to PROs section to ensure PRO and endpoint text 
aligned correctly with PROs and endpoints in objectives table (Table 1-1) 
• Section 10.6 Appendix 6: Updated based on updated Novartis renal safety guidelines (Drug 
Induced Nephrotoxicity) version 2.0 and the corresponding table 10-4 and 10-5 were 
updated. Following the update, the major change with respect to ‘alert criteria’ is the 
monitoring based on creatinine clearance results instead of serum creatinine levels (since 
creatinine clearance is preferred in evaluating renal events over serum creatinine values 
alone, as transient increases in serum creatinine may occur as a result of non-renal factors, 
such as changes in hydration status in conditions such as vomiting or dehydration as well 
as diet or exercise). 
• Minor editorial changes (i.e., typographical errors, grammatical changes, spelling, 
rewording) to improve flow, accuracy/understandability, and consistency have been made 
throughout the protocol.  

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Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.  

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1 
Protocol summary 
1.1 
Summary 
Protocol Title: 
KontRASt-06: An open-label phase II trial evaluating the activity and safety of JDQ443 single-
agent as first-line treatment for patients with locally advanced or metastatic KRAS G12C-
mutated non-small cell lung cancer with a PD-L1 expression < 1% or a PD-L1 expression ≥ 1% 
and an STK11 co-mutation. 
Brief Title: 
Study of efficacy and safety of JDQ443 single-agent as first-line treatment for patients with 
locally advanced or metastatic KRAS G12C- mutated non-small cell lung cancer with a PD-L1 
expression < 1% or a PD-L1 expression ≥ 1% and an STK11 co-mutation. 
Purpose 
This study aims to evaluate the antitumor activity and safety of JDQ443 single-agent as first-
line treatment for participants with locally advanced or metastatic non-small cell lung cancer 
(NSCLC) whose tumors harbor a KRAS G12C mutation and have a PD-L1 expression < 1% 
(cohort A) or a PD-L1 expression ≥ 1% and an STK11 co-mutation (cohort B). 
Study Indication /Medical Condition: 
Locally advanced or metastatic KRAS G12C- mutated non-small cell lung cancer with a PD-
L1 expression < 1% or a PD-L1 expression ≥ 1% and an STK11 co-mutation. 
Treatment type 
Drug 
Study type 
Interventional 
Objectives and Endpoints: 
Table 1-1 
Objectives and related endpoints 
Objectives 
Endpoints 
Primary 
 
• To assess the antitumor activity of JDQ443 single-
agent as first-line treatment for participants with 
locally advanced or metastatic NSCLC whose 
tumors harbor a KRAS G12C mutation and a PD-
L1 expression < 1%, regardless of STK11 mutation 
status (cohort A). 
• Overall response rate (ORR), defined as the 
proportion of participants with a confirmed 
complete response (CR) or partial response (PR) 
as best overall response (BOR) per Response 
Evaluation Criteria in Solid Tumors version 1.1 
(RECIST 1.1) by blinded independent review 
committee (BIRC). 

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Key Secondary 
 
• To assess the antitumor activity of JDQ443 single-
agent as first-line treatment for participants with 
locally advanced or metastatic NSCLC whose 
tumors harbor a KRAS G12C mutation, a PD-L1 
expression ≥1% and an STK11 co-mutation 
(cohort B). 
• ORR per RECIST 1.1 by BIRC. 
• To assess duration of response (DOR) in both 
cohorts. 
• DOR, defined as the time from the first occurrence 
of a PR or a CR per RECIST 1.1 by BIRC to the 
occurrence of disease progression or death due to 
any cause. 
Secondary 
 
• To assess progression-free survival (PFS) in both 
cohorts. 
• PFS, defined as the time from the date of 
enrollment to the date of the first documented 
disease progression per RECIST 1.1 by BIRC or 
date of death due to any cause. 
• To assess overall survival (OS) in both cohorts. 
• OS, defined as the time from the date of 
enrollment to the date of death due to any cause. 
• To assess the antitumor activity of JDQ443 single-
agent in both cohorts. 
• Disease control rate (DCR), defined as the 
proportion of participants with a BOR of confirmed 
CR, PR and stable disease (SD) per RECIST 1.1 
by BIRC. 
Time to response (TTR), defined as the time from 
the date of enrollment to the first documented 
response of either CR or PR per RECIST 1.1 by 
BIRC. 
• To assess the antitumor activity of JDQ443 single-
agent in both cohorts according to local radiology 
assessment. 
• ORR, DOR, DCR, TTR and PFS per RECIST 1.1 
by local radiology assessment. 
• To assess the antitumor activity of JDQ443 single-
agent as first-line treatment for participants whose 
tumors harbor an STK11 mutation regardless of 
PD-L1 expression status (pooled from both 
cohorts). 
• ORR, DOR, DCR and TTR per RECIST 1.1 by 
BIRC and by local radiology assessment. 
 
• To assess PFS and OS in participants whose 
tumors harbor an STK11 mutation regardless of 
PD-L1 expression status (pooled from both 
cohorts). 
• PFS and OS 
• To characterize the safety profile of JDQ443. 
• Type, frequency and severity of adverse events, 
changes in laboratory values, vital signs, 
electrocardiograms (ECGs). 
• To characterize the pharmacokinetics of JDQ443 
in both cohorts. 
• Concentration of JDQ443 in plasma and derived 
PK parameters, as appropriate. 
• To assess the effect of JDQ443 on patient 
reported lung cancer symptoms, health related 
quality of life, health state utility and health status. 
• Time to definitive deterioration (TTDD) in the Non-
Small Cell Lung Cancer Symptom Assessment 
Questionnaire (NSCLC-SAQ) total score (TS), and 
TTDD in the physical functioning (PF) scale of the 
EORTC QLQ-C30  
• Change from baseline to each scheduled 
assessment and to EOT for NSCLC-SAQ total 
score and for each NSCLC-SAQ items/domains. 
• Change from baseline to each scheduled 
assessment and to EOT for all EORTC QLQ-C30 
domains, subscales and items  

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Amended Protocol Version No.01 (Clean) 
 
Protocol No. CJDQ443B12201 
 
Trial Design: 
This is a non-randomized, open-label, single-arm, multicenter, phase II study evaluating the 
antitumor activity and safety of JDQ443 single-agent as first-line treatment for participants with 
locally advanced or metastatic KRAS G12C-mutated NSCLC (Figure 1-1). 
The study will have 2 non-comparative cohorts that will recruit participants in parallel 
according to the following characteristics: 
• Cohort A: participants whose tumors harbor a KRAS G12C mutation and a PD-L1 
expression < 1%, regardless of STK11 mutation status (N=90). 
• Cohort B: participants whose tumors harbor a KRAS G12C mutation, a PD-L1 
expression ≥ 1% and an STK11 co-mutation (N=30). 
Brief Summary: 
This study aims to assess the antitumor activity and safety of JDQ443 single-agent as first-line 
treatment for participants with locally advanced or metastatic NSCLC whose tumors harbor a 
KRAS G12C mutation and a PD-L1 expression < 1% regardless of STK11 mutation status 
(cohort A), or a PD-L1 expression ≥ 1% and an STK11 co-mutation (cohort B). 
For this study, the term "study treatment" refers to Novartis study drug JDQ443. 
The study treatment begins on Cycle 1 Day 1 (C1D1) with the first administration of JDQ443. 
Study completion is defined as the earliest occurrence of one of the following: 
• The last participant completes last study visit (and the assessments associated with this 
visit have been documented and followed-up appropriately by the Investigator), dies, 
withdraws consent, or is lost to follow-up, whichever comes first.] 
• In the event of an early study termination decision, the date of that decision. 
• Another clinical study becomes available that can continue to provide JDQ443 to study 
participants and all participants with ongoing treatment are transferred to that clinical 
study. 
Treatment Duration: 
Discontinuation from study treatment is required under the following circumstances: 
• Participant/guardian decision 
• Investigator decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Disease progression per RECIST 1.1 confirmed by BIRC. In some circumstances, 
participants treated with JDQ443 may be allowed to continue to receive study treatment 
beyond disease progression per RECIST 1.1 confirmed by BIRC (Section 6.1.4.1). 
• Adverse event requiring permanent discontinuation of study treatment 

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Amended Protocol Version No.01 (Clean) 
Protocol No. CJDQ443B12201 
•
Protocol deviation that results in a significant risk to participant's safety
•
Withdrawal of consent
•
Study is terminated by the sponsor
•
Death
•
Lost to follow-up
Visit Frequency:
Study visits will occur as per Table 1-3.
Treatment of interest 
The following agent will be administered to all participants as study treatment: 
•
JDQ443 per os (PO) 200 mg twice a day continuously.
One treatment cycle consists of 21 (±3) days.
Number of Participants: 
A total of 120 participants will be enrolled in 2 separate cohorts (90 in Cohort A and 30 in 
Cohort B). 
Key Inclusion criteria 
•
Histologically confirmed locally advanced (stage IIIb/IIIc not eligible for definitive
chemoradiation or surgical resection with curative intent) or metastatic (stage IV) NSCLC
without previous systemic treatment for metastatic disease. Prior (neo)adjuvant treatment
with chemotherapy and/or immunotherapy, or prior radiotherapy administered
sequentially or concomitantly with chemotherapy and/or immunotherapy for localized or
locally advanced disease are accepted if the time between therapy completion and
enrollment is > 12 months.
•
Presence of a KRAS G12C mutation (all participants) and:
•
Cohort A: PD-L1 expression < 1%, regardless of STK11 mutation status
•
Cohort B: PD-L1 expression ≥ 1% and an STK11 co-mutation
•
At least one measurable lesion per RECIST 1.1.
•
ECOG performance status ≤ 1.
•
Participants capable of swallowing study medication.
Key Exclusion criteria 
•
Participants whose tumors harbor an EGFR-sensitizing mutation and/or ALK
rearrangement by local laboratory testing. Participants with other known druggable
alterations will be excluded, if required by local guidelines
•
Previous use of a KRAS G12C inhibitor or previous systemic treatment for metastatic
NSCLC.
•
A medical condition that results in increased CCI

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Amended Protocol Version No.01 (Clean) 
Protocol No. CJDQ443B12201 
•
Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
•
Participants who are taking a prohibited medication (strong CYP3A inducers) that cannot
be discontinued at least seven days prior to the first dose of study treatment and for the
duration of the study
Treatment Groups: 
The study will have 2 non-comparative cohorts that will recruit participants in parallel 
according to the following characteristics: 
•
Cohort A: participants whose tumors harbor a KRAS G12C mutation and a PD-L1
expression < 1%, regardless of STK11 mutation status
•
Cohort B: participants whose tumors harbor a KRAS G12C mutation, a PD-L1
expression ≥ 1% and an STK11 co-mutation
Data Monitoring/Other Committee: Yes (see Section 10.1.4 Committees 
Structure) 
A Steering Committee (SC) will be established comprising of Investigators participating in the 
trial, or individuals who collectively have experience and expertise in leading the conduct of 
clinical studies within this disease area and Novartis representatives from the Clinical Trial 
Team to ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. 
1.2 
Schema 
Figure 1-1 
Study design 
*KRAS G12C and STK11 mutational status and PD-L1 expression status will be assessed locally or at
the Novartis-designed central laboratory where local testing is not available for any of the applicable
biomarkers (For participants in China only: central testing is not available. Only local results can be
used for enrollment). Participants with local results for all applicable biomarkers may directly proceed
to main screening after signing both the molecular pre-screening ICF and the main ICF.
1.3 
Schedule of activities (SoA) 
The SoA lists all the assessments when they are performed. All data obtained from these 
assessments must be supported in the participant’s source documentation. The “X” in the table 
denotes the assessments to be recorded in the clinical database or received electronically from 
a vendor. The “S” in the table denotes the assessments that are only in the participant’s source 
documentation and do not need to be recorded in the clinical database. 

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Amended Protocol Version No.01 (Clean) 
Protocol No. CJDQ443B12201 
Participants should be seen for all visits/assessments as outlined in the SoA or as close to the 
designated day/time as possible. Missed or rescheduled visits should not lead to automatic 
discontinuation. 
Participants who discontinue from study treatment are to complete the end of treatment visit as 
soon as possible and attend the follow-up visits as indicated in the SoA. 
Participants who discontinue from study should be scheduled for a final evaluation visit if they 
agree, as soon as possible, at which time all the assessments listed for the final visit will be 
performed. At this final visit, all dispensed investigational product should be reconciled, and 
the adverse events and concomitant medications not previously reported must be recorded on 
the eCRF. 
PRO measure(s) must be completed before any clinical assessments are performed at any given 
visit. 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural disaster that limits or prevents on-site study visits, alternative
methods of providing continuing care may be implemented by the Investigator as the situation
dictates. If allowable by a local health authority, national and local regulations and depending
on operational capabilities, phone calls, virtual contacts (e.g., tele consultation) or visits by site
staff/ off-site healthcare professional(s) staff to the participant´s home, can replace certain
protocol assessments, for the duration of the disruption until it is safe for the participant to visit
the site again. If the Investigator delegates tasks to an off-site healthcare professional, the
Investigator must ensure the individual(s) is/are qualified and appropriately trained to perform
assigned duties. The Investigator must oversee their conduct and remain responsible for the
evaluation of the data collected.
Signed informed consent must be obtained before any study specific assessments are 
performed, including those at molecular pre-screening and screening. 
Main screening evaluations and baseline radiological tumor assessments should be performed 
within 28 days (and 42 days for whole body scan) of treatment start. 
Laboratory assessments performed as part of the screening evaluations will not be required to 
be repeated on the first day of dosing (C1D1) (except for hematology/chemistry and serum 
pregnancy test if not done within 72 hours prior to treatment start) unless deemed clinically 
necessary by the Investigator and/or required as per local institutional policies. 
Study treatment will begin on C1D1 with the first administration of the study treatment. 
Treatment cycles are intended to last 3 weeks (21 days), but the treatment can be interrupted in 
order to manage toxicities according to the dose modification criteria in Section 6.5. 
Please refer to Table 1-2 for allowable visits window. 

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Amended Protocol Version No.01 (Clean) 
Protocol No. CJDQ443B12201 
Table 1-2 
Allowable window for participant assessments 
Visit name 
Window 
Screening 
-28 days from the first dose of study treatment (-42 days for whole body scan)
C1D1 
Within 3 days after IRT enrollment
C1D15 onwards 
± 3 days
Imaging evaluations 
± 7 days
ePRO (completion at home) 
Within 3 days prior to the scheduled assessment 
EOT 
Within 7 days after stopping study treatment 
30-day safety follow-up
+ 7 days
Survival
± 14 days

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Clinical Trial Protocol Version No.01(Clean) 
Protocol No. CJDQ443B12201 
Table 1-3 
Assessment Schedule 
Period 
Screening 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Visit Name 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
onwards 
EOT 
Safety follow-up (30 
days after last 
administration of study 
treatment) 
Efficacy 
follow-up 
Survival follow-
up (every 12 
weeks) 
Days 
0 
-28 to -1
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
- 
- 
- 
- 
Molecular Pre-
screening 
Informed Consent 
X 
PD-L1 expression 
status per 
participant's 
record (local test 
result) or central 
test result 
X 
Confirmation of 
KRAS G12C 
mutation status in 
tumor tissue or 
blood as per 
existing local 
result or central 
test when local is 
not available1 
X 
Confirmation of 
STK11 mutation 
status in tumor 
tissue or blood as 
per existing local 
result or central 
test when local is 
not available (For 
cohort B only)1 
X 

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Clinical Trial Protocol Version No.01(Clean) 
 
Protocol No. CJDQ443B12201 
 
Period 
Screening 
Treatment 
Follow-up 
Cycle 
 
Cycle 1 
 
Visit Name 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
onwards 
EOT 
Safety follow-up (30 
days after last 
administration of study 
treatment) 
Efficacy 
follow-up 
Survival follow-
up (every 12 
weeks) 
Days 
0 
-28 to -1 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
- 
- 
- 
- 
Tumor sample for 
assessment of 
PD-L1 
expression, KRAS 
G12C mutation 
and STK11 
mutation status 
and diagnostic 
development2 
X3 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
KRAS 
G12C/STK11 
assessment and 
diagnostic 
development2 
X3 
X 
 
 
 
 
 
 
 
 
 
Collection of ALK 
rearrangement 
status, EGFR-
sensitizing 
mutations and 
other known 
druggable 
alterations per 
local test 
 
X 
 
 
 
 
 
 
 
 
 
Main Informed 
Consent 
 
X 
 
 
 
 
 
 
 
 
 
IRT Registration 
X 
X 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 

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Clinical Trial Protocol Version No.01(Clean) 
Protocol No. CJDQ443B12201 
Period 
Screening 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Visit Name 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
onwards 
EOT 
Safety follow-up (30 
days after last 
administration of study 
treatment) 
Efficacy 
follow-up 
Survival follow-
up (every 12 
weeks) 
Days 
0 
-28 to -1
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
- 
- 
- 
- 
Diagnosis, stage 
and grade of 
cancer 
X 
Medical 
history/current 
medical 
conditions 
X 
Smoking / Vaping 
history 
X 
Prior/concomitant 
medications 
From 28 days prior to starting study treatment until 30 day after the last dose or start of new antineoplastic medications, whichever is sooner. After 
starting a new antineoplastic medications, only report concomitant medications for AEs/ SAEs suspected to be related to study treatment. 
Non-drug 
therapies and 
procedures 
From 28 days prior to starting study treatment until 30 day after the last dose or start of new antineoplastic medications, whichever is sooner. After 
starting a new antineoplastic medications, only report non-drug therapies/procedures for AEs/ SAEs suspected to be related to study treatment. 
Prior anti-
neoplastic 
therapies 
(medications, 
surgery, 
radiotherapy) 
X 
IRT Enrollment 
X 
Physical 
Examination 
S 
S 
S 
S 
S 
S 
ECOG 
performance 
status 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
Body Height 
X 
Body Weight 
X 
X 
X 
X 
X 
X 
Hematology4 
X 
X 
X 
X 
X 
X 
X 
X 

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Clinical Trial Protocol Version No.01(Clean) 
Protocol No. CJDQ443B12201 
Period 
Screening 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Visit Name 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
onwards 
EOT 
Safety follow-up (30 
days after last 
administration of study 
treatment) 
Efficacy 
follow-up 
Survival follow-
up (every 12 
weeks) 
Days 
0 
-28 to -1
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
- 
- 
- 
- 
Blood Chemistry4 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
As clinically indicated 
Hepatitis B virus 
(HBV) or hepatitis 
C virus infection, 
tuberculosis 
and/or HIV testing 
(if required by 
local regulations) 
S 
Urinalysis 
X 
X 
X 
X 
X 
X 
Serum pregnancy 
test 
S5 
S 
Urine pregnancy 
test6 
S 
S 
S 
NSCLC-SAQ7 
Day 1 of Cycle 1, then every 7 days until cycle 3. 
Then on Day 1 only starting at Cycle 4 for all Cycles 
thereafter 
X 
Every 12 
weeks and 
at disease 
progression 
per 
RECIST 
1.17 
Post disease 
progression, 
every 12 weeks 
for a minimum of 
3 timepoints 
EORTC QLQ- 
C307 
Day 1 of Cycle 1, Cycle 2, Cycle 3 and then every 3 
cycles thereafter 
X 
Every 12 
weeks and 
at disease 
progression 
per 
RECIST 
1.17 
Post disease 
progression, 
every 12 weeks 
for a minimum of 
3 timepoints 

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Clinical Trial Protocol Version No.01(Clean) 
Protocol No. CJDQ443B12201 
Period 
Screening 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Visit Name 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
onwards 
EOT 
Safety follow-up (30 
days after last 
administration of study 
treatment) 
Efficacy 
follow-up 
Survival follow-
up (every 12 
weeks) 
Days 
0 
-28 to -1
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
- 
- 
- 
- 
FACT GP57 
Day 8 of Cycle 1, then every 7 days until cycle 3. 
Then on Day 1 only starting at Cycle 4 for all Cycles 
thereafter 
X 
Every 12 
weeks and 
at disease 
progression 
per 
RECIST 
1.17 
Post disease 
progression, 
every 12 weeks 
for a minimum of 
3 timepoints 
PRO CTCAE7 
Day 1 of Cycle 1, then every 7 days until cycle 3. 
Then on Day 1 only starting at Cycle 4 for all Cycles 
thereafter 
X 
Every 12 
weeks and 
at disease 
progression 
per 
RECIST 
1.16 
Post disease 
progression, 
every 12 weeks 
for a minimum of 
3 timepoints 
Patient Global 
Impression of 
Severity of 
Symptoms-
NSCLC 
symptoms) 
(PGIS-NSCLC)7 
Day 1 of Cycle 1, then every 7 days until cycle 3. 
Then on Day 1 only starting at Cycle 4 for all Cycles 
thereafter 
X 
Every 12 
weeks and 
at disease 
progression 
per 
RECIST 
1.17 
Post disease 
progression, 
every 12 weeks 
for a minimum of 
3 timepoints 
EQ5D-5L7 
Day 1 of Cycle 1, Cycle 2, Cycle 3 and then every 3 
cycles thereafter 
X 
Every 12 
weeks and 
at disease 
progression 
per 
RECIST 
1.17 
Post disease 
progression, 
every 12 weeks 
for a minimum of 
3 timepoints 
Blood plasma for 
exploratory 
analysis of 
X 
X 
C3 day 1 
X 

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Clinical Trial Protocol Version No.01(Clean) 
Protocol No. CJDQ443B12201 
Period 
Screening 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Visit Name 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
onwards 
EOT 
Safety follow-up (30 
days after last 
administration of study 
treatment) 
Efficacy 
follow-up 
Survival follow-
up (every 12 
weeks) 
Days 
0 
-28 to -1
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
- 
- 
- 
- 
 
(collected before 
treatment 
administration) 
CT or MRI of 
chest, abdomen 
and pelvis 
X 
Every 6 weeks counting from C1D1 up to 54 weeks and every 12 weeks thereafter until disease 
progression (by RECIST 1.1) is confirmed by BIRC 
CT or MRI of 
brain 
X 
If brain metastases are present at baseline: Every 6 weeks counting from C1D1 up to 54 weeks and 
every 12 weeks thereafter until disease progression (by RECIST 1.1) is confirmed by BIRC. 
If no brain metastases at baseline: Every 12 weeks counting from C1D1 until disease progression (by 
RECIST 1.1) is confirmed by BIRC 
Whole body bone 
scan 
X9 
If clinically indicated 
CT scan or MRI of 
other metastatic 
sites 
If clinically 
indicated 
If positive at baseline, follow same schedule as CT/MRI of chest, abdomen and pelvis. Otherwise, if 
clinically indicated. 
Localized bone 
CT, MRI or X-Ray 
X10
If positive at baseline, follow same schedule as CT/MRI of chest, abdomen and pelvis. Otherwise, if 
clinically indicated. 
Photography (for 
any skin lesions) 
X11 
If positive at baseline, follow same schedule as CT/MRI of chest, abdomen and pelvis. Otherwise, if 
clinically indicated. 
Electrocardiogram 
(ECG)12 
X 
X13 
X13 
If clinically indicated 
X 
Cardiac imaging 
(echocardiogram 
or CMR) 
X 
X 
If clinically indicated 
X 
Drug 
administration 
(JDQ443) 
Daily 
CCI 

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Clinical Trial Protocol Version No.01(Clean) 
Protocol No. CJDQ443B12201 
Period 
Screening 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Visit Name 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
onwards 
EOT 
Safety follow-up (30 
days after last 
administration of study 
treatment) 
Efficacy 
follow-up 
Survival follow-
up (every 12 
weeks) 
Days 
0 
-28 to -1
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
- 
- 
- 
- 
IRT drug 
dispensation 
X 
X 
X 
IRT drug 
discontinuation 
X 
Treatment beyond 
progression 
Informed Consent 
Participants who meet the criteria outlined in 
Section 6.1.4.1 
Adverse Events 
Continuously, from signing of main ICF until 30 days after last dose of study treatment. After starting a 
new antineoplastic therapy, only report AEs suspected to be related to study treatment 
Serious Adverse 
Events 
Continuously, from signing of pre-screening ICF until 30 days after last dose of study treatment. Before signing of main ICF, only 
SAEs suspected to be related to a study procedure are captured. After starting a new antineoplastic therapy, only report SAEs 
suspected to be related to study treatment (unless otherwise specified by local law/regulations). 
SAEs related to 
study treatment 
(unless 
otherwise 
specified by local 
law/regulations) 
FFPE tumor 
tissue sample for 
exploratory 
biomarkers2 
X14 
Newly obtained 
tumor biopsy 
(core needle 
biopsy)2,15 
Optional16 
Optional 
(4 to 8 
hours 
post-
dose) 
Optional17 
Blood for cell-free 
DNA2 
X 
X 
X 
C3 day 1 
and then 
on day 1 
of every 2 
cycles 
thereafter 
X 

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Clinical Trial Protocol Version No.01(Clean) 
Protocol No. CJDQ443B12201 
Period 
Screening 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Visit Name 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
onwards 
EOT 
Safety follow-up (30 
days after last 
administration of study 
treatment) 
Efficacy 
follow-up 
Survival follow-
up (every 12 
weeks) 
Days 
0 
-28 to -1
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
- 
- 
- 
- 
JDQ443 PK 
sampling18, 19 
X 
X 
(C3D1, 
C5D1 and 
C7D1) 
Food 
consumption20 
X 
X 
(C3D1, 
C5D1 and 
C7D1) 
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
X 
X 
X 
X 
Disposition 
assessment 
X 
X 
X 
Survival 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 For participants in China Only: KRAS G12C and/or STK11 mutation and PD-L1 status must be determined by local assessment. 
2 For participants in China only: Collection type and amount may vary, conditional upon approval from local authorities (including but not limited to Human Genetic 
Resource Administration of China (HGRAC)). 
3 Tumor and blood samples are required from all participants as a part of pre-screening. For cases where documented local results from a qualified laboratory are not 
available and the central test results will be used for eligibility testing based on PD-L1 expression in tissue and, KRAS G12C mutation status and/or STK11 mutation 
status (cohort B only) in tissue or blood and the sample must be submitted as part of pre-screening. While awaiting results, patient may proceed to main screening, 
however results must be received with appropriate biomarker status prior to starting treatment (Section 5.1 and Section 8.1). With documented local results for all 
required biomarkers, the participant may enter main screening and submit the sample prior to start of treatment (Section 8.1).  
4. Additional ad hoc hematological and/or biochemistry tests may be required in case of toxicities. Refer to Section 6.5.3, Table 6-3, Section 8.5.4, Table 8-5,
Section 10.5 and Section 10.6.
5 To be performed within 72 hour before the first dose
6 For women of child-bearing potential only
7 Questionnaire completed at home within 3 days of the scheduled visits/follow-up assessments or at site (prior to administration of investigational product or any other
study procedure)
8 At corresponding imaging efficacy follow-up visits
9 Within 42 days prior to start of study treatment

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Clinical Trial Protocol Version No.01(Clean) 
Protocol No. CJDQ443B12201 
Period 
Screening 
Treatment 
Follow-up 
Cycle 
Cycle 1 
Visit Name 
Molecular 
Pre-
screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
onwards 
EOT 
Safety follow-up (30 
days after last 
administration of study 
treatment) 
Efficacy 
follow-up 
Survival follow-
up (every 12 
weeks) 
Days 
0 
-28 to -1
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
- 
- 
- 
- 
10 Mandated for any lesions identified on the whole-body bone scan that are not visible on the chest, abdomen, and pelvis CT or MRI. 
11 if clinically indicated in case of skin metastatic lesions 
12 Triplicate 12 lead ECG assessments (to be recorded approximately 2 minutes apart) 
13 For C1D1 and C1D15, ECGs to be collected at pre-dose and 4 hours post-dose (within 15 minutes prior to PK) 
14 Mandatory where sample is available and to be requested from another institution, if necessary. Not required if tumor tissue block was submitted during pre-
screening/screening for PD-L1, KRAS G12C and/or STK11 assessment or if optional, newly obtained biopsy is provided at C1D1. 
15 Requires optional biopsy consent within the main ICF 
16 Biopsy may be performed during screening to accommodate patient scheduling.  
17 Optional: At EOT if EOT=PD or at the time of first PD prior to the initiation of new anti-cancer therapies ( Table 8-9 ) 
18 Pre-dose samples collected immediately prior to the administration of study treatment 
19 For approximately 10 participants in both Cohorts (A and B) PK blood samples will be collected at time-points described in Table 8-7 (Intensive PK sampling 
scheme). Approximately 2 participants from this intensive PK group will be from China. For the remaining participants in each of the Cohorts (A and B), standard PK 
blood samples will be collected at time-points described in Table 8-8 (standard PK sampling scheme). For all participants in both groups, additional blood samples will be 
collected when the tumor samples are collected. Unscheduled blood samples may be collected as necessary (Refer to Table 8-7 and Table 8-8).  
20 Meal date/time (start/end time) before and after JDQ443 administration should be collected on the PK collection days 

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Amended Protocol Version No.01 (Clean) 
Protocol No. CJDQ443B12201 
2 
Introduction 
2.1 
Study rationale 
KRAS are the most prevalent mutations among patients with non-small cell lung cancer 
(NSCLC) (Jancík et al 2010, Scheffler et al 2019). Promising signs of antitumor activity were 
observed in recent studies with KRAS G12C inhibitors administered to patients with locally 
advanced or metastatic (advanced) NSCLC previously exposed to standard treatments such as 
platinum-based chemotherapy and immunotherapy Skoulidis et al 2021, Riely et al 2021). 
Despite these encouraging results in pretreated patients, the efficacy of KRAS G12C inhibitors 
in the first-line setting remains unknown.  
Immunotherapy is currently an important part of the standard first-line treatment for patients 
with advanced NSCLC whose tumors have no targetable mutations, either administered alone 
or combined with platinum-based chemotherapy (Planchard et al 2018, Hanna et al 2020). 
Notably, prior studies showed that some patients with advanced NSCLC may derive less benefit 
from immunotherapy, such as those whose tumors have a programmed death-ligand 1 (PD-L1) 
expression 
<1% 
or 
an 
STK11 
mutation 
(Skoulidis et al 2018, 
Xu et al 2019, 
Ricciuti et al 2021). 
In the context of first-line NSCLC patients in whom a lower benefit of immunotherapy is 
anticipated, the present study aims primarily to evaluate the antitumor activity and safety of 
JDQ443 single-agent as first-line treatment for participants with locally advanced or metastatic 
NSCLC whose tumors harbor a KRAS G12C mutation and have a PD-L1 expression <1% or a 
PD-L1 expression ≥ 1% and an STK11 co-mutations. 
The study will have 2 non-comparative cohorts that will recruit participants in parallel 
according to the following characteristics: 
Cohort A: participants whose tumors harbor a KRAS G12C mutation and a PD-L1 expression 
<1%, regardless of STK11 mutation status. 
Cohort B: participants whose tumors harbor a KRAS G12C mutation, a PD-L1 expression ≥1% 
and an STK11 co-mutation. 
The sample size of cohorts A and B was determined based on the estimated frequency of the 
molecular profile required to meet eligibility criteria for each cohort: the prevalence of PD-L1 
expression <1% is estimated around 40% in patients with KRAS G12C-mutated NSCLC, 
whereas STK11 co-mutations are found in around 12-15% of these patients 
(Skoulidis et al 2015 , Skoulidis and Heymach 2019 , Aredo et al 2019, Ricciuti et al 2021, 
Skoulidis et al 2021). 
2.2 
Background 
2.2.1 
Overview of non-small cell lung cancer (NSCLC) pathogenesis, 
epidemiology and treatment 
NSCLC is the most frequent histologic subtype of lung cancer, accounting for 85% of all 
cases. Approximately 65% of the patients with NSCLC present with advanced or metastatic 
disease at diagnosis (Travis et al 2015). 

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Platinum-based chemotherapy has been an important component of the standard first-line 
treatment for patients with advanced NSCLC, although over the past 20 years treatment has 
substantially evolved from the use of cytotoxic chemotherapy for all patients to a hallmark of 
personalized therapy driven by tumor and patient characteristics (Yuan et al 2019). The 
identification of oncogenic drivers such as Epidermal Growth Factor Receptor (EGFR), 
Anaplastic Lymphoma Kinase (ALK), B-Raf proto-oncogene (BRAF), and c-ros oncogene 1 
(ROS-1) in subsets of patients has allowed them to be treated according to the genetic alterations 
present in their tumors, dramatically improving the treatment landscape of NSCLC and the 
prognosis of these patients (Yuan et al 2019). 
More recently, immunotherapy has been incorporated as an option for NSCLC treatment, after 
multiple trials that have demonstrated a positive and clinically relevant impact yielded by 
immune checkpoint inhibitors in the overall survival (OS) of patients with advanced NSCLC 
after failure to platinum-based chemotherapy, as well as in the first-line setting in combination 
with chemotherapy or as monotherapy for patients whose tumors express PD-L1 
(Lim et al 2020, Grant et al 2021). 
Notably, in patients with advanced NSCLC, the benefit of immunotherapy – in monotherapy or 
in combination with platinum-based chemotherapy - is associated with PD-L1 expression 
levels: a higher magnitude of benefit from immunotherapy is observed in patients whose tumors 
present higher PD-L1 expression levels (Xu et al 2019). 
Due to the incorporation of targeted therapies and immunotherapy into the treatment landscape 
of patients with advanced NSCLC, the assessment of PD-L1 expression and the evaluation of 
potential driver mutations are fundamental characteristics to be considered by clinicians in order 
to 
identify 
the 
most 
appropriate 
first-line 
treatment 
option 
for 
each 
patient 
(Planchard et al 2018, Hanna et al 2020, Hanna et al 2021). 
2.2.2 
KRAS mutation in NSCLC 
Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most frequently mutated 
oncogene in human solid cancers, being found in around 20–25% of newly diagnosed patients 
with NSCLC, with a higher frequency in the adenocarcinoma subtype (Sequist et al 2011, 
Huang et al 2021). 
The KRAS oncoprotein is a guanosine triphosphate (GTP) binding and hydrolyzing protein 
(GTPase) with an essential role as regulator of intracellular signaling pathways, such as the 
mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and Ras-
related protein (RAL), which are involved in cell proliferation, survival and tumorigenesis ( In 
normal cells, KRAS alternates between inactive guanosine diphosphate (GDP)-bound and 
active GTP-bound states (Pai et al 1989). 
Following mitogenic stimulation, guanine nucleotide-exchange factors (GEF), such as son of 
sevenless (SOS), catalyze the activation of KRAS by mediating its GTP loading. This 
nucleotide exchange causes significant conformational changes in the Switch I and Switch II 
regions of KRAS and subsequent engagement of KRAS with its effector proteins, resulting in 
the activation of KRAS-driven pathways. Signaling of KRAS is terminated by GTP hydrolysis. 
Hereby, the weak intrinsic GTPase activity of KRAS is enhanced by interaction with GTPase-
activating proteins (GAP) (Jancík et al 2010). 

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Oncogenic activation of KRAS in NSCLC occurs predominantly through missense mutations 
in codon 12, with the KRAS G12C mutation being found in approximately 13% of lung 
adenocarcinomas. (Campbell et al 2016, Jordan et al 2017). 
Mutations of KRAS at codon 12, such as G12C, impair GAP-stimulated GTP hydrolysis. The 
conversion of the GTP to the GDP form of KRAS G12C is therefore very slow. Consequently, 
KRAS G12C is shifted to the active, GTP-bound state, thus driving oncogenic signaling ( , 
Patricelli et al 2016). 
KRAS mutations do not generally overlap with classic targetable mutations such as EGFR, 
ROS1, BRAF and ALK in patients with NSCLC (Sequist et al 2011, Li et al 2013). These 
mutations are often associated with a poor prognosis and may also be implicated in resistance 
to targeted therapies and chemotherapy in patients with NSCLC (Guibert et al 2016, 
Del Re et al 2017, Goulding et al 2020). 
2.2.3 
KRAS mutation as a therapeutic target in NSCLC 
Several therapies are currently being investigated in clinical trials to target either KRAS 
mutations, the MAPK pathway or alternative pathways that communicate with MAPK and may 
also drive cell proliferation. Previous attempts to target KRAS mutations and block 
MAPK signaling have mostly not succeeded, due to feedback loops within the MAPK pathway 
and pathway redundancy that prevent an effective blockade of this pathway, as well as due to 
the cross-talk between MAPK and other pathways or alternative intracellular effectors that can 
become active and drive cell proliferation in the presence of MAPK blockade. Hence, new 
therapies that directly and specifically inhibit the oncogenic driver KRAS G12C mutation are 
needed (Huang et al 2021). 
The identification of the first selective KRAS G12C inhibitor targeting the mutated cysteine 
and covalently binding to a novel allosteric pocket under the Switch II (SWII) loop region 
exposed exclusively in the GDP-bound state of KRAS was a major breakthrough in the efforts 
to target KRAS and led to the identification of similar inhibitors with properties suitable for 
clinical development that entered clinical trials (Ostrem et al 2013). 
Sotorasib (AMG-510) - a first-in-class, highly selective, irreversible KRAS G12C inhibitor - 
received accelerated approval from the US FDA for the treatment of adult patients with KRAS 
G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved 
test, who have received at least one prior systemic therapy. Continued approval for this 
indication may be contingent upon verification and description of clinical benefit in a 
confirmatory trial(s). The accelerated approval was based on the overall response rate (ORR) 
and duration of response (DOR) shown in the phase 2 part of CodeBreaK 100 study, which 
included 126 patients with locally advanced or metastatic NSCLC whose tumors had a KRAS 
G12C mutation and who had progressed to immunotherapy or platinum-based chemotherapy 
(or both). Patients received sotorasib at an oral daily dose of 960 mg until disease progression. 
With a median follow-up of 15.3 months, 46 patients had a confirmed response – 4 complete 
responses and 42 partial responses – yielding an objective response rate of 37.1%, with a median 
DOR of 11.1 months (Skoulidis et al 2021, Lumakras FDA label 2021). Updated data from this 
study with a median follow-up of 24.9 months showed an ORR of 40.7% among 172 evaluable 

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patients, a median duration of response of 12.3 months, median PFS of 6.3 months and median 
OS of 12.5 months (Dy et al 2022).  
Adagrasib (MRTX-849) is another selective inhibitor of KRAS G12C that is currently in 
clinical development and has demonstrated promising signs of activity. In the phase I/II 
KRYSTAL-1 trial, 79 patients with pretreated (92% had prior treatment with immunotherapy 
and chemotherapy) KRAS G12C-mutated NSCLC received adagrasib 600 mg twice a day. 
Among the 51 patients evaluable for clinical activity, 45% (23/51) achieved a partial response 
(Riely et 2021). 
The promising antitumor activity observed to date with KRAS G12C inhibitors in the treatment 
of patients with advanced NSCLC raises interest in the evaluation of this class of targeted 
therapies in further studies. 
2.2.3.1 
STK11 and KRAS G12C mutations co-occurring in NSCLC 
The presence of KRAS G12C mutations has been associated with an immunosuppressive tumor 
microenvironment in preclinical studies. This effect can be mediated by high levels of inhibitory 
cytokines such as factor nuclear kappa B (NF-κβ), signal transducer and activator of 
transcription 3 (STAT3), interleukin 6 (IL-6), interleukin 1-β (IL-1β), as well as by a high 
presence of myeloid-derived suppressor cells, regulatory T cells, and M2-differentiated tumor-
associated macrophages in the tumoral stroma, all of which impair antitumor immunity and 
facilitate tumor progression (Hamarsheh et al 2020, Cucurull et 2022). Further supporting this 
concept, KRAS G12C inhibitors stimulate the recruitment and activation of CD8+ T cells, 
dendritic cells and M1-macrophages, and thus promote a shift towards a more immune-
activated tumor microenvironment in preclinical models of NSCLC (Canon et al 2019, 
Briere et al 2021). 
STK11 is a serine-threonine kinase that regulates cellular metabolism and cell cycle, and loss 
of function STK11 mutations promote an immunosuppressive microenvironment as they are 
associated with impaired T-cell recruitment and inhibition of neutrophil function 
(Koyama et al 2016). STK11 mutations are found in around 5% of the patients with advanced 
NSCLC, being more frequent among those with KRAS G12C-mutated NSCLC - around 12-
15% (Skoulidis et al 2018, Scheffler et al 2019, Shire et al 2020, Ricciuti et al 2021).  
Tumors harboring both a KRAS G12C and an STK11 mutation have a gene expression profile 
characterized by a low expression of pro-inflammatory cytokines such as type I interferon, 
stimulator of interferon genes (STING), DExD/H-Box Helicase 58 (DDX58), toll-like receptor 
4 (TLR4), and toll-like receptor 7 (TLR7), and this profile is associated with an 
immunosuppressive tumor microenvironment (Ricciuti et al 2021). 
Previous studies showed that STK11 mutations are associated with a worse prognosis and 
predict a low benefit from immunotherapy-based treatments in patients with advanced NSCLC 
(Ricciuti et al 2021, Shire et al 2020). However, these mutations do not seem to impact the 
responsiveness to KRAS G12C inhibitors, building an interesting rationale to investigate the 
activity of KRAS G12C inhibitors in patients whose tumors harbor both KRAS G12C and 
STK11 mutations (Shire et al 2020, Ricciuti et al 2021, Riely et 2021, Skoulidis et al 2021). 

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Overview of JDQ443 
JDQ443 is a potent, selective KRAS G12C small molecule inhibitor that covalently binds to 
mutated Cys12, trapping KRAS G12C in the inactive GDP-bound state. Pre-clinical data 
indicate that JDQ443 binds to KRAS G12C with low reversible binding affinity to the RAS 
Switch II (SWII) pocket, inhibiting downstream cellular signaling and proliferation. Treatment 
with JDQ443 showed deep and sustained target occupancy resulting in anti-tumor activity in 
different KRAS G12C-mutated xenograft models (Brachmann et al 2021). 
2.2.3.2 
Non-clinical experience 
2.2.3.2.1 Non-clinical pharmacology 
JDQ443 selectively inhibited downstream effector protein recruitment to KRAS G12C, but not 
to any other RAS wild-type isoform. JDQ443 inhibited KRAS-driven oncogenic signaling and 
proliferation specifically in KRAS G12C-mutated cell lines, but not KRAS wild type (WT) or 
MEK Q56P-mutated cell lines. In KRAS G12C-mutated xenograft models, JDQ443 showed a 
consistent PK/PD relationship with linear exposure in blood. Upon JDQ443 treatment, free 
tumor KRAS G12C levels were robustly reduced in a dose-dependent manner and correlated 
with inhibition of tumor expression of the MAPK pathway target gene, dual-specificity 
phosphatase 6 (DUSP-6) (Figure 2-1). 
Figure 2-1 
PK/PD Relationship of JDQ443 in MIA PaCa-2 and NCI-H2122 tumor-
bearing nude mice after a single oral treatment. 
Nude mice bearing subcutaneous MIA PaCa-2 tumors (A) or NCI-H2122 tumors (B) were treated with 
a single oral dose of JDQ443 at indicated doses. Blood and tumor samples (n=3) were collected at 
indicated time points. Total drug concentrations in blood (left) and free KRASG12C levels in tumors 
(middle) were determined by LC/MS. DUSP6 expression vs control in tumors was measured by qPCR 
(right). A: amorphous material, solution formulation; B: crystalline material, suspension formulation. 
Moreover, daily oral JDQ443 treatment resulted in dose-dependent anti-tumor activity in MIA 
PaCa-2 and NCI-H2122 xenograft models in mice. In MIA PaCa-2, JDQ443 produced tumor 
stasis at  mg/kg and tumor regression at 
 mg/kg, 
 mg/kg and 
 mg/kg. In NCI-H2122, 
JDQ443 produced weak tumor-growth inhibition at 
 mg/kg, a moderate tumor-growth 
inhibition at 
 mg/kg and approximately tumor stasis at 
 mg/kg. Likewise, a twice daily 
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oral treatment with JDQ443 at 
 mg/kg achieved also approximately tumor stasis in NCI-
H2122, indicating that efficacy was associated with AUC (area under curve) (Figure 2-2). 
Figure 2-2 
Anti-tumor activity after repeated treatments of MIA PaCa-2 and NCI-
H2122 tumor-bearing nude mice. 
The anti-tumor activity elicited by JDQ443 in the two xenograft models MIA PaCa-2 and NCI-
H2122 in mice was comparable to the one observed with AMG-510 and MRTX-849 when 
administered at clinically relevant doses. [JDQ443 Investigator’s Brochure] 
In addition, there is evidence that oncogenic KRAS signaling induces the expression of immune 
modulatory features (e.g., TGF-ß, interleukin-6 (IL-6) and IL-10) in tumor cells, overall 
imposing 
an 
immuno-suppressive 
tumor 
microenvironment 
(Cullis et al 2018, 
Van Maldegem and Downward 2020). Pre-clinical models demonstrated a substantial increase 
in immune cell infiltration after treatment with KRAS inhibitors (Canon et al 2019). In 
particular, intra-tumoral CD8+ T cell numbers increased and a shift in the tumor 
microenvironment was observed (e.g., macrophage polarization from M2 to M1; reduction in 
myeloid derived suppressor cells (Canon et al 2019,Briere et al 2021). 
For further details, please refer to the [JDQ443 Investigator’s Brochure]. 
2.2.3.2.2 Animal toxicology studies 
Safety pharmacology assessments indicate that JDQ443 is not expected to cause effects on vital 
functions of the CNS, and the respiratory systems. 
Repeat dose toxicology studies were conducted in rats and dogs. 
In toxicity studies up to 4-weeks of treatment, main target organs of toxicity identified in both 
species were the hematopoietic system (decreases in hemoglobin, hematocrit, red blood cells, 
and/or reticulocytes) and the adrenal gland (cortical hypertrophy, increased or decreased 
vacuolation). Histopathological effects on the cardiovascular system (hypertrophy of medial 
smooth muscle cells in medium to large coronary arteries; increased heart rate), the kidney 
(tubular degeneration/regeneration) and the liver (bile duct hyperplasia) were limited to dogs. 
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In addition, effects on the skin/subcutis (follicular hyperplasia), the thymus (increased or 
decreased lymphocytes), the spleen (increased extramedullary hematopoiesis), the stomach 
(inflammation) and the lung (increased alveolar macrophage) were observed in rats. All 
findings were minimal to slight and demonstrated a partial to complete reversibility during a 4-
week recovery phase. 
In the 13-week dog toxicity study, additional findings were observed in the testes (seminiferous 
tubule degeneration), epididymis (single-cell necrosis/apoptosis, luminal cell debris) and 
prostate (hypoplasia). At the recovery necropsy, JDQ443-related findings had completely 
reversed in prostate and partially reversed in epididymis and testis. In the 13-week rat toxicity 
study, additional target organs of toxicity identified were the brain (mineralization, gliosis 
and/or necrosis), spinal cord (axonal degeneration, gliosis and/or necrosis), sciatic nerve 
(axonal degeneration), lung (alveolar macrophage, alveolar eosinophilic material, increased 
eosinophils infiltrate and/or increased pneumocyte vacuolation), parotid and mandibular 
salivary glands (apoptosis, vacuolation and/or mononuclear cell infiltrate; cytoplasmic 
alteration), skeletal muscle (myocyte degeneration, regeneration and/or mononuclear cell 
infiltrate) and ovary (interstitial cell degeneration, increased corpora lutea and/or follicular 
cyst). At recovery necropsy, microscopic findings had completely reversed in skeletal muscle 
and ovary. A partial recovery was observed in salivary glands. Microscopic findings were still 
present in spinal cord, sciatic nerve and lung at the recovery necropsy, although with an overall 
decreased severity when compared to the terminal euthanasia, except for the lung. Following 
the recovery period, mineralization was present in the brain of males, while in the brain of 
females mineralization and gliosis persisted and necrosis was reversed. 
JDQ443 did not show evidence of a genotoxic potential in in vitro and in vivo genotoxicity 
studies. The rat embryofetal development study showed that JDQ443 is embryotoxic and 
embryolethal. 
A 
. 
Further details on the risk/benefit assessment for treatment with JDQ443 are provided in 
Section 2.3 and detailed instructions for safety monitoring of study participants are provided in 
Section 6.5 and Section 8.5. 
For further details, please refer to the [JDQ443 Investigator’s Brochure]. 
2.2.3.2.3 In vitro and in vivo cardiac evaluation of JDQ443 
The IC50 for JDQ443 in the hERG patch clamp is > 
 µM. Despite hERG inhibition occurring 
in vitro at low concentration, this potential hERG inhibition did not translate into QTc 
prolongation in vivo in dogs up to 
 mg. The hERG inhibition provides a safety margin of > 
 when compared to the free Cmax in patients at 
 mg b.i.d. (
 µM). Transient increases 
in mean heart rate were observed in dogs at JDQ443 doses ≥ 
 mg/kg. At 
 mg/kg the mean 
(male and female) exposures (Cmax of 
 ng/mL and AUC0-24h of 
ng/mL•h) were 
below the exposures in patients at a dose of 
 mg b.i.d. at steady state (Cmax of 
 ng/mL 
and AUC0-24h of 
 ng/mL•h). Additionally in the 13-week dog toxicity study 
echocardiogram results showed a 
 increase of left ventricular ejection fraction (LVEF) at 
 mg/kg/day; most prominent at day  
For further details, please refer to the [JDQ443 investigator’s brochure]. 
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2.2.3.2.4 JDQ443 absorption, metabolism, distribution and excretion 
JDQ443 is a preliminary Biopharmaceutics Classification System (BCS) class 2 compound with 
high permeability and limited aqueous solubility, and the solubility is not pH-dependent from 
pH range of  to 
. Following low dose intravenous administration to rat and dog, JDQ443 
exhibited a rapid distribution to tissues with volume of distribution ranging from ~ 
 to 
 
L/kg (Vss), high blood clearance values that exceed liver blood flow in each species, suggesting 
extrahepatic clearance mechanisms (CL). Terminal half-life is short ranging from 
 to 
 
hours (T1/2) in all species tested. After oral administration, the time to reach maximum drug 
concentrations in systemic circulation (Tmax) occurred between 
 and 
 hours, depending on 
the dose levels. Dose-proportional or under-dose proportional increase of AUClast was observed 
over the dose range tested in Good Laboratory Practice (GLP) toxicology studies. The oral 
bioavailability was estimated to be 
% in rat. A 
-fold positive food effect was observed 
in dog at a dose of 
mg/kg. 
Following oral administration of [14C]JDQ443, total radiolabeled components were rapidly 
distributed throughout the body, with highest concentration observed in the harderian gland, 
pituitary gland, liver and in the intestinal wall of the colon. The radiolabeled material passed 
though the blood-brain barrier to a minimal extent. 
[14C]JDQ443 was predominantly eliminated via fecal excretion. Urinary excretion was minor 
with less than % of the radioactive dose. Based on in vitro metabolism studies in cryopreserved 
hepatocytes across species, the apparent primary biotransformation pathway involved 
 
 at the 
 moiety as well as 
 
) and 
 
. CYP3A is the isoform mainly contributing to the oxidative metabolism. 
 is 
an active metabolite with 
 potency as the parent drug and was present in the GLP 
toxicology studies with exposure 
% and 
% relative to the parent exposure in rat 
and dog, respectively. 
Based on transporter phenotyping studies, JDQ443 is likely a substrate for efflux transporters 
P-gp, BCRP and MRP2. However, given the high passive permeability, co-administration of 
inhibitors of P-gp (MDR1), MRP2 and BCRP are expected to have little impact on rate and/or 
extent of JDQ443 absorption. 
In vitro, JDQ443 showed weak reversible inhibition of CYP2B6, 2C8, 2C9, 2C19 and 3A4 
(based on midazolam) with IC50 (unbound) values lower than 
μM. There is a potential risk 
for reversible inhibition of CYP2C8, CYP2C9 and CYP2C19 by JDQ443 in human at clinically 
relevant exposure. In vitro, JDQ443 showed reversible inhibition of OATP1B1, OATP1B3 and 
P-gp, and may interact with substrates of these transporters at the clinically relevant 
concentrations. 
For further details, please refer to the [JDQ443 Investigator’s Brochure]. 
2.2.3.3 
Clinical Experience with JDQ443 
JDQ443 is currently being evaluated as a single agent in the first in human (FIH) study 
CJDQ443A12101. 
A data cutoff of 03-Nov-2021 was utilized to assess data from the dose escalation portion of 
the JDQ443 single agent arm of CJDQ443A12101 and to confirm the recommended dose of 
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JDQ443 single agent. A maximum tolerated dose (MTD) for JDQ443 single agent was not 
reached. Based on the collective PK, PK/PD, safety and efficacy data collected across the 39 
patients treated with JDQ443 single agent in dose escalation, a recommended dose of 200 mg 
b.i.d., given continuously and with food, was selected. 
For further details, please refer to the [JDQ443 Investigator’s Brochure]. 
2.2.3.3.1 Efficacy 
In the CJDQ443A12101 study, the activity of JDQ443 as a single agent was evaluated in 39 
patients with KRAS G12C-mutated solid tumors who had been previously exposed to standard 
of care therapies, out of whom 20 had advanced NSCLC. With a data cutoff of 05-Jan-2022, 
responses were assessed by RECIST1.1 criteria based on investigator's assessment. Seven out 
of the 20 patients with NSCLC had a confirmed PR and further 2 patients had a yet unconfirmed 
PR (pending confirmation), leading to an overall response rate (confirmed + unconfirmed) of 
45%. Among the 7 patients who were treated at the RD (200 mg b.i.d.), 4 had a PR (all 
confirmed), leading to an overall response rate in this group of 57%. The median duration of 
exposure was 15.9 weeks (range 2.0 – 27.1), with the majority of patients (70%) ongoing on 
treatment at time of data cutoff. The data are not sufficiently mature to make conclusions about 
DoR at this time, and the data will continue to mature (Tan DS et 2022). 
2.2.3.3.2 Safety 
In the CJDQ443A12101 study, overall 39 patients were treated across 4 dose levels: 200 mg 
QD (n=10), 400 mg QD (n=11), 200 mg b.i.d. (n=11) and 300 mg b.i.d. (n=7). With a data 
cutoff of 05-Jan-2022, the treatment related adverse events (AEs) occurring in ≥ 10% of patients 
across dose levels were fatigue (30.8%), nausea (17.9%), edema (15.4%), diarrhea (12.8%), 
vomiting (12.8%), arthralgia (10.3%) and pruritus (10.3%). Most treatment related AEs were 
grade 1 or 2. QTc prolongation (grade < 3) was observed in 2 patients (5.1%), whereas no heart 
failure or cardiac dysfunction were observed. There were 
 
 
 
 
 
 
 A maximum tolerated dose (MTD) was not reached. Treatment related AEs leading to 
dose interruption occurred in 0/10 (0%), 2/11 (18.2%), 1/11(9.1%), and 4/7 (57.1%) of patients 
treated at 200 mg QD, 400 mg QD, 200 mg b.i.d. and 300 mg b.i.d., respectively. 
2.2.3.3.3 Clinical pharmacokinetics 
Following oral administration with food, JDQ443 tablets showed prolonged absorption with a 
median Tmax of 3 to 4 hours post dose. The geometric mean half-life was estimated to be  to 
hours. No accumulation was observed following QD or b.i.d. dosing. The exposure increase 
(both Cmax and AUC0-24) was less than dose proportional from 
 to 
 mg at steady state 
for the QD dosing schedule, likely due to saturation of absorption. The AUC0-24 at 
 mg 
b.i.d. was > 
% higher than the exposure of AUC0-24 at 
 mg and 
 mg QD dose levels. 
The geometric mean CLss/F was 
 L/h at 
 mg QD and b.i.d., and 
 L/h at 
 mg QD. 
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Moderate variability was observed for Cmax (geomean CV%: 
% to 
%) and AUCtau 
(geomean CV%: 
% to 
%). 
Exposure (AUC) of active metabolite 
 (
) was low, accounting for 
to % and to % of the parent AUC following single dose and at steady state, respectively. 
PK data demonstrated that at 
 mg b.i.d., exposure (AUC0-24) of JDQ443 was at least -fold 
above the efficacious exposure required for maximum efficacy in less sensitive xenograft 
models. At this dose level, a >
% average KRASG12C target occupancy was predicted based 
on PK-PD modeling and was higher than the 
% average target occupancy required for tumor 
regression in various xenograft models. 
For further details, please refer to the [JDQ443 Investigator’s Brochure]. 
2.2.4 
Rationale to evaluate JDQ443 as first-line treatment for selected 
patients with NSCLC 
Although KRAS G12C inhibitors have demonstrated initial signs of antitumor activity in 
patients with advanced NSCLC previously exposed to standard treatments - such as platinum-
based chemotherapy and immunotherapy - the efficacy of KRAS G12C inhibitors in the first-
line setting remains unknown and under investigation in ongoing studies (Riely et 2021, 
Skoulidis et al 2021, Kwan et al 2022). Hence, patients with advanced NSCLC whose tumors 
harbor a KRAS G12C mutation currently receive the same first-line treatment as those whose 
tumors have no targetable mutations. This consists in most cases of platinum-based 
chemotherapy combined with immunotherapy or immunotherapy alone for patients whose 
tumors have a PD-L1 expression ≥50% (Planchard et al 2018, Hanna et al 2020). 
Approximately 40 to 50% of the patients with advanced NSCLC are not eligible to subsequent 
treatments after discontinuation of first-line therapy, mainly due to clinical deterioration at the 
moment of disease progression (Davies et al 2017). Hence, effective treatments administered at 
earlier lines have the potential to benefit more patients with NSCLC. 
Although the incorporation of immunotherapy into the first-line setting has significantly 
improved the survival of patients with advanced NSCLC, previous studies have shown that a 
lower magnitude of benefit from immunotherapy is observed in patients whose tumors have a 
PD-L1 expression < 1% or an STK11 mutation: in a retrospective study that included 1,261 
patients (out of whom 42.5% and 20.6% had KRAS and STK11 mutations, respectively) with 
advanced lung adenocarcinoma treated with immunotherapy, the presence of an STK11 
mutation co-occurring with a KRAS mutation was associated with worse PFS (HR= 2.04; 95% 
confidence interval [CI], 1.66–2.51; p<0.0001) and OS (HR 2.09, 95% CI, 1.68–2.61; 
p<0.0001) (Ricciuti et al 2021). In a meta-analysis that included 15 randomized-controlled 
trials involving a total of 10,074 patients, Xu et al demonstrated that the magnitude of 
OS benefit yielded by immunotherapy added to chemotherapy was associated with PD-L1 
expression levels: for PD-L1 < 1%, HR 0.60, 95% CI, 0.43-0.83; for PD-L1 1-49%, HR 0.56, 
95% CI, 0.40-0.78; for PD-L1 ≥ 50%, HR 0.50, 95% CI, 0.35-0.72 (Xu et al 2019). Hence, 
alternatives to improve the outcomes of these 2 subgroups of patients (PD-L1 expression < 1% 
and STK11 mutation) who presumably benefit less from immunotherapy-based treatment are 
needed. In this context, the encouraging antitumor activity of KRAS G12C inhibitors in 
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previously treated patients with advanced NSCLC raises interest in the evaluation of these 
agents in the first-line setting (Skoulidis et al 2021, Riely et 2021). 
2.3 
Benefit/Risk assessment 
The CJDQ443B12201 trial will enroll patients with advanced NSCLC with no previous 
systemic treatment for advanced disease whose tumors harbor a KRAS G12C mutation and 
either a PD-L1 expression <1% (cohort A) or a PD-L1 expression ≥1% and an STK11 co-
mutation (cohort B). These 2 subgroups of patients presumably derive less benefit from 
immunotherapy-based treatment in the first-line setting and thus are good candidates to 
alternative therapeutic strategies that aim to improve their outcomes. 
Based on pre-clinical toxicology findings, it is recommended that patients in clinical studies of 
JDQ443 are monitored for potential hematopoietic, gastrointestinal, renal, dermatologic, 
hepatic, adrenal, cardiac, ophthalmologic, pulmonary, central and peripheral nervous system, 
muscular, salivary gland and reproductive organ effects. 
JDQ443 has shown 
. The Investigators 
should recommend the use of precautionary measures against 
 to the 
participants during treatment with JDQ443
 
 
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the participant will 
not reliably comply, they should not be entered or continue in the study. 
Appropriate eligibility criteria, as well as specific dose modification and discontinuation 
guidance, are included in this protocol. 
The central tests used to determine PD-L1, KRAS G12C and/or STK11 status for enrollment 
(where local test results are not available) are investigational. The tests are verified to assess 
PD-L1 expression (<1% or ≥1%) in tumor tissue and to detect the presence of the KRAS G12C 
and STK11 mutations in NSCLC tumor tissue or blood samples, however they have not been 
fully established to identify patients who are most likely to benefit from JDQ443 or whether the 
benefits will outweigh any potential serious side effects or risks from the use of these tests. 
The risk to participants in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring and KRAS G12C/STK11 assay 
monitoring. 
Considering the expected antitumor activity and safety profile of JDQ443, as well as a potential 
low magnitude of benefit from standard first-line treatment based on immunotherapy in the 
study population, a favorable risk-benefit ratio is estimated for study participation. 
3 
Objectives, endpoints, and estimands 
The study objectives are described in Table 3-1. All objectives described in the table below will 
be assessed in both cohorts (A and B), unless specified otherwise in the respective objective. 
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Table 3-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• To assess the antitumor activity of JDQ443 
single-agent as first-line treatment for 
participants with locally advanced or metastatic 
NSCLC whose tumors harbor a KRAS G12C 
mutation and a PD-L1 expression <1%, 
regardless of STK11 mutation status (cohort A). 
• Overall response rate (ORR), defined as the 
proportion of participants with a confirmed 
complete response (CR) or partial response (PR) 
as best overall response (BOR) per Response 
Evaluation Criteria in Solid Tumors version 1.1 
(RECIST 1.1) by blinded independent review 
committee (BIRC). 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• Key secondary objective 
To assess the antitumor activity of JDQ443 
single-agent as first-line treatment for 
participants with locally advanced or metastatic 
NSCLC whose tumors harbor a KRAS G12C 
mutation, a PD-L1 expression ≥1% and an 
STK11 co-mutation (cohort B). 
• ORR per RECIST 1.1 by BIRC. 
• Key secondary objective 
To assess duration of response (DOR) in both 
cohorts. 
• DOR, defined as the time from the first occurrence 
of a PR or a CR per RECIST 1.1 by BIRC to the 
occurrence of disease progression or death due to 
any cause. 
• Secondary objective 
To assess progression-free survival (PFS) in 
both cohorts. 
• PFS, defined as the time from the date of the first 
dose of study treatment to the date of the first 
documented disease progression per RECIST 1.1 
by BIRC or date of death due to any cause. 
• Secondary objective 
To assess overall survival (OS) in both cohorts. 
• OS, defined as the time from the date of 
enrollment to the date of death due to any cause. 
• Secondary objective 
To assess the antitumor activity of JDQ443 
single-agent in both cohorts. 
• Disease control rate (DCR), defined as the 
proportion of participants with a BOR of confirmed 
CR, PR and stable disease (SD) per RECIST 1.1 
by BIRC. 
• Time to response (TTR), defined as the time from 
the date of enrollment to the first documented 
response of either CR or PR per RECIST 1.1 by 
BIRC. 
• Secondary objective 
To assess the antitumor activity of JDQ443 
single-agent in both cohorts according to local 
radiology assessment. 
• ORR, DOR, DCR, TTR and PFS per RECIST 1.1 
by local radiology assessment. 
• Secondary objective 
To assess the antitumor activity of JDQ443 
single-agent as first-line treatment for 
participants whose tumors harbor an STK11 
mutation regardless of PD-L1 expression status 
(pooled from both cohorts). 
• ORR, DOR, DCR and TTR by BIRC and local 
radiology assessment. 
• Secondary objective  
To assess PFS and OS in participants whose 
tumors harbor an STK11 mutation regardless of 
PD-L1 expression status (pooled from both 
cohorts). 
• PFS and OS 
• Secondary objective 
To characterize the safety profile of JDQ443. 
• Type, frequency and severity of adverse events, 
changes in laboratory values, vital signs, 
electrocardiograms (ECGs). 

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Objective(s) 
Endpoint(s) 
• Secondary objective 
To characterize the pharmacokinetics of JDQ443 
in both cohorts. 
• Concentration of JDQ443 in plasma and derived 
PK parameters, as appropriate. 
• Secondary objective 
To assess the effect of JDQ443 on patient 
reported lung cancer symptoms, health related 
quality of life, health utility and health status 
• Time to definitive deterioration (TTD) in the 
NSCLC-SAQ total score, and TTD in the physical 
functioning (PF) scale of the EORTC QLQ-C30  
• Change from baseline to each scheduled 
assessment and to EOT for NSCLC-SAQ total 
score, and for each NSCLC-SAQ item/domain.  
• Change from baseline to each scheduled 
assessment and to EOT for all EORTC QLQ-C30 
domains, subscales and items  
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g., premature discontinuation of treatment). 
The primary clinical question of interest is: What is the effect of JDQ443 monotherapy in 
inducing radiological response per RECIST 1.1 assessed by BIRC when administered as first-
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line treatment for participants with locally advanced or metastatic NSCLC whose tumors harbor 
a KRAS G12C mutation and a PD-L1 expression < 1% (cohort A), regardless of study treatment 
discontinuation and any unforeseen events resulting from a public health emergency? 
The justification for the primary estimand is that it will capture the treatment effect irrespective 
of study treatment discontinuation but avoids the confounding effect of any new anti-cancer 
therapy that is not a part of the originally assigned treatment. 
The primary estimand is described by the following attributes: 
1. Population: Adult participants with locally advanced or metastatic NSCLC without 
previous systemic treatment for metastatic disease whose tumors harbor a KRAS G12C 
mutation and a PD-L1 expression < 1%, irrespective of STK11 mutation status (cohort A). 
2. Primary variable: BOR defined as the best response recorded from the start of the 
treatment until disease progression per RECIST 1.1 by BIRC, with responses documented 
after the use of any new anti-neoplastic therapy considered as non-response. 
3. Treatment of interest: All participants enrolled in this study will be treated with JDQ443 – 
a selective and irreversible KRAS G12C inhibitor – administered p.o. 200 mg twice a day 
continuously. 
4. Handling of remaining intercurrent events: 
• Treatment discontinuation for any reason: Tumor assessment data collected 
irrespective of treatment discontinuation will be included to derive BOR (treatment 
policy strategy). 
• Any public health emergency as declared by local or regional authorities, i.e., 
pandemic, epidemic or natural disaster: tumor assessment data collected irrespective 
of such unforeseen events will be considered for the BOR (treatment policy strategy). 
• New anti-cancer therapy: If any new anti-neoplastic therapy is initiated, responses 
documented after the use of new anti-neoplastic therapy will be considered as non-
response (composite strategy). 
5. Summary measure: ORR defined as the proportion of participants with a confirmed 
CR/PR as BOR, with its corresponding two-sided exact binomial 95% confidence interval. 
3.2 
Secondary estimands 
One secondary clinical question of interest is: What is the effect of JDQ443 monotherapy in 
inducing radiological response per RECIST 1.1 assessed by BIRC when administered as first-
line treatment for participants with locally advanced or metastatic NSCLC whose tumors harbor 
a KRAS G12C mutation, a PD-L1 expression ≥ 1% and an STK11 co-mutation (cohort B), 
regardless of study treatment discontinuation and any unforeseen events resulting from a public 
health emergency? 
The justification for the secondary estimand is that it will capture the treatment effect 
irrespective of study treatment discontinuation but avoids the confounding effect of any new 
anti-cancer therapy that is not a part of the originally assigned treatment. 

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This secondary estimand is described by the following attributes: 
1. Population: Adult participants with locally advanced or metastatic NSCLC without 
previous systemic treatment for metastatic disease whose tumors harbor a KRAS G12C 
mutation, a PD-L1 expression ≥ 1%, and an STK11 co-mutation (cohort B). 
2. Primary variable: BOR defined as the best response recorded from the start of the 
treatment until disease progression per RECIST 1.1 by BIRC, with responses documented 
after the use of any new anti-neoplastic therapy considered as non-response. 
3. Treatment of interest: All participants enrolled in this study will be treated with JDQ443 – 
a selective and irreversible KRAS G12C inhibitor – administered p.o. 200 mg twice a day 
continuously. 
4. Handling of remaining intercurrent events: 
• Treatment discontinuation for any reason: Tumor assessment data collected 
irrespective of treatment discontinuation will be included to derive BOR (treatment 
policy strategy). 
• Any public health emergency as declared by local or regional authorities, i.e., 
pandemic, epidemic or natural disaster: tumor assessment data collected irrespective 
of such unforeseen events will be considered for the BOR (treatment policy strategy) 
• New anti-cancer therapy: If any new anti-neoplastic therapy is initiated, responses 
documented after the use of new anti-neoplastic therapy will be considered as non-
response (composite strategy). 
5. Summary measure: ORR defined as the proportion of participants with a confirmed 
CR/PR as BOR, with its corresponding two-sided exact binomial 95% confidence interval. 
A further secondary clinical question of interest is: In participants who respond to the JDQ443 
monotherapy based on RECIST 1.1 assessed by BIRC, how long does the response to first-line 
treatment for participants in cohort A or in cohort B last, regardless of study treatment 
discontinuation and any unforeseen events resulting from a public health emergency? 
The justification for this secondary estimand is that it will capture the duration of the treatment 
effect irrespective of study treatment discontinuation but avoids the confounding effect of any 
new anti-cancer therapy that is not a part of the originally assigned treatment. 
This secondary estimand will be evaluated for both cohorts and is described by the following 
attributes: 
1. Population: 
• Cohort A: Adult participants with locally advanced or metastatic NSCLC without 
previous systemic treatment for metastatic disease whose tumors harbor a KRAS 
G12C mutation and a PD-L1 expression < 1%, irrespective of STK11 mutation status. 
• Cohort B: Adult participants with locally advanced or metastatic NSCLC without 
previous systemic treatment for metastatic disease whose tumors harbor a KRAS 
G12C mutation, a PD-L1 expression ≥ 1%, and an STK11 co-mutation. 
2. Primary variable: DOR defined as time from the date of first documented response of CR 
or PR to the date of the first documented progression or death due to any cause, according 
to RECIST 1.1 assessed by BIRC for participants whose best overall response is CR or 
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3. Treatment of interest: All participants enrolled in this study will be treated with JDQ443 – 
a selective and irreversible KRAS G12C inhibitor – administered p.o. 200 mg twice a day 
continuously. 
4. Handling of remaining intercurrent events: 
• Treatment discontinuation for any reason: Tumor assessment data collected 
irrespective of treatment discontinuation will be included to derive DOR (treatment 
policy strategy). 
• Any public health emergency as declared by local or regional authorities, i.e., 
pandemic, epidemic or natural disaster: tumor assessment data collected irrespective 
of such unforeseen events will be considered for the DOR (treatment policy strategy) 
• New anti-cancer therapy: If any new anti-neoplastic therapy is initiated, progression or 
death occurring after the use of new anti-neoplastic therapy will not be considered and 
the DOR censored. 
5. Summary measure: Median duration of response estimated by the Kaplan-Meier method 
(for cohort A and B, resp.). 
4 
Study design 
4.1 
Overall design 
This is a non-randomized, open-label, single-arm, multicenter, phase II study evaluating the 
antitumor activity and safety of JDQ443 single-agent as first-line treatment for participants with 
locally advanced or metastatic KRAS G12C-mutated NSCLC (Figure 1-1). 
The study will have 2 non-comparative cohorts that will enroll approximately 120 participants 
in parallel according to the following characteristics: 
• Cohort A: participants whose tumors harbor a KRAS G12C mutation and a PD-L1 
expression < 1%, regardless of STK11 mutation status (N=90). 
• Cohort B: participants whose tumors harbor a KRAS G12C mutation, a PD-L1 
expression ≥ 1% and an STK11 co-mutation (N=30). 
The sample size of cohorts A and B was determined based on the estimated frequency of the 
molecular profile required to meet eligibility criteria for each cohort: the prevalence of PD-L1 
expression <1% is estimated as around 40% in patients with KRAS G12C- mutated NSCLC, 
whereas STK11 co-mutations are found in around 12-15% of these patients 
(Skoulidis et al 2015, Skoulidis and Heymach 2019, Aredo et al 2019, Ricciuti et al 2021 
and Skoulidis et al 2021). Due to the differences in terms of sample size, the antitumor activity 
of JDQ443 will be assessed as primary objective in cohort A, and as a key secondary objective 
in cohort B. 
The statistical analyses will be performed separately for each of the two cohorts. For both cohort 
A and cohort B, an interim analysis is planned to stop early for lack of efficacy (futility). The 
interim analysis in cohort A will be performed based on ORR in approximately the first 30 
participants enrolled who have been followed for at least two tumor assessments or have 
discontinued the study earlier. In cohort B, the interim analysis will be based on approximately 

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the first 15 participants enrolled who have been followed for at least two tumor assessments or 
discontinued the study earlier. 
Details are described in Section 9.8. 
JDQ443 treatment may be continued beyond initial disease progression as per RECIST 1.1 by 
BIRC if, in the judgement of the Investigator, there is evidence of clinical benefit, and the 
participant wishes to continue on the study treatment (for additional details please refer to 
Section 6.1.4.1). 
4.2 
Scientific rationale for study design 
The rationale for the study design is described below in Table 4-1. 
Table 4-1 
Rationale for study design 
Study Design Aspect 
Rationale 
Participant population 
KRAS G12C mutations are found in around 13% of NSCLC patients and are 
associated with treatment resistance, as well as with a poor prognosis 
(Guibert et al 2016, Del Re et al 2017, Goulding et al 2020). Although KRAS 
G12C inhibitors have demonstrated antitumor activity in previously treated 
patients with advanced NSCLC, their efficacy in the first-line setting remains 
unknown (Skoulidis et al 2021, Riely et 2021). Hence, the current standard 
first-line treatment for patients with advanced NSCLC whose tumors harbor a 
KRAS G12C mutation is the same as for patients whose tumors have no 
targetable mutations, consisting of an immune checkpoint inhibitor alone or in 
combination with platinum-based chemotherapy in most cases. 
(Planchard et al 2018, Hanna et al 2020). 
Patients whose tumors have a PD-L1 expression < 1% or an STK11 mutation 
derive less benefit from immunotherapy-based treatment, hence alternative 
treatments for these individuals are needed. 
In this phase II study, the antitumor activity and safety of the KRAS G12C 
inhibitor JDQ443 administered as single-agent in the first-line setting will be 
evaluated in 2 subgroups of participants with advanced NSCLC in whom a low 
benefit of immunotherapy is expected: participants whose tumors harbor a 
KRAS G12C mutation and a PD-L1 expression < 1% (cohort A) and those 
whose tumors harbor a KRAS G12C mutation, a PD-L1 expression ≥ 1% and 
an STK11 co-mutation (cohort B). 
Open-label 
Considering the available evidence showing that patients with a PD-L1 
expression < 1% or with an STK11 mutation derive less benefit from 
immunotherapy-based treatment, as well as the encouraging activity observed 
with KRAS G12C inhibitors in patients with advanced NSCLC, the non-
randomized design(open-label) is appropriate for this study (Xu et al 2019, 
Ricciuti et al 2021). 
Treatment beyond disease 
progression 
After the discontinuation of targeted therapies, accelerated tumor progression 
and tumor lesion growth can occur in some patients, hence those patients who 
are deriving clinical benefit from JDQ443 treatment according to Investigator's 
judgment will be allowed to continue study treatment beyond initial RECIST 1.1 
progression by BIRC (Chaft et al 2011). 
Interim analyses 
Interim analyses for futility were implemented in this study to allow an early 
assessment of the antitumor activity of JDQ443, as well as to allow 
discontinuation of the respective cohort in case futility criteria are met. 

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4.3 
Justification for dose 
The recommended Phase II dose of JDQ443 is 200 mg twice a day (b.i.d.). This was determined 
based on the clinical assessment of safety, PK, PK-PD modeling as well as the Bayesian 
hierarchical logistic regression model (BHLRM) assessing the probability of dose limiting 
toxicities (DLTs) from the dose escalation phase of FIH CJDQ443A12101 study, a phase Ib/II 
open-label, multi-center dose escalation study of JDQ443 in patients with advanced solid 
tumors harboring the KRAS G12C mutation. Four dose levels of JDQ443 tablets (
 mg QD., 
 mg QD., 
 mg b.i.d. and 
 mg b.i.d.) were investigated in the dose escalation phase. 
The 
 mg b.i.d. dose was evaluated and determined to be safe and tolerable. The highest 
AUC0-24h was obtained at 
 mg b.i.d. among all dose levels tested, >
% higher than the 
exposure for 
 mg and 
mg QD dose levels, and was at least -fold above the efficacious 
exposure required for maximum efficacy in less sensitive xenograft models which had the 
highest exposure requirement for tumor regression. At this dose level, a >
% average KRAS 
G12C target occupancy was predicted based on PK-PD modeling and was higher than the 
% 
average target occupancy required for tumor regression in various xenograft models. 
The 
 mg b.i.d. dose level satisfied the escalation with overdose control (EWOC) criteria (i.e. 
<
% chance that the true DLT rate was greater than or equal to 
% during DLT evaluation 
period) by Bayesian hierarchical logistic regression model (BHLRM) with posterior probability 
of excessive toxicity less than 
%. No DLTs were observed at this dose level. For detailed 
information on clinical experience of JDQ443 including safety assessments, please refer to 
Section 2.2.4.2. 
4.4 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable 
4.5 
Rationale for public health emergency mitigation procedures 
During a public health emergency as declared by local or regional authorities e.g., pandemic, 
epidemic, or natural disaster, mitigation procedures to ensure participants’ safety and trial 
integrity may be implemented. Notification of the public health emergency as declared by local 
or regional authorities should be discussed among investigators and Novartis. All procedures 
adapted to the situation must be submitted, if required as per local regulations, through a 
protocol amendment for approval by local or regional Health Authorities and Ethics 
Committees prior to implementation of mitigation procedures. 
4.6 
Purpose and timing of interim analyses/design adaptations 
One interim futility analysis per cohort is planned to assess ORR independently in each cohort 
when approximately 30 and 15 participants, in cohort A and cohort B, respectively, have been 
enrolled and followed for 2 tumor assessments or have discontinued the study earlier, with the 
objective to allow an early assessment of the antitumor activity of JDQ443, as well as to allow 
the discontinuation of the respective cohort in case the futility criteria are met. For further details 
please refer to Section 9.8. 
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4.7 
End of study definition 
Study completion is defined as the earliest occurrence of one of the following: 
• The last participant completes last study visit (and the assessments associated with this 
visit have been documented and followed-up appropriately by the Investigator), dies, 
withdraws consent or is lost to follow-up, whichever comes first. 
• In the event of an early study termination decision, the date of that decision. 
• Another clinical study becomes available that can continue to provide JDQ443 to study 
participants and all participants with ongoing treatment are transferred to that clinical 
study.  
See Section 6.6 for information on continued access to study treatment after the end of the study. 
5 
Study population 
The study population will include adult participants with locally advanced or metastatic 
squamous or non-squamous NSCLC whose tumors harbor a KRAS G12C mutation and a PD-
L1 expression <1% (cohort A) or a PD-L1 expression ≥ 1% and an STK11 co-mutation (cohort 
B), who have not received any prior systemic treatment for metastatic disease. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Participant is an adult ≥ 18 years of age at the time of informed consent. 
3. Histologically confirmed locally advanced (stage IIIb/IIIc not eligible for definitive 
chemoradiation or surgical resection with curative intent) or metastatic (stage IV) NSCLC. 
4. Presence of a KRAS G12C mutation (all participants) and: 
• For cohort A: PD-L1 expression <1%, regardless of STK11 mutation status. 
• 
For cohort B: PD-L1 expression ≥ 1% and an STK11 co-mutation. 
KRAS G12C and/or STK11 mutation status assessed in tumor tissue or blood as 
determined by a local test, validated according to local regulation at a Clinical 
Laboratory Improvement Amendments CLIA-certified USA laboratory or an 
accredited local laboratory outside of the USA or centrally assessed at a Novartis-
designated laboratory prior to enrollment.  
PD-L1 tumor proportion score (TPS) status assessed determined by local assessment 
at a CLIA-certified USA laboratory or an accredited local laboratory outside of the 
USA or centrally assessed at a Novartis designated laboratory prior to enrollment. 
For participants in China only: PD-L1 expression, KRAS G12C status and STK11 
mutation status (cohort B only) must be determined by local assessment, according to 
criteria listed above. 
5. No previous systemic treatment for metastatic disease. Prior (neo)adjuvant treatment with 
chemotherapy and/or immunotherapy, or prior radiotherapy administered sequentially or 
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advanced disease are accepted if the time between therapy completion and enrollment is > 
12 months. 
6. ECOG performance status ≤ 1. 
7. At least 1 measurable lesion by RECIST 1.1. 
8. Participant must have recovered from all toxicities related to prior treatments to grade ≤ 1 
(CTCAE v 5.0). Exception to this criterion are alopecia and vitiligo of any grades. 
9. Adequate organ function including the following laboratory values at the screening visit: 
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (without growth factor support), 
• Platelets ≥ 100 x 109/L (without growth factor support), 
• Hemoglobin (Hgb) > 9 g/dL (7 days without transfusions or growth factor support), 
• Aspartate transaminase (AST) ≤ 3 x upper limit of normal (ULN), 
• Alanine transaminase (ALT) ≤ 3 x ULN, 
• Total bilirubin ≤ 1.5 ULN, 
• Serum amylase ≤ 2 x ULN, 
• Serum lipase ≤ 1.5 x ULN, 
• Creatinine clearance ≥ 45 mL/min by calculation using Cockcroft-Gault formula. 
10. Participant is capable of swallowing study medication and following instructions 
regarding study treatment administration, or have a daily caregiver(s) who will be 
responsible for administering study treatment. 
11. Participant must be able to communicate with the Investigator and comply with the 
requirements of the study procedures. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Participants who previously received a KRAS G12C inhibitor or any other systemic 
therapy for metastatic NSCLC. 
• Prior (neo)adjuvant treatment with chemotherapy or immunotherapy, or prior 
radiotherapy administered sequentially or concomitantly with chemotherapy and/or 
immunotherapy for localized or locally advanced disease are not allowed if the time 
between therapy completion and enrollment is ≤ 12 months. 
2. Participants whose tumors harbor an EGFR-sensitizing mutation and/or ALK 
rearrangement by local laboratory testing. Participants with NSCLC of pure squamous cell 
histology are eligible if EGFR-sensitizing mutation or ALK status is unknown; however, 
if the presence of an EGFR-sensitizing mutation or ALK rearrangement is known, 
participants will be excluded. 
• Note: Participants with other known druggable alterations will be excluded, if 
required by local guidelines 
3. History of severe hypersensitivity reaction to JDQ443 or its excipients. 
4. Known active (unstable/symptomatic) central nervous system (CNS) metastases and/or 
carcinomatous meningitis. 

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• Participants with previously treated, and at the time of screening, stable brain metastases 
may participate provided they meet all of the following criteria:  
• Brain imaging at screening shows no evidence of interim progression since previous 
imaging. Patients with brain metastasis found on screening are eligible to the study if 
asymptomatic 
• Subjects clinically stable for ≥2 weeks. 
• Have measurable and/or evaluable disease outside CNS 
• corticosteroids are allowed as therapy for CNS disease at a dose of 10 mgs 
prednisolone (or equivalent) or less 
• No stereotactic radiation or whole-brain radiation ≤14 days before randomization. 
• Recovered from brain metastasis surgery 
• Stable brain metastasis by this definition should be established prior to the first dose 
of study medication 
5. Presence or history of a malignant disease, other than the resected NSCLC, that has been 
diagnosed and/or required therapy within the past 3 years. Exceptions to this criterion are 
completely resected basal cell and squamous cell skin cancers, and completely resected 
carcinoma in situ of any type. 
6. Participant has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) 
within 4 weeks prior to starting study treatment or has not recovered from side effects of 
such procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be 
counted as major surgery and the participant can be enrolled in the study ≥ 1 week after 
the procedure. 
7. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting the study treatment or 
participants who have not recovered from radiotherapy-related toxicities. For all other 
anatomic sites (including radiotherapy to thoracic vertebrae and ribs) radiotherapy ≤ 2 
weeks prior to starting the study treatment or has not recovered from radiotherapy-related 
toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study 
treatment is allowed. 
8. Clinically significant, uncontrolled cardiac disease and/or recent cardiac events (within 6 
months), such as: 
• Unstable angina or myocardial infarction within 6 months prior to screening. 
• Symptomatic congestive heart failure (defined as New York Heart Association Grade 
II or greater). 
• Documented cardiomyopathy. 
• Clinically significant cardiac arrhythmias. 
• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, unless controlled prior to first 
dose of study treatment.  
9. History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
study participation such as: 

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• Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker. 
• History of familial long QT syndrome or known family history of Torsades de 
Pointes. 
• Resting QT interval corrected with Fridericia’s formula (QTcF) > 480 msec on 
screening ECG or congenital long QT syndrome 
10. A medical condition that results in increased
 
 
11. History of interstitial lung disease or pneumonitis grade ≥ 2. 
12. Current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (i.e., 
uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or 
hypercoagulability syndromes etc.). 
13. Any other concurrent severe and/or uncontrolled medical condition that would, in the 
Investigator’s judgment cause unacceptable safety risks, contra-indicate participation in 
the clinical study or compromise compliance with the protocol (e.g., chronic pancreatitis, 
uncontrolled diabetes, hepatic disorders including cirrhosis). 
14. Any other medical condition (such as active infection, treated or untreated), which in the 
opinion of the Investigator represents an unacceptable risk for participation in the study. 
• Note: testing for hepatitis B virus (HBV) or hepatitis C virus infection, tuberculosis 
and/or HIV (by local laboratory) is not mandatory at screening unless if required by 
local regulations. 
15. Any medical condition or prior surgical resection that may affect the absorption of the 
investigational drug. Examples of medical conditions that may affect investigational drug 
absorption include (but are not limited to) inflammatory bowel disease (i.e., ulcerative 
colitis, Crohn’s disease) and gastrointestinal disease such as ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, and malabsorption syndrome. 
16. Participants who are taking a prohibited medication (strong CYP3A inducers) that cannot 
be discontinued at least seven days prior to the first dose of study treatment and for the 
duration of the study (see Section 6.8.2). 
17. Use of any live vaccines against infectious diseases within four weeks before initiation of 
study treatment. 
18. Participant is concurrently using other anti-cancer therapy. 
19. Participation in any additional, parallel, investigational drug or device studies. 
20. Pregnant or breast-feeding women or women who plan to become pregnant or breast-feed 
during the study. Pregnant women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
21. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for 7 days after the last dose of JDQ443. Highly effective 
contraception methods include: 
CCI 

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• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
• Female bilateral tubal ligation, female sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy) or total hysterectomy at least 6 weeks 
before taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level 
assessment. 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant. 
• Use of oral (estrogen and progesterone), injected or implanted combined hormonal 
methods of contraception or placement of an intrauterine device (IUD) or intrauterine 
system (IUS), or other forms of hormonal contraception that have comparable 
efficacy (failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception. 
• In case of use of oral contraception women should have been stabilized on the same 
pill for a minimum of 3 months before taking study treatment. 
• Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, 
history of vasomotor symptoms). Women are considered not of child-bearing 
potential if they are post-menopausal or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least 
six weeks 6 weeks prior to enrollment on study. In the case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow-up 
hormone level assessment is she considered to be not of child-bearing potential. 
22. Sexually active males unless they use a condom during intercourse while taking study 
treatment and for 7 days after the last dose of JDQ443. Male participants should not father 
a child in this period. A condom is required to be used also by vasectomized men in order 
to prevent delivery of the study treatment via seminal fluid. In addition, male participants 
must not donate sperm and women participants must not donate oocytes for the time 
period specified above. 
If local regulations are more stringent than the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the Informed Consent Form (ICF). 
5.3 
Screen failures 
A screen failure occurs when a participant who consents to participate in the clinical study is 
subsequently found to be ineligible and therefore not assigned to study treatment. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. 
Participants who signed an informed consent form (i.e., pre-screening molecular ICF and/or 
Main ICF) and are subsequently found to be ineligible will be considered as screen failures. 

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The reason for screen failure should be recorded on the appropriate eCRF. The demographic 
information, informed consent, inclusion/exclusion, information on prior local testing on tumor 
and blood for KRAS G12C, STK11, EGFR and ALK rearrangement/mutation status, other 
known druggable alteration information (if available) and PD-L1 expression status, tumor 
sample collection (archival or newly obtained) for central confirmation of KRAS G12C and 
STK11 mutation and PD-L1 expression status and future in vitro diagnostic development, blood 
sample for future in vitro diagnostic development, NSCLC diagnosis and extent of disease, 
screening period disposition, withdrawal of consent/opposition to use of data/biological 
samples if applicable and death if applicable pages must also be completed for screen failure 
participants. No other data will be entered into the clinical database for participants who are 
screen failures, unless the participant experienced a serious adverse event during the screening 
period (see Section 8.7.3 for reporting details). For molecular pre-screening failures, only SAEs 
possibly related to a study procedure will be reported. Data and samples collected from 
participants prior to screen failure may still be analyzed. 
Participants who sign the main ICF and are considered eligible (enrolled) but fail to be started 
on treatment for any reason will be considered an early terminator. The reason for early 
termination should be captured on the appropriate disposition eCRF. 
IRT should be notified within 2 days if the participant did not start treatment or is not enrolled. 
A new ICF will need to be signed if the Investigator chooses to re-screen the participant after a 
participant has screen failed. All re-screening evaluations must be performed within 28 days 
prior to start of study treatment. All required screening activities must be performed when the 
participant is rescreened for participation in the study. If the participant completes all re-
screening evaluations and still does not meet the eligibility criteria, the participant is a screen 
failure and cannot be re-screened again (only one re-screening allowed). Once the number of 
participants screened and enrolled is likely to reach the target enrollment, the Sponsor may close 
the study to further screening. In this case, the participants who screen failed will not be 
permitted to be re-screened. 
5.3.1 
Participant numbering 
Participant numbering can be configured as a four-digit site number followed by a consecutive 
three-digit number, e.g., 1234001, 1234002 where the site number is 1234. 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is rescreened. The Participant No. consists of the Site 
Number (Site No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available. 
A new ICF will need to be signed if the Investigator chooses to rescreen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 

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6 
Study treatment(s) and concomitant therapy 
6.1 
Study treatment(s) 
For this study, the term "study treatment" refers to Novartis study drug JDQ443, which will be 
labeled and provided to sites by Novartis in compliance with legal requirements for each 
country. The study treatment begins on Cycle 1 Day 1 (C1D1) with the first administration of 
JDQ443. 
All doses prescribed, dispensed to the participant and all dose changes during the study, 
including the reason, must be recorded on the appropriate electronic case report form (eCRF) 
page. 
Table 6-1 
Investigational drug 
Treatment Title 
JDQ443 
Treatment Description 
Tablets given as 200 mg b.i.d. with food 
Type  
Drug 
Dose Formulation 
Tablet 
Unit Dose Strength(s) 
100 mg 
Dosage Level(s) 
200 mg b.i.d. 
Route of Administration 
Oral 
Use 
Experimental 
IMP (Investigational medicinal 
product) 
Yes 
Sourcing 
Provided centrally by the sponsor  
Packaging and Labelling 
Study treatment will be provided in HDPE bottles. Each bottle will be 
labelled as required per country requirement. 
6.1.1 
Additional study treatments 
No other study treatment beyond JDQ443 is included in this trial. 
6.1.2 
Treatment arms/group 
The study will have 2 non-comparative cohorts that will recruit participants in parallel 
according to the following characteristics: 
• 
Cohort A: participants whose tumors harbor a KRAS G12C mutation and a PD-L1 
expression <1%, regardless of STK11 mutation status. 
• 
Cohort B: participants whose tumors harbor a KRAS G12C mutation, a PD-L1 
expression ≥ 1% and an STK11 co-mutation. 
Participants will be assigned at enrollment to one of the cohorts. Participants in both cohorts 
will receive JDQ443 200 mg b.i.d. administered continuously with food. The day of the first 
tablet taken defines C1D1. Each treatment cycle is 21 days for both arms. 
6.1.3 
Guidelines for continuation of treatment 
Participants should continue to receive the study treatment until one or more criteria for 
treatment discontinuation described in Section 7 are met. 

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Guidelines on the management of common JDQ443 associated toxicities and dose modification 
instructions are provided in Section 6.5. 
6.1.4 
Treatment duration 
Participants will be treated until they experience any of the following: unacceptable toxicity, 
disease progression per RECIST 1.1 by BIRC and/or treatment is discontinued at the discretion 
of the Investigator or the participant. A complete list of the circumstances requiring study 
treatment discontinuation is provided in Section 7.1 
While the Investigator is waiting for the results from the central imaging vendor to confirm 
disease progression, the participant should continue on study treatment. However, during this 
time, the Investigator should do whatever is medically necessary and indicated for the 
participant. 
Participants treated with JDQ443 may continue treatment beyond disease progression per 
RECIST 1.1 by BIRC if in the judgment of the Investigator there is evidence of clinical benefit 
and the participant wishes to continue on the study treatment. Criteria for treatment beyond 
progression are described in Section 6.1.4.1 . 
See Section 6.6 for information on continued access to study treatment after the end of the study. 
6.1.4.1 
Treatment beyond disease progression 
Participants treated with JDQ443 will be permitted to continue study treatment beyond initial 
disease progression per RECIST 1.1 by BIRC, provided they meet all the following criteria: 
• Evidence of clinical benefit assessed by Investigator 
• No rapid disease progression 
• Adequate tolerance to study treatment as defined by no grade 3 or 4 toxicities within the 
past 21 days on current therapy 
• Should not jeopardize critical interventions to treat/prevent severe complications, or 
prevent participants from receiving adequate care 
• Participant performance status is stable 
• Participant wishes to continue on the study treatment 
• No new antineoplastic therapy has been initiated 
Treatment beyond disease progression should not jeopardize critical interventions to 
treat/prevent severe complications or prevent participants from receiving adequate care. 
The reasons for the participant continuing treatment beyond progression will be documented in 
the eCRF. 
Participants who meet the above criteria and continue treatment beyond initial disease 
progression will continue all study procedures as outlined in the visit scheduled assessments. 
Clinical deterioration or suspicion of further disease progression will require a follow-up 
imaging assessment to be performed promptly rather than waiting for the next scheduled 
assessment. Participants who are no longer deriving clinical benefit, or who meet other protocol 
discontinuation criteria must be discontinued from study treatment. 

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6.2 
Preparation, handling, storage, and accountability 
Each study site will be supplied with study treatment in packaging as described under 
Section 6.1. 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document. 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, delivery 
of IMP directly to a participant's home may be permitted (if allowed by local or regional health 
authorities and ethics committees as appropriate) in the event the Investigator has decided that 
an on-site visit by the participant is no longer appropriate or possible, and that it is in the interest 
of the participant's health to administer the study treatment even without performing an on-site 
visit. The dispatch of IMP from the site to the participant’s home remains under the 
accountability of the Investigator. Each shipment/provisioning will be for a maximum of 3 
cycles supply. In this case, regular phone calls or virtual contacts (every 3 weeks minimum, or 
more frequently if needed) will occur between the site and the participant for instructional 
purposes, safety monitoring, investigation of any adverse events, ensuring participants continue 
to benefit from treatment, and discussion of the participant's health status until the participants 
can resume visits at the study site. 
6.2.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the Investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the JDQ443 bottle label. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The Investigator or designated site staff must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Monitoring of drug accountability 
will be performed by field monitors during site or remote monitoring visits, and at the 
completion of the trial. 
Participants will be asked to return all unused study treatment and packaging at the end of the 
study or at the time of discontinuation of study treatment. 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging, as appropriate in compliance with site processes, monitoring processes, and per local 

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regulation/guidelines. Otherwise, the Investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the Investigator folder at each site. 
6.2.2 
Handling of other treatment 
Not Applicable 
6.2.3 
Instruction for prescribing and taking study treatment 
All dosages prescribed and dispensed to participants and all dose changes during the study must 
be recorded on the Dose Administration Record eCRF. Doses and treatment schedules are 
described in Table 6-2. 
Table 6-2 
Dose and treatment schedule 
Investigational Drug (Name and Strength) 
Dose 
Frequency and/or Regimen 
JDQ443 (100 mg) 
200 mg (2 x 100 mg) 
Twice a day (b.i.d) 
JDQ443 will be administered orally as a flat-fixed dose. 
A sufficient supply of JDQ443 should be provided to participants to allow study treatment self-
administration at home until at least the next study visit at the clinic. At subsequent visits, site 
staff will provide additional bottles to ensure the study treatment supply until discontinuation 
of study treatment. 
Participants should take their dose at approximately the same time each day. The first daily dose 
should be taken in the morning and the second dose should be taken approximately 12 h after 
the first dose (e.g., 08:00 and 20:00). If a dose is not taken within 4 h of the planned dosing 
time, the missed dose should not be replaced 
JDQ443 should be administered with food. Participants should take JDQ443 immediately 
(within 30 minutes) following a meal. 
Each dose of JDQ443 is to be taken with a glass of water and consumed over as short time as 
possible. 
The tablets should be ingested whole and should not be chewed or crushed. 
If vomiting occurs during the course of treatment, no re-dosing of the participant is allowed 
before the next scheduled dose. If the vomiting occurs on PK sampling days within the first 4 h 
post-dosing, this event should be recorded on the dose administration PK electronic eCRF page, 
as well as on the AE eCRF, as appropriate. 
On days when PK blood samples are to be collected, participants will be instructed to hold their 
dose until arrival at the study center. JDQ443 will be administered with food at the site in the 
morning prior to the PK blood draws, except for pre-dose samples which will be collected 
immediately before JDQ443 administration. The administration will be supervised by a member 
of the research team. The dose, exact date and time of drug administration, exact date and time 
of PK blood draws, and meal record (start/end time) should be recorded in the appropriate 
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The Investigator or responsible site personnel should instruct the participant to take the study 
treatment exactly as prescribed to promote compliance. 
Participants should inform the investigational site staff of any missed or delayed doses. 
 
 
 
 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
All dosages prescribed and dispensed to the participant and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF. 
6.3 
Measures to minimize bias: randomization and blinding 
6.3.1 
Treatment assignment, randomization 
No randomization will be performed in this study. The assignment of a participant to a particular 
cohort will be driven by eligibility criteria and coordinated by Novartis. The response 
assessment for the study's primary endpoint according to RECST 1.1 will be performed by 
BIRC in order to mitigate the risk of bias. 
6.3.2 
Treatment blinding 
Not Applicable 
6.3.3 
Emergency breaking of assigned treatment code 
Not Applicable 
6.4 
Study treatment compliance 
The date and time of study treatment administration during the study and any deviations from 
the protocol treatment schedule will be captured on the appropriate study treatment dispensation 
form. 
The Investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
Investigator if he/she is unable for any reason to take the study treatment as prescribed. 
For JDQ443, compliance will be assessed by the Investigator and/or study personnel at each 
visit using pill counts and information provided by the participant. This information should be 
captured in the source document at each visit. All study treatment dispensed and returned must 
be recorded in the Drug Accountability Log. 
CCI 

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6.5 
Dose modification 
6.5.1 
Dose modification guidelines 
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions, 
and/or reductions are either recommended or mandated in order to allow participants to continue 
the study treatment. 
These dose modifications for JDQ443 are summarized in Table 6-3 and Table 6-4. Deviations 
to mandatory dose interruptions and/or reductions are not allowed. Permanent discontinuation 
from study treatment is mandatory for specific events indicated as such in Table 6-3 and 
Table 6-4. 
Dose reductions are allowed for JDQ443 and should follow the dose reduction steps described 
in Table 6-3 and Table 6-4. For each participant, a maximum of two consecutive dose level 
reductions is allowed after which the participant must be discontinued. Dose reductions of 
JDQ443 below 100 mg QD. are not permitted. 
Dose re/escalation of JDQ443 to previous dose level is allowed only once, and if no AE leading 
to dose modification is observed after at least 1 cycle (21 days) of study treatment at the reduced 
dose. 
For toxicities related to study treatment that resolve within 7 days of event onset, treatment may 
be resumed at the same or a lower dose level at the Investigator’s discretion, except for toxicities 
that require permanent treatment discontinuation (Table 6-3 and Table 6-4). 
For toxicities related to study treatment that result in dose interruptions of more than 7 but not 
more than 21 days, study treatment may be resumed but only at a lower dose level. If the 
participant is already at the lowest dose level, participant might continue receiving treatment at 
the same dose level if participant is deriving clinical benefit from JDQ443. In such situation, 
the Investigator must discuss and receive approval from Novartis Medical Monitor or designee 
prior to continuing JDQ443 and rationale should be captured in the source document. 
If the participant requires a dose interruption of more than 21 days from the intended day of the 
next scheduled dose, then the participant must be discontinued from the study treatment. 
Exceptions to this criterion may be considered if the participant is deriving clinical benefit from 
the treatment. The Investigator must discuss and receive approval from Novartis Global 
Medical Director or designee prior to continuing study treatment in this situation and rationale 
should be captured in the source documents. If study treatment is reintroduced after an 
interruption of more than 21 days caused by an adverse event, study treatment can only be 
reintroduced at a lower dose level. If study treatment is reintroduced after an interruption of 
more than 21 days that was not caused by an adverse event, study treatment may be reintroduced 
without dose reduction. 
All dose changes must be recorded on the appropriate eCRF.  

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Table 6-3 
Criteria for dose reduction / interruption and re-initiation of JDQ443 
treatment for adverse drug reactions. 
Dose modifications for JDQ443 
Worst toxicity 
CTCAE Gradea (value) during a cycle of therapy 
 
Investigations (Hematologic) 
Neutropenia (ANC) 
Grade 1 (ANC < lower limit of normal (LLN) - 
1500/mm3) 
Recommendation: Maintain study treatment and dose 
level. 
Grade 2 (ANC < 1500 - 1000/mm3) 
Recommendation: Maintain study treatment and dose 
level. 
Grade 3 (ANC < 1000 - 500/mm3) 
Recommendation: Interrupt study treatment until 
resolved to ≤ Grade 2, then: 
If resolved in ≤ 7 days, maintain dose level. 
If resolved in > 7 days, reduce 1 dose level. 
Grade 4 (ANC < 500/mm3) 
Mandatory: Interrupt study treatment until resolved to 
≤ Grade 2, then reduce 1 dose level. 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75,000/mm3) 
Recommendation: Maintain study treatment and dose 
level. 
Grade 2 (PLT < 75,000 - 50,000/mm3) 
Recommendation: Maintain study treatment and dose 
level. 
Grade 3 (PLT < 50,000 - 25,000/mm3) 
Recommendation: Interrupt study treatment until 
resolved to ≤ Grade 2, then: 
If resolved in ≤ 7 days, maintain dose level. 
If resolved in > 7 days, reduce 1 dose level. 
Mandatory: For Grade 3 thrombocytopenia associated 
with major bleeding, permanently discontinue study 
treatment. 
Grade 4 (PLT < 25,000/mm3) 
Mandatory: Interrupt study treatment until resolved to 
≤ Grade 2, then reduce 1 dose level. 
Mandatory: For Grade 4 thrombocytopenia associated 
with major bleeding, permanently discontinue study 
treatment. 
Febrile neutropenia (ANC < 1.0 × 109/L, with a single 
temperature of >38.3 degrees C [101 degrees F] or a 
sustained temperature of ≥ 38 degrees C [100.4 
degrees F] for more than one hour) 
Mandatory: Interrupt study treatment until resolved, 
then reduce 1 dose level. 
Anaemia 
 
Grade 1 (Hemoglobin [Hgb] < LLN - 10.0 g/dL; < LLN 
- 6.2 mmol/L; < LLN - 100 g/L) 
Recommendation: Maintain study treatment and dose 
level. 
Grade 2 (Hgb < 10.0 - 8.0 g/dL; < 6.2 – 4.9 mmol/L; < 
100 - 80 g/L) 
Recommendation: Maintain study treatment and dose 
level. 
Grade 3 (Hgb < 8.0 g/dL; < 4.9 mmol/L; < 80 g/L; 
transfusion indicated) 
Recommendation: Interrupt study treatment until 
resolved to ≤ grade 2, then: 
If resolved in ≤ 7 days, resume study treatment at the 
same dose level; 
If resolved in > 7 days, reduce 1 dose level. 
Grade 4 (Life-threatening consequences; urgent 
intervention indicated) 
Mandatory: Interrupt study treatment until resolved to 
≤ grade 2, then reduce 1 dose level. 

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Investigations (Renal) 
Serum creatinine 
Grade 1 (> ULN - 1.5 × ULN) 
Recommendation: Maintain study treatment and dose 
level. 
Grade 2 (> 1.5 - 3.0 × ULN) 
Recommendation: Interrupt study treatment and 
manage according to institutional practice. 
Upon resolution to ≤ Grade 1, may reintroduce study 
treatment at the same dose level if clinically indicated. 
Grade 3 (> 3.0 - 6.0 × ULN) and Grade 4 (> 6.0 × 
ULN) 
Mandatory: Permanently discontinue study treatment. 
Investigations (Hepatic) 
Isolated total Bilirubin elevation 
Grade 1 (> ULN – 1.5 × ULN) 
Recommendation: Maintain study treatment and dose 
level. 
Grade 2 (> 1.5 - 3.0 × ULN) 
Recommendation: Interrupt study treatment. 
Repeat LFTsb within 48-72 hours, then monitor 
LFTs at least weekly, until resolved to ≤ 1.5 × ULN or 
to baseline, then: 
• 
If resolved in ≤ 7 days, resume study treatment at 
the same dose level; 
• 
If resolved in > 7 days, reduce 1 dose level. 
Grade 3 (> 3.0 - 10.0 × ULN)* 
Recommendation: Interrupt study treatment. 
Repeat LFTsb within 48-72 hours, then monitor LFTs 
at least weekly, until resolved to ≤ 1.5 × ULN or to 
baseline. May reintroduce study treatment at 1 lower 
dose level if clinically indicated. 
Grade 4 (> 10.0 × ULN)* 
Mandatory: Permanently discontinue study treatment. 
The participant should be monitored at least weekly 
(including LFTsb), or as clinically indicated, until total 
bilirubin has resolved to ≤ 1.5 × ULN or to baseline. 
Note: An isolated bilirubin elevation is not typical for 
treatment-induced liver injury. Bilirubin can be 
elevated either as part of a “Hy’s law” constellation 
with a preceding elevation of ALT/AST, or as part of a 
cholestatic reaction with simultaneous elevation of 
other cholestatic parameters (ALP, GGT). Isolated 
bilirubin elevation can be seen in conjunction with 
treatments that inhibit bilirubin conjugation or 
excretion, but both scenarios do not typically 
represent liver injury. Alternative causes of bilirubin 
elevation should be excluded before basing dose 
modification decisions on bilirubin values alone. 
Isolated AST or ALT elevation 
If normal at baseline: 
Grade 1 (> ULN - ≤ 3.0 × ULN) 
Recommendation: Maintain study treatment and dose 
level. 
Grade 2 (> 3.0 - ≤ 5.0 x ULN) 
Recommendation: Interrupt study treatment. 
Repeat LFTsb within 48-72 hours, then monitor 
LFTs at least weekly, until resolved to ≤ Grade 1, 
then: 
• 
If resolved in ≤ 7 days, resume study treatment at 
the same dose level; 

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•
If resolved in > 7 days, reduce 1 dose level.
Grade 3 (> 5.0 - ≤ 20.0 x ULN) 
Recommendation: Interrupt study treatment. 
Repeat LFTsb within 48-72 hours, then monitor 
LFTs at least weekly, until resolved to ≤ Grade 1, then 
reduce 1 dose level. 
Grade 4 (> 20.0 x ULN) 
Mandatory: Permanently discontinue study treatment. 
Repeat LFTsb as soon as possible, preferably within 
48-72 hours from awareness of the abnormal results;
monitor LFTsb at least weekly, until resolved to grade
<1or stabilization over 4 weeks.
If elevated at baseline (up to Grade 1: ≤ 3.0 x ULN): 
> 5.0 x ULN AND ≤ 3.0 x baseline
Recommendation: Interrupt study treatment. 
Repeat LFTsb within 48-72 hours, then monitor 
LFTs at least weekly, until resolved to ≤ Grade 1, 
then: 
•
If resolved in ≤ 7 days, resume study treatment at
the same dose level;
•
If resolved in > 7 days, reduce 1 dose level.
>10 x ULN AND > 3.0 x baseline
Recommendation: Interrupt study treatment. 
Repeat LFTsb within 48-72 hours, then monitor 
LFTs at least weekly, until resolved to ≤ Grade 1, then 
reduce 1 dose level. 
> 20.0 x ULN
Mandatory: Permanently discontinue study treatment. 
Repeat LFTsb as soon as possible, preferably within 
48-72 hours from awareness of the abnormal results;
monitor LFTsb at least weekly, until resolved to
baseline or stabilization over 4 weeks.
Combinedc elevations of AST or ALT and total bilirubin 
For participants with normal baseline ALT and 
AST and total bilirubin value: 
AST or ALT >3.0 × ULN combined with total 
bilirubin > 2.0 × ULN without evidence of cholestasisd 
and Gilbert's syndrome 
For participants with elevated baseline AST or 
ALT or total bilirubin value: 
AST or ALT > 3 × baseline OR > 8.0 × ULN, 
whichever is lower, combined with total bilirubin > 2 × 
baseline AND > 2.0 × ULN 
Note: For participants with Gilbert’s syndrome, at 
least 2-fold increase in direct bilirubin. 
Mandatory: Interrupt study treatment and adjudicate 
for DILI: 
Repeat as soon as possible, preferably within 48 
hours from awareness of the abnormal results, 
monitor LFTsb at least weekly, or as clinically 
indicated, until AST, ALT, and total bilirubin have 
resolved ≤ Grade 1 or to baseline. 
If causality assessment indicates that DILI is 
confirmed: Permanently discontinue study treatment. 
If not DILI: Treat the identified cause according to 
institutional guidelines. Once resolved to ≤ Grade 1 or 
to baseline, may reintroduce study treatment at 1 
lower dose level if clinically indicated, following 
discussion with Novartis medical monitor. 
Refer to Section 6.5.3.1 for further details on the 
follow up of potential drug-induced liver injury (DILI) 
cases. 
Investigation (metabolic) 
amylase and/or lipase elevation 
Grade 1 (> ULN - 1.5 × ULN) 
Recommendation: Maintain study treatment and dose 
level. 
Grade 2 (> 1.5 - 2.0 × ULN) 
Recommendation: Maintain study treatment and dose 
level. 

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Grade 3 (> 2.0 - 5.0 × ULN) with signs or 
symptoms; > 5.0 × ULN and asymptomatic.** 
Recommendation: Interrupt study treatment until 
resolved to Grade ≤ 1 or baseline, then: 
If resolved in ≤ 7 days, resume study treatment at the 
same dose level. 
If resolved in > 7 days, reduce 1 dose level. 
Grade 4 (> 5.0 × ULN with signs or symptoms)** 
Mandatory: Permanently discontinue study treatment. 
Cardiac Investigations 
Left Ventricular Ejection Fraction (LVEF) 
LVEF < 40% 
Mandatory: Interrupt study treatment, obtain 
consultation with cardiologist and repeat cardiac 
imaging after 3 weeks. If improved to > 45%, restart 
study treatment at the same dose. If not improved 
to >45%, permanently discontinue study treatment. 
LVEF 40%- ≤45% and decrease is ≥ 10%-points 
below baseline 
Mandatory: Interrupt study treatment, obtain 
consultation with cardiologist and repeat cardiac 
imaging after 3 weeks. If LVEF has recovered to 
within 10%-point below baseline, restart study 
treatment at the same dose. 
If LVEF has not recovered to within 10%-points below 
baseline, permanently discontinue study treatment. 
LVEF 40% to ≤45% and decrease is < 10%-points 
below baseline 
Mandatory: Continue treatment. Obtain consultation 
with a cardiologist and repeat LVEF assessment 
within 3 weeks. If LVEF is stable/improving, no further 
action is needed. If there is a further decrease in 
LVEF, please follow the above guidance. 
ECG QTc-Interval prolonged 
Grade 1 and 2 
Recommendation: Maintain treatment and dose level. 
Grade 3 
Mandatory: Interrupt study treatment. Upon resolution 
to Grade ≤ 1 or baseline or < 30 msec difference from 
baseline (QTc), reduce 1 dose level. May resume 
JDQ443 treatment without dose modification after 
discussion with the Novartis Medical Monitor if other 
contributing factors have been identified. Baseline 
ECG refers to the ECG(s) collected at screening. 
Grade 4 
Mandatory: Permanently discontinue study treatment. 
Vascular disorders 
Hypertension 
Grade 1 and 2 
Recommendation: Maintain study treatment and dose 
level. 
Grade 3 
Recommendation: Interrupt study treatment until 
resolved to ≤ Grade 1, then reduce 1 dose level. 
Grade 4 
Mandatory: Permanently discontinue study treatment. 
Gastrointestinal 
Diarrhea*** 
Grade 1 
Recommendation: Maintain study treatment and dose 
level. Treat the patient per institutional practice. 
Grade 2 
Recommendation: Interrupt study treatment until 
resolved to ≤ grade 1, treat the patient per institutional 
practice, then reintroduce study treatment at the same 
dose level. 

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If diarrhea returns as ≥ grade 2, then interrupt study 
treatment until resolved to ≤ grade 1 and reduce 1 
dose level. 
Grade 3 
Recommendation: Interrupt study treatment until 
resolved to ≤ Grade 1, treat the patient per 
institutional practice, then: 
If resolved in ≤ 48 hours, maintain dose level. 
If resolved in > 48 hours despite the use of optimal 
anti-diarrhea therapy, reduce 1 dose level. 
Grade 4 
Mandatory: Permanently discontinue study treatment. 
Nausea & Vomiting 
 
Grade 1 and 2 
Recommendation: Maintain study treatment and dose 
level, provide anti-emetic treatment per institutional 
practice. 
Nausea Grade 3 and Vomiting Grade ≥ 3 (despite 
standard anti-emetics) 
Recommendation: Maintain dose level. If not resolved 
to ≤ Grade 2 within 48 hours after start of optimal anti-
emetic therapy, interrupt study treatment until 
resolved to ≤ Grade 2, and resume study treatment at 
1 lower 1 dose level. 
Dose modifications apply to participants who experience nausea and/or vomiting despite appropriate anti-
emetic treatment, which should be initiated at the first sign of nausea and/or vomiting. 
Endocrine toxicities 
Hypothyroidism or Hyperthyroidism 
Grade 1 and Grade 2 
Recommendation: Maintain study treatment and dose 
level. 
Grade 3 and Grade 4 
Mandatory: Interrupt study treatment. Obtain 
endocrinology consultation. Upon resolution to Grade 
≤ 1 with appropriate management, may resume study 
treatment without dose modification. Consideration to 
restart study treatment before resolution to Grade ≤ 1 
with appropriate management may be considered 
following discussion with Novartis medical monitor. 
Other endocrine disorders 
Grade 1 
Recommendation: Maintain study treatment and dose 
level. 
Grade 2 and Grade 3 
Recommendation: Interrupt study treatment. Upon 
resolution to Grade ≤ 1 with appropriate management, 
may resume study treatment without dose 
modification. 
Grade 4 
Mandatory: Interrupt study treatment, obtain 
endocrinologist consultation. 
Upon resolution to Grade ≤ 1 with appropriate 
management, may resume study treatment at 1 lower 
dose level after discussion with the Novartis Medical 
Monitor and consultation with an endocrinologist. 
Grade 4 treatment-related endocrinopathies, such as 
adrenal insufficiency, adrenocorticotropic hormone 
(ACTH) deficiency, hyper- or hypothyroidism, or 
glucose intolerance, which resolve or are adequately 
controlled with physiologic hormone replacement 
(corticosteroids, thyroid hormones) or glucose-
controlling agents, respectively, may not require dose 
reduction after discussion with and approval from the 
Novartis Medical Monitor. 

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Pulmonary toxicity 
Suspected interstitial lung disease (ILD) or non-infectious pneumonitis 
Grade 1 
Recommendation: Maintain study treatment and dose 
level. Exclude infections and other etiologies. 
Grade 2 
Recommendation: Interrupt study treatment during 
diagnostic workup for ILD/pneumonitis. Exclude 
infections and other etiologies. 
First occurrence: Upon resolution to ≤ Grade 1 in ≤ 7 
days, study treatment may be reintroduced at 1 lower 
dose level. Monitor pulse oximetry daily for 2 weeks 
and perform chest x-ray 2 weeks after re-initiation, or 
sooner if clinically indicated. 
If symptoms fail to resolve within 7 days or recur after 
reintroduction of study treatment, permanently 
discontinue study treatment. 
Second occurrence: Permanently discontinue study 
treatment. 
Grade 3 and Grade 4 
Mandatory: Confirmed ILD 
Permanently discontinue study treatment. 
Skeletal muscle toxicity 
Grade 1 
Recommendation: Maintain study treatment and dose 
level. 
Grade 2 and Grade 3 
Recommendation: Interrupt study treatment. 
Consider resuming study treatment without dose 
modification upon resolution to ≤ Grade 1 with 
appropriate management. 
Grade 4 
Mandatory: Permanently discontinue study treatment. 
In some cases, reintroduction of study treatment may 
be considered after discussion with the Novartis 
Medical Monitor and consultation with a 
rheumatologist. 
Neurological toxicity 
Any neurological adverse events 
Grade 1 
Recommendation: Maintain study treatment and dose 
level. 
Grade 2 and above 
Mandatory: Interrupt study treatment until evaluation 
by neurologist and discussion with Novartis Medical 
Monitor. 
Skin and subcutaneous tissue disorders 
Rash/
 
Grade 1 
Recommendation: Maintain study treatment and dose 
level and treat the participant per institutional practice. 
Consider initiating appropriate therapy for cutaneous 
toxicity (such as antihistamines, topical corticosteroids 
or low-dose systemic corticosteroids). 
Grade 2 
Recommendation: Consider interrupting study 
treatment and treat the participant per institutional 
practice initiate/intensify appropriate therapy for 
cutaneous toxicity (such as antihistamines, topical 
corticosteroids or low-dose systemic corticosteroids). 
If study treatment is interrupted, upon resolution to ≤ 
CCI 

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Grade 1, resume study treatment at the same dose 
level. 
Grade 3, despite appropriate therapy for cutaneous 
toxicity 
Recommendation: Interrupt study treatment until 
resolved to Grade ≤ 1 and treat the participant per 
institutional practice then: 
If resolved in ≤ 7 days, reduce 1 dose level. 
If resolved in > 7 days (despite appropriate therapy for 
cutaneous toxicity), permanently discontinue study 
treatment. 
Grade 4, despite appropriate therapy for cutaneous 
toxicity 
Mandatory: Permanently discontinue study treatment. 
Fatigue/ Asthenia (General disorders and administration site conditions) 
Grade 1 and 2 
Recommendation: Maintain study treatment and dose 
level. 
Grade 3 
Recommendation: Interrupt study treatment until 
resolved to ≤ grade 1, then: 
If resolved in ≤ 7 days, maintain dose level. 
If resolved in > 7 days, reduce 1 dose level. 
Ocular (uveitis, eye pain, blurred vision) 
 
Grade 1 
Recommendation: Maintain study treatment and dose 
level. Ophthalmology consultation is required within 
72 hours, except for dry eye. 
Grade 2 
Recommendation: Interrupt study treatment. 
Urgent ophthalmology consultation. 
Upon resolution to ≤ Grade 1 in < 14 days, may 
consider reintroducing study treatment without dose 
reduction after discussion with the Novartis medical 
Monitor and consultation with ophthalmology. 
Upon resolution to ≤ Grade 1 in ≥ 14 days, study 
treatment may be reintroduced at 1 lower dose level 
after discussion with the Novartis Medical Monitor and 
consultation with ophthalmology. 
Grade 3 and Grade 4 
Mandatory: Permanently discontinue study treatment. 
Urgent ophthalmology consultation. 
Retinal vein occlusion or Retinal detachment 
 
Any Grade 
Mandatory: Permanently discontinue study treatment. 
Urgent ophthalmology consultation. 
Other adverse events 
Grade 1 and 2 
Recommendation: Maintain study treatment and dose 
level. 
Grade 3 
Recommendation: Interrupt study treatment until 
resolved to ≤ grade 1, then reduce 1 dose level. 
Mandatory: Interrupt study treatment for ≥ grade 3 
vomiting or grade 3 nausea only if the vomiting or 
nausea cannot be controlled with optimal anti-emetic 
therapy (as per local practice). 
Grade 4 
Mandatory: Permanently discontinue study treatment. 
a Common Toxicity Criteria for Adverse Events (CTCAE Version 5.0) 
b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x 
ULN), and alkaline phosphatase (fractionated [quantification of isoforms], if alkaline phosphatase > 2.0 x ULN) 
c “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold 

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If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g., permanently discontinue treatment at the situation when 
omit dose is needed for one parameter and permanently discontinue treatment is required for another 
parameter). After all elevations resolve to the defined thresholds that allow treatment re-initiation, re-start the 
treatment either at the same dose or at one dose lower if meeting a criterion for dose reduction 
d “Cholestasis” defined as ALP elevation (> 2.0 × ULN and R value < 2) in participants without bone metastasis 
or elevation of ALP liver fraction in participants with bone metastasis 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It 
denotes whether the relative pattern of ALT and/or ALP elevation is due to cholestatic (R ≤ 2), hepatocellular 
( R ≥ 5), or mixed (R > 2 and < 5) liver injury 
* Note: If total bilirubin > 3.0 × ULN is due to the indirect (non-conjugated) component only, and hemolysis as 
the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and 
haptoglobin determination), then reduce 1 dose level and continue treatment at the discretion of the 
Investigator. 
** Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed 
within 1 week of the first occurrence of any ≥ Grade 3 elevation of amylase and/or lipase. If asymptomatic 
Grade 2 elevations of lipase and/or amylase occur again at the reduced dose, participants will be permanently 
discontinued from study treatment. 
*** Note: Antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools, or 
overt diarrhea 
**** Note: JDQ443 has shown 
. The Investigators 
should recommend the use of precautionary measures against 
 to the participants during 
treatment with JDQ443 
 
 
Table 6-4 
Dose reduction steps for JDQ443 
Dose reduction* 
Starting dose level 0 
Dose level – 1 
Dose level – 2 
JDQ443 
200 mg b.i.d. 
100 mg b.i.d. 
100 mg QD. (once a day)** 
*Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
**Dose reduction below 100 mg once a day is not allowed. 
6.5.2 
Definitions of dose limiting toxicities (DLTs) 
Not Applicable 
6.5.3 
Follow-up for toxicities 
Participants whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologists, endocrinologists, 
dermatologists, psychiatrists, neurologists etc., should be consulted as deemed necessary. All 
participants must be followed up for adverse events and serious adverse events for 30 days 
following the last doses of study treatment. 
Table 6-5 outlines the follow-up evaluation recommended for toxicities of specific types and 
CTCAE grades. 
CCI 
CCI 
CCI

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Table 6-5 
Follow-up evaluations for selected toxicities  
TOXICITY 
FOLLOW-UP EVALUATION 
Blood and lymphatic system disorders 
Test once a week until ≤ CTCAE grade 1, then restart treatment. 
Continue to test weekly until resolution to baseline or stabilization. 
Investigations (hematologic) 
Neutropenia ≥ CTCAE grade 3 
Thrombocytopenia ≥ CTCAE grade 3 
Test once a week until ≤ CTCAE grade 1, then restart treatment. 
Continue to test weekly until resolution to baseline or stabilization. 
Perform physical exam for check on bruising in case of major 
thrombocytopenia. 
Investigations (metabolic) 
Amylase or lipase ≥ CTCAE grade 3 
Test once a week until ≤ CTCAE grade 2, then restart treatment. 
Continue to test weekly until resolution to ≤ CTCAE grade 1 or 
stabilization. 
A CT scan or equivalent imaging procedure to assess the pancreas, 
liver, and gallbladder is recommended within 7 days of the first 
occurrence of any ≥ CTCAE grade 3 result, to exclude disease 
progression or potential other liver disease. 
In participants with serum triglycerides ≥ 500 mg/dL, urine amylase 
also needs to be tested. 
Cardiac disorders 
QT and ECG 
ECG changes indicative of ischemic 
event 
Twice weekly ECGs until normalization or stabilization of ECG 
findings then restart treatment. 
6.5.3.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Transaminase increase combined with total bilirubin increase may be indicative of potentially 
severe DILI. These cases should be considered as clinically important events and assessed 
appropriately to establish the correct diagnosis. The required clinical information, as detailed 
below, should be sought to obtain the medical diagnosis of the most likely cause of the observed 
laboratory abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below: 
• For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 × ULN combined with total bilirubin > 2.0 × ULN 
• For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT >3.0 × baseline] OR [ALT or AST > 8.0 × ULN], whichever occurs first, combined 
with [total bilirubin > 2.0 × baseline AND > 2.0 × ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed to be the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, 
Gamma-glutamyl transferase (GGT), prothrombin time (PT)/ International Normalized Ratio 
(INR), alkaline phosphatase, albumin, and creatine kinase. If available, testing of Glutamate 
Dehydrogenase (GLDH) is additionally recommended. 

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Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – e.g. using CT, 
Magnetic Resonance Imaging (MRI), or duplex sonography. 
Perform 
relevant 
examinations 
(Ultrasound 
or 
MRI, 
Endoscopic 
retrograde 
cholangiopancreatography (ERCP)) as appropriate, to rule out an extrahepatic cause of 
cholestasis. Cholestasis (is defined as an ALP elevation > 2.0 × ULN with R value < 2 in 
participants without bone metastasis, or elevation of the liver-specific ALP isoenzyme in 
participants with bone metastasis). 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 
can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury. 
Table 6-6 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities. 
If required, these laboratory tests will be performed at the local laboratory. 
Table 6-6 
Guidance on specific clinical and diagnostic assessments 
Disease 
Assessment 
Hepatitis A, B, C, E 
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, HCV 
RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV 
Autoimmune hepatitis 
Antinuclear Antibodies (ANA) & Anti-Smooth Muscle Antibody (ASMA) 
titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
Medical history: acute or chronic congestive heart failure, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or MRI. 
Biliary tract disease 
Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 years old) 
Caeruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
Alpha-1-antitrypsin 
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes mellitus / glycogenic hepatitis). 
If required, these laboratory tests will be performed at the local laboratory. 
Obtain PK sample to determine exposure to study treatment and metabolites. 
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” (i.e., > 50% likely), if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE. 

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All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as a SAE using the 
term “potential treatment-induced liver injury.” All events should be followed up with the 
outcome clearly documented. 
6.6 
Continued access to study treatment after the end of the study 
Novartis will make every effort to supply JDQ443 to participants who may benefit from 
continued treatment as per the Investigator’s opinion. Safety will be monitored and reported to 
health authorities per regulatory requirements. 
6.6.1 
Post-trial access 
Participants who complete participation in this trial and continue to derive clinical benefit from 
the treatment based on the Investigator’s evaluation may receive post-trial access. Post-Trial 
Access (PTA) means the provision of treatment to trial participants following their completion 
of trial participation. PTA will be provided until one of the following is met: participant no 
longer derives clinical benefit, Investigator discontinues treatment, launch or reimbursement 
(where applicable), treatment fails to achieve registration in the trial participant’s country, or 
the clinical program is discontinued for any other reason. 
Mechanisms for provision of PTA may include a rollover protocol, or provision of the Novartis 
investigational product in a non-trial setting (known as post-study drug supply [PSDS]), or any 
other mechanism appropriate for the country. 
The PTA mechanism must comply with local laws and regulations in the participating trial 
countries. If Novartis discontinues the PTA for this trial, Novartis will work with Investigators 
to transition participants to locally available alternative treatments, or standard of care, where 
permitted and in accordance with local laws and regulations. 
6.7 
Treatment of overdose 
In the event of an overdose, the Investigator should: 
• Contact the medical monitor immediately. 
• Evaluate the participant to determine, in consultation with the medical monitor, whether 
study treatment should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
• Document the quantity of the excess dose as well as the duration of the overdose. 
Refer to [JDQ443 Investigator’s Brochure] for further details related to the treatment of 
overdose of JDQ443. 
Refer to Section 8.7 for more details on safety reporting. 
6.7.1 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 

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Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE. Study 
treatment errors and uses outside of what is foreseen in the protocol, misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
within 24 hours of Investigator’s awareness. 
For more information on AE and SAE definition and reporting requirements, please see 
Section 8.7. 
6.8 
Concomitant and other therapy 
6.8.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded in the appropriate Case Report Forms. 
Each concomitant drug must be individually assessed against all exclusion criteria and 
prohibited medication. If in doubt, the Investigator can contact the Novartis Medical Monitor 
before enrolling a participant or allowing a new medication to be started. If the participant is 
already enrolled, the investigator should contact Novartis Medical Monitor to determine if the 
participant should continue participation in the study. 
The participant must be told to notify the investigational site about any new medications he/she 
takes after the start of the study treatment. Medications include not only physician prescribed 
medications, but also all over-the counter medications, herbal medications, food supplements 
and vitamins. 
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g. such as anti-emetics, anti-diarrhea) and safety of the participant are allowed except when 
specifically prohibited (see Section 6.2.2). 
All medications (excluding study treatment and prior antineoplastic treatments), blood 
transfusions, surgeries and procedures (including physical therapy) administered within 28 days 
prior to the first dose administration of study treatment until 30 days after the last dose of study 
treatment will be recorded in the Concomitant Medications or Surgical and Medical Procedures 
eCRF, respectively. After starting a new antineoplastic therapy, only concomitant medications 
used to treat AEs or SAEs suspected to be related to study treatment should be reported. 
The following restrictions apply during the entire duration of the study: 
• No other investigational therapy should be given to participants 
• No anticancer agents other than the study medication should be given to participants 

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6.8.1.1 
Permitted concomitant therapy requiring caution and/or action 
Permitted therapy to be used with caution when concomitantly used with JDQ443 include: 
• Strong CYP3A inhibitors 
Co-administration of JDQ443 with strong CYP3A inhibitors may increase the exposure to 
JDQ443. Monitor participants closely for symptoms that may be related to the increase of 
JDQ443 exposure. 
• Sensitive substrates or substrates with narrow therapeutic index for CYP2B6, CYP2C8, 
CYP2C9, CYP2C19 and CYP3A 
JDQ443 is likely to inhibit these cytochrome P450 (CYP) isoforms at clinically relevant 
concentrations. When used concomitantly with JDQ443, monitor participants closely for 
symptoms of increased exposure of these substrates. Consult the product information for these 
substrates when considering dose adjustment. 
• P-gp, OATP1B1/3 substrates 
JDQ443 is likely to inhibit hepatic OATP1B1 and OATP1B3, as well as intestinal P-gp in 
humans. When used concomitantly with JDQ443, monitor participants closely for symptoms of 
increased exposure to P-gp or OATP1B1/3 substrates. Consult the concomitant P-gp or 
OATP1B1/3 substrate product information when considering dose adjustment. 
• Herbal preparations/medications. 
Refer to Section 10.7 (Appendix 7) for a list of medications that should be used with caution. 
6.8.1.2 
Use of bone modifying agents 
Treatment with bisphosphonates or receptor activator of nuclear factor kappa-B ligand 
(RANKL) inhibitors for pre-existing bone metastases is permitted, if clinically indicated and at 
the Investigator's discretion following existing local guidelines. Treatment with 
bisphosphonates or RANKL inhibitors should preferably begin before the study treatment is 
initiated, but can also be initiated during study treatment only if absence of radiological bone 
disease progression is well documented (in this case, the reason for its use must be clearly 
documented, i.e., “pre-existing, non-progressing, bone metastases”).  
6.8.1.3 
Palliative radiotherapy 
Local bone radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be 
performed if required. Radiotherapy should not be delivered to a target lesion. If palliative 
radiotherapy is initiated after start of study treatment, the reason for its use must be clearly 
documented and disease progression per RECIST 1.1 must be ruled out. The study treatment 
must be interrupted during the days of radiotherapy and can be resumed the day after its 
completion. The radiotherapy must be documented in the appropriate eCRF. 
6.8.2 
Prohibited medication 
During the course of the study, participants must not receive other additional investigational 
drugs, devices, chemotherapy, or any other therapies that may be active against cancer. 

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The following medications are prohibited 7 days prior to the start of JDQ443 treatment and for 
the duration of the study: 
• Strong CYP3A inducers 
The primary biotransformation pathway for JDQ443 was 
 with some 
contribution from oxidative metabolism mainly via CYP3A4. Despite that oxidative 
metabolism via CYP3A4 being a minor pathway compared to 
, upon 
induction, it may become significant and lead to a large impact on the overall clearance of 
JDQ443. Therefore, coadministration of strong CYP3A inducers is prohibited during treatment 
with JDQ443 (refer to Appendix 7, Section 10.7). 
The use of live vaccines is not allowed for the duration of the study. Inactivated vaccines are 
allowed. 
7 
Discontinuation of study treatment and participant 
discontinuation/withdrawal 
7.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study treatment administration, if 
any) and can be initiated by either the participant or the Investigator. 
The Investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Discontinuation from study treatment is required under the following circumstances: 
• Participant/guardian decision 
• Investigator decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
(see Section 10.7 ) 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Disease progression per RECIST 1.1 by BIRC. In some circumstances, participants treated 
with JDQ443 may be allowed to continue to receive study treatment beyond disease 
progression per RECIST 1.1 by BIRC. These participants will continue assessments as 
outlined in Section 1.3, as applicable, and will complete the EOT visit only after 
permanent discontinuation of study treatment (see Section 6.1.4) 
• Adverse event requiring permanent discontinuation of study treatment (see Section 6.5.1) 
• Protocol deviation that results in a significant risk to participant's safety 
• Withdrawal of consent (see Section 7.3) 
• Study is terminated by the sponsor (see Section 7.5) 
• Death 
• Lost to follow-up 
CCI
CCI

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If discontinuation from study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participants who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits indicated in Section 1.3 Schedule of Activities. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The Investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
7.1.1 
Follow-up for safety evaluations 
All treated participants should have a safety follow-up conducted at least 30 days after the last 
administration of study treatment. All SAEs reported during this time period must be reported 
as described in Section 8.7.3 
7.1.2 
Follow-up for efficacy evaluations and PROs 
Participants who discontinue study treatment without prior documented disease progression 
will continue efficacy assessments during the post-treatment efficacy follow-up, until 
documented disease progression per RECIST 1.1 by BIRC, participant withdrawal of 
consent/opposition to use of data /biological samples, investigator's decision, lost to follow-up, 
death or if study is terminated by the sponsor. For all participants, PRO will also continue to be 
collected (PRO Follow-up) until documented progression, and at a minimum of three time 
points following disease progression (refer to Section 8.6.1). All SAEs reported during this time 
period must be reported as described in Section 8.7 . 
7.1.3 
Overall Survival 
All participants will enter the survival follow-up period once they complete the safety follow-
up and efficacy follow-up after treatment discontinuation (whichever is longer). Survival status 
will be collected every 12 weeks (+/- 14 days) regardless of treatment discontinuation reason 
(except if consent is withdrawn or participant is lost to follow-up) until death, lost to follow-up, 
or withdrawal of consent for survival follow-up. 
Additional survival assessments may be performed outside the 12-week follow-up schedules if 
a survival update is required due to safety or regulatory needs. 
Survival information can be obtained via phone, and information will be documented in the 
source documents and relevant eCRFs. Information on the therapies received for NSCLC, if 

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any, after study treatment has been completed will be collected. All SAEs reported during this 
time period must be reported as described in Section 8.7. 
Figure 7-1 illustrates study flow. 
Figure 7-1 
Study Flow 
 
7.2 
Participant discontinuation from the study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment and further protocol-required assessments or follow-up for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 1.3). 
See Section 6.6 for information on continued access to study treatment after the end of the study 
7.3 
Withdrawal of informed consent and exercise of participants’ 
data privacy rights 
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
• Explicitly requests to stop use of their data 
AND 
• No longer wishes to receive study treatment 
AND 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be as per local regulations (e.g., in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g., to respond to data queries) and potentially other country-specific restrictions. It is 
therefore very important to ensure accurate recording of withdrawal vs. discontinuation based 
on the protocol definitions of these terms. 
In this situation, the Investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/exercise data privacy rights and record this information. The Investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
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Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in Section 1.3 Schedule of 
Activities. 
Further details on withdrawal of consent or the exercise of participants’ data privacy rights are 
included in the corresponding informed consent form. 
7.4 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), the Investigator must show “due diligence” by documenting in the source 
documents steps taken to contact the participant, e.g., dates of telephone calls, registered letters, 
etc. A participant should not be considered as lost to follow-up until due diligence has been 
completed. 
7.5 
Early study termination by the Sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination (but not limited to) 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment (instructions will be provided to the 
Investigator for contacting the participant, when the participant should stop taking the drug and 
when the participant should come for a final visit). The Investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the participant’s interests. The Investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
8 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in Section 1.3. Protocol waivers or 
exemptions are not allowed. 
• Immediate safety concerns should be discussed with Novartis upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment. 

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• Adherence to the study design requirements, including those specified in Section 1.3, is 
essential and required for study conduct. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
8.1 
Molecular pre-screening 
All participants will be asked to sign and date an IRB/IEC approved “Molecular pre-screening 
informed consent form” before starting screening procedures (see Section 8.10). 
In order to be considered eligible for the study, participants must have the following local or 
central (from a Novartis-designated central laboratory) test results: 
• presence of the KRAS G12C mutation, 
•  known PD-L1 expression status 
•  presence of an STK11 mutation (for cohort B only). 
For participants in China only: PD-L1 expression, KRAS G12C mutation status and STK11 
mutation status (STK11 for cohort B only) must be determined by local assessment, according 
to criteria described below. 
For local testing, results must be determined using a test which is validated according to local 
regulation at a Clinical Laboratory Improvement Amendments (CLIA)-certified USA 
laboratory or an accredited laboratory outside of the USA. Available information on the local 
assessment of KRAS G12C and STK11 mutations and PD-L1 expression status must be 
documented in the participant’s medical record and will be collected during pre-screening. 
Participants who have local documentation of the status of all required biomarkers (KRAS 
G12C mutation and PD-L1 status for patients eligible to cohort A; KRAS G12C mutation, PD-
L1 status and STK11 mutation for patients eligible for Cohort B) will be allowed to 
simultaneously sign the molecular pre-screening ICF and main ICF and begin screening 
procedures. These patients will be enrolled in the study on the basis of their local biomarker 
results after successful completion of the screening procedures. 
Participants who do not have local documentation on the status of all required biomarkers must 
submit a tissue and/or blood sample for testing to the Novartis-designated central laboratory as 
part of pre-screening (after signature of the molecular pre-screening ICF) and prior to entering 
main screening. Participants will be allowed to sign the main ICF and begin screening 
procedures while waiting for the central test results which must be received prior to treatment, 
during the 28-day screening period (Section 8.2) and results may take up to 2 weeks (10 
business days) once the sample is received at the Novartis-designated central laboratory. The 
pre-screening results from central testing for all tested participants (whether the participant is 
eligible or not for the study) will be communicated to the respective study center by the 
Novartis-designated central laboratory. The sample collection information must be entered on 
the appropriate sample collection log eCRF page(s) and requisition form(s). Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to Investigators in a separate Laboratory Manual. 

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During pre-screening, information will be collected on local assessment of EGFR-sensitizing 
mutation status, ALK rearrangement status and/or other known druggable alteration 
information (if available). 
KRAS G12C mutation status (all participants) 
All participants must have a local or central (from a Novartis-designated central laboratory) 
tissue or blood-based test result that is positive for the presence of the KRAS G12C mutation 
to be eligible for the study. 
For local testing, KRAS G12C mutation must be determined using a molecular test that detects 
mutations in DNA derived from tumor tissue or in circulating tumor DNA (ctDNA) derived 
from blood plasma. Immunohistochemistry results are not accepted. 
Central testing for KRAS G12C mutation status will be done using investigational NGS tests 
that detect mutations in DNA derived from formalin fixed, paraffin-embedded tumor tissue or 
ctDNA derived from blood plasma at a Novartis-designated central laboratory. Participants who 
submit a blood sample for KRAS G12C mutation status determination can be enrolled based on 
the blood-based results, but site will be required to submit a tissue sample before enrollment for 
subsequent central analysis on tissue. 
Participants with tissue sample submitted for KRAS G12C mutation status determination are 
required to submit a pre-screening blood sample any time before enrollment (in addition to the 
screening blood sample) for subsequent central analysis on blood. For participants whose 
plasma sample produces an inconclusive or negative KRAS G12C result, a FFPE tumor tissue 
sample should be reflexively tested for the presence of a KRAS G12C mutation during pre-
screening due to lower mutation detection rates in ctDNA. 
PD-L1 expression status (all participants) 
For enrollment in cohort A, participants must have PD-L1 expression status <1% and for cohort 
B, PD-L1 expression status ≥1%, assessed by immunohistochemistry (IHC) in tumor tissue. 
This analysis could be either performed locally or centrally for enrollment. 
For local testing, PD-L1 status must be determined according to tumor proportion score (TPS) 
by the PD-L1 IHC 22C3 or 28-8 pharmDx assays or tumor cell (TC) membrane expression by 
the Ventana PD-L1 SP263 assay. 
Central testing for PD-L1 expression status will be done using the PD-L1 IHC 22C3 pharmDx 
or Ventana PD-L1 SP263 assay at a Novartis-designated central laboratory. 
STK11 mutation status (cohort B only) 
Cohort B participants must have a local or central (from a Novartis-designated central 
laboratory) tissue- or blood-based test result that is positive for the presence of an STK11 
mutation to be eligible for the study. 
For local testing, STK11 mutations must be determined using a molecular test that detects 
mutations in DNA derived from tumor tissue or in circulating tumor DNA (ctDNA) derived 
from blood plasma. Immunohistochemistry results are not accepted. 

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If local STK11 results are available, for patient eligibility purposes, the following are 
acceptable:  
• STK11 loss of function mutations, including splice site mutations, nonsense mutations, 
frameshift mutations, and missense mutations as defined below 
• Any splice alterations within the splice donor or acceptor site (defined as the first two or 
last two bases of the intron), any in-frame insertion or deletion affecting amino acids 49 – 
309 
Central testing for STK11 mutation status will use the same investigational (see Section 2.3) 
NGS tests that will be used for KRAS G12C mutation testing (described above). If STK11 
status is centrally determined, the KRAS G12C status must also be confirmed by the Novartis 
central laboratory for eligibility.  
Participants with tissue sample submitted for STK11 mutation status determination are required 
to submit also a pre-screening blood sample any time prior to treatment (in addition to the 
screening blood sample). Participants with a positive STK11-mutated blood result can be 
enrolled based on those results, but sites are required to submit a tissue sample during screening 
for subsequent central analysis. For participants with an inconclusive or negative STK11 
mutation blood result, a tissue sample should be reflexively tested during pre-screening due to 
lower detection rates in blood. 
Sample requirements (all participants) 
As detailed in Section 8.9, a tumor tissue and blood sample must be submitted to the Novartis-
designated laboratories for all participants, independently of the presence of local test results. 
The tumor tissue sample will be used for centralized PD-L1 expression, KRAS G12C mutation 
and/or STK11 mutation status determination for eligibility during pre-screening (for 
participants without local results) or for retrospective, central confirmation (for 
participants enrolled using qualified local results, samples are to be collected prior to study 
treatment initiation). A blood sample may be used for KRAS G12C mutation and/or STK11 
mutation status determination for eligibility during pre-screening (for participants without local 
results) or for retrospective, central confirmation (for participants enrolled using qualified local 
results). The tissue and blood samples may also be used for development of one or more in vitro 
diagnostic tests, such as companion diagnostic test(s) and/or exploratory biomarkers. 
Tumor tissue samples must contain 20% tumor content. Tumor tissue samples obtained from 
bone metastases and cytology samples are not acceptable. 
Remaining tumor tissue from pre-screen failure samples will be returned if requested by the 
site. However, a small amount of any remaining tissue will be retained from all participants 
(both enrolled and pre-screen/screen failed), under control of Novartis, to support the potential 
development of in vitro diagnostic tests, such as companion diagnostic test(s). If the participant 
is enrolled, the remaining tissue will be kept at a Novartis-designated laboratory. If the site 
requests the tumor tissue to be returned, additional material will be retained for diagnostic 
development and exploratory analyses prior to returning the remaining tissue back to site. 
Additional tissue may be requested, retrospectively, if available, to support development of 
future companion diagnostic test if the remaining tissue sample is insufficient for analysis. 

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Blood samples from pre-screen failures will also be retained to support the potential 
development of in vitro diagnostic tests, such as companion diagnostic test(s). 
8.2 
Screening 
All participants must provide a signed main ICF prior to performing any study specific 
procedures and will be evaluated for eligibility. 
The screening assessments will be done within 28 days prior to the enrollment (Section 8). 
Laboratory parameters may be retested within the 28-day screening period for an individual 
participant if such parameters meet an exclusion criterion when initially tested. 
Laboratory values obtained during the Screening period from the central laboratory will be used 
to assess participant’s eligibility, except for China, where local laboratory results can be used 
for eligibility. If necessary, for immediate clinical decision locally unscheduled testing may be 
performed and used for eligibility. 
Laboratory assessments performed as part of the screening evaluations will not be required to 
be repeated on the first day of dosing (except for hematology/chemistry and serum pregnancy 
test if not done within 72 hours prior to treatment start) unless considered clinically necessary 
by Investigator and/or required as per local institutional policies. 
Imaging assessments will be performed at screening between Day -28 and Day -1. Imaging 
assessments already completed during the regular work-up of the participant within 28 days 
prior to start of treatment (-42 days for whole body scan), including before signing the main 
study ICF can be considered as the baseline images for this study. Any imaging assessments 
obtained after enrollment cannot be considered baseline images. 
Participants who are enrolled in the IRT system and failed to start treatment, e.g. participants 
confirmed in IRT in error, will be considered as early terminators. The reason for early 
termination should be recorded on the appropriate eCRF. 
8.2.1 
Eligibility screening 
When all screening procedures are completed and once the participant’s eligibility has been 
checked and confirmed (i.e., all inclusion/exclusion criteria have been verified), the key 
eligibility criteria checklist will be completed prior to the first dose of study treatment in the 
IRT system by the Investigator or designee. The eligibility check will be embedded in the IRT 
system. 
Please refer Section 6.3.1 and comply with detailed guidelines in the IRT manual. 
8.3 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. 
Data to be collected on participant characteristics at pre-screening include: 
• Demography: age, sex, race/predominant ethnicity (if permitted). Participant race/ethnicity 
data should be collected wherever allowable by local laws and regulations. These data are 
collected and analyzed to identify any differences in the safety and/or efficacy profile of 

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the treatment due to these characteristics. In addition, these data are necessary to assess 
the diversity of the study population as required by Health Authorities. 
• Cancer characteristics including diagnosis, history, extent of disease 
• Information on tumor samples submitted to the central laboratory for testing 
• PD-L1 status per participant's record (where available) 
• KRAS G12C and STK11 mutation status per participant's record (where available) 
Data to be collected on participant characteristics at screening include: 
• Molecular alteration status of EGFR, ALK and other genes which are druggable, 
per participant's record 
• Other background or relevant medical history/current medical conditions (until date of 
signature of informed consent) including smoking / vaping history 
• Prior antineoplastic therapies (medications, radiation, surgeries), and date of 
progression/recurrence prior to study entry 
• Tumor imaging assessment 
• Other assessments to be completed for the purpose of determining eligibility (ECOG, 
PS, complete physical examination, vital signs, hematology, blood chemistry, coagulation, 
urinalysis, serum pregnancy test for women of child-bearing potential [only recorded in 
source documentation], 12-Lead ECG and Cardiac Imaging) 
• Prior and current concomitant medications and surgical and medical procedures (All 
prescription medications, over-the-counter drugs and significant non-drug therapies prior 
to the start of the study must be documented. See the protocol Section 6.8 Concomitant 
Therapy for further details on what information must be recorded on the appropriate page 
of the eCRF). 
Data to be collected on participant characteristics at C1D1 (pre-dose) include: 
• PRO assessments 
8.4 
Efficacy assessments 
Planned time points for all efficacy assessments are provided in Section 1.3 Schedule of 
Activities. 
8.4.1 
Tumor assessment 
Tumor response will be assessed both locally and centrally according to the Novartis guideline 
version 3.2 (Appendix 8 Section 10.8) based on RECIST 1.1 (Eisenhauer et al 2009). 
The central review of the scans will be carried out in a blinded fashion. Imaging data will be 
centrally collected and checked for quality by an imaging Contract Research Organization 
(CRO) designated by Novartis (Details of the central review process will be described in the 
independent review charter). 
Information regarding biopsy results, prior interventions (e.g., radiotherapy), pre-existing 
radiographic findings that mimic metastatic disease at baseline/screening and prior 
interventions should be transmitted to the imaging CRO with the baseline images for review by 

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the independent radiologist. Sites must transfer information as specified in the imaging CRO 
site manual and ensure the data is consistent with the data entered in the clinical database. 
The CT scan component of the FDG-PET/CT should be used for treatment response assessment 
only if the CT is of similar diagnostic quality as a CT performed without PET, including the 
utilization of i.v. contrast media. At the discretion of the Investigators, FDG-PET scans may be 
performed to document progressive disease per RECIST 1.1 (Section 10.8). 
The imaging assessment collection plan is presented in Table 8-1. 
Table 8-1 
Imaging Assessment Collection Plan  
Procedure 
Screening/Baseline 
(within 28 days prior to 
start of treatment) 
During Treatment/Follow-up 
Chest, abdomen and 
pelvis CT or MRI (with 
intravenous contrast 
enhancement)# 
Mandated 
During Treatment: 
Mandated, every 6 weeks (+/- 7 days) from C1D1 until 
Week 54, then every 12 weeks (+/- 7 days) until 
confirmed PD* 
During Post Treatment Follow-Up: participants with 
EOT reason other than disease progression, 
withdrawal of consent/opposition to use 
data/biological samples or death will 
continue to collect imaging and follow the same 
schedule of every 6 weeks (+/- 7 days) for the 54 
weeks after C1D1, then every 12 weeks (+/- 7 days), 
thereafter until confirmed PD* 
Brain MRI or CT 
Mandated 
If brain metastases are present at baseline 
During Treatment: 
Every 6 weeks (+/- 7 days) from C1D1 up to 54 weeks 
and every 12 weeks (+/- 7 days) thereafter until 
confirmed PD*. 
During Post Treatment Follow-Up: 
Participants with EOT reason other than disease 
progression, withdrawal of consent/opposition to use 
data/biological samples or death will continue to 
collect imaging and follow the same schedule 
proposed during treatment. 
If no brain metastases are present at baseline 
During Treatment: 
Every 12 weeks (+/- 7 days) from C1D1 until 
confirmed PD*. 
During Post Treatment Follow-Up: 
Participants with EOT reason other than disease 
progression, withdrawal of consent/opposition to use 
data/biological samples or death will continue to 
collect imaging and follow the same schedule 
proposed during treatment. 
Otherwise, if clinically indicated 
Whole body bone scan 
(Per institutional 
standard of care 
[e.g., Tc-99m bone 
scan, whole body bone 
MRI, 18F - 
fluorodeoxyglucose 
positron emission 
tomography (FDG-
Mandated (within 42 days 
prior to start of treatment) 
If clinically indicated. 

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Procedure 
Screening/Baseline 
(within 28 days prior to 
start of treatment) 
During Treatment/Follow-up 
PET) or 18 F - sodium 
fluoride (NaF) PET]) 
Localized bone CT, 
MRI, or x-ray 
Mandated for any lesions 
identified on the whole-
body bone scan that are 
not visible on the chest, 
abdomen, and pelvis CT or 
MRI. 
If lesions were documented at baseline, follow same 
schedule as CT/MRI of chest, abdomen, and pelvis. 
Otherwise, if clinically indicated 
Color photography 
(with scale/ruler) 
If clinically indicated,in 
case skin metastatic 
lesions are present. 
If lesions were documented at baseline, follow same 
schedule as CT/MRI of chest, abdomen, and pelvis. 
Otherwise, if clinically indicated 
CT or MRI of other 
metastatic sites (e.g., 
neck) 
If clinically indicated 
If lesions were documented at baseline, follow same 
schedule as CT/MRI of chest, abdomen, and pelvis. 
Otherwise, if clinically indicated 
*Progression by RECIST 1.1 as confirmed by BIRC. 
# Combined Positron Emission Tomography (PET)/CT may be used for treatment response assessment if the 
CT component is of similar diagnostic quality as a CT performed without PET, including the utilization of i.v. 
contrast media. 
Baseline imaging assessments 
Any imaging assessments already completed during the regular work-up of the participant 
within 28 days prior to start of treatment (42 days for whole body bone scan), including before 
signing the main study ICF, can be considered as the baseline images for this study. Any 
imaging assessments obtained after C1D1/enrollment cannot be considered baseline images. 
The following assessments are required at screening/baseline: 
• Chest, abdomen, and pelvis CT or MRI (Combined Positron Emission Tomography 
(PET)/CT may be used if the CT component is of similar diagnostic quality as a CT 
performed without PET, including the utilization of i.v. contrast media) 
• Brain MRI or CT 
• Whole body bone scan 
• Localized bone CT, MRI, or x-ray, for any lesions identified on the whole-body bone scan 
that are not visible on the chest, abdomen and pelvis CT or MRI 
• Color photography for any skin metastatic lesions present, if clinically indicated 
• CT or MRI of other metastatic sites (e.g., neck), if clinically indicated 
If a participant is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts; however, if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed. 
Brain MRI or CT should be completed. Contrast enhanced brain MRI is preferred. However, if 
MRI contrast is contraindicated, then MRI without contrast or CT with contrast are acceptable. 
A whole-body bone scan should be performed per institutional standard of care [e.g., Tc-99m 
bone scan, whole body bone MRI, 18F- fluorodeoxyglucose positron emission tomography 

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(FDG-PET) or 18 F-sodium fluoride (NaF) PET]. Localized CT, MRI, or X-rays should be 
acquired for all skeletal lesions identified on the screening whole body bone scan which are not 
visible on the chest, abdomen and pelvis CT/MRI. 
If clinically indicated, CT or MRI of other areas (e.g., neck) of disease should be performed. 
If skin metastatic lesions are present at screening, color photography should be acquired (if 
clinically indicated) using a digital camera in clear focus, including a scale/ruler, in such a way 
that the size of the lesion(s) can be determined from the photograph. 
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion. 
Chest x-rays and ultrasound should not be used to measure tumor lesions. 
Post-baseline imaging assessment 
Imaging assessments as described in Table 1-3 and Table 8-1 should be performed using the 
same imaging modality used at baseline, irrespective of study treatment interruption or actual 
dosing. 
Imaging assessments should be scheduled using the date of first dose (C1D1) as the reference 
date (not the date of the previous tumor assessment), and this schedule should be respected 
regardless of whether treatment with study treatment is temporarily withheld or unscheduled 
assessments performed. 
Additional imaging assessments may be performed at any time during the study at the 
Investigator’s discretion to support the efficacy evaluations for a participant, as necessary. 
Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment. 
If an off-schedule imaging assessment is performed because progression is suspected, 
subsequent imaging assessments should be performed in accordance with the original imaging 
schedule. 
Time points at which progression is determined locally 
For participants who have disease progression determined by the local Investigator, an 
expedited central review is required. Rapid image transmission to the imaging CRO should be 
accomplished by transferring the images electronically. In all instances, the process at the 
imaging CRO will ensure that the central reviewers remain blinded to the results of the local 
assessment and the expedited nature of the review. The Investigator seeking an expedited 
review must indicate this request to the imaging CRO at the time of image submission. The 
imaging will undergo expedited central review (within 5 business days from the time of image 
receipt at the imaging CRO and once all applicable queries are resolved) and the results of the 
central review will be communicated to the site. While the Investigator is awaiting the results 

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of the central review, it is preferable that the participant continues on study treatment. However, 
during this time, the Investigator should do whatever is medically necessary for the participant. 
If the central review confirms disease progression, then the participant will discontinue study 
treatment and subsequent tumor assessments are no longer required unless the criteria are met 
to continue study treatment beyond disease progression per RECIST 1.1 (for participants treated 
with JDQ443 only) as described in Section 6.1.4.1. 
If the central review does not confirm disease progression, the participant should continue 
receiving the study treatment until disease progression has been confirmed by BIRC at a 
subsequent visit or, as a minimum requirement, until at least one additional tumor assessment 
has been completed, unless there is a medical need (i.e., rapid progression or clinical 
deterioration) for an immediate change in therapy. 
In summary, for expedited timepoints (assessed as progressive disease by local): 
Rapid image transmission to the central imaging CRO may be accomplished by uploading all 
digital images acquired by the Investigator in a secured website, while preserving the blinded 
status of the images. 
• If central radiology confirms progressive disease, the study site will be informed. This 
participant should then discontinue study treatment. Participants treated with JDQ443 may 
continue study treatment beyond disease progression per RECIST 1.1 if according to 
investigator's judgement the participant is benefiting from study treatment and if certain 
conditions are met, as described in Section 6.1.4.1. 
• If central radiology does not confirm progressive disease, the study site will be informed. 
As long as it is clinically acceptable, every effort should be made to continue the 
participant on study treatment until progressive disease is confirmed by BIRC or for at 
least one subsequent radiological timepoint. 
Time points without locally determined progression 
All imaging time points without locally determined progression will be read on an ongoing, 
non-expedited basis as detailed in the imaging manual to be provided by the designated imaging 
CRO and independent review charter. Results of these readings will not be communicated to 
the sites. 
Treatment beyond disease progression 
Following determination of disease progression, if the Investigator believes the participant 
treated with JDQ443 may derive benefit from continuing study treatment, the participant will 
be permitted to continue treatment beyond initial disease progression as per RECIST 1.1 by 
BIRC. Please see Section 6.1.4.1 for additional information. 
Efficacy follow-up imaging assessments 
For participants who discontinue treatment for reasons other than initial disease progression as 
per RECIST 1.1, tumor assessments must continue to be performed as outlined in Table 1-3 
regardless if participants start on new antineoplastic therapy before documented disease 
progression. Please refer to Section 8.4 for additional information. 

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As per Section 4.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, the collection of images (e.g., change of imaging center or imaging frequency) may be 
modified by Novartis and will be communicated to the Investigator.  
8.4.2 
Appropriateness of efficacy assessments 
Tumor assessments performed every 6-12 weeks of study treatment are consistent with the 
standard clinical practice for patients with advanced NSCLC. Conducting tumor evaluations 
more than 6 weeks apart may expose a participant to an unnecessary treatment if the disease 
progression event takes place between the infrequent assessments or prevent early identification 
of progression and appropriate treatment. 
8.5 
Safety assessments 
Safety assessments are specified below with Section 1.3 detailing when each assessment is to 
be performed. 
For details on AE collection and reporting, refer to Section 8.7 
As per Section 4.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, regular phone or virtual calls can occur (every 3 weeks or more frequently if needed) for 
safety monitoring and discussion of the participant´s health status until it is safe for the 
participant to visit the site again. 
Table 8-2 
Physical Assessments 
Assessment 
Specification 
Physical examination 
A complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular, and complete neurological examination. If 
indicated based on medical history and/or symptoms, rectal, external genitalia, breast, 
and pelvic exams will be performed. Complete physical examination will be performed 
at screening, C1D1 and at EOT.. 
A direct and oriented physical exam including the examination of general appearance, 
vital signs (blood pressure [SBP and DBP] and pulse) and complete neurological 
examination will be performed at all visits starting from C2D1 as per Table 1-3 except 
where a complete physical examination is required (see above). 
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior to 
signing informed consent must be recorded on the appropriate eCRF that captures 
medical history. Significant findings made after signing informed consent which meet 
the definition of an Adverse Event must be recorded as an adverse event. 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is collected), 
pulse measurement, respiratory rate and body temperature. They will be measured at 
screening and at subsequent timepoints as specified in Table 1-3. 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but preferably without shoes) will be measured as specified in Table 1-3 . 
ECOG performance 
status 
ECOG performance status will be measured at screening and at subsequent time 
points as specified in Table 1-3 . 
ECOG performance status scale will be used as described in Table 8-3 (Oken et al 1982). 

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Table 8-3 
ECOG Performance Status 
Grade 
ECOG performance status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
8.5.1 
Physical examinations 
Physical examination should be performed as specified in Table 8-2 . 
8.5.2 
Vital signs 
Vital signs should be monitored according to the instructions in Table 8-2 . 
8.5.3 
Electrocardiograms 
Electrocardiograms (ECGs) will be centrally evaluated and must be recorded after 10 minutes 
rest in the supine position to ensure a stable baseline. The preferred sequence of cardiovascular 
data collection during study visits is ECG collection first, followed by vital signs, blood 
sampling, and any remaining assessments for that visit. 
The Fridericia QT correction formula (QTcF) must be used for clinical decisions, e.g., at 
Screening to assess eligibility. The Investigator must calculate corrected QT interval (QTc) if 
it is not auto-calculated by the ECG machine. 
ECGs will be performed at screening, C1D1, C1D15 and at EOT (Table 8-4). 
Triplicate 12 lead ECGs are to be recorded approximately 2 minutes apart. The mean QTc value 
for each visit will be calculated from the triplicate ECGs for each participant. 
Table 8-4 
Central ECG collection plan 
Cycle 
Day 
Time 
ECG Type 
Screening 
Anytime (before C1D1) 
12 Lead, triplicate 
1 
1 
Pre-dose and 4 hours post-dose (within 
15 minutes prior to PK) 
12 Lead, triplicate 
1 
15 
Pre-dose and 4 hours post-dose (within 
15 minutes prior to PK) 
12 Lead, triplicate 
EOT 
Anytime 
12 Lead, triplicate 
Unscheduled or Unplanned ECG 
Anytime if clinically indicated 
12 Lead, triplicate 
In order to enable ECG evaluation by the central ECG laboratory for eligibility assessment, 
ECGs should be submitted to the central ECG laboratory prior to enrollment (to refer to the 
ECG manual for the turn around time). 
In the event that a QTcF value of > 500 ms is observed or if an unscheduled ECG is performed 
for safety reasons, it is recommended to collect a time-matched PK sample and record the time 

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and date of the last study treatment intake to determine the drug exposure. Dose adjustments in 
case of QT prolongation should be performed per Section 6.5. 
In the event that a clinically significant ECG abnormality is identified at the site (e.g., severe 
arrhythmia, conduction abnormality of QTcF > 500 ms), a copy of the assessment is sent to the 
central ECG laboratory for expedited review and the ECG is repeated at the site to confirm the 
diagnosis. If the participant is hemodynamically compromised, the Investigator or a medically 
qualified person must initiate appropriate safety procedures without delay (for example 
cardioversion). 
All ECGs, including unscheduled safety ECGs with clinically relevant findings collected during 
the study need to be transmitted to the central ECG laboratory for review. 
The original ECGs on non-heat sensitive paper or a certified copy on non-heat sensitive paper 
and appropriately signed must be archived at the study site. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the Investigator at 
any time during the study as clinically indicated. For any ECGs with participant safety concerns, 
two additional ECGs must be performed to confirm the safety finding. ECG safety monitoring, 
or a review process, should be in place for clinically significant ECG findings at baseline before 
administration of study treatment and during the study. 
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate. 
8.5.3.1 
Cardiac imaging - echocardiogram or cardiac magnetic resonance 
(CMR) 
Echocardiogram or CMR to assess LVEF will be performed at screening, C2D1, at EOT and as 
clinically indicated. 
This assessment will be performed locally. The modality of the cardiac function assessments 
must be consistent throughout the study i.e., if echocardiogram is used for the baseline 
assessment then echocardiogram should also be used for subsequent scans. The participant 
should also be examined using the same machine and operator whenever possible. 
8.5.3.2 
Cardiac enzymes 
Creatine kinase (CK) assessment has to be performed at the same schedule as the other blood 
biochemistry tests. Isoenzyme (CK-MB) and Troponins (I and/or T) will be performed if 
clinically indicated by the Investigator (refer to Table 8-5). 
8.5.4 
Clinical safety laboratory tests 
All laboratory parameters assessed for safety purposes (Table 8-5) will be evaluated centrally 
except for urinalysis (dipstick for macroscopic panel) and urine pregnancy tests (dipstick) that 
will be performed locally. In the case of any macroscopic out of range parameters, a urine 
sample will be sent to central laboratory for further analysis (microscopic panel). Dipstick for 
urinalysis test (macroscopic panel) and dipstick for urine pregnancy test will be performed 
unless local institution policies dictate otherwise. For China only, local laboratories can be used 
for all specimens collected (i.e, central laboratory assessments not mandatory). 

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Samples for these parameters will be collected prior to study treatment administration. 
Local laboratory assessments may be performed if medically indicated or when the treating 
physician cannot wait for central laboratory results for decision making. In this particular 
situation, the blood sample obtained at the same time point should be submitted to the central 
laboratory for analysis in parallel with local analysis. 
The results of the local laboratory will be recorded in the eCRF if the following criteria are met: 
• A treatment decision was made based on the local results, or 
• There are no concomitant central results available. 
Laboratory values obtained during the Screening period from the central laboratory will be used 
to assess participant’s eligibility. 
The site does not need to wait for the results of centrally-analyzed laboratory assessments when 
an immediate clinical decision needs to be made (e.g., confirmation of eligibility, study 
treatment interruption, re-initiation, and/or termination) and in those cases locally unscheduled 
testing may be performed and used for eligibility assessments. 
Details on the collections, shipment of samples and reporting of results by the central laboratory 
are provided to Investigators in the Laboratory Manual. 
As per Section 4.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, if participants cannot visit the site for protocol specified safety lab assessments, an 
alternative lab (local) collection site may be used. 
Table 8-5 
Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hemoglobin, Platelets, Erythrocytes, Leukocytes, Erythrocyte Cell Morphology (if 
possible), Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils 
in percentage or absolute) 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Calcium, Magnesium, Phosphate, Sodium, 
Potassium, Creatinine, Creatinine clearance, Total Bilirubin, Direct Bilirubin (only if 
total bilirubin is ≥ grade 2), Blood Urea Nitrogen (BUN) or Urea, Serum Amylase, 
Lipase, Fasting Glucose (non-fasting allowed post-baseline), Bicarbonate, Chloride, 
Creatine Kinase (CK) 
Uric Acid at screening and thereafter if clinically indicated 
Urinalysis 
Macroscopic Panel (Dipstick) (Color, Bilirubin, Occult Blood, Macroscopic Blood, 
Glucose, Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, 
Urobilinogen) 
Microscopic Panel if indicated, (Erythrocytes, Leukocytes, Casts, Crystals, Bacteria, 
Epithelial cells) 
Coagulation 
Prothrombin time (PT), International normalized ratio (INR), Activated partial 
thromboplastin time (APTT) 
Liver event testing and 
liver follow-up testing 
To refer to Section 10.5 (Liver safety monitoring) 
Renal follow-up 
To refer to Section 10.6 (Renal safety monitoring) 
Pregnancy Test and 
assessment of fertility 
Serum / Urine pregnancy test. If local requirements dictate otherwise, local 
regulations should be followed. 
Confirmatory serum pregnancy required in case of positive urine pregnancy test. 
Urine pregnancy test will be performed locally. Follicle Stimulating Hormone (FSH), 

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Test Category 
Test Name 
Luteinizing Hormone (if required to confirm the menopausal status): these tests will 
be performed locally and documented in source document.  
At screening a serum pregnancy test is to be performed within 72 hr before the first 
dose, while during the study (Day 1 of each cycle) urine pregnancy tests are 
sufficient. An End of Treatment serum pregnancy test is also required to be 
performed. 
For women considered to be post-menopausal and not of childbearing potential, 
pregnancy testing is not required. If a serum pregnancy test is required as per local 
practice at day 1 of every cycle, the urine pregnancy test does not need to be 
repeated. 
Cardiac enzymes 
Isoenzyme (CK-MB) and Troponins (I and/or T) if clinically indicated. 
8.5.5 
Pregnancy testing 
A condom is required for all sexually active male participants to prevent them from fathering a 
child and to prevent delivery of study treatment via seminal fluid to their partner. In addition, 
male participants should not donate sperm and female participants should not donate oocytes 
for at least 7 days post discontinuation of study treatment. 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. 
All women of child-bearing potential will have a serum pregnancy test within 72 hours prior to 
the first dose of study treatment. hCG may also be considered a tumor marker, therefore if hCG 
levels are detected, another blood sample at least 4 days later must be taken to assess the kinetics 
of the increase, and a transvaginal ultrasound must be performed to rule out pregnancy. Urine 
pregnancy tests will be required to be performed on Day 1 of every cycle beginning with Cycle 
2, followed by serum pregnancy test at the end of treatment visit. Women of child-bearing 
potential will be instructed to contact the site immediately at any time during the study (on-
treatment or during follow-up) should they have a positive pregnancy test. 
In case of positive urine pregnancy testing, additional testing must be performed to confirm the 
pregnancy, and, if confirmed, follow the reporting requirements as described in Section 8.7.4. 
A positive pregnancy test requires immediate discontinuation of study treatment. If a positive 
pregnancy test is performed in between study visits, the participant must immediately notify the 
Investigator. Male participants must notify the Investigator in case their partner is confirmed 
with positive pregnancy test results during the treatment period. See Section 8.7.4 for pregnancy 
reporting. 
Local pregnancy test and associated results will not be collected on the eCRF. 
As per Section 4.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, if participants cannot visit the site to have serum pregnancy tests, urine pregnancy test 
kits may be shipped or provided directly to participants (e.g., together with the study treatment). 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. It is important that participants are instructed to perform the urine pregnancy test first and 
only if the test result is negative proceed with the administration of the study treatment. A 
communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g., following country specific measures). 

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Assessments of fertility 
A woman is considered of childbearing potential from menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile. 
In absence of the medical documentation confirming permanent sterilization, or if the post-
menopausal status is not clear, the Investigator should use his medical judgment to appropriately 
evaluate the fertility state of the woman and document it in the source document. 
When non-child-bearing potential status is determined during the study, further pregnancy 
testing will not be continued. For further details on the assessment of fertility, please refer to 
the study exclusion criteria in Section 5.2. 
If local requirements dictate otherwise, local regulations should be followed. 
8.5.6 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. The 
inclusion / exclusion criteria, dose modification guidelines, and safety assessments in this trial 
account for both the disease indications and the available safety data for JDQ443 [JDQ443 
Investigator's Brochure]. 
8.6 
Additional assessments 
8.6.1 
Clinical Outcome Assessments (COAs) 
The PRO measures in this study have been included to assess the effects of the study treatment 
on participants' lung cancer symptoms, functioning and other areas of health-related quality of 
life (QoL). These include the following: 
The Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) is a 7-
item, patient-reported outcome measure which assesses patient-reported symptoms associated 
with advanced NSCLC. It contains five domains and accompanying items that were identified 
as symptoms of NSCLC: cough (1 item), pain (2 items), dyspnea (1 item), fatigue (2 items), 
and appetite (1 item). The NSCLC-SAQ has been developed in patients with NSCLC including 
both males and females, varying levels of age, race, education, marital status, and ECOG 
performance status, and has been qualified by the US Food and Drug Administration as a 
measure of lung cancer symptoms (McCarrier et al 2016). 
The European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30) is a 
questionnaire developed to assess the health-related quality of life of cancer patients. The 
questionnaire contains 30 items and is composed of both multi-item scales and single-item 
measures based on the participants experience over the past week. These include five domains 
(physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, 

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nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, 
diarrhea and financial impact) and a global health status/QoL scale. All of the scales and single-
item measures range in score from 0 to 100. A high scale score represents a higher response 
level. Thus a high score for a functional scale represents a higher level of functioning; a high 
score for the global health status represents a high health-related quality of life (HRQoL), but a 
high score for a symptom scale represents a high level of symptomatology. All scorings will 
follow the scoring procedures defined by the EORTC Scoring Manual (Fayers et al 2001). 
The National Cancer Institute (NCI) Patient Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE) was developed to evaluate patient-
reported tolerability in cancer clinical trial participants. The PRO-CTCAE characterizes the 
frequency, severity, interference, and presence/absence of symptomatic adverse events that can 
be meaningfully reported from the patient perspective. For this study, a subset of eight items 
were selected that represent possible adverse experiences from common oncology drugs and 
medications 
of 
this 
drug 
class 
that 
are 
not 
covered 
adequately 
in 
other 
PRO questionnaires (Kluetz et al 2016). 
In order to ascertain the overall burden of the side effect profile, the single item, GP5, of the 
Functional Assessment of Cancer Therapy-General (FACT-G) will be included to assess global 
side effect impact. Together with the PRO-CTCAE these items will help us to better understand 
the patient-reported experience of benefits versus risks of the treatment and impact over the 
treatment course (Pearman et al 2018). 
The Patient Global Impression of Severity of Symptoms questionnaire (PGIS) asks the study 
participant about overall severity of lung cancer symptoms and will be used as a tool to assess 
clinical 
meaningfulness 
of 
symptom 
change 
in 
participants 
during 
the 
study 
(FDA Core PROs in Cancer 2021). 
The EQ-5D-5L is a generic instrument for describing and valuing health. It is based on a 
descriptive system that defines health in terms of 5 dimensions: Mobility, Self-Care, Usual 
Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has five response 
categories corresponding to no problems, some problems, and extreme problems. The 
instrument is designed for self-completion, and respondents also rate their overall health on the 
day of the interview on a 0–100 hash-marked, vertical visual analogue scale (EQ-VAS). The 
EQ-5D has been adopted as a tool to calculate health utilities for the purpose of cost-
effectiveness 
analyses 
to 
present 
to 
health 
technology 
assessment 
agencies 
(Herdman et al 2011). 
PRO data will be collected by self-report using an electronic device during the treatment, 
efficacy follow-up (if applicable) and survival periods. Participants will be given the 
opportunity to complete PRO questionnaires at site or at home before arriving at the site on 
scheduled visit days. Completion at home must be performed within 3 days before the 
scheduled visit (for more details, refer to vendor manual). 
The following back-up options are available during the treatment period, efficacy follow-up (if 
applicable) and survival period for participants who might not return to the clinic: 
PRO completion can be done from home using a web-based application or by interview over 
the phone provided the interviewer has received the appropriate training on recording the 
participant's responses. These are only to be used if there is a valid reason for employing them 

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such as public health emergency, or patient unable to complete on provisioned device/web-
based application (for more details, refer to vendor manual). 
The NSCLC-SAQ, EORTC QLQ-C30, FACT GP5, PRO-CTCAE, PGIS-NSCLC and EQ-5D-
5L PROs will be administered as indicated in Table 1-3 while the participant is on treatment, at 
EOT visit, during the post-treatment efficacy follow-up period (at corresponding imaging 
efficacy follow-up visits, if the participant is still followed for efficacy) and during the survival 
period. 
• For participants who have discontinued study treatment due to progressive disease by 
RECIST 1.1 as assessed by BIRC and enter the safety and survival follow-up periods, 
NSCLC-SAQ, EORTC QLQ-C30, FACT GP5, PRO CTCAE, PGIS-NSCLC and EQ-5D-
5L will be collected at EOT and every 12 weeks post progressive disease for a minimum 
of 3 timepoints. 
• For participants, who continue study treatment beyond progressive disease by RECIST 1.1 
as assessed by BIRC, PROs will continue to be collected at the same timepoints as defined 
during the treatment period. Once the participants discontinue study treatment and enter 
safety and survival follow-up periods, NSCLC-SAQ, EORTC QLQ-C30, FACT GP5, 
PRO CTCAE, PGIS-NSCLC and EQ-5D-5L will be collected at EOT and every 12 weeks 
post progressive disease for a minimum of 3 timepoints. 
• For participants who have discontinued study treatment for any other reason than 
progressive disease by RECIST 1.1 as assessed by BIRC and enter the efficacy follow-up 
period, PROs will be collected at EOT and every 12 weeks for NSCLC-SAQ, EORTC 
QLQ-C30, FACT GP5, PRO CTCAE, PGIS-NSCLC and EQ-5D-5L and at the time of 
progressive disease by RECIST 1.1 as assessed by BIRC. Following progressive disease 
by RECIST 1.1as assessed by BIRC, NSCLC-SAQ, EORTC QLQ-C30, FACT GP5, 
PRO CTCAE, PGIS-NSCLC and EQ-5D-5L will be collected every 12 weeks post 
progressive disease for a minimum of 3 timepoints.  
All PRO assessments should be administered in the participant’s local language, at the 
scheduled visit (if not completed at home), prior to any tests, treatments, or receipt of results 
from any test, to avoid biasing the participant’s perspective. Participant’s refusal to complete 
all or any part of a PRO measure should not be captured as a protocol deviation. Participant 
questionnaires should be completed in the language most familiar to the participant. 
The participant should be given sufficient space and time to complete the PRO measure(s), 
should be made aware that completed measure(s) are not reviewed by the Investigator/ study 
personnel and that they should report any discomfort, unusual symptoms or medical problems 
directly to the Investigator/ study personnel, according to the ICF. 
If PRO questionnaires are completed by participant, and study treatment is delayed, actions will 
be taken according to scenarios listed in Table 8-6: 

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Table 8-6 
PRO completion schedule if study treatment is delayed/rescheduled 
Treatment delay 
length of time 
PROs COMPLETED prior to re-
scheduled visit? 
Ask patient to complete PROs at rescheduled 
visit? 
≤ 7 days, 
YES 
Do not ask participants to complete the PROs 
again  
NO 
Ask participants to complete PROs for re-
scheduled visit 
> 7 days, 
YES 
Ask participant to complete PROs again for re-
scheduled visit 
NO 
Ask participant to complete PROs for re-
scheduled visit 
As per Section 4.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, study site staff may administer the questionnaires to the participants via interview over 
the phone (for more details, refer to the vendor manual). 
8.7 
Adverse events (AEs), serious adverse events (SAEs), and other 
safety reporting 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, regular 
phone or virtual contact will occur at least every 3 weeks (± 3 days) as per the visit scheduled, 
or more frequently if needed for safety monitoring and discussion of the participant´s health 
status until the participant can again visit the site. Events qualifying for being reported in the 
eCRF (e.g., AE, infection) should be entered as appropriate. 
When a negative urine test is required for continued IMP administration, if participants cannot 
visit the site to have serum pregnancy tests done, urine pregnancy test kits may be shipped or 
provided directly to participants (e.g., together with the study treatment). The participant will 
be instructed by the site on their requirements to perform these urine pregnancy tests remotely 
and the communication process with site prior to participant self-administration (refer to 
Section 8.5.5 for details). 
Depending on local regulations and capabilities, study site staff or Home Nursing Services may 
visit the participant at home to draw blood/urine samples if needed. Alternatively, safety lab 
tests and ECGs performed locally (e.g., by the participant's general practitioner or at another 
facility) will be allowed as appropriate. 
8.7.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign, including abnormal laboratory findings, symptoms or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The Investigator has the responsibility for managing the safety of individual participant and 
identifying AEs. Novartis qualified medical personnel will be readily available to advise on trial 
related medical questions or problems. 

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For participants who sign the molecular pre-screening ICF, AEs which occur after signature of 
this consent will only be captured if they meet the definition of serious as outlined in 
Section 8.7.2 and are reported to be causally related with study procedures (e.g., an invasive 
procedure such as biopsy). Once the main study ICF is signed, all AEs per the descriptions 
below will be captured as adverse events. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 8.7.2): 
AEs will be assessed and graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE V5.0). If CTCAE grading does not exist for an AE, the severity of mild, 
moderate, severe, life-threatening, and fatal corresponding to grades 1 - 5, will be used. 
Information about any deaths (related to an AE or not) will also be collected through a 
Death form. 
1. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e., progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant. 
2. Its duration (start and end dates) or if the event is ongoing, and an outcome of not 
recovered/ not resolved must be reported. 
3. Whether it constitutes a SAE (see Section 8.7.2 for definition of SAE) and which 
seriousness criteria have been met. 
4. Action taken regarding study treatment. All AEs must be treated appropriately. Treatment 
may include one or more of the following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/permanently discontinued 
• Its outcome: recovery status or whether it was fatal 
If the event worsens, then the event should be reported a second time in the eCRF noting the 
start date when the event worsens in toxicity. For grade 3 and 4 AEs only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the eCRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of main informed consent should be recorded 
in medical history of the participant. 

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AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. Adverse event 
monitoring should be continued for at least 30 days following the last dose of study treatment. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (.e.g., continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST 1.1), should not be reported as a SAE, except if the 
Investigator considers that progression of malignancy is related to study treatment (Note: If 
more stringent, local regulations regarding reporting criteria and timelines prevail). 
AEs separate from the progression of malignancy (i.e., deep vein thrombosis at the time of 
progression or hemoptysis concurrent with finding of disease progression) will be reported as 
per usual guidelines used for such events with proper attribution regarding relatedness to the 
drug. 
Further information about adverse drug reactions for JDQ443 can be found in the [JDQ443 
Investigator's Brochure]. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. 
8.7.2 
Serious adverse events 
An SAE is defined as any AE [appearance of (or worsening of any pre-existing)] undesirable 
sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria: 
• Fatal 
• Life-threatening 
Note: life-threatening in the context of a SAE refers to a reaction in which the participant was 
at risk of death at the time of the reaction; it does not refer to a reaction that hypothetically 
might have caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect or results in fetal death 
• Is medically significant, e.g., defined as an event that jeopardizes the participant or may 
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• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• Treatment of an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered SAEs, such as important medical events that might not be immediately life 
threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the [ICH-
E2D Guidelines]). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered SAEs irrespective 
if a clinical event has occurred. 
8.7.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting criteria and timelines prevail). Detailed 
instructions regarding the submission process and requirements are to be found in the 
Investigator folder provided to each site. 
Information about all SAEs is collected and recorded on the electronic Serious Adverse Event 
(eSAE) form (with paper backup if eSAE is unavailable); all applicable sections of the form 
must be completed in order to provide a clinically thorough report. 
For participants who sign the molecular pre-screening ICF, SAE collection will start upon 
signing the molecular pre-screening ICF and will only be reported if the event is suspected to 
be causally related to a study procedure as assessed by the Investigator (e.g., an invasive 
procedure such as biopsy). SAEs will be followed until resolution or until clinically relevant 

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improvement or stabilization. If the main ICF is not signed (e.g., molecular pre-screen failure), 
SAE collection ends 30 days after the last study related procedure. 
For participants who failed the molecular pre-screening or screening, SAEs will be collected 
until the time the participant is deemed a molecular pre-screening or screen failure. 
For participants who are enrolled, SAEs will be collected until 30 days after the participant has 
discontinued or stopped study treatment. 
Any SAEs experienced after the 30 days period following the last administration of the study 
treatment should only be reported to Novartis if the Investigator suspects a causal relationship 
to the study treatment, unless otherwise specified by local law/regulations. 
Progression of malignancy (including fatal outcomes), should not be reported as a serious 
adverse event, except if the Investigator considers that the progression is related to study 
treatment (Note: If more stringent, local regulations regarding reporting criteria and timelines 
prevail). 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting criteria and timelines prevail). An SAE occurring at a different time interval 
or otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the [JDQ443 Investigator’s Brochure] (new 
occurrence) and is thought to be related to the study treatment, a PS & PV Department associate 
may urgently require further information from the Investigator for health authority reporting. 
Novartis may need to issue an Investigator Notification (IN) to inform all Investigators involved 
in any study with the same study treatment that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees (EC) in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
8.7.4 
Pregnancy 
If a female trial participant becomes pregnant, the study treatment must be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the Investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. 
However, pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
The pregnancy should be followed up at 1, 3 and 12 (for a live birth only) months after the 
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termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded and reported by the Investigator to the Novartis Patient Safety & 
Pharmacovigilance (PS&PV). Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the study treatment and pregnancy 
outcome. Any SAE experienced during pregnancy must be reported. 
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
8.7.5 
Disease-related events and/or disease related outcomes not qualifying 
as AEs or SAEs 
The following disease-related events (DREs) are common in participants with NSCLC, and can 
be serious/life threatening: 
• Disease progression 
• Lack of efficacy 
• Death (related to study indication) 
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the 
event may meet the definition of an SAE (Note: If more stringent, local regulations regarding 
reporting criteria and timelines prevail). 
8.8 
Pharmacokinetics 
Serial blood samples will be collected from all participants to characterize the pharmacokinetics 
of JDQ443 at the visits defined in Section 1.3 (Schedule of Activities). In addition, residual 
samples used for PK and biomarker analyses may also be used for exploratory PK or PK/PD 
analysis. This could include using leftover plasma samples for protein binding analysis, 
metabolite profiling, other biomarker or bioanalytical purposes (e.g., cross validation between 
different sites, stability assessment), or other assays if there is sufficient sample remaining. 
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume collected 
will not exceed those stated in the protocol. Collection of PK samples may be stopped upon 
decision of the Sponsor, (i) if/when sufficient data are collected, (ii) after the primary CSR cut-
off date is reached, or (iii) following decision to halt enrollment. 
JDQ443 concentration data will be listed by study cohort, participant, and visit/sampling time 
point using SAS. Descriptive summary statistics will be provided by study cohort and 
visit/sampling time point using PAS. Concentrations below LLOQ will be treated as zero in 
summary statistics and for PK parameter calculations. 

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8.8.1 
Pharmacokinetic blood collection and handling 
PK blood samples will be taken by either direct venipuncture or an indwelling cannula inserted 
in a forearm vein at the visits defined in the pharmacokinetic log ( Table 8-7 or Table 8-8). 
Refer to the laboratory manual for detailed instructions regarding sample collection, numbering, 
processing and shipment. 
Complete dosing and blood sampling information, including the date/time of actual blood draw 
and date/time of the last study treatment dose prior to the sampling, should be obtained on all 
sampling days and recorded on the PK eCRF. Time of vomiting, if it occurs within 4 hours 
following investigational drug(s) administration, should be documented in eCRF. Meal 
date/time before and after JDQ443 administration should be collected on the PK collection days. 
An unscheduled PK blood sample will be collected, 1) if a participant experiences an AE 
suspected to be related to study treatment that results in an unscheduled visit or fits the criteria 
of an SAE, 2) whenever an unscheduled post-baseline tumor sample is collected during the 
treatment. 
The date and time of the unscheduled blood sample collection, and the date, time and dose of 
the investigational drug taken prior to the unscheduled blood sample collection should be 
entered in the appropriate eCRF. 
On days and time points where blood PD samples are to be drawn, the PK sample should be 
drawn first. On days and time points where ECG are collected, take ECG prior to PK blood 
draw. 
For approximately 10 participants in each of the Cohorts (A and B), PK blood samples will be 
collected at time-points described in Table 8-7 (Intensive PK sampling scheme). Approximately 
2 participants from this intensive PK group will be from China. For the remaining participants 
in each of the Cohorts (A and B), standard PK blood samples will be collected at time-points 
described in Table 8-8 (standard PK sampling scheme). 
Table 8-7 
PK blood collection log for JDQ443 treatment (intensive sampling; for 
approximately 10 participants in Cohort A and approximately 10 
participants in Cohort B) 
Treatment 
Period or 
Cycle 
Day 
Scheduled Time Point 
Dose 
reference ID 
Sample 
number 
Analyte 
1 
1 
hour* /pre-dose 
11 
101 
JDQ443 
1 
1 
hour (± 30 minutes) 
11 
102 
JDQ443 
1 
1 
hour (± 30 minutes) 
11 
103 
JDQ443 
1 
15 
hour* /pre-dose 
12 / 121# 
104 
JDQ443 
1 
15 
hour (±10 minutes) 
12 
105 
JDQ443 
1 
15 
hours (±15 minutes) 
12 
106 
JDQ443 
1 
15 
hours (±15 minutes) 
12 
107 
JDQ443 
1 
15 
hours (± 30 minutes) 
12 
108 
JDQ443 
1 
15 
hours (± 30 minutes) 
12 
109 
JDQ443 
1 
15 
hours (± 30 minutes) 
12 
110 
JDQ443 
1 
15 
 hours (± 2 hours)/pre-
evening dose) 
12 / 122& 
111 
JDQ443 
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3 
1 
hour*/pre-dose 
13 / 131# 
112 
JDQ443 
5 
1 
hour*/pre-dose 
14 / 141# 
113 
JDQ443 
7 
1 
hour*/pre-dose 
15/ 151# 
114 
JDQ443 
-- 
-- 
At time of on-treatment 
tumor sample collection** 
-- 
115 
JDQ443 
-- 
-- 
Unscheduled*** 
-- 
1001+ 
JDQ443 
*Collect samples immediately prior to the administration of study treatment. 
# These 3-digit dose reference ID refers to the dose taken prior to the corresponding PK sample. 
& These 3-digit dose reference ID refers to the dose taken after the corresponding PK sample. 
**if the scheduled biopsy sample collection is postponed for any reason, a PK sample is to be collected at the 
time of the biopsy collection. 
***Collected if a participant experiences an AE suspected to be related to study treatment that results in an 
unscheduled visit or fits the criteria of an SAE. Unscheduled PK sample may be collected at any time if 
clinically indicated, and must be sequentially numbered as 1001, 1002, 1003, etc.. 
Note: PK sample to be prioritized over the biopsy sample collection (optional tumor biopsy) 
Table 8-8 
PK blood collection log for JDQ443 treatment (standard sampling; 
remaining participants in Cohort A and Cohort B) 
Treatment 
Period or 
Cycle 
Day 
Scheduled Time Point 
Dose 
reference ID  
 
Sample 
number 
 
Analyte 
1 
1 
hour* /pre-dose 
11 
101 
JDQ443 
1 
1 
hour (± 30 minutes) 
11 
102 
JDQ443 
1 
1 
hour (± 30 minutes) 
11 
103 
JDQ443 
1 
15 
hour* /pre-dose 
12/121# 
104 
JDQ443 
1 
15 
hours (±30 minutes) 
12 
108 
JDQ443 
1 
15 
hours (± 30 minutes) 
12 
109 
JDQ443 
3 
1 
hour*/pre-dose 
13/131# 
112 
JDQ443 
5 
1 
hour*/pre-dose 
14/141# 
113 
JDQ443 
7 
1 
hour*/pre-dose 
15/151# 
114 
JDQ443 
-- 
-- 
t time of on-treatment tumor 
sample collection** 
-- 
115 
JDQ443 
-- 
-- 
Unscheduled*** 
-- 
1001+ 
JDQ443 
*Collect samples immediately prior to the administration of study treatment. 
# These 3-digit dose reference ID refers to the dose taken prior to the corresponding PK sample. 
**: If the scheduled biopsy sample collection is postponed for any reason, a PK sample is to be collected at the 
time of the biopsy collection. 
***Collected if a participant experiences an AE suspected to be related to study treatment that results in an 
unscheduled visit or fits the criteria of an SAE. Unscheduled PK sample may be collected at any time if 
clinically indicated, and must be sequentially numbered as 1001, 1002, 1003, etc.  
Note: PK sample to be prioritized over the biopsy sample collection (optional tumor biopsy) 
8.8.2 
Analytical method 
Concentrations of JDQ443 in human plasma will be determined with a validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) assay. 
Concentrations below the lower limit of quantification (LLOQ) will be reported as “zero” and 
missing data will be labeled as such in the Bioanalytical Data Report. 
8.9 
Biomarkers 
Biomarker analyses in tumor and/or in blood will be used to investigate the 
 
and to determine 
 
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. In addition, 
 
, as well as 
 may be explored. Samples and 
data may be also used to
 
. 
While the goal of the biomarker assessments is to provide supportive data for the clinical 
study, there may be circumstances when a decision is made by Novartis to stop a 
biomarker collection or to not perform or discontinue analysis based on emerging data and/or 
due to practical or strategic reasons. 
During the study, both blood and tumor samples will be collected to perform exploratory 
biomarker assessments as detailed in Table 8-9 , depending on sample availability, resources, 
participants' outcomes and as new scientific evidence or alternative methods become available 
(e.g., as indicated by new findings from the literature as well as from Novartis internal data). If 
a particular assay is not available for samples collected in a particular region/country, sample 
collection and/or analysis may be omitted. 
For participants in China only, the collection of biomarker samples or the collection type or 
amount may vary, conditional upon approval from local authorities (including but not limited 
to HGRAC). 
The sample collection information must be entered on the appropriate sample collection eCRF 
page(s) and requisition form(s). Detailed instructions for the collection, processing, and 
shipment of biomarker samples are outlined in the laboratory manual for the study. Sample(s) 
should be collected at the visit/time point(s) defined in the biomarker Table 8-9 . 
Table 8-9 
Biomarker sample collection plan 
Sample Type 
Volume 
Visit 
Timepoint 
Tumor and Blood Samples at Pre-Screening* 
Mandatory for 
eligibility** Tumor 
sample for PD-L1 
expression, KRAS G12C 
mutation and STK11 
mutation (cohort B only) 
status assessment 
(participant eligibility) and 
diagnostic development 
FFPE tissue block 
(preferred) or 16 to 20 
freshly cut, 5 µm tissue 
sections 
Pre-screening 
 
Molecular pre-screening 
requires participant’s 
written consent on the 
molecular pre-screening 
ICF. 
Samples to be submitted 
prior to main screening - 
participants who have 
locally assessed PD-L1 
expression status, KRAS 
G12C mutation and 
STK11 mutation (cohort 
B only) status, may 
directly enter main 
screening in parallel to 
sending the tumor 
samples 
Mandatory** Blood 
plasma to determine 
KRAS G12C mutation 
and STK11 mutation 
status 
May be used to 
determine eligibility 
where local results are 
not available 
2 × 10 mL whole blood 
Pre-screening 
 
Molecular pre-screening 
requires participant’s 
written consent on the 
molecular pre-screening 
ICF. 
Prior to main screening 
Tumor Samples in Treatment Period* 
Mandatory, where 
available*** Tumor 
Archival FFPE block 
(preferred) or 6 to 10 
C1D1 
Any time prior to 
treatment 
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Sample Type 
Volume 
Visit 
Timepoint 
sample for exploratory 
analysis 
freshly cut, 4 to 5 µm 
tissue sections 
Optional Newly obtained 
tumor biopsy for 
exploratory 
analysis (requires 
optional biopsy consent 
within the main ICF) 
3-6 passes core needle 
biopsy as formalin fixed 
tissue or FFPE block 
C1D1 
 
Prior to start of treatment 
- Biopsy may be 
performed during 
screening to 
accommodate patient 
scheduling 
C1D15 
 
4 and 8 hours post-dose 
EOT/PD 
At EOT if EOT=PD or at 
the time of first disease 
progression, prior to the 
initiation of the new anti-
cancer therapies 
Blood samples in Screening and Treatment Period* 
Mandatory Blood 
plasma sample for KRAS 
G12C/STK11 
assessment and 
diagnostic development 
2 × 10 mL whole blood 
Screening 
Day -28 to D-1 
Mandatory Blood 
plasma sample for 
exploratory cfDNA 
analysis 
2 × 10 mL whole blood 
C1D1 
Pre-dose 
C1D15 
Pre-dose 
C2D1 
Pre-dose 
C3D1 
Pre-dose 
D1 of every 2 cycles 
thereafter 
Pre-dose 
EOT 
EOT 
Mandatory Blood 
plasma for exploratory 
analysis of
 
1 × 3 mL whole blood 
C1D1 
Pre-dose 
C1D15 
Pre-dose 
C3D1 
Pre-dose 
EOT 
EOT 
* For participants in China only: PD-L1 expression, KRAS G12C status and STK11 mutation status (cohort B 
only) must be determined by local assessment . Biomarker sample collection is conditional upon approval from 
local authorities (including but not limited to HGRAC).  
** Tissue and blood samples are required from all participants as a part of pre-screening. For cases 
where documented local results from a qualified laboratory are not available and the central test results will be 
used for eligibility testing based on PD-L1 expression in tissue, KRAS G12C mutation status and STK11 
mutation status (cohort B only) in tissue or blood, the sample must be submitted as part of pre-screening. 
While awaiting results, patient may proceed to main screening, however results must be received with 
appropriate biomarker status prior to starting treatment (Section 5.1 and Section 8.1). With documented local 
results for all required biomarkers, the participant may simultaneously sign the pre-screening and main consent 
forms, enter main screening and submit the tissue sample prior to start of treatment (Section 8.1). 
*** Mandatory where sample is available and to be requested from another institution. Not required if tumor 
tissue block was submitted during pre-screening/screening for PD-L1, KRAS G12C and/or STK11 assessment 
or if optional, newly obtained biopsy is provided at C1D1. 
Biomarker assessments for molecular pre-screening 
A tumor sample (archival tumor block or slides, as detailed in Table 8-9 ) and a blood sample 
are required from all participants as part of the molecular pre-screening assessments of this trial. 
The samples will be used for centralized eligibility assessment for PD-L1 expression, 
KRAS G12C and STK11 (cohort B only) mutation status, when local test results confirming 
eligibility are not available or for retrospective confirmation of biomarker status where local 
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test results are available for any of the biomarkers (as described in Section 8.1). For participants 
in China only: PD-L1 expression, KRAS G12C status and STK11 mutation status (STK11 
mutation for cohort B only) must be determined by local assessment. Tumor sample material 
and blood may also be used to support diagnostic test development. If available, a copy of the 
corresponding de-identified pathology report should be submitted with archival tumor samples. 
Tumor samples must contain at least 20% tumor content. Samples obtained from bone 
metastases and cytology samples are not acceptable. 
Exploratory biomarker assessments in tumor 
At C1D1, all participants are required to submit a tumor sample (where available) as an archival 
tissue block or slides or may optionally provide a newly acquired core or excisional formalin-
fixed biopsy sample. The sample is not required to be submitted if tumor tissue block was 
submitted during pre-screening/screening for PD-L1, KRAS G12C and/or STK11 assessment. 
All participants will also be asked to optionally provide newly acquired, core or excisional, 
formalin-fixed biopsy samples at C1D1, C1D15 collected 4 to 8 hours post-dose and at first 
disease progression, prior to the initiation of any new anti-cancer therapies. Participants must 
sign the relevant section of the ICF to consent to the optional biopsy collection(s). 
Tumor tissue material collected at pre-screening, C1D1 (if a tissue block was not submitted at 
pre-screening or optionally from a newly obtained biopsy) and optionally at C1D1, C1D15 and 
disease progression will be used to support exploratory biomarker assessments including 
 
 
. Analysis methods may include 
, 
 
 and 
. 
including but not limited to 
 and 
 
may be investigated in baseline and on-treatment samples (if available) to assess quantitative 
changes as well as the 
 
to the treatment, as measured by 
, 
 by 
 
 or using additional techniques deemed suitable. The biopsy at disease progression 
will be used to unveil potential 
, or to 
highlight
 
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Biomarker assessments in blood 
Blood will be collected as detailed in Table 8-9 to allow for sequencing of plasma cell 
 
 
to support diagnostic test development, and/or for 
 
 
Baseline levels and longitudinal changes over time of 
 and selected
 may 
be assessed with respect to clinical endpoints. 
All blood samples collected on the study for biomarker analysis may be interchangeably 
used for analyzing 
 and other circulating markers of interest to address 
scientific questions related to KRAS inhibition, lung cancer, treatment response or clinical 
outcome. 
A targeted 
 may be used to assess 
 
associated with NSCLC and the 
 to understand 
 
. When there is a matching tissue sample available, correlation of markers 
with tumor tissue will be assessed. Additional 
 and 
 associated with 
NSCLC and 
 may also be analyzed. 
8.9.1 
Use of residual biological samples 
Optional additional biomarker studies 
If the participant agrees (for participants enrolled in China, conditional upon approval from 
local authorities [including but not limited to HGRAC]), the biological samples (tumor, blood, 
plasma, and serum) may be kept for up to 15 years to be used for additional studies related to 
JDQ443 or cancer, including research to help develop ways to detect, monitor or treat cancer. 
Soluble/protein markers may also be measured on those samples to better understand the disease 
and response to treatment. A decision to perform such exploratory biomarker research studies 
would be based on outcome data from this study or from new scientific findings related to the 
drug class or disease, as well as assay availability.  
8.10 
 assessments 
 is not evaluated in this study. 
9 
Statistical considerations 
The efficacy and safety analyses will be performed separately for each of the two cohorts and 
the STK11-mutated participants pooled from the two cohorts. The primary analysis of the 
primary and key secondary endpoint will be conducted on all participant data when participants 
in the respective cohort who are still receiving study treatment will have completed at least 4 
tumor assessments (approximately 24 weeks). 
Any additional data for participants continuing to receive study treatment past the data cut-off 
date for the primary analysis in each of the groups will be reported at completion of the study 
in a final CSR. 
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9.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned and who received at least one dose of study treatment.  
The Safety Set includes all participants who received at least one dose of study treatment. 
The FAS and Safety Set in this study are identical. 
The Pharmacokinetic Analysis Set (PAS) includes all participants who received at least one 
planned dose of study treatment and provide an evaluable pharmacokinetic concentration. 
Criteria described below need to be considered for a concentration to be evaluable: 
• Participant did not vomit within 4 hours after dosing of JDQ443 
• For all pre-dose samples, PK draw occurred before the next dose intake 
• For post-dose PK samples, PK draw with concentration following planned dose 
• Any PK blood samples with missing collection date or time, or missing associated study 
treatment dosing date or time will be excluded.  
The Full Pharmacokinetic Analysis Set (FPAS) includes PAS participants with intensive PK 
collection schedule who provide an evaluable PK profile. A profile is considered evaluable if 
the conditions listed for the PK Analysis Set (Section 9.4.3) and the following conditions are 
met: 
• Participant receives planned dose 
• Participant provides at least one valid primary PK parameter 
Further details will be included in the Statistical Analysis Plan (SAP). 
9.2 
Statistical analyses 
9.2.1 
General considerations 
The efficacy analyses will be performed separately for each of the two cohorts. An additional 
group including all participants whose tumors harbor an STK11 mutation will be formed by 
pooling participants from cohorts A and B. Unless otherwise specified, efficacy analyses 
conducted for the 2 cohorts will also be performed for the pooled group. The description "by 
cohort" or "for each cohort" will include these analyses. 
The criteria for the targeted ORR and the respective 95% confidence interval assumptions 
adopted for both cohorts, i.e., for both the primary and the key secondary endpoint, were based 
on the assumption that JDQ443 will present a similar level of antitumor activity than the one 
observed in previous studies with KRAS G12C inhibitors in patients with KRAS G12C-mutated 
advanced NSCLC (Riely et 2021, Skoulidis et al 2021). For cohort B, the criterion chosen for 
success (ORR of 40% and the CI lower limit of 20%) was slightly more conservative than for 
cohort A. Due to the sample size of cohort B, a difference in responders of a single participant 
may generate a high impact in the efficacy assessments. 

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9.2.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by cohort for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by cohort. 
9.2.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented. The exposure related analyses will be presented by cohort. 
The duration of exposure to JDQ443 in weeks as well as the dose intensity and the relative dose 
intensity will be summarized by means of descriptive statistics. The number of participants with 
dose adjustments (reductions, interruption, or permanent discontinuation) and the reasons will 
be summarized. All dosing data will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by cohort. 
9.3 
Primary endpoint(s)/estimand(s) analysis 
The primary objective of the study is to assess the antitumor activity of JDQ443 single-agent 
as first-line treatment for participants with locally advanced or metastatic NSCLC whose 
tumors harbor a KRAS G12C mutation and a PD-L1 expression < 1%, regardless of STK11 
mutation status (cohort A). 
9.3.1 
Definition of primary endpoint(s) 
The primary endpoint of the study is ORR, defined as the proportion of participants with a 
confirmed CR/PR as BOR. BOR is defined as the best response recorded from the start of the 
treatment until disease progression per RECIST 1.1 by BIRC. CR and PR must be confirmed 
by repeat assessments that should be performed not less than 4 weeks after the criteria for 
response were first met. Responses documented after the use of any new anti-neoplastic therapy 
will be considered as non-response. 
9.3.2 
Statistical model, hypothesis, and method of analysis 
The primary analysis will be performed on the FAS. The primary efficacy endpoint ORR will 
be estimated and the exact 95% confidence interval (CI) (Clopper and Pearson 1934) provided. 
Treatment with JDQ443 will be considered to have clinically relevant efficacy if an ORR 
of 
 (per RECIST 1.1 by BIRC assessment) is observed with the lower bound of the 95% 
confidence interval 
. The following statistical hypotheses will be tested: 
H0: ORR 
 vs. H1 ORR ≥ 35%. 
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The tests will be performed based on the exact confidence interval for ORR using a one-sided 
α=0.025 level. The null hypothesis will be rejected if the lower bound of the two-sided 95% 
exact CI is ≥ 35%. 
An interim analysis for futility will be performed to assess ORR in approximately the first 30 
evaluable participants. Evaluable participants are defined as enrolled participants who have 
been followed for at least two tumor assessments or have discontinued the study earlier (see 
Section 9.8). 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) 
The primary analysis will account for different intercurrent events as explained in the following: 
1. Discontinuation of study treatment: Tumor assessment data collected after discontinuation 
of study treatment for any reason will be included to derive BOR (treatment policy 
strategy). 
2. Start of a new anti-neoplastic therapy: If any new anti-neoplastic therapy is initiated, 
responses documented after the use of new anti-neoplastic therapy will be considered as 
non-response (composite strategy). 
3. Any public health emergency as declared by local or regional authorities, i.e., pandemic, 
epidemic or natural disaster: Tumor assessment data collected irrespective of such 
unforeseen events will be considered for the BOR (treatment policy strategy). 
9.3.4 
Handling of missing values not related to intercurrent event 
Confirmed PR or CR reported prior to any additional anticancer therapy will be considered as 
responses in the calculation of the ORR irrespective of the number of missed assessments before 
response. 
Participants with a BOR of ‘Not evaluable’ per RECIST 1.1 will be considered as non-
responders when estimating ORR. Participants who have disease progression and continue to 
receive study treatment after progression per RECIST 1.1 by BIRC will qualify for PD at the 
time of progression and will be counted as PD in the derivation of BOR. 
9.3.5 
Multiplicity adjustment (if applicable) 
As the 2 cohorts represent different patient populations, a multiplicity adjustment for the 
analysis of the primary and first key secondary endpoints is not applicable. For the analysis of 
the other key secondary endpoints there is also no multiplicity adjustment planned. 
9.3.6 
Sensitivity analyses 
Not applicable. 
9.3.7 
Supplementary analysis 
A supplementary estimand is defined by the same target population, treatment of interest, 
intercurrent events, and summary measure as for the primary estimand. Differently from the 
primary estimand, the primary variable is the BOR per RECIST 1.1 assessed by the Investigator 
(local assessment), with responses documented after the use of any new anti-neoplastic therapy 
considered as non-response. 

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The method of analysis, handling of intercurrent events, and missing data will be the same as 
described in Section 9.3.2, Section 9.3.3, and Section 9.3.4. 
9.4 
Secondary endpoint(s)/estimand(s) analysis 
The secondary objectives in this study are to assess the antitumor activity of JDQ443 single-
agent as first-line treatment for participants with locally advanced or metastatic NSCLC whose 
tumors harbor a KRAS G12C mutation, a PD-L1 expression ≥ 1% and an STK11 co-mutation 
(cohort B), and to evaluate the duration of response (DOR), disease control rate (DCR), 
progression-free survival (PFS), time to response (TTR), overall survival (OS), 
pharmacokinetics, safety, as well as patient-reported symptoms, impacts, functioning and 
tolerability with patient-outcomes (PRO). 
ORR per RECIST 1.1 by BIRC for cohort B and DOR per RECIST 1.1 by BIRC in both cohorts 
are identified as the key secondary endpoints. No multiplicity adjustment is foreseen in the 
analysis of the key secondary or other secondary endpoints. 
9.4.1 
Efficacy and/or pharmacodynamic endpoint(s) 
The secondary efficacy endpoints will be assessed using the FAS. 
9.4.1.1 
Key secondary endpoints 
For the key secondary endpoint, ORR per RECIST 1.1 by BIRC in cohort B, the same definition 
as in Section 9.3.1 applies. 
Treatment with JDQ443 will be considered to have clinically relevant efficacy in cohort B if an 
ORR of ≥ 40% is observed with the lower bound of the 95% confidence interval ≥ 20%. The 
following statistical hypotheses will be tested: 
H0: ORR < 20% vs. H1: ORR ≥ 20%. 
The test will be performed based on the exact confidence interval for ORR using a one-sided 
α=0.025 level. The null hypothesis will be rejected if the lower bound of the two-sided 95% 
exact CI is ≥ 20%. The ORR and its 95% confidence interval will be presented. 
An interim analysis for futility will be performed to assess the ORR in approximately the first 
 participants. Evaluable participants are defined as enrolled participants who have 
been followed for at least two tumor assessments or have discontinued the study earlier (see 
Section 9.8). 
As a supportive analysis, ORR per RECIST 1.1 as assessed by local review along with 95% 
confidence intervals will be presented for both cohort A and cohort B. 
DOR only applies to participants whose best overall response is CR or PR according to RECIST 
1.1 by BIRC. The start date is the date of first documented response of CR or PR (i.e. the start 
date of response, not the date when response was confirmed), and the end date is defined as the 
date of the first documented progression or death due to any cause. Participants continuing 
without progression or death will be censored at the date of their last adequate tumor 
assessment. 
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DOR will be listed and summarized by cohort for all participants with confirmed BOR of CR 
or PR. The DOR distribution will be estimated using the Kaplan-Meier method, and the Kaplan-
Meier curves, medians and 95% confidence intervals of the medians will be presented for each 
cohort. 
As a supportive analysis, DOR per RECIST 1.1 as assessed by local review, will be summarized 
by cohort. 
9.4.1.2 
Other secondary efficacy endpoints 
DCR is defined as the proportion of participants with a BOR of confirmed CR, PR and stable 
disease (SD) according to RECIST 1.1 (see Appendix 8 Section 10.8). DCR will be assessed 
by BIRC as well as by local review. DCR and the corresponding 95% confidence intervals 
based on the exact binomial distribution (Clopper and Pearson 1934) will be presented. 
PFS is defined as the time from the date of first dose of study treatment to the date of the first 
documented progression or death due to any cause. PFS will be assessed by BIRC as well as by 
local review according to RECIST 1.1 (see Section 10.8 for further details). PFS will be 
censored if no PFS event is observed before the first to occur between: (i) the analysis cut-off 
date, and (ii) the date when a new anti-neoplastic therapy is started. The censoring date will be 
the date of the last adequate tumor assessment prior to cut-off/start of new anti-neoplastic 
therapy. The PFS distribution will be estimated using the Kaplan-Meier method, and the 
Kaplan-Meier curves, medians and 95% confidence intervals of the medians will be presented 
for each cohort. 
Time to response (TTR) is defined as the time from the date of first dose of study treatment to 
the first documented response of either CR or PR, which must be subsequently confirmed 
(although date of initial response is used, not date of confirmation). CR and PR are based on 
tumor response data by BIRC as well as per local review and according to RECIST 1.1 (see 
Section 10.8 for details). All participants in the FAS will be included in TTR calculations. 
Participants without a confirmed CR or PR will be censored at the study-maximum follow-up 
time (i.e., LPLV−FPFV) for participants with a PFS event (i.e., disease progression or death 
due to any cause), or at the date of the last adequate tumor assessment for participants without 
a PFS event. TTR will be listed and summarized by cohort. The TTR distribution will be 
estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% 
confidence intervals of the medians will be presented for each cohort. 
OS is defined as the time from the date of first dose of study treatment to the date of death due 
to any cause. If a participant is not known to have died, then OS will be censored at the latest 
date the participant was known to be alive (on or before the cut-off date). The OS distribution 
will be estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 
95% confidence intervals of the medians will be presented for each cohort. 
9.4.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
cohort.  
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g., change from 

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baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of participant’s informed consent to the day before first 
dose of the study treatment 
2. On-treatment period: from day of first dose of the study treatment to 30 days after last 
dose of the study treatment 
3. Post-treatment period: starting at day 31 after last dose of the study treatment. 
9.4.2.1 
Adverse events 
All information obtained on AEs will be displayed by cohort and participant. 
The number (and percentage) of participants with treatment emergent AEs (events started after 
the first dose of study medication or events present prior to start of treatment but increased in 
severity based on preferred term) will be summarized in the following ways: 
• By treatment, primary system organ class and preferred term 
• By treatment, primary system organ class, preferred term and maximum severity 
Separate summaries will be provided for study medication related AEs, deaths, SAEs, other 
significant AEs leading to discontinuation, and AEs leading to dose adjustment. 
The number (and proportion) of participants with adverse events of special interest (AESI) will 
be summarized by cohort. AESIs will be defined based on the case retrieval strategy (CRS) 
available at the time of the analysis. 
A participant with multiple AEs within a primary system organ class is only counted once 
towards the total of the primary system organ class. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths and serious adverse events (including those from the pre- and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 
9.4.2.2 
Clinical laboratory evaluations 
Grading of laboratory values will be assigned programmatically as per CTCAE version 5.0. The 
calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. For laboratory tests where grades are not defined by CTCAE version 5.0, 
results will be categorized as low/normal/high based on laboratory normal ranges. 
All laboratory data will be summarized by cohort. The following summaries/listings will be 
generated separately for hematology and biochemistry tests: 

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• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
version 5.0 grades if applicable and the classifications relative to the laboratory normal 
ranges 
For laboratory tests where grades are defined by CTCAE version 5.0 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant 
will be counted only once for the worst grade observed post-baseline 
• Shift tables using CTCAE version 5.0 grades to compare baseline to the worst on-
treatment value 
For laboratory tests where grades are not defined by CTCAE version 5.0, 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value. 
In addition to the above-mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots may be 
specified in the analysis plan. 
9.4.2.3 
Vital signs 
Vital signs parameter measured include blood pressure (supine position preferred when ECG is 
collected), pulse measurement, respiratory rate and body temperature. 
Data on vital signs will be tabulated and listed by cohort, visit/time, notable values will be 
flagged. Summary statistics will be provided by cohort. 
9.4.2.4 
12-lead ECG 
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. ECG data will be read and interpreted centrally. 
Notable ECG abnormalities will be summarized. In addition, a listing of these participants will 
be produced by cohort. 
9.4.3 
Pharmacokinetics 
The FAS will be used to list individual concentration data. The PAS will be used for summary 
statistics of JDQ443 concentration data and the FPAS for all PK analyses (non-compartmental 
and pharmacometric) including summary statistics of PK parameters. 
JDQ443 concentration data will be listed by cohort, participant, and visit/sampling time point. 
Descriptive summary statistics will be provided by cohort and visit/sampling time point, 
including the frequency (n, %) of concentrations below the LLOQ and reported as zero. 
Summary statistics of concentration data will include mean (arithmetic and geometric), SD, CV 
(arithmetic and geometric), median, minimum, and maximum. Concentrations below LLOQ 
will be treated as zero in summary statistics and for PK parameter calculations. A graphical 
presentation will be provided on mean concentration at each scheduled time point when the full 
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Individual and mean PK parameters such as listed in Table 9-1 will be derived using non-
compartmental analysis using Phoenix WinNonlin (Version 5.0 or higher) and reported, if 
feasible. 
Descriptive summary statistics of PK parameters will include mean (arithmetic and geometric), 
SD, and CV (arithmetic and geometric), median, minimum, and maximum. An exception to this 
is Tmax where median, minimum, and maximum will be presented. 
Table 9-1 
JDQ443 plasma pharmacokinetic parameters - non-compartmental 
analysis 
AUClast,ss 
The AUC from time zero to the last measurable concentration sampling time (tlastss) at steady-
state (mass × time × volume-1) 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount × time × 
volume-1) 
Cmax,ss 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentrations 
after single dose administration (mass × volume-1) 
Tmax,ss 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration 
at stead-state (time) 
Cmin,ss 
Observed concentration at the end of a dosing interval (taken directly before next administration) 
at steady-state 
Lambda_z 
Smallest (slowest) disposition (hybrid) rate constant (time-1) may also be used for terminal 
elimination rate constant at steady-state (time-1) 
T1/2,ss 
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration-time curve at steady-state (time). 
CL/F 
The total body clearance of drug from the plasma (volume × time-1) 
Vz/F 
The apparent volume of distribution during terminal phase (associated with λz) (volume) 
9.4.4 
Patient-reported outcomes 
The following patient-reported outcomes (PRO) questionnaires will be assessed: the NSCLC-
SAQ, EORTC QLQ-C30, the FACT-GP5, PRO-CTCAE and the EQ-5D-5L. Of these the 
NSCLC-SAQ, EORTC QLQ-C30, and FACT-GP5 will be analyzed by cohort (A and B) to 
assess the secondary objectives. The other questionnaires may be evaluated in exploratory 
analyses.  
The FAS will be used for analyzing PRO data. 
Scoring of PRO data and methods for handling of missing items or missing assessments will be 
according to the scoring manual and user guide for each respective participant questionnaire 
(Aaronson et al 1993, Fayers et al 2001, McCarrier et al 2016). No imputation procedures will 
be applied for missing items or missing assessments. 
Time to definitive deterioration in the NSCLC-SAQ total score is the primary PRO variable of 
interest. Time to definitive deterioration (TTDD) in physical functioning (PF)of the QLQ-C30 
is the secondary PRO variable of interest.  
The time to definitive 10-point deterioration for SAQ total score (TS) or C30 PF, respectively, 
is defined as the time from the date of enrollment to the date of meaningful worsening. For the 
TS it is defined as at least 1-point absolute increase in score from baseline (worsening), and for 
PF it is defined as at least 10-point absolute decrease in score from baseline (worsening) , with 
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due to any cause (within 3 weeks of the last assessment). If a participant has not had an event, 
time to definitive deterioration will be censored at the date of the last adequate PRO assessment. 
Only assessments collected while the participant is on treatment and at the end of treatment visit 
will be included in the PRO TTDD. Participants with no baseline data or no post-baseline data 
will be censored at baseline. 
The distribution of time to definitive deterioration will be summarized using the Kaplan-Meier 
method, and the Kaplan-Meier curves, medians, and two-sided 95% confidence intervals of the 
medians will be presented. Additionally, time to definitive deterioration with different cut-off 
definitions for deterioration may be specified in the SAP as deemed appropriate. 
Descriptive statistics will be used to summarize the scores, as well as change from baseline, of 
the EORTC QLQ-C30, EQ-5D-5L,NSCLC-SAQ and PGIS-NSCLC at each scheduled 
assessment and to EOT. Additionally, change from baseline scores will assess SAQ total score, 
pain and fatigue domains, and cough, dyspnea and appetite loss items; C30 GHS/QoL and 
functional domains as well as symptom items/domains and financial problems item. 
Participants with an evaluable baseline score and at least one evaluable post-baseline score 
during the on-treatment period will be included in the change from baseline analyses. 
The number of participants completing each PRO and the number of missing or incomplete 
assessments will be summarized by cohort for each scheduled assessment timepoint. No formal 
statistical tests will be performed for PRO data and hence no multiplicity adjustment will be 
applied. 
9.5 
Exploratory endpoint(s)/estimand(s) analysis 
Further details for the analysis of exploratory endpoints might be provided in the statistical 
analysis plan. 
9.5.1 
Biomarkers 
The statistical goals of exploratory biomarker analysis should be considered as promoting the 
generation of new scientific hypotheses and are exploratory in nature. 
There may be circumstances when a decision is made to stop sample collection, or not perform 
or discontinue their analysis due to either practical or strategic reasons (e.g., issues related to 
the quality and/or quantity of the samples or issues related to the assay). Under such 
circumstances, the number of samples may be inadequate to perform a rigorous data analysis 
and the available data will only be listed and potentially summarized. 
9.5.1.1 
Outline of the data analysis 
The proposed data analysis will be aligned with the exploratory biomarker objectives of the 
protocol: 
• To assess 
 
• To assess 
 
 
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• To explore the
 
• To assess the relationship 
 
 
9.5.1.2 
Data analysis principles 
The FAS will be used for all biomarker analyses unless otherwise specified. 
Depending on the endpoint of interest, graphical displays such as box plots or strip plots may 
be used to assess the relationship of different biomarkers with clinical benefit. These may be 
separated by cohort and include either baseline or change from baseline values, where 
applicable. 
For continuous markers, baseline and change from baseline (absolute change, percent change 
and fold change) at each time point will be summarized in tables that include sample size, mean, 
standard deviation, CV%, median, minimum and maximum. For fold change from baseline, 
geometric mean and geometric CV% will also be included. For categorical markers such as 
mutation status, 2×2 contingency tables may be used to assess the relationship with clinical 
benefit and/or Kaplan-Meier curves may be generated given the number of events warrant such 
an assessment. 
If additional analyses are needed to be performed after the completion of the end-of-study 
clinical study report (CSR), they will be documented in separate reports. The data analysis will 
be described in an addendum of the statistical analysis plan (SAP) or in a stand-alone analysis 
plan document, as appropriate. 
9.5.2 
Pharmacokinetics 
Pharmacokinetic data from this study will be analyzed using population PK approach, which 
may include exploring the effect of covariates on PK, if data allow. The PK data from this study 
may be combined with similar data from other studies and explored using population PK. 
Exploratory analyses may also be conducted to identify possible relationships of JDQ443 
exposure (e.g., Cmax, Cmin or AUC) with PD markers, clinical efficacy (ORR, PFS, and OS) 
or safety variables as appropriate. The results of such exploratory analyses will be reported 
separately from the CSR. 
9.6 
(Other) Safety analyses 
Not applicable 
9.7 
Other analyses 
Not applicable 
9.8 
Interim analysis 
The planned interim analyses will be performed separately for each of the two cohorts. In case 
the interim analysis (IA) of the two cohorts happens at a similar time, the IA will be reported 
together. 
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9.8.1 
Primary endpoint: ORR in cohort A 
One IA is planned for cohort A based on approximately the first 30 evaluable participants. 
Evaluable participants are defined as enrolled participants who have been followed for at least 
two tumor assessments or have discontinued the study earlier. The primary intent of the interim 
analysis is to stop the cohort early for lack of efficacy (futility). 
The decision whether to continue or stop enrollment and/or treatment will be based on the 
predictive probability of success (PPoS). PPoS is the predictive probability of a positive 
conclusion of the study (regarding cohort A) if it continued beyond the interim analysis (i.e., 
until the final analysis), given the interim observed data (x) and successes among n participants.  
PPoS = Prob[Final observed ORR ≥ 
% | x, n] 
A minimally informative Beta distribution prior (Neuenschwander et al 2008) with prior mean 
equal to 
% will be used, i.e., the prior distribution will be Beta (
 for the PPoS 
calculations at the interim analysis. 
The cohort will be stopped for futility at the interim analysis if the observed ORR is ≤ 
% 
corresponding to 9 or less responders (at least 
responders out of 30 participants are required 
for the study to proceed). If the futility criterion is met, the predictive probability of observing 
a success in the future based on the existing data will be < %. 
All evaluable participants in cohort A at the time of the data cut-off for the interim analysis will 
be used. 
If futility is concluded, the enrollment of participants in the cohort will be stopped. The 
enrollment in cohort B will continue, if applicable. 
Table 9-2 provides the PPoS at the primary analysis based on different numbers of responders 
observed at the interim analysis. For 
 responders, PPoS exceeds % and the cohort 
will continue after the interim analysis. 
Table 9-2 
PPoS at the primary analysis based on various numbers of 
responders observed at the IA 
Responders at IA out of 30 evaluable participants 
Predictive probability of success (%) 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
11 
 
12 
 
9.8.2 
Key secondary endpoint: ORR in cohort B 
One interim analysis is planned for cohort B based on approximately the first 
evaluable 
participants. Evaluable participants are defined as enrolled participants who have been followed 
for at least two tumor assessments or have discontinued the study earlier. The primary intent of 
the interim analysis is to stop the cohort early for lack of efficacy (futility). 
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The decision whether to continue or stop enrollment and/or treatment will be based on the PPoS. 
PPoS = Prob[ Final observed ORR ≥ 
% | x, n] 
A minimally informative Beta distribution prior (Neuenschwander et al 2008) with prior mean 
equal to 
% will be used, i.e., the prior distribution will be Beta(
 for the PpoS 
calculations at the interim analysis. 
The cohort will be stopped for futility at the interim analysis if the observed ORR is ≤ 
% 
corresponding to 
or less responders (at least 
responders out of 
 participants are required 
for the cohort to proceed). If the futility criterion is met, the predictive probability of observing 
a success in the future based on the existing data will be < %. 
All evaluable participants in the cohort at the time of the data cut-off for the interim analysis 
will be used. 
If futility is concluded, the enrollment of participants in the cohort will be stopped. The 
enrollment in cohort A will continue, if applicable. 
Table 9-3 provides the PPoS at the primary analysis based on different numbers of responders 
observed at the interim analysis. For 
or more responders, PPoS exceeds
% and the cohort 
will continue after the interim analysis. 
Table 9-3 
PPoS at the final analysis based on various numbers of responders 
observed 
Responders at IA out of 
 participants 
Predictive probability of success (%) 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
9.9 
Sample size determination 
A total of 120 participants will be enrolled in 2 separate cohorts that will recruit in parallel: 90 
in cohort A and 30 in cohort B, if none of the cohorts is stopped for futility at the time of the 
corresponding interim analysis. 
An additional group including all participants whose tumors harbor an STK11 mutation will be 
formed by pooling participants from cohorts A and B. Around 30 of these participants are 
anticipated in cohort B and another ~30 STK11 mutated participants are expected from cohort 
A based on the prevalence of STK11 mutation among patients with KRAS G12C-mutated 
advanced NSCLC in prior studies, hence the STK11 mutated group should have approximately 
60 participants (Ricciuti et al 2021). 
9.9.1 
Primary endpoint(s) 
The calculation of sample size and operating characteristics for the analysis of the primary 
endpoint, ORR estimate and confidence interval, are based on the model and assumptions in 
Section 9.3.2. 
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The exact 95% CIs for various sample sizes and potential observed ORRs are shown in 
Table 9-4. 
Table 9-4 
Exact binomial 95 percent confidence intervals for various sample 
sizes and observed ORRs (cohort A) 
Sample size (N) 
Number of 
responders 
Observed ORR 
(%) 
95% exact CI (%) 
The operating characteristics (for 90 participants) are shown in Table 9-5. The table presents 
the probability of stopping at the interim, the probability for a positive conclusion (i.e., not 
stopped at IA for futility and success criteria met at final analysis), and a negative conclusion 
(i.e., not stopped at IA for futility but success criteria not met at final analysis) under different 
underlying true ORR. 
Table 9-5 
Operating Characteristics (cohort A) 
True ORR (%) 
Prob. to stop at IA* (%) 
Prob. of success at 
final analysis (%) 
Prob. of failure at final 
analysis (%) 
*Assuming IA at 30evaluable participants  
The operating characteristics at this sample size have around 
 probability of stopping the 
trial for futility when the true ORR is 
 or less. Also, when the true ORR is 
, the 
probability of a positive conclusion at the final analysis with 90 participants is around 
. For 
a true ORR of 50% or higher, the probability of a positive conclusion at the final analysis is 
 
The calculations were made using the software R. 
9.9.2 
Secondary endpoint(s) 
The calculation of sample size and operating characteristics for the analysis of the key 
secondary endpoint, cohort B ORR estimate and confidence interval, are based on the model 
and assumptions in Section 9.4.1.1. 
The exact 95% CIs for various sample sizes and observed ORRs are shown in Table 9-6 . 
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Table 9-6 
Exact binomial 95 percent confidence intervals for various sample 
sizes and observed ORRs (cohort B) 
Sample size (N) 
Number of 
responders 
Observed ORR 
(%) 
95% exact CI (%) 
The operating characteristics (for 30 participants) are shown in Table 9-7. The table presents 
the probability of stopping at the interim, the probability for a positive conclusion (i.e., not 
stopped at IA for futility and success criteria met at final analysis), and a negative conclusion 
(i.e., not stopped at IA for futility but success criteria not met at final analysis) under different 
underlying true ORR. 
Table 9-7 
Operating characteristics (cohort B) 
True ORR 
Prob. to stop at IA* (%) 
Prob. of success at 
final analysis (%) 
Prob. of failure at final 
analysis (%) 
*Assuming IA at 
 participants  
The operating characteristics at this sample size have around 
 probability of stopping the 
trial for futility when the true ORR is 
 or less. Also, when the true ORR is 
, the 
probability of a positive conclusion at the final analysis with 30 participants is circa 
. If the 
true ORR is 50% or higher, the probability of a positive conclusion at the final analysis is 
 
The calculations were made using the software R. 
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10 
Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
• Applicable ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochure, [IDFU], and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments/modifications to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
Signing a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
Providing oversight of the conduct of the study at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations 
Inform Novartis immediately if an inspection of the clinical site is requested by a regulatory 
authority 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 

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local regulations (including European Directive 2001/20/EC or European Clinical Trial 
Regulation 536/2014, US CFR 21), and with the ethical principles laid down in the Declaration 
of Helsinki. 
10.1.2 
Informed consent process 
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant or their legally authorized representative and answer all questions 
regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center. 
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the participant source documents. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative. 
Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional additional research. The Investigator or authorized designee will explain to each 
participant the objectives of the additional research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during 
the storage period. A separate signature will be required to document a participant’s agreement 
to allow any remaining specimens to be used for additional research. Participants who decline 
to participate in this optional additional research will document this. 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document. 
Information about common side effects already known about the investigational treatment can 
be found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant upon obtaining consent and also 
during the study as needed. Any new information regarding the safety profile of the 
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for example, via an Investigator notification or an aggregate safety finding. New information 
might require an update to the informed consent and then must be discussed with the participant. 
The following informed consents are included in this study: 
• Molecular pre-screening consent 
• Main study consent, which also included:  
• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study 
• A subsection that requires a separate signature for the ‘Optional Collection of Tumor 
Biopsy’ 
• Optional consent for activities that may be done outside of the study site 
• As applicable, Treatment Beyond Progression Consent  
• As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment 
• Patient information sheet for female partners of any male participants who took study 
treatment 
Declining to participate in these optional assessments will in no way affect the participant’s 
ability to join the main research study. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural disaster, that may challenge the ability to obtain a standard 
written informed consent due to limits that prevent an on-site visit, Investigator may conduct 
the informed consent discussion remotely (e.g., telephone, videoconference) if allowable by a 
local health authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g., the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
10.1.3 
Data protection 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used 
by Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 

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Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 
10.1.4 
Committees structure 
10.1.4.1 Steering Committee 
The Steering Committee (SC) will be established comprising Investigators participating in the 
trial or experts in the disease area and Novartis representatives from the Clinical Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the SC will be defined in the SC charter. 
10.1.5 
Data quality assurance 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan, contracts. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of Novartis. No records may be transferred to 
another location or party without written notification to Novartis. 
Efforts should be made to collect all data that are relevant to support a statistical analysis aligned 
with the estimands of interest. If the estimands that are required to support regulatory decision 
making do not require the collection of the variable after an intercurrent event, then the benefits 
of collecting such data for other estimands should be weighed against any complications and 
potential drawbacks of the collection. 
10.1.5.1 Data collection 
Designated Investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the Investigator staff. 
The Investigator/designee is responsible for assuring that the data (recorded on eCRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the Investigator will receive copies of the participant data for 
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All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
10.1.5.2 Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated Investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of pre-screenings, screenings, enrollments, screen failures and study completion, and data 
about all study treatment (s) dispensed to the participant and all dosage changes will be tracked 
using an Interactive Response Technology (IRT). The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis (or a designated 
CRO) at specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management. 
10.1.6 
Source documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. The Investigator must also keep the original 
informed consent form signed by the participant (a signed copy is given to the participant). 
Definition of what constitutes source data and its origin can be found in relevant monitoring 
guidances. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered into the eCRF. Study monitors will perform ongoing source data 
verification to confirm that data entered into the eCRF by authorized site personnel are accurate, 
complete, and verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the currently approved 
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Key study personnel must be available to assist the field monitor during scheduled and ad hoc 
on-site or remote monitoring visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis /CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight. 
10.1.7 
Publication policy 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT or CTIS public website. In addition, after study completion 
(Section 4.7) and finalization of the study report the results of this trial will be submitted for 
publication and posted in a publicly accessible database of clinical trial results, such as 
the Novartis clinical trial results website and all required health authority websites (e.g., 
Clinicaltrials.gov, EudraCT or CTIS public website etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to 
the Novartis publication policy training materials that were provided to you at the trial 
Investigator meetings. 
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation. 
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV. 
10.1.8 
Protocol adherence and protocol amendments 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the Investigator shall immediately disclose it 
to Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
10.1.8.1 Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
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Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 
10.2 
Appendix 2: Abbreviations and definitions 
10.2.1 
List of abbreviations 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear Antibodies 
ANCOVA 
Analysis of covariance 
ASMA 
Anti-smooth muscle antibody  
AST 
Aspartate Aminotransferase 
b.i.d. 
bis in die/twice a day 
BUN 
Blood Urea Nitrogen 
CK 
Creatine Kinase 
COA 
Clinical Outcome Assessment 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria Adverse Event 
CV 
coefficient of variation 
DBP 
Diastolic Blood Pressure 
DIN 
Drug Inducted Nephrotoxicity 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCOA 
Electronic Clinical Outcome Assessment 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EORTC 
European Organisation for Research and Treatment of Cancer 
ERCP 
Endoscopic retrograde cholangiopancreatography 
eSAE 
Electronic Serious Adverse Event 
eSource 
Electronic Source 
FDA 
Food and Drug Administration 
FIH 
First in Human 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
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GLDH 
Glutamate Dehydrogenase 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HGRAC 
Human Genetic Resource Administration Of China 
HIV 
Human immunodeficiency virus 
HRQoL 
Health-Related Quality of Life 
i.v. 
intravenous 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human 
Use 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LDH 
lactate dehydrogenase 
LFT 
Liver function test  
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
mL 
milliliter(s) 
MTD 
Maximum Tolerated Dose 
p.o. 
oral(ly) 
PD 
Pharmacodynamic(s) / Progressive disease 
PK 
Pharmacokinetic(s) 
PRO 
Patient Reported Outcomes 
PS&PV 
Patient safety and pharmacovigilance 
PT 
prothrombin time 
QD 
Once a day 
QoL 
Quality of life 
QTcF 
QT interval corrected by Fridericia’s formula 
R Value 
ALT/ALP x ULN 
RAP 
The Report and Analysis Plan  
RD 
Recommended Dose 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
standard deviation / stable disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 

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ULN 
upper limit of normal 
UTI 
Urinary Tract Infection 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 
10.2.2 
Definitions 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study participant  
Clinical Outcome 
Assessment (COA) 
A measure that describes or reflects how a participant feels, functions, or survives 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of all clinical 
trial activities. Examples of team members include the Study Lead, Medical Monitor, 
Trial Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center team by 
replacing personal identifiers with a code. 
Cohort 
A group of individuals who share a common exposure, experience or characteristic, 
or a group of individuals followed-up or traced over time 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g., q28 days) 
Discontinuation from 
study 
Point/time when the participant permanently stops receiving the study treatment and 
further protocol required assessments or follow-up, for any reason. No specific 
request is made to stop the use of their samples or data. 
Discontinuation from 
study treatment 
Point/time when the participant permanently stops receiving the study treatment for 
any reason (prior to the planned completion of study drug administration, if any). 
Participant agrees to the other protocol required assessments including follow-up. No 
specific request is made to stop the use of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data using 
data collection systems, such as Web-based applications, interactive voice response 
systems and clinical laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed from source 
data/documents used at the point of care 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last participant 
Enrollment 
Point/time of participant entry into the study at which informed consent must be 
obtained. The action of enrolling one or more participants 
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines source 
documents and case report forms (eCRFs) into one application, allowing for the real 
time collection of clinical trial information to sponsors and other oversight authorities, 
as appropriate 
Estimand  
As defined in the ICH E9(R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It 
summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as 
well as the specification of how the remaining intercurrent events are addressed and 
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Healthy volunteer 
A person with no known significant health problems who volunteers to be a study 
participant  
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Investigational 
Product/ 
Investigational 
Medicinal product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference (such as an active comparator) in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way 
different from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use. 
Investigational 
Medical Device 
Medical Device being assessed for safety or performance in a clinical investigation. 
This includes devices already on the market and being evaluated for new intended 
uses, new populations, new materials, or design changes 
Medication number 
A unique identifier on the label of medication kits 
Off-site 
Describes trial activities that are performed at remote location by an off-site 
healthcare professional, such as procedures performed at the participant's home. 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Part  
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple 
dose part, or a part in participants with established disease and in those with newly-
diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" terminology is 
used in the protocol whereas term "Subject" is used in data collection 
Participant number 
A unique number assigned to each participant upon signing the informed consent. 
This number is the definitive, unique identifier for the participant and should be used 
to identify the participant throughout the study for all data collected, sample labels, 
etc. 
Patient-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the patient about the 
status of a participant's health condition without amendment or interpretation of the 
patient's report by a clinician or anyone else 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical 
trial database setup and eventually in analysis 
Perpetrator drug 
A drug which affects the pharmacokinetics of the other drug 
Personal data 
Participant information collected by the Investigator that is coded and transferred to 
Novartis for the purpose of the clinical trial. This data includes participant identifier 
information, study information and biological samples. 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the assignments in 
order to reduce bias. 
Re-screening 
If a participant fails the initial screening and is considered as a Screen Failure, he/she 
can be invited once for a new Screening visit after medical judgment and as specified 
by the protocol 
Remote 
Describes any trial activities performed at a location that is not the investigative site 
where the investigator will conduct the trial, but is for example a home or another 
appropriate location 
Screen Failure 
A participant who did not meet one or more criteria that were required for participation 
in the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-
coded data, such as paper or eSource 

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Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the 
original site to other parts of the body 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed consent by the 
first participant 
Study treatment 
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy 
Tele-visit 
Procedures or communications conducted using technology such as telephone or 
video-conference, whereby the participant is not at the investigative site where the 
investigator will conduct the trial. 
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. 
Treatment of interest 
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g. as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is 
the treatment of interest used in describing the related clinical question of interest, 
which might or might not be the same as the study treatment. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include whether 
the participant experiences an intercurrent event. 
Withdrawal of consent  
Withdrawal of consent from the study occurs when the participant explicitly requests 
to stop use of their data and/or biological samples AND no longer wishes to receive 
study treatment, AND does not agree to further protocol required assessments. This 
request should be in writing (depending on local regulations) and recorded in the 
source documentation. 
This request should be distinguished from a request to discontinue the study. Other 
study participant's privacy rights are described in the corresponding informed consent 
form. 
10.3 
Appendix 3: Clinical laboratory tests 
10.3.1 
Clinically notable laboratory values and vital signs 
Not Applicable 
10.4 
Appendix 4: Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the time points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis 
• Thank You letter 
• Plain language trial summary - after CSR publication 
10.5 
Appendix 5: Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed 
Please refer to Table 10-1 in Section 10.5 for complete definitions of liver laboratory triggers. 

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Once a participant is exposed to study treatment, every liver event defined in Table 6-3 should 
be followed up by the Investigator or designated personnel at the trial site, as summarized 
below. Additional details on actions required in case of liver events are outlined in Table 10-1 
and Table 10-2. Repeat liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to 
confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate eCRF 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
• These investigations can include based on Investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
Table 10-1 
Liver event and laboratory trigger definitions 
 
Definition/ threshold 
Liver laboratory 
triggers If ALT, AST 
and total bilirubin 
normal at baseline: 
• 
ALT or AST > 5 x ULN 
• 
ALP > 2 x ULN (in the absence of known bone pathology) 
• 
Total bilirubin > 3 x ULN (in the absence of known Gilbert syndrome) 
• 
ALT or AST > 3 x ULN and INR > 1.5 
• Potential Hy’s Law cases (defined as ALT or AST > 3 x ULN and Total bilirubin > 2 
x ULN [mainly conjugated fraction] without notable increase in ALP to > 2 x ULN) 
• 
Any clinical event of jaundice (or equivalent term) 
• ALT or AST > 3 x ULN accompanied by (general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia 
• 
Any adverse event potentially indicative of a liver toxicity 
If ALT or AST 
abnormal at baseline: 
• 
ALT or AST > 3 x baseline or > 300 U/L (whichever occurs first) 
Table 10-2 
Follow-up requirements for liver laboratory triggers - ALT, AST, 
bilirubin 
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
 

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ALT 
TBL 
Liver Symptoms 
Action 
If normal at baseline: 
ALT > 3 x ULN 
Normal 
For participants with 
Gilbert’s syndrome: No 
change in baseline TBL 
None 
· No change to study 
treatment 
· Measure ALT, AST, 
ALP, GGT, TBIL, INR, 
albumin, CK, and GLDH 
in 48-72 hours. 
· Follow-up for 
symptoms. 
If elevated at baseline: 
ALT > 2 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) 
If normal at baseline: 
ALT > 5 x ULN for more 
than two weeks 
Normal 
For participants with 
Gilbert’s syndrome: No 
change in baseline TBL 
None 
· Interrupt study 
treatment 
· Measure ALT, AST, 
ALP, GGT, TBIL, INR, 
albumin, CK, and GLDH 
in 48-72 hours. 
· Follow-up for 
symptoms. 
· Initiate close monitoring 
and workup for 
competing etiologies. 
· Study treatment can be 
restarted only if another 
etiology is identiﬁed and 
liver enzymes return to 
baseline. 
If elevated at baseline: 
ALT > 3 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) for more than 
two weeks 
If normal at baseline: 
ALT > 8 x ULN 
Normal 
None 
ALT increase with bilirubin increase: 
If normal at baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN (or INR > 
1.5) 
For participants with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at baseline: 
ALT > 2 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) 
If normal at baseline: 
ALT > 3 x ULN 
Normal or elevated 
Severe fatigue, nausea, 
vomiting, right upper 
quadrant pain 
If elevated at baseline: 
ALT > 2 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) 
Table 10-3 
Follow-up requirements for liver laboratory triggers - isolated 
hyperbilirubinemia  
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
 
 
>1.5 – 3.0 ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 
hours 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence of 
known Gilbert syndrome) 
• 
Interrupt treatment 
• 
Repeat LFT within 48-72 
hours 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in the 
appropriate eCRF 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline (ALT, AST, total bilirubin, 
Alb, PT/INR, ALP and GGT) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
> 10 x ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the participant 
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 

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Criteria 
Actions required 
Follow-up monitoring 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in the 
appropriate eCRF 
resolution (frequency at 
Investigator discretion) 
Any AE potentially indicative of a 
liver toxicity 
• 
Consider study treatment 
interruption or discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g., 
conmeds, med hx, lab)in the 
appropriate eCRF 
Investigator discretion 

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10.6 
Appendix 6: Renal safety monitoring 
Upon diagnosis and confirmation of a renal event, some general procedures and some event 
specific activities (Table 10-4 and Table 10-5) are indicated depending on the severity of the 
event and the clinical status of the subject. Note, all events should be documented in the CRF 
Table 10-4 
Specific renal alert criteria and actions 
Renal events 
Actions 
Creatinine clearance decrease 25 - 49% 
• 
Consider causes and possible interventions 
• 
Repeat laboratory values within 48 hrs of receipt of abnormal 
test results. Assess patient for signs and symptoms of illness, 
AKI (acute kidney injury), etc. 
Creatinine clearance decrease ≥ 50 % + 
OR if <18 years old, Creatinine clearance 
< 35 mL/min/1.73 m2 
• 
Consider causes and possible interventions 
• 
Repeat assessment within 24-48h if possible 
• 
Repeat laboratory values within 48 hrs of receipt of abnormal 
test results. Assess patient for signs and symptoms of illness, 
AKI, etc  
• 
Consider drug interruption or discontinuation unless other 
causes are diagnosed and corrected 
• 
Consider referral to nephrologist for diagnosis and 
management 
• 
Consider patient hospitalization and specialized treatment 
• 
Confirm presence of true proteinuria by quantification: 
protein:creatinine on first morning void 
New onset dipstick proteinuria ≥ 3+ 
OR 
Protein-creatinine ratio (PCR) ≥ 1g/g 
Creatinine (Cr)  
• 
Consider causes and possible interventions 
• 
Assess serum albumin & serum total protein 
• 
Repeat assessment to confirm 
• 
Consider drug interruption or discontinuation unless other 
causes are diagnosed and corrected 
• 
Consider referral to a nephrologist 
New onset hematuria ≥ 3+ on urine 
dipstick 
• 
Obtain urine microscopy to distinguish hemoglobinuria or 
myoglobinuria from hematuria 
• 
 Assess serum creatinine (sCr) 
• 
Exclude infection, trauma, calculi, bleeding from the distal 
urinary tract/bladder, menstruation 
• 
Consider bleeding disorder 
+Corresponds to Kidney Disease Improving Global Outcomes (KDIGO) criteria for Acute Kidney Injury 
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event: 
• Blood pressure assessment (after 5-minute rest, with an appropriate cuff size) 
• Signs and symptoms like fever, headache, shortness of breath, cardiac murmur, back or 
abdominal pain, hepatomegaly, dysuria or hematuria, dependent or periorbital edema 
• Changes in body weight, fluid intake, voiding pattern, or urine output 
• Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumor lysis 

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• Additional specialized assessments are available to assess renal function or renal 
pathology. (Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is 
recommended to make slide specimen available for evaluation by the RSG to potentially 
identify project wide patterns of nephrotoxicity). 
Table 10-5 
Renal event follow-up 
FOLLOW-UP OF RENAL EVENTS 
• Monitor patient regularly ((frequency dependent on clinical course and consultant advisement) until – 
•  Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) 
or 
• Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio stabilization 
at a new level with ±50% variability over last 6 months. 
• Analysis of urine markers in samples collected over the course of the drug induced nephrotoxicity (DIN) 
event 

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10.7 
Appendix 7: Drugs that are prohibited or to be used with caution 
while on JDQ443 treatment 
In general, the use of any concomitant medication/therapy deemed necessary for the care of the 
patient is permitted except when specifically prohibited. 
Drugs which are strong CYP3A inducers are prohibited (Table 10-6). If a drug listed as to be 
used with caution is also listed under the prohibited drug list then use of that drug is prohibited. 
Table 10-6 
Drugs to be prohibited while on treatment with JDQ443 
Category 
Drug Name 
Strong CYP3A 
inducers 
apalutamide, avasimibe, carbamazepine, enzalutamide, ivosidenib, mitotane, 
lumacaftor, phenobarbital, phenytoin, rifampicin, rifapentine, St. John’s wort (Hypericum 
perforatum)1 
The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (Jan 2021): 
drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s 
Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction 
Studies”. 
This is not a comprehensive list. Please contact the medical monitor with any questions. 
1 Herbal product 
Table 10-7 
Drugs to be used with caution while on treatment with JDQ443 
Category 
Drug Name 
Strong CYP3A inhibitors 
boceprevir, ceritinib, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir4, elvitegravir/ritonavir4, grapefruit juice3 , idelalisib, 
indinavir, indinavir/ritonavir4, itraconazole, josamycin, ketoconazole, 
lopinavir/ritonavir4, mibefradil, mifepristone, nefazodone, nelfinavir, 
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak)4, posaconazole, 
ribociclib, ritonavir, saquinavir, saquinavir/ritonavir4, telaprevir, telithromycin, 
tipranavir/ritonavir4, troleandomycin, tucatinib, voriconazole 
CYP2B6 sensitive substrates 
or substrates with NTI 
ifosfamide, tamoxifen, thiotepa 
CYP2C8 sensitive substrates 
or substrates with NTI 
carbamazepine, dabrafenib, erlotinib, paclitaxel, dasabuvir, repaglinide, 
daprodustat 
CYP2C9 sensitive substrates 
or substrates with NTI 
(S)-warfarin, celecoxib, erdafitinib, phenytoin, quinidine, siponimod, tamoxifen, 
benzbromarone, glimepiride, glipizide, ibuprofen, lornoxicam, meloxicam, 
piroxicam, tolbutamide 
CYP2C19 sensitive 
substrates or substrates with 
NTI 
(S)-mephenytoin, clobazam, (R)-lansoprazole (dexlansoprazole), diazepam, 
gliclazide, (S)-lansoprazole, (R)-mephobarbital, (R)-omeprazole, omeprazole, 
pantoprazole, proguanil, rabeprazole, tilidine, amitriptyline, clomipramine, 
imipramine, R)-(-)-hexobarbital, voriconazole 
CYP3A sensitive substrates 
or substrates with NTI 
abemaciclib, acalabrutinib, alectinib amiodarone, amitriptyline, astemizole, 
axitinib, baricitinib, bosutinib, brigatinib, cabazitaxel, cabozantinib, 
carbamazepine, ceritinib, clomipramine, cobimetinib, conivaptan, copanlisib, 
crizotinib, cyclosporine, dabrafenib, dasatinib, dihydroergotamine, docetaxel, 
dronedarone, entrectinib, erdafitinib, ergotamine, everolimus, imipramine, 
ivosidenib, ixazomib, lomitapide, midostaurin, neratinib, nilotinib, panobinostat, 
pexidartinib, pimozide, ponatinib, quinidine, regorafenib, romidepsin, sirolimus, 
sonidegib, sorafenib, sunitinib, tacrolimus, tamoxifen, temsirolimus, tolvaptan, 
trabectedin, venetoclax, vinblastine, zanubrutinib 
abemaciclib, acalabrutinib, alisporivir, almorexant, alfentanil, alpha-
dihydroergocryptine, aplaviroc, aprepitant, asunaprevir, atazanavir, 
atorvastatin, avanafil, avapritinib, blonanserin, bosutinib, brecanavir, brigatinib, 
brotizolam, budesonide, buspirone, cabazitaxel, carbamazepine, capravirine, 

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Category 
Drug Name 
casopitant, cobicistat, cobimetinib, conivaptan, cyclosporine, danoprevir, 
darifenacin, darunavir, dasatinib, dronedarone, ebastine, eletriptan, eliglustat, 
elvitegravir, entrectinib, eplerenone, everolimus, felodipine, fluticasone, 
grazoprevir, ibrutinib, indinavir, isavuconazole, itacitinib, ivabradine, ivacaftor, 
levomethadyl (LAAM), lomitapide, lopinavir, lovastatin, lumefantrine, 
lurasidone, maraviroc, midazolam, midostaurin, morphothiadin, naloxegol, 
neratinib, nisoldipine, paritaprevir, perospirone, quetiapine, ridaforolimus, 
saquinavir, sildenafil, simeprevir, simvastatin, sirolimus, tacrolimus, ticagrelor, 
tilidine, tipranavir, tolvaptan, triazolam, ubrogepant, ulipristal, vardenafil, 
venetoclax, vicriviroc, vilaprisan, voclosporin, voriconazole, zanubrutinib 
OATP1B1/3 Substrates or 
substrate with NTI 
aliskiren, ambrisentan, anacetrapib, atenolol, asunaprevir, atorvastatin, 
bosentan, bromocriptine, caspofungin, celiprolol, danoprevir, digoxin, 
docetaxel, eliglustat, empangliflozin, ezetimibe, fimasartan, fexofenadine, 
fluvastatin, glyburide, maraviroc, methotrexate, montelukast, nateglinide, 
olmesartan, revefenacin, paclitaxel, pirataprevir, pitavastatin, pravastatin, 
repaglinide, rifampicin, rosuvastatin, saquinavir, simvastatin, telmisartan, 
tezacaftor, thyroxine, ticlopidine, valsartan 
P-gp Substrates 
P-gp substrates with NTI1 
cyclosporine, digoxin, docetaxel, doxorubicin, eribulin, everolimus, fentanyl, 
idelalisib, ivosidenib, paclitaxel, pazopanib, phenytoin, quinidine, sirolimus, 
sorafenib, tacrolimus, talazoparib, tolvaptan, topotecan, vincristine 
P-gp substrates with ≥2X 
AUC change2 
aliskiren, ambrisentan, atorvastatin, azithromycin, berotlarastat, colchicine, 
dabigatran, digoxin, docetaxel, domperidone, doxorubicin, elexacaftor, 
fedratinib, fentanyl, fexofenadine, lapatinib, lefamulin, linezolid, loperamide, 
maraviroc, nadolol, nevirapine, paclitaxel, proguanil, quinidine, ranolazine, 
relugolix, ritonavir, saquinavir, simvastatin, sirolimus, sofosbuvir, tacrolimus, 
tezacaftor, ticagrelor, topotecan 
Herbal Medications 
Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, black cohosh, ginseng, etc. 
1 These drugs have both a narrow therapeutic index and an in vivo DDI outcome partly ascribed to P-gp 
inhibition or induction that exceeds 20% change in AUC. 
2 These drugs have in vivo DDI outcomes (i.e., inhibition resulting in ≥2x increase in AUC and partly ascribed to 
P-gp). 
3 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). 
4 Combination ritonavir-boosted regimens are listed here in the DDI memo as strong CYP3A inhibitors (to avoid 
potential confusion), even though some are considered moderate CYP3A inhibitors in the UW DDI Database. 
NTI: Narrow Therapeutic Index 
The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (Jan 2021): 
drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s 
Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction 
Studies”. 
This is not a comprehensive list. Please contact the medical monitor with any questions. 

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10.8 
Appendix 8: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival, and Overall 
Survival (based on RECIST 1.1) 
Document type: 
TA Specific Guideline 
Document status: 
Version 3.2: February 11, 2016 
Version 3.1: November 29, 2011 
Version 3: October 19, 2009 
Version 2: January 18, 2007 
Version 1: December 13, 2002 
Release date: 
11-Feb-2016 
Authors (Version 3.2): 
 
 
Authors (Version 3.1): 
 
Authors (Version 3): 
 
 
 
Authors (Version 2): 
 
 
Authors (Version 1): 
 
Glossary 
CR 
Complete response 
CSR 
Clinical Study Report 
CT 
Computed tomography 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
ITT 
Intent-to-treat 
MRI 
Magnetic resonance imaging 
LPLV 
Last patient last visit 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable disease 
SOD 
Sum of Diameter 
TTF 
Time to treatment failure 
TTP 
Time to progression 
10.8.1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
PPD
PPD
PPD
PPD
PPD

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is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009). 
The efficacy assessments described in Section 10.8.2 and the definition of best response in 
Section 10.8.3.1are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response Section 10.8.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 10.8.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming. 
10.8.2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria by Therasse et al (2000) and revised 
RECIST guidelines (version 1.1) by Eisenhauer et al (2009). 
10.8.2.1 Definitions 
10.8.2.1.1 
Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed 
by cytology/histology. 
For participants without measurable disease, even if not expected as per eligibility criteria in 
this protocol, see Section 10.8.3.2.9 
Measurable lesions (both nodal and non-nodal) 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5 mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ≥ 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ≥ 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease. 
• Cystic lesions: Lesions that meet the criteria for radiographically defined simple cysts 
(i.e., spherical structure with a thin, non-irregular, non-nodular and non-enhancing wall, 
no septations, and low CT density [water-like] content) should not be considered as 

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malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
≥ 10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
10.8.2.1.2 
Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the participant may be allowed to enter the 
study in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, 
it is recommended that participants be excluded from trials where the main focus is on the 
Overall Response Rate (ORR). Guidance on how participants with just non-measurable disease 
at baseline (even if not expected as per eligibility criteria of this protocol) will be evaluated for 
response and also handled in the statistical analyses is given in Section 10.8.3.2.9 
10.8.2.2 Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (IV) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of participants, the same methods of assessment and technique 
should be used to characterize each identified and reported lesion at baseline and during 
follow- up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be 
performed using a 5 mm slice thickness with a contiguous reconstruction algorithm. 
CT/MRI scan slice thickness should not exceed 8 mm cuts using a contiguous 
reconstruction algorithm. If, at baseline, a participantis known to have a medical 
contraindication to CT contrast or develops a contraindication during the trial, the 
following change in imaging modality will be accepted for follow-up: a non-contrast CT 
of chest (MRI not recommended due to respiratory artifacts) plus contrast-enhanced MRI 
of abdomen and pelvis. 
• ·A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 

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to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 
another response assessment than the Novartis calculated UNK response may be accepted 
from the Investigator or the central blinded reviewer if a definitive response assessment 
can be justified, based on the available information. 
• FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• No FDG-PET at baseline with a positive FDG-PET at follow-up: 
• If new disease is indicated by a positive PET scan but is not confirmed by CT (or some 
other conventional technique such as MRI) at the same assessment, then follow-up 
assessments by CT will be needed to determine if there is truly progression occurring at 
that site. In all cases PD will be the date of confirmation of new disease by CT (or some 
other conventional technique such as MRI) rather than the date of the positive PET scan. 
If there is a positive PET scan without any confirmed progression at that site by CT, then a 
PD cannot be assigned. 
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• Physical exams: Evaluation of lesions by physical examination is accepted when lesions 
are superficial, with at least 10mm size, and can be assessed using calipers. 
• Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound should not be used to measure tumor lesions, unless pre-specified by the 
protocol. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions and thyroid nodules. Ultrasound might also 
be useful to confirm the complete disappearance of superficial lesions usually assessed by 
clinical examination. 
• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained. 
• Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 

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must normalize for a participant to be considered in complete clinical response when all 
lesions have disappeared. 
• Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
10.8.2.3 Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions: 
• Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the eCRF 
(even if it resides in the same organ). 
Minimum target lesion size at baseline 
• Non-nodal target:Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 10.8.2.1.1 
• Nodal target:  
• See Section 10.8.2.1.1 
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
• Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
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10.8.2.4 Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 10-10) and non-target lesions (Table 10-11) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 10-12) as well as the presence or absence of new lesions. 
10.8.2.4.1 
Follow-up and recording of lesions 
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the Investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number. 
Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size). 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated. 
Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 

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However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 
10.8.2.4.2 
Determination of target lesion response 
Table 10-8 
Response criteria for target lesion 
Response Criteria 
Evaluation of target lesions 
Complete 
Response (CR) 
Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes 
assigned as target lesions must have a reduction in short axis to < 10 mm 1 
Partial Response 
(PR) 
At least 30% decrease in the sum of diameter of all target lesions, taking as reference 
the baseline sum of diameters 
Progressive 
Disease (PD) 
At least a 20% increase in the sum of diameter of all measured target lesions, taking as 
reference the smallest sum of diameter of all target lesions recorded at or after baseline. 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm 2 
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR or CR nor and increase in lesions which 
would qualify for PD 
Unknown (UNK) 
Progression has not been documented and one or more target lesions have not been 
assessed or have been assessed using a different method than baseline 3 
1. SOD for CR may not be zero when nodal lesions are part of target lesions 
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all 
nodal lesions are <10 mm in size. In this case, the target lesion response is CR 
3. In exceptional circumstances an UNK response due to change in method could be over-ruled by the 
Investigator or central reviewer using expert judgement based on the available information (see Notes on target 
lesion response and methodology change in Section 10.8.2.2 
Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the Investigator/radiologist has to decide between the following 
possibilities: 
• The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease 
• The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the eCRF and the tumor assessment will remain 
based on the sum of tumor measurements as presented in Table 10-10 above (i.e., a PD 
will be determined if there is at least 20% increase in the sum of diameters ) 
• For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
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is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK. 
• Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes. 
• Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the case report form under the original lesion number. This value will be included 
in the sum of diameters when deriving target lesion response. The individual split lesions 
will not be considered as new lesions, and will not automatically trigger a PD designation. 
• Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced. 
• The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
• Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non-
nodal target lesions have disappeared. 
• Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions. 
• Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters. 
• A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 
have been evaluated by the same method. In exceptional circumstances an Investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression 
in which case the Investigator might assign an SD target lesion response; however, this 
should be done with caution and conservatively as the response categories have well 
defined criteria. 

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10.8.2.4.3 
Determination of non-target lesion response 
Table 10-9 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesion must be non-pathological in size (< 10 mm short axis) 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions 1 
Non-CR/Non-PD 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using different method than baseline 
2 
1. The assignment of PD solely based on change in non-target lesions in light of target lesion response of CR, 
PR or SD should be exceptional. In such circumstances, the opinion of the Investigator or central reviewer does 
prevail  
2. It is recommended that the Investigator and/or central reviewer should use expert judgement to assign a Non-
UNK response whenever possible (see notes section for more details) 
Notes on non-target lesion response 
• The Investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned. 
• The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e., < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e., ≥ 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless there is unequivocal progression of the non-target lesions (in which 
case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK). 
• Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 10.8.2.4.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied. 

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10.8.2.4.4 
New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF page. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the first 
observation of the lesion. 
If new disease is observed in a region which was not scanned at baseline or where the particular 
baseline scan is not available for some reason, then this should be considered as a PD. The one 
exception to this is when there are no baseline scans at all available for a participant in which 
case the response should be UNK, as for any of this participant's assessment Section 10.8.2.4.5 
• A lymph node is considered as a "new lesion" and, therefore, indicative of progressive 
disease if the short axis increases in size to ≥ 10 mm for the first time in the study plus 5 
mm absolute increase 
• FDG-PET: can complement CT scans in assessing progression (particularly possible for 
"new" disease). Section 10.8.2.2 
10.8.2.4.5 
Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in 
Table 10-10 
Table 10-10 
Overall response lesion to each assessment 
Target lesions 
Non-target lesions 
New lesions 
Overall lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD 1,2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. This overall lesion response also applies when there are no non-target lesions identified at baseline 
2. Once confirmed PR was achieved, all these assessments are considered PR 
3. As defined in Section 10.8.2.4 
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 

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10.8.3 
Efficacy definitions 
The following definitions primarily relate to participants who have measurable disease at 
baseline. Section 10.8.3.2.9 outlines the special considerations that need to be given to 
participants with no measurable disease at baseline in order to apply the same concepts. 
10.8.3.1 Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• For non-randomized trials where response is the primary endpoint, confirmation is needed 
• For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required 
• SD = at least one SD assessment (or better) > 5 weeks after randomization/start of 
treatment (and not qualifying for CR or PR 
• PD = progression ≤ 13 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD) 

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• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 5 weeks or early progression within the first 13 weeks) 
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 6-
week tumor assessment frequency taking into account assessment windows. E.g. if the 
assessment occurs every 6 weeks with a time window of +/- 7 days, a BOR of SD would require 
a SD or better response longer than 5 weeks after randomization/start of treatment. 
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD. 
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (≥30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not ≥20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable. 
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments. 
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources: 
• Investigator overall lesion response 
• Central Blinded Review overall lesion response 
• Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 

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The primary analysis of the best overall response will be based on the sequence of 
Investigator/central blinded review/calculated (Investigator)/calculated (central) overall lesion 
responses. 
Based on the participants’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of participants with a best overall response of 
CR or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications. 
Disease control rate (DCR) is the proportion of participants with a best overall response of 
CR or PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth. 
Clinical benefit rate (CBR) is the proportion of participants with a best overall response of 
CR or PR , or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum 
time duration (with a default of at least 24 weeks in breast cancer studies). This endpoint 
measures signs of activity taking into account duration of disease stabilization. 
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 
Early progression rate (EPR) is the proportion of participants with progressive disease within 
8 weeks of the start of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all participants who at the specified assessment (in this example the assessment would 
be at 8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Participants 
with an unknown (UNK) assessment at that time point and no PD before, will not be counted 
as early progressors in the analysis but may be included in the denominator of the EPR rate, 
depending on the analysis population used. Similarly, when examining overall response and 
disease control, participants with a best overall response assessment of unknown (UNK) will 
not be regarded as “responders” but may be included in the denominator for ORR and DCR 
calculation depending on the analysis population (e.g. populations based on an ITT approach). 
10.8.3.2 Time to event variables 
10.8.3.2.1 
Progression-free survival 
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 
Progression-free survival (PFS) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to any cause. If a patient 
has not had an event, progression-free survival is censored at the date of last adequate tumor 
assessment. 

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PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint 
10.8.3.2.2 
Overall survival 
All participants should be followed until death or until patient has had adequate follow-up time 
as specified in the protocol whichever comes first. The follow-up data should contain the date 
the patient was last seen alive / last known date patient alive, the date of death and the reason 
of death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive. 
10.8.3.2.3 
Time to progression 
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer. 
Time to progression (TTP) is the time from date of randomization/start of treatment to the date 
of event defined as the first documented progression or death due to underlying cancer. If a 
participant has not had an event, time to progression is censored at the date of last adequate 
tumor assessment. 
10.8.3.2.4 
PFS2 
A recent EMA (2012) guidance recommends a substitute end point intermediate to PFS and OS 
called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses the 
impact of the experimental therapy on next-line treatment. The main purpose of this endpoint 
is to assess long-term maintenance strategies, particularly of resensitizing agents and where it 
is necessary to examine the overall “field of influence”. 
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol. 
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments. 
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues w.r.t. censoring foreseen. 
10.8.3.2.5 
Time to treatment failure 
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study treatment. In some protocols, time to treatment 

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failure may be considered as a sensitivity analysis for time to progression. The list of 
discontinuation reasons to be considered or not as treatment failure may be adapted according 
to the specificities of the study or the disease. 
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to the 
earliest of date of progression, date of death due to any cause, or date of discontinuation due to 
reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for participants who did not experience treatment failure will be censored at last adequate 
tumor assessment. 
10.8.3.2.6 
Duration of response 
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows. It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do 
respond. Potent agents induce a response in both good risk and poor risk patients. Less potent 
agents induce a response mainly in good risk patients only. This is described in more detail by 
Morgan (1988). 
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate (specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For participants with a CR or PR (which may have 
to be confirmed the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression. 
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen. 
Duration of overall complete response (CR): For participants with a CR (which may have to 
be confirmed) the start date is the date of first documented CR and the end date and censoring 
is defined the same as that for time to progression. 

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Duration of stable disease (CR/PR/SD): For participants with a CR or PR (which may have 
to be confirmed) or SD the start and end date as well as censoring is defined the same as that 
for time to progression. 
10.8.3.2.7 
Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 10.8.3.2.6. It is recommended that 
an analysis of all participants (both responders and non-responders) be performed whether or 
not a “responders only” descriptive analysis is presented. Where an inferential statistical 
comparison is required, then all participants should definitely be included in the analysis to 
ensure the statistical test is valid. For analysis including all participants, participants who did 
not achieve a response (which may have to be a confirmed response) will be censored using one 
of the following options: 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for participants who had 
a PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case participants have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
10.8.3.2.8 
Definition of start and end dates for time to event variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number. 
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations. 

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Start Dates 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 
For the calculation of duration of response the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed. 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
• Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 10.8.3.2.8 ) 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery 
10.8.3.2.9 
Handling of participants with non-measurable disease only at baseline 
It is possible that participants with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. in Phase III studies with 
PFS as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations. 

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It is recommended that any participants with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints. 
Although the text of the definitions described in the previous sections primarily relates to 
participants with measurable disease at baseline, participants without measurable disease should 
also be incorporated in an appropriate manner. The overall response for participants with non-
measurable disease is derived slightly differently according to Table 10-11  
Table 10-11 
Overall lesion response at each assessment: participants with non-
target disease only 
Non-target lesions 
New lesions 
Overall lesion response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/Non-PD 
UNK 
No 
UNK 
PD 
No or Yes 
PD 
Any 
Yes 
PD 
1. As defined in Section 10.8.2.4 
In general, the non-CR/non-PD response for these participants is considered equivalent to an 
SD response in endpoint determination. In summary tables for best overall response participants 
with only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular 
by displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these participants into the analysis the importance 
to each endpoint of being able to identify a PR and/or to determine the occurrence and timing 
of progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from participants with 
only non-measurable disease at baseline, handling participants with a best response of CR as 
“responders” with respect to ORR and all other participants as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
participants with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular participants. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from participants with only 
non-measurable disease. 
10.8.3.2.10 Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed. 
Based on definitions outlined in Section 10.8.3.2.7and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer and Biologics 2005) as a 
reference, the following analyses can be considered:  

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Table 10-12 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date (progression or censoring)1 (1)= 
default unless specified differently in the protocol or RAP 
Outcome 
A 
(1) Date of randomization/start of treatment3 
Censored 
B 
(1) Date of progression 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C1 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C2 
(1) Date of last adequate assessment2 
(2) Date of next scheduled assessment2 
(3) Date of progression (or death) 
Censored 
Progressed 
Progressed 
D 
(1) Date of last adequate assessment 
Censored 
E 
(1) Ignore clinical progression and follow situations above 
(2) Date of discontinuation (visit date at which clinical 
progression was determined) 
As per above situations 
Progressed 
F 
(1) Ignore the new anticancer therapy and follow the situations 
above (ITT approach) 
(2) Date of last adequate assessment prior to new anticancer 
therapy 
(3) Date of secondary anticancer therapy(4) Date of secondary 
anticancer therapy 
As per above situations 
 
Censored 
 
CensoredEvent 
G 
(1) Date of last adequate assessment 
Censored (only TTP and 
duration of response) 
1. Definitions can be found in Section 10.8.3.2.7 
2. After the last adequate tumor assessment. "Date of next scheduled assessment" is defined in  
Section 10.8.3.2.7 
3. The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death 
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F. 
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e. 
• (C1) taking the actual progression or death date, in the case of only one missing 
assessment 
• (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments 
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as participants without documented 
PD should be followed for progression after discontinuation of treatment. However, option (2) 
may be used as sensitivity analysis. If progression is claimed based on clinical deterioration 
instead of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high 
early progression rate or difficulties to assess the tumor due to clinical deterioration. 

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Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy. 
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan. 
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis. 
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy. 
Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in 5 the “Date of 
last adequate assessment” by the “Date of previous scheduled assessment (from baseline)”, with 
the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment. 
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation. 
10.8.4 
Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates). 

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10.8.4.1 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation. 
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 
10.8.4.2 End of treatment period completion 
Participants may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the Investigator at any time. For participants who are lost to 
follow-up, the Investigator or designee should show "due diligence" by documenting in the 
source documents steps taken to contact the patient, e.g., dates of telephone calls, registered 
letters, etc. 
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment. 
Participants may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Participant/guardian decision 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
 Death is a reason which “must” lead to discontinuation of patient from trial. 
10.8.4.3 End of post-treatment follow-up (study period completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up. 
Participants may provide study period completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 

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• Pregnancy 
• Protocol deviation 
• Technical problems 
• Participant/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
10.8.4.4 Medical validation of programmed overall lesion response 
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local Investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore consequently 
discrepancy between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local Investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the Investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the Investigator or central reader’s 
response assessment will never be overruled. 
If Novartis elect to invalidate an overall lesion response as evaluated by the Investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only participants with documented deterioration 
of symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
10.8.4.5 Programming rules 
The following should be used for programming of efficacy results: 
10.8.4.5.1 
Calculation of time to event variables 
Time to event = end date - start date + 1 (in days) 
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 

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10.8.4.5.2 
Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 10.8.3.2.7. If all measurement dates have 
no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
10.8.4.5.3 
Incomplete dates for last known date patient alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
10.8.4.5.4 
Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
10.8.4.5.5 
Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
10.8.4.5.6 
Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
• Alive 
• Lost to follow-up 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
• Ongoing without event 
• Lost to follow-up 
• Withdrew consent 
• Adequate assessment no longer available 
• Event documented after two or more missing tumor assessments (optional, see 
Table 10-12) 
• Death due to reason other than underlying cancer (only used for TTP and duration of 
response) 

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• Initiation of new anti-cancer therapy 
* Adequate assessment is defined in Section 10.8.3.2.7 This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted: 
• This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when participants are 
not followed for progression after treatment completion or when only UNK assessments 
are available just prior to data cut-off) 
• The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment 
• This reason will also be used to censor in case of no baseline assessment 
10.8.5 
References (available upon request) 
Dent S, Zee B, Dancey J, et al (2001) application of a new multinomial phase II stopping rule 
using response and early progression. J Clin Oncol: 19:785-91. 
Eisenhauer EA, Therasse P, BogaertsJ, et al (2009) New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Euro JCancer; 45:228-47. 
Ellis S, Carroll KJ, Pemberton K, et al (2008) Analysis of duration of response in oncology 
trials. Contemp Clin Trials; 29:456-65. 
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man 
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007 
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18 
Therasse P, Arbuck SG, Eisenhauer EA, et al (2000) New Guidelines to Evaluate the 
Response to Treatment in Solid Tumors. J Natl Cancer Inst;, 92; 205-16 

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Del Re M, Tiseo M, Bordi P, et al (2017) Contribution of KRAS mutations and c.2369C > T 
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