Clinical trial NCT02323126
Conditions: Non Small Cell Lung Cancer
Keywords: Non small cell lung cancer NSCLC EGFR-mutated EGF816 INC280 Nivolumab EGFR-T790M NSCLC EGFR wild-type (wt) cMET positive NSCLC cMET negative NSCLC
Sponsor: Novartis Pharmaceuticals
Start date: 2015-02-09; Completion date: 2021-02-05
Enrollment: 64 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To determine the efficacy and safety of nivolumab in combination with EGF816 and of nivolumab in combination with INC280 in previously treated NSCLC patients

Detailed description:
This was a phase II, multi-center, open-label study in patients with advanced non-small cell lung cancer (NSCLC). Patients were allocated based on their epidermal growth factor receptor (EGFR) status to one of the 2 groups: Group 1 - EGFR T790M NSCLC treated with EGF816 150 mg once daily (QD) + nivolumab 3 mg/kg every 2 weeks (Q2W), and Group 2 - EGFR wild type (wt) NSCLC treated with INC280 400 mg twice daily (BID) + nivolumab 3 mg/kg Q2W. Patients in Group 2 were subdivided into 2 subgroups based on c-Mesenchymal-epithelial transition (cMet) status: Subgroup A - high cMet (referred to as Group 2A) and Subgroup B- low cMet (referred to as Group 2B).

Patients could continue study treatment until patients experienced unacceptable toxicity that precluded any further treatment, disease progression and/or treatment was discontinued at the discretion of the investigator or withdrawal of consent, or the patient was transferred to a Novartis roll-over study or an alternative treatment option that could continue to provide study treatments. Following the approval of a protocol amendment, the maximum treatment duration for nivolumab could not exceed 2 years and patients who had received nivolumab beyond 2 years were discontinued from nivolumab treatment and continued on EGF816 or INC280 alone.

The primary objective of the trial was to estimate the clinical activity of nivolumab in combination with EGF816 or INC280.

Arms: arm 1: Group 1: EGF816 150 mg QD + Nivolumab 3 mg/kg Q2W arm 2: Group 2A: INC280 400 mg BID, High cMET + Nivolumab 3 mg/kg Q2W arm 3: Group 2B: INC280 400 mg BID, Low cMet + Nivolumab 3 mg/kg Q2W
Interventions: intervention 1: EGF816 intervention 2: INC280 intervention 3: Nivolumab
Intervention descriptions: intervention 1: EGF816 150 mg once daily (QD) administered orally as a capsule intervention 2: INC280 400 mg twice daily (BID) administered orally as a tablet intervention 3: Nivolumab 3 mg/kg every 2 weeks (Q2W) administered by intravenous infusion

Protocol documents:
SAP_002.pdf: 




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Table of contents
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods...............................................................................................................9
2.1
Data analysis general information ...........................................................................9
2.1.1
General definitions................................................................................10
2.2
Analysis sets ..........................................................................................................11
2.2.1
Subgroup of interest ..............................................................................12
2.3
Patient disposition, demographics and other baseline characteristics ...................13
2.3.1
Patient disposition.................................................................................13
2.3.2
Demographics and other baseline characteristics .................................13
2.3.3
Medical history......................................................................................14
2.3.4
Prior antineoplastic therapy...................................................................14
2.3.5
Diagnosis and extent of cancer .............................................................14
2.4
Protocol deviations ................................................................................................14
2.5
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................15
2.5.1
Study treatment .....................................................................................15
2.5.2
Concomitant and post therapies ............................................................16
2.5.3
Compliance ...........................................................................................17
2.6
Analysis of the primary objective..........................................................................17
2.6.1
Primary endpoint...................................................................................17
2.6.2
Statistical hypothesis, model, and method of analysis..........................17
2.6.3
Handling of missing values/censoring/discontinuations.......................18
2.6.4
Supportive analysis ...............................................................................18
2.7
Analysis of secondary efficacy objective(s)..........................................................18
2.7.1
Secondary endpoints .............................................................................19
2.7.2
Statistical hypothesis, model, and method of analysis..........................19
2.7.3
Handling of missing values/censoring/discontinuations.......................19
2.8
Safety analyses.......................................................................................................20
2.8.1
Adverse events (AEs)............................................................................20
2.8.2
Deaths....................................................................................................21
2.8.3
Laboratory data .....................................................................................22
2.8.4
Vital signs, weight and physical examinations .....................................23
2.8.5
Electrocardiograms ...............................................................................23




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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BCS
Biopharmaceutics Classification System
BLRM
Bayesian Logistic Regression Model
BOR
Best Overall Response
CI
Confidence Interval
Cmax
Maximum plasma concentration after a single dose
CR
Complete Response
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease Control Rate
DMC
Data Monitoring Committee 
DDS
Dose Determining Set
DLT
Dose-Limiting Toxicity
DOR
Duration Of Response
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
EGF
Epidermal growth factor
EGFR
Epidermal Growth Factor Receptor; also known as ErbB1
EOT
HGF
End of Treatment
Hepatocyte Growth Factor
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MTD
Maximum Tolerated Dose
NCA
NCI
Non-Compartmental Analysis
National Cancer Institute
o.d.
Once Daily
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PD
Pharmacodynamics or Progressive disease
PFS
Progression-Free Survival
PK
Pharmacokinetics
PR
Partial Response
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings


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Tmax
Peak plasma concentration 
WHO
World Health Organization


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1
Introduction
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study CEGF816X2201C that will be presented in the Clinical Study Report (CSR). 
The output shells (in-text and post-text) accompanying this document can be found in the 
Tables, Figures, Listings (TFL) shells document. The specifications for derived variable and 
datasets can be found in the Programming Datasets Specifications (PDS) document.
All changes to the planned analysis described in this document required before or after database 
lock will be made through an amendment or addendum, respectively. Note that obvious 
corrections will be made at the time of analysis to address minor formatting or spelling mistakes 
present in the TFL shells document without the need to amend.
The SAP, TFL shells and PDS documents may also serve as a reference for the creation of any 
outputs required outside of the CSR, e.g., Investigator’s Brochure (IB) updates, abstracts, 
posters, presentations, manuscripts and management updates. Data used for these analyses will 
have a status aligned to the database lock guidance.
1.1
Study design
This is a phase II, multi-center, open-label study of patients with advanced NSCLC.
Patients will be allocated based on their EGFR status to one of the two groups:

Group 1: EGFR-T790M NSCLC. As of December 17, 2015, enrollment to Group 1 has 
been halted.

Group 2: EGFR wild-type (wt) NSCLC. For the purpose of this protocol, EGFR wt is 
defined as negative for exon 19 deletions and for the L858R mutation in EGFR at a 
minimum; however, if more extensive EGFR mutation testing has been performed, the 
tumor must not harbor any known activating EGFR mutations in Exons 18-21 in order to 
be considered EGFR wt. Patients in Group 2 will be subdivided into two sub-groups:

Sub-group A : high cMet

Sub-group B: low cMet.
Based on group allocation, patients will be treated as follows:

Group 1: EGF816+nivolumab. As of January 28, 2016, nivolumab was required to be 
discontinued from all ongoing patients in Group 1. Ongoing patients who re-consent to 
remain on study will be treated with EGF816 as a single agent.

Group 2: INC280+nivolumab
A cycle will be defined as 28 days.
See Figure 1-1 for an overview of the study design


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Figure 1-1
Study design
1.2
Study objectives and endpoints
Objectives and related endpoints are described respectively in Table 1-1 below:
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To estimate the clinical activity of 
Nivolumab in combination with 
EGF816 or INC280
6 month PFS rate using RECIST 
version1.1
(6mo PFS rate=6 cycles=168 days)
Refer to 2.6.1
Secondary
To evaluate the preliminary antitumor 
activity of EGF816 and Nivolumab and 
of INC280 and Nivolumab
ORR, DCR, other PFS measures, 
OS
Refert to 2.7
To characterize the safety and 
tolerability of EGF816 and Nivolumab 
or of INC280 and Nivolumab
Safety, incidence and severity of 
AEs, including changes in 
hematology and chemistry values, 
vital signs and ECGs
Tolerability: Dose interruptions, 
reductions, and dose intensity
Refer to 2.8
To evaluate PK of EGF816, INC280 
and Nivolumab in the combination 
setting
PK parameters of 
Nivolumab,EGF816 and INC280 
such as Cmax, AUC and Cmin
Refer to 2.9


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Objective
Endpoint
Analysis
2
Statistical methods
2.1
Data analysis general information
The data will be analyzed by Novartis personnel and/or designated CRO(s) using SAS version 
9.4, and for Bayesian modeling, R version 3.6.1 or later. PK parameters will be calculated using 
non-compartmental methods available in Phoenix WinNonlin version 8.0 or later.
The study data will be analyzed and reported  in a final CSR that includes all outputs planned 
within the TFL shells document. 
Data from participating centers in this study protocol will be combined, so that an adequate 
number of patients will be available for analysis. No center effect will be assessed. The data 
will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and all relevant 
pharmacokinetic (PK) and pharmacodynamics (PD) measurements. Quantitative data will be 
summarized using descriptive statistics (n, mean, standard deviation, median, minimum, and 
maximum) and categorical data will be summarized using contingency tables (frequencies and 
percentages).
Both pre and post intra-patient dose escalation data will be listed and summarized together 
under the one dose level/treatment group.
Data from patients in safety monitoring cohorts treated at doses different from the respective 
selected dose will be analyzed as separate groups for safety and BOR.
Sub-group A and sub-group B in Group 2 will be considered as separate treatment groups. 
Including Group 1 there will be total 3 treatment groups for all analyses. For analyses of safety 
and pharmacokinetics, additional information with sub-group A and sub-group B in Group 2 
pooled will also be presented.


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2.1.1
General definitions
Study drug and study treatment
Study drug refers to the individual compound, i.e., EGF816, INC280, and Nivolumab. Study
treatment refers to any combination of study drugs, i.e.

Group 1: EGF816+Nivolumab

Group 2: INC280+Nivolumab
Study day
The study day for all assessments/events will be calculated using the start date of study 
treatment as reference. For assessments/events occurring on or after the start date of study 
treatment, study day will be calculated as:
Study day (days) = Event date – Start date of study treatment + 1
Therefore, the first day of study treatment is study day 1.
For all assessment/events occurring prior to the start of the study treatment, study day will be 
negative and will be calculated as:
Study day (days) = Event date – Start date of study treatment
Study day will be displayed in the data listings.
On-treatment assessment/event
An on-treatment assessment/event is defined as any assessment/event obtained in the time 
interval from the start date of study treatment until the last date of study treatment + 100 days 
inclusive.
Baseline
Baseline is the last available and valid assessment performed or value measured within 28 days 
before the first dose, i.e. first administration of study treatment. Baseline can be on a day before 
or on the same day as first dose if a pre-dose assessment/value is available (e.g., ECG, PK 
samples, 
).
If time is recorded for the first dose and for a specific assessment performed on the day of first 
dose, this assessment will be considered as baseline only if it is actually performed before the 
first dose, as checked using both times.
If time is not recorded, a specific assessment performed on the day of first dose will be 
considered as baseline if, according to protocol, it should be performed before the first dose.
Patients with no data on a particular parameter before the first dose will have a missing baseline 
for that parameter.
For pregnancy test, baseline will be within 72 hours before first dose. 
Computation of baseline for ECG, 
 other endpoints are described in each specific 
section.


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2.2
Analysis sets
The number (%) of patients in each of the defined analysis set will be summarized using the 
FAS. 
Full analysis set
The Full Analysis Set (FAS) comprises all patients who have received at least one dose of 
INC280, EGF816 or Nivolumab. Patients will be analyzed according to the planned treatment 
they have been assigned to. Unless otherwise specified, the FAS will be used for all listings of 
raw data.
Safety set
The Safety Set includes all patients who received at least one dose of INC280, EGF816 or 
Nivolumab and have at least one valid post-baseline safety assessment. Please note that the 
statement that a patient had no AEs (on the AE eCRF page) constitutes a safety assessment. 
Patients will be analyzed according to the study treatment (regimen) they actually received, 
where treatment actually received is defined as:

The treatment assigned if it was received at least once, or

If the assigned treatment was never received, then the first treatment received when starting 
therapy with study treatment will be used for classification
The safety set will be the primary population for all safety related endpoints.
Per-Protocol set
All major protocol deviations leading to exclusion from the PPS are listed below:

Patients without written informed consent prior to any screening procedures

Patients without presence of at least one measurable lesion according to RECIST v.1.1.

Patients who have been treated with prior PD-1 and PD-L1 agents

Group 1 patients

without EGFR T790M NSCLC (adenocarcinoma);

or without documented progression of disease according to RECIST v1.1 following 
primary standard of care (e.g. erlotinib, gefitinib);

or have received more than one prior line of EGFR TKI therapy.

Group 2 patients

without EGFR wild-type NSCLC;

or without documented progression of disease according to RECIST v1.1 following 
primary standard of care (e.g. platinum doublet);

or had previous treatment with a cMet inhibitor or HGF-targeting therapy.
Patients will be classified according to treatment received.
The PPS will be used in the sensitivity analysis of the primary endpoint. If the PPS and the FAS 
are identical, then analyses described by the PPS below will not be performed.


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Pharmacokinetic Analysis Set (PAS)
Each of the EGF816 and INC280 PAS includes two sets, the EGF816/INC280 full 
pharmacokinetic analysis set (EGF/INC-FPAS) which will be used for non-compartmental
analysis (NCA) and EGF816/INC280 pharmacokinetic analysis set (EGF/INC-PAS).
The EGF816/INC-PAS includes all patients who have provided at least one evaluable 
EGF816/INC280 PK concentration. For an EGF816/INC280 PK concentration to be evaluable, 
a patient must: 

Have taken at least one planned dose of  EGF816/INC280 prior to sampling 

for INC280 PK samples taken on or after Cycle 1 Day 15, the patient took study drug 
according to the originally assigned dose for at least 3 consecutive days without 
interruption or dose modification prior to the PK sampling day (ensuring steady state is 
reached)

for EGF816 take the same dose of EGF816 for at least 5 consecutive days prior to 
sampling on or after cycle 1 day 15

For pre-dose samples, do not vomit within 4 hours after the dosing of EGF816/INC280 
prior to sampling

For post-dose samples, do not vomit within 4 hours after the dosing of EGF816/INC280

For pre-dose sample of INC280, have the sample collected before the next dose 
administration and 9-15 hours after the last dose administration.

For pre-dose sample of EGF816, have the sample collected 20 to 28 hours after the last dose
administration and before the next dose administration.
The EGF/INC-FPAS includes all EGF/INC-PAS patients
who have provided an
EGF816/INC280 evaluable PK profile on cycle 1 day 15 (only applicable to patients with 
extensive PK sampling in the safety monitoring cohort). An EGF816/INC280 PK profile is 
considered evaluable if all of the following conditions are satisfied:
•
Patient has received planned doses
•
Patient has provided at least one valid primary PK parameter (AUClast, AUCtau, Cmax, 
Tmax )
•
The NIVO-PAS includes all patients who have provided at least one evaluable Nivolumab PK 
concentration. For a Nivolumab PK concentration to be evaluable, a patient must:
•
Have received one of the planned doses (complete infusion) of Nivolumab prior to 
sampling
•      For pre-dose samples, have the sample collected before the next dose administration
2.2.1
Subgroup of interest


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The following two subgroups in Group 2 will be considered.

Group 2A (cMet high): if any one of the following criteria is satisfied:
o
IHC score = 3+ in at least 50% of tumor cells (regardless of gene copy number 
(GCN))
o
IHC score = 2+ in at least 50% of tumor cells and GCN>=5
o
cMet exon 14 activating mutation positive

Group 2B (cMet low): if negative or unknown for cMet exon 14 activating mutation AND 
any one of the following criteria is satisfied
o
IHC score = 2+ in at least 50% of tumor cells and GCN < 5
o
IHC score = 2+ in less than 50% of tumor cells (regardless of GCN)
o
IHC score = 0 or 1+ (regardless of GCN)
2.3
Patient disposition, demographics and other baseline 
characteristics
Unless noted otherwise, summaries and listings described in this section will be based on the 
FAS.
2.3.1
Patient disposition
The FAS will be used for the patient disposition summary tables and listings. The followings
will be tabulated:

Number (%) of patients who are still on-treatment (based on non-completion of the ‘End 
of Treatment’ page),

Number (%) of patients who discontinued treatment (based on completion of the ‘End of 
Treatment’ page with discontinuation date and reason entered),

Primary reasons for study treatment discontinuation (based on discontinuation reason 
entered in the ‘End of Treatment’ page),

Number (%) of patients who discontinued from study (based on completion of the ‘End of 
Post Treatment Phase Disposition’ page with discontinuation date and reason entered),

Primary reasons for study evaluation completion (based on discontinuation reason entered 
in the ‘End of Post Treatment Phase Disposition’ page).
2.3.2
Demographics and other baseline characteristics
Demographic data including age, sex, race, ethnicity, height, baseline weight and ECOG
performance status will be listed and summarized. In addition, child bearing potential and
pregnancy test results will be listed, and age (18-<65, 65-<85, ≥85 years) and weight (<55, 55-
75, ≥75 kg) categories summarized. For patients from Germany, HIV test results will be listed 
by treatment group.


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2.3.3
Medical history
Medical history and current medical conditions will be coded using the latest Medical 
Dictionary for Regulatory Activities (MedDRA) terminology available at the time of reporting.
Medical history and current (ongoing) medical conditions, including cancer-related conditions 
and symptoms will be listed. 
2.3.4
Prior antineoplastic therapy
Prior anti-neoplastic therapy will be summarized and listed for medication, radiotherapy and 
surgery by treatment group.
The number (%) of patients who received, separately, any prior anti-neoplastic medication, 
radiotherapy or surgery will be summarized.
Prior anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD). 
The following summary tables will be presented:

Summary table of number and percentage of patients who received any prior anti-
neoplastic medications, number of regimens, therapy type (e.g. chemotherapy, hormonal 
therapy, etc.) at last medication, setting (e.g. adjuvant, metastatic, etc.) at last medication, 
best response at last medication, time (days) from end of last treatment to start of study 
treatment.

Summary table of ATC class and preferred term.
The summary of prior anti-neoplastic radiotherapy will include the radiotherapy locations, 
(including all locations recorded for each patient), and setting at last radiotherapy.
The summary of prior anti-neoplastic surgery will include the time between the last surgery 
(non-biopsy procedure) to start of study treatment, procedure at last surgery, and residual 
disease at last surgery.
2.3.5
Diagnosis and extent of cancer
The summary and listing of diagnosis and extent of cancer (disease history) will include primary 
site of cancer, details of tumor histology/cytology, histological grade, stage at time of study 
entry, time from initial diagnosis of primary site to start of study treatment, time since most 
recent recurrence/relapse or progression to start of study treatment, and time from initial 
diagnosis of primary site to first recurrence/relapse or progression.
2.4
Protocol deviations
The FAS will be used for the protocol deviation summary tables and listings. The number (%) 
of patients with any CSR-reportable protocol deviation will be tabulated by the deviation 
category (entry criteria not satisfied; wrong treatment or incorrect dose; developed withdrawal 
criteria, but not withdrawn; took an excluded concomitant medication; others). The full list of 
protocol deviations are documented in the Study Specification Document (SSD).


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2.5
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
Unless otherwise stated, the Safety set will be used for all medication data summaries and 
listings. 
2.5.1
Study treatment
2.5.1.1
Treatment exposure
Date of first/last administration of study treatment
The date of first/last administration of study treatment is derived as the first (last) date when a 
non-zero dose of any component of study treatment was administered and recorded on the 
Dosage Administration Record (DAR) eCRF. For the sake of simplicity, the date of first (last) 
administration of study treatment will also be referred as start (last) date of study treatment.
Last date of exposure to study drug 
For EGF816 and INC280 the last date of exposure to study drug is the last date of study drug.
For Nivolumab the last date of exposure to study drug is defined as follows.

Last day of exposure = last day of administration + 13 days. 
Last date of exposure to study treatment
Last date of exposure to study treatment = max (last date of exposure to any component of the 
study treatment).
Duration of study drug exposure
Duration of study drug exposure (days) = last date of exposure to the study drug – date of first 
administration of the study drug + 1.
For patients who did not take any of the study drug, the duration of exposure is by definition 
equal to zero.
Duration of study treatment exposure
Duration of study treatment exposure (days): last date of exposure to study treatment − first 
date of study treatment + 1. 
The exposure duration may include periods of temporary interruption. If a patient is still on 
treatment at the time of data cut-off, the end date of treatment will be replaced by the data cut-
off date and the above respective algorithm will be used. 
Actual cumulative dose (mg): sum of all doses of study drug taken by a patient.
Planned cumulative dose (mg): sum of all doses of study drug planned to be have been taken
during the study treatment period by a patient.
Percentage of days dosed: 100 × number of actual doses taken  ⁄ number of doses scheduled per 
protocol during treatment period.


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Percentage of days at planned dose: 100 × number of doses at planned dose ⁄ number of doses 
scheduled per protocol during treatment period
Actual dose intensity (ADI):

For EGF816 and INC280 (unit: mg/day): Actual cumulative dose (mg) / duration of 
exposure (days).

For Nivolumab (unit: mg/kg biweekly): [Actual cumulative dose (mg/kg) / duration of 
exposure (days)]*14 days
Planned dose intensity (PDI), fixed for all patients:

For EGF816 and INC280 (unit: mg/day): planned daily dose (i.e., 150 mg/day for 
EGF816 and 800 mg/day for INC280)

For Nivolumab (unit: dose unit/cycle): planned dose per cycle (i.e., 3mg/kg biweekly)
Relative dose intensity (%): 100*ADI/PDI. 
The duration of exposure to study treatment and study drug (including categories: <6, 6-<12, 
12-<18,  18-<24, 24-<48, 48-<72, >=72 weeks) will be summarized. In addition, the cumulative 
dose, percentage of days dosed, percentage of days the planned/intended dose was received, DI, 
and RDI (including categories: <=0.5, 0.5<-<=0.75, 0.75<-<=0.9, 0.9<-<=1.1, >1.1) will be 
summarized for each study drug. The number (%) of patients who have dose reductions and 
interruptions (and/or delays), and the corresponding reasons, will be provided for each study 
drug. The number of dose reductions and interruptions (and/or delays) per patient and the 
duration of dose reductions/interruptions/delays (days) will be summarized for each study drug.
All doses of the study treatment along with reasons for any dose change will be listed.
Dose delay/interruption: Actual dose equal to zero where the planned dose is not zero, between 
the first and last non-zero doses, following a non-zero actual dose (if not the first dose).
Dose reduction: A non-zero actual dose that is less than the immediate previous non-zero actual 
dose (if not the first dose) and below the treatment received (see safety set) dose. No dose 
reduction is allowed for Nivolumab. 
Intra-patient dose escalation: Dose change flag checked with reason “as per protocol”, and
actual dose that is greater than any previous actual dose.
2.5.2
Concomitant and post therapies
2.5.2.1
Concomitant therapy
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and
blood transfusions) administered in the study and are recorded in the Concomitant
Medications/significant non-drug therapies eCRF. These therapies will be coded using the 
WHO Drug Reference Listing (WHO DRL) dictionary that employs the WHO Anatomical 
Therapeutic Chemical (WHO ATC) classification system.
Any concomitant therapies starting prior to or after the start of study treatment will be listed.


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The imputation of a concomitant medication start date will follow the same conventions as for 
an AE start date (see Section 2.8.1 Adverse events). No imputation will be performed for 
concomitant medication end dates.
2.5.2.2
Post treatment anti-cancer therapy
Anti-neoplastic therapies since discontinuation of study treatment will be listed.
2.5.3
Compliance
Compliance to the study treatment within each treatment group will be assessed by the number 
of dose reductions, number of dose interruptions and percent of days received planned dose for 
both study drugs separately in summary tables by treatment group for the safety set.
2.6
Analysis of the primary objective
The primary objective is to estimate the clinical activity of Nivolumab in combination with 
EGF816 or INC280.
2.6.1
Primary endpoint
The primary efficacy variable is PFS rate assessed at 6 months (more precisely after 6 cycles = 
168 days) following either Nivolumab and EGF816 treatment or Nivolumab and INC280 
treatment. CT/MRI assessments will be used for efficacy assessments of anti-tumor activity on 
study. PFS will be defined as per RECIST v1.1.
2.6.2
Statistical hypothesis, model, and method of analysis
For each treatment group a Bayesian design will be used. PFS will be modeled using a Weibull 
distribution (details are described in protocol Appendix 3). Assuming a weakly informative 
prior distribution for the PFS rate at 6 months, the distribution will be updated with all available 
data from patients treated at the confirmed dose in the FAS. The PFS rate at 6 months will be 
estimated from the posterior distribution. Inferential summaries (e.g., mean, median, standard 
deviation, 95% credible intervals, and interval probabilities) based on the posterior distribution 
will also be presented.
Group 1: Nivolumab and EGF816
For PFS rate at 6 months the indifference point is set at 70% and the inferential intervals are 
given below:

[0, 55%) unacceptable anti-tumor activity

[55%, 70%) limited anti-tumor activity

[70%, 85%) moderate anti-tumor activity

[85%, 100%] strong anti-tumor activity
If the posterior mean PFS rate at 6 months is equal to or greater than 70% and the posterior risk 
of being in the unacceptable anti-tumor activity interval [0, 55%) is lower than 5%, then 
preliminary anti-tumor activity of the study treatment will be declared. Posterior summaries for 
the 4 inferential intervals above will also be assessed.


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Group 2: Nivolumab and INC280
Sub-group A: EGFR wild-type high cMet
For PFS rate at 6 months the indifference point is set at 50% and the inferential intervals are 
given below:

[0, 35%) unacceptable anti-tumor activity

[35%, 50%) limited anti-tumor activity

[50%, 65%) moderate anti-tumor activity

[65%, 100%] strong anti-tumor activity
If the posterior mean PFS rate at 6 months is equal to or greater than 50% and the posterior risk 
of being in the unacceptable anti-tumor activity interval [0, 35%) is lower than 5%, then 
preliminary anti-tumor activity of the study treatment will be declared. Posterior summaries for 
the 4 inferential intervals above will also be assessed.
Sub-group B: EGFR wild-type low cMet
For PFS rate at 6 months the indifference point is set at 40% and the inferential intervals are 
given below:

[0, 25%) unacceptable anti-tumor activity

[25%, 40%) limited anti-tumor activity

[40%, 55%) moderate anti-tumor activity

[55%, 100%] strong anti-tumor activity
If the posterior mean PFS rate at 6 months is equal to or greater than 40% and the posterior risk 
of being in the unacceptable anti-tumor activity interval [0, 25%) is lower than 5%, then 
preliminary anti-tumor activity of the study treatment will be declared. Posterior summaries for 
the 4 inferential intervals above will also be assessed.
2.6.3
Handling of missing values/censoring/discontinuations
The PFS time of patients who have not died or progressed at time of the primary analysis will 
be censored at the last adequate tumor assessment. For patients who initiate a new antineoplastic 
therapy without experiencing disease progression under study treatment, their PFS time will be 
censored at time of initiating the new antineoplastic therapy.
2.6.4
Supportive analysis
For each group the primary analysis of PFS rate at 6 months will be repeated using PPS, if PPS 
is different from FAS. In addition, the PFS rate at 6 months and the corresponding 95% 
confidence interval will be presented using Kaplan-Meier estimate.
Additional supportive 
 analyses will be conducted to support the primary 
objective if appropriate.
2.7
Analysis of secondary efficacy objective(s)
The secondary efficacy objective is to evaluate the preliminary antitumor activity of EGF816 
and Nivolumab and of INC280 and Nivolumab. 


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2.7.1
Secondary endpoints
The secondary efficacy endpoints include ORR, DCR, PFS, PFS rate at 3 months, and OS at 1 
year. CT/MRI assessments will be used for all efficacy assessments of anti-tumor activity on 
study. BOR, ORR, DCR, PFS, and OS will be defined as per RECIST v1.1. 
Secondary efficacy endpoints will be listed and summarized by treatment group. Median PFS 
and PFS rate at 3 months with the corresponding 95% confidence interval will be estimated 
using the Kaplan-Meier method. The Kaplan-Meier estimate of PFS will also be plotted. OS at 
1 year with 95% confidence interval will be estimated using the Kaplan-Meier method.
2.7.2
Statistical hypothesis, model, and method of analysis
Waterfall plot to depict anti-tumor activity
Waterfall plot will be used to depict the anti-tumor activity. These plots will display the 
best percentage change from baseline in the sum of diameters of all target lesions for each 
patient. Only patients with measurable disease at baseline will be included in the waterfall 
plots. Patients without any valid assessments at baseline or post-baseline will be excluded from 
the waterfall plot.
Overall response summary
A summary table of investigator assessment will be presented with count and percentage of 
each BOR category (CR, PR, SD, PD, Unknown), point estimate and the 95% confidence 
interval (CI) based on the exact binomial distribution for ORR and DCR. A listing will be 
presented with overall responses at all assessment timepoints, with percentage change from 
nadir or baseline, and BOR per patient.
PFS and OS
Median PFS and PFS rate at 3 months with the corresponding 95% confidence interval will be 
estimated using the Kaplan-Meier method. The Kaplan-Meier estimate of PFS will also be 
plotted.
For PFS and OS, Kaplan-Meier plot by treatment group will be produced. A summary table by 
treatment group with estimated median (in months), 25th and 75th percentiles with 
correspoinding 95% CIs as well as estimated probability at 3, 6, 12, 18 and 24 months with 
corresponding 95% CIs will be presented. 
Individual overall response, time to progression and death, and time to onset and duration of 
overall response will be listed. 
2.7.3
Handling of missing values/censoring/discontinuations

ORR: If there is no baseline tumor assessment, all post-baseline overall lesion responses 
are expected to be ‘Unknown’. If no valid post-baseline tumor assessments are available, 
the BOR must be “Unknown” unless progression is reported. Patients with unknown or 
missing BOR will be counted as failures.

DOR: A patient who has not progressed or died at the date of the analysis or when he/she 
receives any further anticancer therapy in the absence of disease progression will be 


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censored at the time of the last adequate tumor evaluation before the earlier of the cut-off 
date or the anticancer therapy date.

PFS: A patient who has not progressed or died at the date of the analysis or when he/she 
receives any further anticancer therapy in the absence of disease progression will be 
censored at the time of the last adequate tumor evaluation before the earlier of the cut-off 
date or the anticancer therapy date. By default, if disease progression or death is 
documented after one single missing tumor evaluation, the actual event date of disease 
progression/death will be used for the PFS event date. If disease progression or death is 
documented after two or more missing tumor evaluations, the PFS time of these patients 
will be censored at the date of the last adequate tumor evaluation without PD.
2.8
Safety analyses
The assessment of safety is based on the type and frequency of Adverse Events (AEs) as well 
as on the number of laboratory values that fall outside of pre-determined ranges (Common 
Toxicity Criteria for Adverse Events (CTCAE) grading limits or normal ranges as appropriate). 
Other safety data include electrocardiogram and vital signs.
The Safety set will be used for summaries and listings of safety data with the exception of dose 
limiting toxicities (DLTs) for which the DDS will be used.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication,
2. On-treatment period: from day of first dose of study medication to 100 days after last 
dose of study medication,
3. Post-treatment period: starting at Day 101 after last dose of study medication.
The safety summary tables will include assessments collected no later than 100 days after study 
treatment discontinuation.
2.8.1
Adverse events (AEs)
AEs will be coded and graded using the latest version of MedDRA and CTCAE, respectively,
available at the time of reporting. If CTCAE grading does not exist for an AE, grades 1, 2, 3, or 
4 corresponding to the severity of mild, moderate, severe, and life-threatening, respectively, 
will be used. CTCAE grade 5 (death) will not be used in this study. Death information will be 
collected on the “End of Treatment” or “Survival Information” eCRF pages.
The following AE summaries will be produced:

AEs regardless of study drug relationship (including CTC grade 3/4)

AEs suspected to be study drug related (including CTC grade 3/4)

AEs regardless of study drug relationship leading to discontinuation of study drug

AEs suspected to be study drug related leading to discontinuation of study drug

AEs regardless of study drug relationship requiring dose adjustment or study drug 
interruption

AEs which are not SAEs regardless of study drug relationship


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
SAEs regardless of study drug relationship

SAEs suspected to be study drug related
A patient with multiple CTC grades for an AE will be summarized under the maximum CTC 
grade recorded for the event. A patient with multiple occurrences of an AE is counted only once 
in the AE category (e.g. system organ class, preferred term).
A missing AE start date will be imputed using the following logic matrix described in Table 2-
1.
Table 2-1
Imputation rules for a partially missing AE start date
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
No imputation
No imputation
No imputation
No imputation
AEY < TRTY
(D)
(C)
(C)
(C)
AEY = TRTY
(B)
(C)
(B)
(A)
AEY > TRTY
(E)
(A)
(A)
(A)
AEM: Month AE started; AEY: Year AE started
TRTM: Month treatment started; TRTY: Year treatment started
Table 2-2 is the legend to the logic matrix shown in Table 2-1 and details the relationship of 
AE start date to study treatment start date.
Table 2-2
Imputation legend and AE/treatment start date relationship
AE start date relationship
Imputation
(A)
After treatment start or Uncertain
MAX( 01MONYYYY, TRTSTD+1 )
(B)
Uncertain
TRTSTD+1
(C)
Before treatment start
15MONYYYY
(D)
Before treatment start
01JULYYYY
(E)
After treatment start
01JANYYYY
Before treatment start: Partial date indicates AE start date is prior to treatment start date.
After treatment start: Partial date indicates AE start date is after treatment start date.
Uncertain: Partial date insufficient to determine relationship of AE start date to treatment start date.
No imputation will be performed for AE end dates.
2.8.2
Deaths
All deaths occurred in the study will be listed with principal cause reported/preferred term and 
following summaries will be produced:

On-treatment deaths with cause of death by preferred term

All deaths with cause of death by primary system organ class and preferred term


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2.8.3
Laboratory data
Laboratory data will be converted into SI units and classified (by Novartis statistical 
programming) into CTC grades according to CTCAE. Grade 5 will not be used.
For cases when the CTC grade definition includes change from baseline criteria (e.g., 
Creatinine, Ejection fraction, Fibrinogen, Hemoglobin, INR): When a lab value is of grade X 
based on threshold/ranges, but grade X+1 when considering change from baseline, the final 
Grade is set to X+1. For other cases, a Grade 0 CTC grade will be set when laboratory value is:

Within LLN and ULN and grading in both direction,

Below ULN and grading in hyper direction,

Above LLN and grading in hypo direction.
Laboratory data for which a CTC grading does not exist will be classified into low, normal, or 
high based on local laboratory normal ranges as applicable.
The following summaries will be produced for hematology and biochemistry parameters:

For parameters with CTC grades: Shifts from baseline to the worst post-baseline CTC  
grade,

For parameters with no CTC grades defined: Shifts from baseline to the worst post-
baseline using low/normal/high classifications,
The following listings will be produced:

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges 
Table 2-3 and Table 2-4 list all laboratory parameters that will be summarized. 
Table 2-3
Laboratory parameters for which CTCAE grades are defined
Hematology and 
coagulation
Biochemistry
White Blood Cells 
(WBC)
↑↓
Creatinine
↑
Hemoglobin
↓
Sodium
↑↓
Platelet counts
↓
Calcium
↑↓
Absolute Neutrophils
↓
Magnesium 
↑↓
Absolute Lymphocytes
↑↓
Albumin
↓
INR
↑
AST (SGOT)
↑
ALT (SGPT)
↑
Chloride                     
↓
Total Bilirubin
↑
Glucose*
↑↓
↑ Indicates that CTC grade increases as the parameter increases.
↓ Indicates that CTC grade increases as the parameter decreases.
* Separate by fasting status if applicable (fasting or non-fasting)


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Table 2-4
Laboratory parameters (without CTCAE grades) for which lab
reference ranges are defined
Hematology and 
coagulation
Biochemistry
Prothrombin time (PT)
Blood urea nitrogen (BUN)
Urea
Total protein
2.8.4
Vital signs, weight and physical examinations
Vital sign parameters collected are systolic and diastolic blood pressure (mmHg), pulse rate 
(beats per minute), respiratory rate (breaths per minute), body temperature (°C), and weight 
(kg). Vital sign values considered notably abnormal are defined in Table 2-5.
Table 2-5
Criteria for notable vital sign values
Vital sign
Criteria for clinically notable vital sign values
Systolic blood pressure 
[mmHg]
≥180 mmHg/≤90 mmHg with increase/decrease from baseline of 
≥20 mmHg
Diastolic blood pressure 
[mmHg]
≥105 mmHg/≤50 mmHg with increase/decrease from baseline of 
≥15 mmHg
Pulse rate [bpm]
≥100 bpm/≤50 bpm with increase/decrease from baseline of >25%
Body temperature [°C]
39.1
Weight [kg]
≥10% decrease/increase from baseline
Vital signs shift table based on values classified as notable low, normal, notable high or notable 
(high and low) at baseline and worst post-baseline will be produced.
Patients with any clinically notable vital sign value will be listed.
2.8.5
Electrocardiograms
Baseline for ECG analysis is defined as the average of all available ECG measurements
associated with the baseline assessment. Scheduled study day 1 pre-dose ECGs will be
considered to have been obtained prior to study drug administration if dosing time is missing.
If a patient has more than one post-baseline measurement at a specific time point, the average 
of all available measurements associated with the nominal time point will be used for the 
analyses.
The following summaries will be provided for each applicable ECG parameter:

For each ECG interval (QTcF, QT, QRS, PR, HR), descriptive statistics at baseline, at 
worst post-baseline and change from baseline to worst post-baseline value for each 
parameter,

For each QT interval (QT, QTcF), shift tables based on notable QT interval categories
(≤450, >450 - ≤480, >480 - ≤500, >500 ms) at baseline to the worst post-baseline value
observed,

Number (%) of patients having notable ECG values according to Table 2-6.


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Table 2-6
Criteria for notable ECG values
ECG parameter
Criteria for notable ECG values
QT, QTcF (ms)
Increase from baseline >30 ms to ≤60 ms, >60 ms
HR (bpm)
Increase from baseline >25% and value >100 bpm
Decrease from baseline >25% and value <50 bpm
PR (ms)
Increase from baseline >25% and value >200 ms
New PR >200 ms
QRS (ms)
Increase from baseline >25% and value >120 ms
New QRS >120 ms
Patients with any notable change from baseline for each QT/QTc interval will be listed.
2.8.6
Tolerability
Tolerability of study treatment will be assessed by summarizing the number of dose 
interruptions and dose reductions by treatment group. Reasons for dose interruption and dose 
reductions will be listed by patient and treatment group and summarized by treatment group in 
Phase I part and by Group in Phase II part. Cumulative dose, dose intensity and relative dose 
intensity of study treatment will be also be used to assess tolerability.
2.9
Pharmacokinetic data
PK concentration analyses and PK concentration summary statistics will be performed based 
on the INC-PAS, EGF-PAS and Nivo-PAS. Patient data may be removed on an individual basis. 
Only PK blood samples with the date and time and for which the last prior dose date and time 
are adequately recorded will be included in the calculation of PK parameters. 
Concentration values below the lower limit of quantitation (LLOQ) will be displayed in listings 
as zero with a flag and handled as zero in the calculations for mean, CV for mean, standard 
deviation, minimum, median, maximum, but handled as missing for the calculation of the 
geometric means and their CV. Zero concentrations will not be included in the geometric mean 
calculation.
Sub-group A and sub-group B in Group 2 will be considered as separate treatment groups. In 
addition, results with sub-group A and sub-group B in Group 2 pooled will also be presented.
INC280, EGF816 and Nivolumab concentration data will be listed and summarized by time 
point, patient and treatment group. Descriptive statistics will include arithmetic and geometric 
mean, median, standard deviation, coefficient of variation (CV), geometric CV, minimum and 
maximum. Individual concentration-time profile as well as mean concentration-time profile will 
be plotted.
PK parameters for INC280, EGF816 will be calculated using noncompartmental methods based 
on FPAS-INC and FPAS-EGF. PK parameters including but not limited to those described in 
Table 2-7 will be summarized. AUCtau will only be summarized for INC280. Only median 
values and ranges will be given for Tmax. The PK parameters considerd primary are AUCtau, 
AUClast,, Cmax, and Tmax. Other PK parameters (CL/F, Vz/F, T1/2, Cmin) are considered as 
secondary. All PK parameters will be listed.








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Group 2: Nivolumab and INC280
Sub-group A: High cMet
With a sample size of 20 patients, including potentially 15% drop-outs and loss to follow-up 
per patient-year prior to cut-off for primary CSR:

If the true PFS rate at 6 months is low at 35%, the probability to wrongly declare success 
is low at 0.05;

If the true PFS rate at 6 months is moderate at 55%, the probability to correctly declare 
success is high at 0.73;

If the true PFS rate at 6 months is high at 65%, the probability to correctly declare success 
is very high at 0.95.
Such operating characteristics are satisfactory.
Sub-group B: Low cMet
With a sample size of 30 patients, including potentially 15% drop-outs and loss to follow-up 
per patient-year prior to cut-off for primary CSR:

If the true PFS rate at 6 months is low at 25%, the probability to wrongly declare success 
is low at 0.02;

If the true PFS rate at 6 months is moderate at 45%, the probability to correctly declare 
success is high at 0.80;

If the true PFS rate at 6 months is high at 55%, the probability to correctly declare success 
is very high at 0.98.
Such operating characteristics are satisfactory.
4
Change to protocol specified analyses
Not applicable.
5
Appendix
Not applicable.
6
References
Not applicable.

Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................10
Protocol summary:.............................................................................................................12
Amendment 8 (12-Mar-2020) ...........................................................................................14
Amendment 7 (21-Jun-2018) ............................................................................................17
Amendment 6 (29-Jan-2018).............................................................................................18
Amendment 5 (13-Apr-2017)............................................................................................20
Amendment 4 (19-May-2016)...........................................................................................22
Amendment 3 ....................................................................................................................26
Amendment 2 ....................................................................................................................29
Amendment 1 ....................................................................................................................31
1
Background........................................................................................................................35
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............35
1.2
Introduction to investigational treatment(s) and other study treatment(s).............37
1.2.1
Overview of EGF816............................................................................37
1.2.2
Overview of INC280.............................................................................42
1.2.3
Overview of Nivolumab........................................................................46
2
Rationale............................................................................................................................49
2.1
Study rationale and purpose...................................................................................49
2.2
Rationale for the study design ...............................................................................49
2.3
Rationale for dose and regimen selection..............................................................50
2.4
Rationale for choice of combination drugs............................................................51
2.5
Rationale for maximum 2-year duration of Nivolumab treatment ........................51
3
Objectives and endpoints...................................................................................................52
4
Study design ......................................................................................................................54
4.1
Description of study design ...................................................................................54
4.2
Timing of interim analyses and design adaptations...............................................56
4.3
Definition of end of the study................................................................................57
4.4
Early study termination..........................................................................................57
5
Population..........................................................................................................................57
5.1
Patient population..................................................................................................57
5.2
Inclusion criteria ....................................................................................................58


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5.3
Exclusion criteria...................................................................................................58
6
Treatment...........................................................................................................................61
6.1
Study treatment......................................................................................................61
6.1.1
Dosing regimen.....................................................................................62
6.1.2
Sequence of drug administration...........................................................63
6.1.3
Treatment duration................................................................................64
6.2
Dose modification and dose delay.........................................................................64
6.2.1
Dose modification and dose interruption for EGF816, INC280 and 
Nivolumab.............................................................................................64
6.2.2
Follow-up for toxicities.........................................................................75
6.2.3
Follow up on potential drug-induced liver injury (DILI) cases ............82
6.2.4
Criteria to resume treatment with Nivolumab after dose delay ............82
6.2.5
Treatment of Nivolumab-related infusion reactions and other 
immune-related AEs..............................................................................83
6.3
Concomitant medications ......................................................................................85
6.3.1
Permitted concomitant therapy requiring caution and/or action...........85
6.3.2
Prohibited concomitant therapy ............................................................86
6.4
Patient numbering, treatment assignment, or randomization ................................87
6.4.1
Patient numbering .................................................................................87
6.4.2
Treatment assignment or randomization...............................................87
6.5
Study drug preparation and dispensation...............................................................87
6.5.1
Study drug packaging and labeling.......................................................87
6.5.2
Study drug supply and storage..............................................................87
6.5.3
Study drug compliance and accountability ...........................................88
6.5.4
Disposal and destruction .......................................................................88
7
Visit schedule and assessments .........................................................................................88
7.1
Study flow and visit schedule................................................................................88
7.1.1
Molecular pre-screening........................................................................97
7.1.2
Screening...............................................................................................97
7.1.3
Treatment period...................................................................................98
7.1.4
End of treatment visit including study completion and premature 
withdrawal.............................................................................................99
7.1.5
Follow up period .................................................................................101
7.1.6
Lost to follow-up.................................................................................102
7.2
Assessment types.................................................................................................102
7.2.1
Efficacy assessments...........................................................................102
7.2.2
Safety and tolerability assessments.....................................................105


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7.2.3
Pharmacokinetics ................................................................................108
7.2.4
Biomarkers..........................................................................................111
8
Safety monitoring and reporting......................................................................................114
8.1
Adverse events.....................................................................................................114
8.1.1
Definitions and reporting ....................................................................114
8.1.2
Laboratory test abnormalities..............................................................115
8.2
Serious adverse events.........................................................................................116
8.2.1
Definitions...........................................................................................116
8.2.2
Reporting.............................................................................................116
8.3
Pregnancies..........................................................................................................117
8.4
Warnings and precautions....................................................................................118
8.5
Data Monitoring Committee................................................................................118
9
Data collection and management.....................................................................................118
9.1
Data confidentiality .............................................................................................118
9.2
Site monitoring ....................................................................................................119
9.3
Data collection.....................................................................................................119
9.4
Database management and quality control..........................................................120
10 Statistical methods and data analysis ..............................................................................120
10.1
Analysis sets ........................................................................................................121
10.1.1
Full Analysis Set .................................................................................121
10.1.2
Safety Set ............................................................................................121
10.1.3
Per-Protocol Set ..................................................................................121
10.2
Patient demographics/other baseline characteristics ...........................................122
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................122
10.3.1
Study treatment ...................................................................................122
10.3.2
Concomitant medications....................................................................122
10.3.3
Compliance .........................................................................................122
10.4
Primary objective.................................................................................................122
10.4.1
Variable...............................................................................................122
10.4.2
Statistical hypothesis, model, and method of analysis........................123
10.4.3
Handling of missing values/censoring/discontinuations.....................124
10.4.4
Supportive analyses.............................................................................124
10.5
Secondary objectives ...........................................................................................124
10.5.1
Safety objectives .................................................................................124
10.5.2
Efficacy objectives..............................................................................126
10.5.3
Pharmacokinetics ................................................................................126


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127
10.7
Interim analysis....................................................................................................127
10.8
Sample size calculation........................................................................................127
10.9
Power for analysis of key secondary variables....................................................128
11 Ethical considerations and administrative procedures ....................................................128
11.1
Regulatory and ethical compliance......................................................................128
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................129
11.3
Informed consent procedures...............................................................................129
11.4
Discontinuation of the study................................................................................129
11.5
Publication of study protocol and results.............................................................130
11.6
Study documentation, record keeping and retention of documents.....................130
11.7
Confidentiality of study documents and patient records .....................................131
11.8
Audits and inspections.........................................................................................131
11.9
Financial disclosures............................................................................................131
12 Protocol adherence ..........................................................................................................131
12.1
Amendments to the protocol................................................................................131
13 References (available upon request)................................................................................133
14 Appendices ......................................................................................................................138
14.1
Appendix 1: List of concomitant medications to be used with caution...............138
14.2
Appendix 2: Prohibited concomitant medications...............................................141
14.3
Appendix 3: Bayesian study design set-up, posterior analysis and operating 
characteristics ......................................................................................................142
14.3.1
Statistical model..................................................................................142
14.3.2
Prior specifications..............................................................................142
14.3.3
Operating characteristics.....................................................................143
14.4
Appendix 4: Guidelines for response, duration of overall response, TTF, TT, 
progression-free survival and overall survival (based on RECIST 1.1)..............146
14.5
Appendix 5: Management algorithms .................................................................171
14.6
Appendix 6: Guidelines for viral hepatitis testing for ongoing and new 
patients.................................................................................................................180


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List of figures
Figure 1-1
Best percentage change from baseline in sum of diameters of target 
lesions as per investigator by treatment (Capsule) – Full analysis 
set ..........................................................................................................42
Figure 4-1
Study design..........................................................................................54
Figure 4-2
Study visit flow .....................................................................................55
Figure 6-1
Sequence of drug administration (Group 1: EGF816 and 
Nivolumab; Group 2: INC280 (AM dose) and Nivolumab).................64
List of tables
Table 3-1
Objectives and related endpoints ..........................................................53
Table 6-1
Dose and treatment schedule.................................................................62
Table 6-2
Criteria for omission, delay, or discontinuation of Nivolumab, 
EGF816 and INC280 for patients receiving Nivolumab and 
EGF816 or Nivolumab and INC280 .....................................................66
Table 6-3
Follow-up evaluations for selected toxicities........................................76
Table 6-4
Guidelines for prevention and symptomatic care of rash/skin 
toxicities for all patients........................................................................78
Table 6-5
Guidelines for dose modification and management related to rash 
for Group 1 patients1.............................................................................79
Table 6-6
Criteria for omission, delay, or discontinuation of Nivolumab and 
INC280 for skin toxicity for patients receiving Nivolumab and 
INC280..................................................................................................81
Table 6-7
Guidelines for treatment for Nivolumab induced infusion reactions....84
Table 7-1
Visit evaluation schedule ......................................................................90
Table 7-1b
Visit evaluation schedule (effective after protocol amendment 08 is 
approved)...............................................................................................95
Table 7-2
Imaging or disease assessment collection plan...................................104
Table 7-3
ECOG performance status...................................................................106
Table 7-4
Local clinical laboratory parameters collection plan ..........................106
Table 7-4b
Local clinical laboratory parameters collection plan (effective after 
protocol amendment 08 is approved)..................................................106
Table 7-5
Central ECG collection plan ...............................................................107
Table 7-6
Schedule of blood collection for EGF816 (QD), PK for patients 
participating in the safety monitoring cohort......................................109
Table 7-7
Schedule of blood collection for INC280 (BID) PK for patients 
participating in the safety monitoring cohort......................................109
Table 7-8
Schedule of blood collection for Nivolumab (1 hour infusion) PK 
and immunogenicity for all patients....................................................110


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Table 7-9
Schedule of blood collection for EGF816 (QD) PK for patients 
NOT participating in the safety monitoring cohort.............................110
Table 7-10
Schedule of blood collection for INC280 (BID) PK for patients 
NOT participating in the safety monitoring cohort.............................111
Table 7-11
Biomarker sample collection...............................................................112
Table 10-1
Noncompartmental pharmacokinetic parameters................................127
Table 14-1
Permitted concomitant medications requiring caution........................138
Table 14-2
Prohibited concomitant medication.....................................................141
Table 14-3
Specifications for prior distributions...................................................143
Table 14-4
Operating characteristics of Group 1 Bayesian study design..............145
Table 14-5
Operating characteristics of Group 2 Bayesian study design..............145
Table 14-6
Response criteria for target lesions .....................................................154
Table 14-7
Response criteria for non-target lesions..............................................156
Table 14-8
Overall lesion response at each assessment ........................................157
Table 14-9
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................164
Table 14-10
Options for event dates used in PFS, TTP, duration of response........165


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List of abbreviations
AE
Adverse Event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil Count
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area Under the Curve
BCG
Bacillus Calmette-Guerin
b.i.d.
bis in diem/twice a day
BLRM
Bayesian Logistic Regression Model
BSA
Body Surface Area
CDP
Clinical Development Plan
Cmax
Maximum concentration
CNS
Central Nervous System
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CSR addendum
An addendum to Clinical Study Report (CSR) that captures all the additional 
information that is not included in the CSR
CTCAE
Common criteria terminology for Adverse Events
DCR
Disease control rate
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
DS&E
Drug Safety and Epidemiology Chief Medical Office and Patient Safety (CMO&PS)
ECG
Electrocardiogram
EGFR wt
EGFR wild-type
FISH
Fluorescence In Situ Hybridization
GCN
Gene Copy Number
GGT
Gamma-glutamyl transpeptidase
HBV
Hepatitis B virus
HCV
Hepatitis C Virus
HGF
Hepatocyte Growth Factor
i.v.
intravenous(ly)
ICH
International Conference on Harmonization
ID
Infectious Disease
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IRB
Institutional Review Board
LFT
Liver function test
MTD
Maximum Tolerated Dose
NSCLC
Non-Small Cell Lung Cancer
o.d.
omnia die/once a day
ORR
Overall Response Rate


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PBMC
Peripheral Blood Mononuclear Cells
PD-1
Programmed death-1
PD-L1
Programmed death-ligand 1
PFS
Progression Free Survival
p.o.
per os/by mouth/orally
PHI
Protected Health Information
PPI
Proton Pump Inhibitor
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses
RDE
Recommended dose for expansion
REB
Research Ethics Board
RP2D
Recommended phase two dose
SAE
Serious Adverse Event
SJS
Stevens-Johnson Syndrome
SOP
Standard Operating Procedure
T3
Triiodothyronine
T4
Thyroxin
TBIL
Total Bilirubin
TEN
Toxic Epidermal Necrolysis
TSH
Thyroid-stimulating hormone
Tmax
Time to reach maximum concentration
TTP
Time to Progression
ULN
Upper Limit of Normal
UNK
Unknown
WBC
White Blood Cells
WT
Wild type
WCLC
World Congress on Lung Cancer


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biological samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject or study 
patient
Control drug
A study treatment used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Cohort
A group of newly enrolled patients treated at a specific dose and 
regimen (i.e. treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
EGFR wt
For the purpose of this protocol, EGFR wt is defined as negative for 
exon 19 deletions and for the L858R mutation in EGFR at a minimum; 
however, if more extensive EGFR mutation testing has been 
performed, the tumor must not harbor any known activating EGFR 
mutations in Exons 18-21 in order to be considered EGFR wt.
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). 
This also includes approved drugs used outside of their 
indication/approved dosage, or that are tested in a fixed combination. 
Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required 
or allowed by the protocol when used in within approved 
indication/dosage
Medication number
A unique identifier on the label of each study treatment package which 
is linked to one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment
Subject Number
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller 
functional segments such as screening, baseline, titration, washout, 
etc.
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; 
at this time all study treatment administration is discontinued and no 
further assessments are planned, unless the patient will be followed 
for progression and/or survival


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Randomization number
A unique treatment identification code assigned to each randomized 
patient, corresponding to a specific treatment arm assignment
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc.
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
Stop study participation
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; 
study treatment in this case refers to the investigational and non-
investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently discontinues study treatment for 
any reason
Supportive treatment
Refers to any treatment required by the exposure to a study treatment, 
e.g. premedication of vitamin supplementation and corticosteroid for 
pemetrexed disodium.
Treatment group
A treatment group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts. Cohorts are not expanded, new 
cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints
Withdrawal of Consent
Withdrawal of consent from the study occurs only when a patient does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data


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Protocol summary:
Protocol number
CEGF816X2201C
Title
A phase II, multicenter, open-label study of EGF816 in combination with 
Nivolumab in adult patients with EGFR mutated non-small cell lung cancer 
and of INC280 in combination with Nivolumab in adult patients with cMet 
positive non-small cell lung cancer
Brief title
Study of efficacy and safety of Nivolumab in combination with EGF816 and 
of Nivolumab in combination with INC280 in patients with previously 
treated non-small cell lung cancer
Sponsor and Clinical 
Phase
Novartis and Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
To determine the efficacy and safety of Nivolumab in combination with 
EGF816 and of Nivolumab in combination with INC280 in previously 
treated Non-Small Cell Lung Cancer (NSCLC) patients
Primary Objective(s) 
and Key Secondary 
Objective
To assess 6 month PFS rate of Nivolumab in combination with EGF816 in 
EGFR mutated NSCLC patients and of Nivolumab in combination with 
INC280 in patients with EGFR wild-type (wt) NSCLC
Secondary Objectives
Objective 1: To assess clinical activity of Nivolumab in combination with 
EGF816 and of Nivolumab in combination with INC280 as measured by 
progression free survival, overall response rate, disease control rate and 
overall survival.
Objective 2: To characterize the safety and tolerability of Nivolumab in 
combination with EGF816 and of Nivolumab in combination with INC280
Study design
Open label, phase II study including a safety monitoring cohort
Population
The study will be conducted in patients with histologically and/or 
cytologically confirmed advanced, unresectable and/or metastatic NSCLC
Inclusion criteria

Advanced metastatic and/or unresectable NSCLC

Measurable disease as determined by RECIST version 1.1

ECOG performance ≤2

Patients in Group 1: confirmed T790M EGFR mutation

Patients in Group 2: confirmed EGFR wt
Exclusion criteria

For Group 1: Patients who have received more than one prior line of 
EGFR TKI therapy

For Group 2: Previous treatment with a cMet inhibitor or HGF-targeting 
therapy

Prior treatment with PD1/PD-L1 targeting therapies

Patients who require emergent use of systemic steroids, emergent 
surgery and/or radiotherapy

Patients with interstitial lung disease

Patients with any known or suspected current or past history of 
autoimmune disease
Investigational and 
reference therapy

Nivolumab

INC280

EGF816




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Amendment 8 (12-Mar-2020)
Amendment rationale
The main purpose of this protocol amendment is to introduce the timing for primary Clinical 
Study Report (CSR) and its impact on study conduct. The cut-off date for the primary analysis
will take place after 12 months has elapsed from last patient first treatment. By then, the ongoing 
patients will have been on treatment for between 12 and 60 months, and there will be sufficient 
data for both primary and secondary efficacy objectives evaluation. The duration of disease 
progression follow-up period is modified to remove the efficacy assessment after 12 months 
from last patient first treatment. This amendment also aims to reduce the assessment burden for 
patients while maintaining access to study treatment and monitoring safety. Besides, the 
definition of end of study is refined to allow earlier closure of study by incorporating language 
to include option for ongoing patients in Group 2, who are eligible and are still deriving clinical 
benefit in the opinion of the investigator, to transfer to a Novartis roll-over study or an 
alternative treatment option after the data cut-off for primary analysis as a possible means to 
ensure continued access to study treatment.
In addition, the dose modification guidance and adverse event management algorithm have been 
updated based on new information from INC280 Investigator Brochure edition 11 and 
Nivolumab Investigator Brochure edition 18. This amendment also implements a maximum 
duration of 2 years for Nivolumab treatment as per emerging data from clinical trials conducted 
with Nivolumab.
Other minor changes and corrections were made throughout the protocol for consistency and/or 
clarifications. 
Study Update
This study is currently ongoing. Enrollment in Group 1 has been halted since 17-Dec-2015. 
Enrollment in Group 2 has been halted since 16-Apr-2019. In total, 64 patients have received 
study treatment. As of 16-Jan-2020, all patients in Group 1 have discontinued study treatment 
and there are 4 patients remain on treatment in Group 2 (INC280 + Nivolumab). When this 
amendment becomes effective, the 2 patients in Group 2 who have received Nivolumab beyond 
2 years will discontinue Nivolumab treatment and continue on INC280 alone. These 2 patients 
are immediately eligible for transfer to a Novartis roll-over study or an alternative treatment 
option after the data cut-off for primary analysis. There is 1 patient in Group 2 who have 
previously discontinued INC280 and have been receiving Nivolumab alone. This patient will 
discontinue Nivolumab treatment, have an end of treatment visit and continue with the safety 
and survival follow-up as per Table 7-1b. The remaining patient is still receiving INC280 + 
Nivolumab combination treatment and will reach the 2-year cap in Apr-2021. By then, this 
patient will also become eligible for transfer to a Novartis roll-over study or an alternative 
treatment option.
Changes to the protocol
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.


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
Section 1.2.3.2.2: updated to include the recent events of myocarditis and hepatitis 
experienced by 1 patient who received INC280 in combination with PDR001 (a PD-1 
inhibitor) in Novartis study CPDR001J2201

Section 2.5: added this section to illustrate the rationale for implementing a maximum 
duration of 2 years for Nivolumab treatment.

Section 4.1: updated the definition of end of treatment period, added language to include 
the possibility of patients being transferred to a Novartis roll-over study or an alternative 
treatment option after the data cut-off for primary analysis, added that the maximum 
treatment duration of Nivolumab cannot exceed 2 years, added instruction on treatment 
and study visit arrangement following the approval of protocol amendment 08, and 
clarified that for patients who transfer to a Novartis roll-over study will not enter the
safety follow-up period.

Section 4.3: updated the definition of end of study and removed an obsolete definition on
when to perform primary analysis for purpose of clarification. 

Section 6.1: added language to specify that the maximum duration of Nivolumab 
treatment will be 2 years and instruction on treatment and study visit arrangement 
following the approval of protocol amendment 08.

Table 6-2: dose modification criteria for myocarditis have been added.

Section 7.1: added Table 7-1b for a simplified study assessment schedule, added 
instruction to refer to Table 7-1b after protocol amendment 08 is approved, and modified 
the duration of disease progression follow-up period and the definition of end of survival 
follow-up period.

Section 7.1.3: updated the definition of end of treatment period and added instruction on 
treatment and study visit arrangement following the approval of protocol amendment 08.

Section 7.1.4: added language to specify that patients who transfer to a Novartis roll-over 
study or an alternative treatment option to continue provision of study treatment will 
complete end of treatment procedures.

Section 7.1.4.1: updated language to describe the data that would have been collected at 
subsequent visits will be considered missing, to specify all efforts should be made to 
complete a final assessment upon withdrawal of consent, and how is Novartis handling the 
already collected study information. 

Section 7.1.5: added language to specify that patients who transfer to a Novartis roll-over 
study or an alternative treatment option to continue provision of study treatment will not 
complete the follow-up for safety, disease progression and survival.

Section 7.2: amended to reduce assessments, to remove central review of ECG, to remove 
PK and immunogenicity samples collection, to inform no efficacy assessments will be 
done after 12 months has elapsed from last patient first treatment for the still ongoing 
patients and patients in disease progression follow-up. Table 7-4b is added for a simplified 
local clinical laboratory parameters collection plan.

Section 10: added definitions of the timing of primary analysis.

Section 10.4: updated the timing of primary analysis.

Appendix 5: updated the immuno-oncology related adverse event management algorithm.


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
Other minor changes and corrections were made throughout the protocol for consistency 
and/or clarifications. 
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 approval 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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Amendment 7 (21-Jun-2018)
Amendment rationale
The main purpose of this protocol amendment is to update the guidelines for EGF816/INC280 
dose modification/ discontinuation in the context of non-infectious pneumonitis/interstitial lung 
disease, to be consistent across different INC280 studies, as requested by a regulatory authority. 
Study Status
This study is currently on-going. As of 6-June-2018, 59 patients have been enrolled into this 
study: 18 in Group 1 (EGF816 + Nivolumab) and 41 in Group 2 (INC280 + Nivolumab). 
Enrollment in Group 1 has been halted since 17-Dec-2015.
Changes to the Protocol
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.

Table 6-2, Dose reduction and interruption criteria: Recommended dose modifications for 
ILD like events/pneumonitis have been added.

Section 6.2.2 and Table 6-3, Follow-up for toxicities are updated to include guidance for 
ILD/pneumonitis.

Section 14.6, Appendix 6 – Guidelines for EGF816/INC280 dose modification and 
discontinuation for pneumonitis/ILD have been removed. 
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 approval prior to
implementation.


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Amendment 6 (29-Jan-2018)
Amendment rationale
The rationale for this amendment is as follows:

The nivolumab Investigator’s Brochure (IB) Edition 16 (Version date 23-Jun-2017) has 
been updated with new recommendations for management of myotoxicity. In response to a 
health authority request, this amendment will add these recommendations. Since clinical 
safety information provided for nivolumab in Section 1.2.3.2.2 is outdated, the single 
agent safety data were replaced with a reference to the nivolumab prescribing information 
and the current IB.

New data on effects of food and concomitant medications on INC280 exposures became 
available.  Therefore, the protocol has been updated accordingly to allow INC280 to be 
taken with or without food and to update the prohibited concomitant medications and the 
permitted concomitant medications to be used with caution for Group 2 patients.

Pneumonitis/interstitial lung disease has been added as a potential risk for INC280.

Recommendations for discontinuing patients from study treatment versus from only one 
study drug in the setting of specific adverse events were clarified in Table 6-2.
Study status
This study is currently on-going. As of 07-Dec-2017, 43 patients have been enrolled into this 
study: 18 in Group 1 (EGF816 + Nivolumab) and 25 in Group 2 (INC280 + Nivolumab). 
Enrollment in Group 1 has been halted since 17-Dec-2015.
Changes to the protocol
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 underline for insertions.
Section 1.2.2.2 Clinical experience – Updated clinical safety text to align with the program 
standard language for INC280 protocols.
Section 1.2.2.2.2: Updated the clinical pharmacokinetics text for INC280 based on newly 
available drug-drug interaction (DDI) data and added a statement based on the preliminary PK 
data from study CINC280A2108 that showed no food effect of high fat meal on INC280 
exposure.
Section 5.3 Exclusion Criteria – The following changes were made to this section

Exclusion criterion 17 was updated to reflect changes in INC280 PK and concomitant 
medication restriction related changes.

Exclusion criterion 22 was added to exclude patients with a history of Long QT syndrome 
or family history of idiopathic sudden death, to align with current standard program 
exclusion criteria

Exclusion criterion 23 was added to exclude patients who cannot discontinue medications 
with a known risk of Torsades de Pointes, to align with current standard program 
exclusion criteria


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Section 6.1.1: Several changes were made to allow administration of INC280 with or without 
food.
Table 6-2 Criteria for omission, delay, or discontinuation of Nivolumab, EGF816 and INC280 
for patients receiving Nivolumab and EGF816 or Nivolumab and INC280—

Added a dedicated entry for myotoxicity, specifying nivolumab dose delay and specialist 
referral for any nivolumab-related Grade ≥ 2 myotoxicity and nivolumab discontinuation 
for nivolumab-related Grade 3 myocarditis or nivolumab-related Grade 4 other 
myotoxicity

Where applicable, changed “study drug” to “study treatment” for circumstances in which a 
patient should be discontinued from study treatment rather than from only one study drug.
Section 6.3.1: Permitted concomitant therapy requiring caution was updated based on the newly 
available preliminary DDI data from other INC280 studies. Patients receiving INC280 are 
affected by this change.
Section 6.3.2: Updated text based on available preliminary DDI data from other INC280 studies.
Section 14:

Appendix 1 and 2 have been updated to reflect recent revisions to prohibited and 
permitted concomitant therapies for patients receiving INC280.  These changes align with 
the program standard language for INC280 protocols.

Appendix 6 “Guidelines for EGF816/INC280 dose modification/ discontinuation in the 
context of non-infectious pneumonitis/interstitial lung disease” the title and the text was 
updated to include INC280.  Where applicable in this section, “study drug” was changed 
to “study treatment” for circumstances in which a patient should be discontinued from 
study treatment rather than from only one study drug.
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 approval 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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Amendment 5 (13-Apr-2017)
Amendment rationale

The primary purpose of this amendment is to introduce the 150 mg strength of INC280 
tablet formulation. This is to allow patients to take a dose of 300 mg when the 50 mg
strength  is discontinued.

Further, clarifications have been made to the exclusion criteria for Hepatitis B and 
Hepatitis C to ensure consistent interpretation. Previously the clarification was included in 
Appendix 7. With this amendment the key points from Appendix 7 have been included as 
a clarification note immediately under exclusion criterion 10.

Updates were made to section 1.2.2, Overview of INC280, subsections 1.2.2.2.1 Clinical 
Safety and 1.2.2.2.2 Clinical Pharmacokinetics to reflect the recently updated INC280 
Investigator’s Brochure (IB).

A requirement was added that pregnancy tests occurring between screening and the 30-
day safety follow-up, inclusive, must be serum tests because of the higher sensitivity of 
serum pregnancy tests as compared to urine pregnancy tests.
Changes for consistency and administrative purposes have also been made where necessary 
throughout the protocol.
Study status
This study is currently on-going. As of 02-Mar-2017, 27 patients have been enrolled into this 
study: 18 in Group 1 (EGF816 + Nivolumab) and 9 in Group 2 (INC280 + Nivolumab). 
Enrollment in Group 1 has been halted since 17-Dec-2015.
Changes to the protocol
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 underline for insertions.
Section 1.2.2.2 Clinical experience - Added information to reflect the recently updated INC280 
Investigator Brochure (IB). 
Section 1.2.2.2.2 Clinical Pharmacokinetics – Updated to include the most recent data 
Section 5.3 Exclusion Criteria – Added information to clarify that viral hepatitis screening tests 
related exclusion apply to all patients.
Section 5.3 Exclusion Criteria – Added a new exclusion criterion related to Gastro Interstinal 
(GI) function impairment for patients participating in Group 2 (INC280 and Nivolumab 
combination arm). 
Section 6.2.1 Dose modification and dose interruption for EGF816, INC280 and Nivolumab –
Table 6-2 updated to include criteria for dose modification of INC280 for nausea, vomiting and 
peripheral edema.
Section 6.5.1 Study drug packaging and labeling – Added information about the new INC280 
strength of 150 mg.
Section 7.1 Visit evaluation schedule – Added serum pregnancy tests.


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Section 7.2.2.5.4 Pregnancy and assessments of fertility – Language was updated to require the 
serum pregnancy tests during the treatment phase.
Section 11.5 – Publication of study protocol and results – Language updated to match recent 
revisions in the publication policy and the revised new protocol template 
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 approval 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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
Section 4.1: Text was updated to reflect the plan to sub-divide Group 2 (EGFR-wild-type) 
into Sub-group A (high cMet) and Sub-group B (low cMet). Additional changes to this 
section include insertion of a reference to Section 5.1 for the target enrollment and 
deletion of repetitive text.

Section 5.1: Clarified that enrollment in Group 1 has been halted. Target enrollment in 
group 2 is now updated to at least 50, such that approximately 20 patients with high cMet 
are enrolled in Sub-group A and approximately 30 patients with low cMet are enrolled in 
Sub-group B. Though cMet criteria for cMet high have not changed, the previous version 
of the protocol did not provide the cMet requirement to qualify for high cMet, this has 
now been added.

Section 5.3: Deleted exclusion criteria related to the use of long acting proton pump 
inhibitors. Safety laboratory related exclusion criteria were updated for patients being 
screened for Group 2. Additional clarifications were made to other exclusion criteria to 
match revised INC280 concomitant medication restrictions.

Section 6.2.1: Clarified the circumstances under which a patient must be discontinued 
from EGF816 or INC280 following treatment interruption. Clarified exceptions to the 
requirement to discontinue nivolumab following a nivolumab dose interruption of >6 
weeks.

Table 6-2: Clarification and editorial changes were made to this table.

Section 6.2.2: This section was added to provide recommendations on follow-up 
evaluations for patients experiencing hepatic toxicities.

Section 6.2.3: Added a section to provide guidance on follow-up on potential drug induced 
livery injury observed in patients.

Section 6.3: Clarified the requirements to taper the dose of systemic corticosteroids prior 
to resuming nivolumab.

Section 6.3.1: Several changes have been made to match recent updates to permitted 
concomitant therapy for patients receiving INC280 treatment. Also clarified that Localized 
palliative non-invasive therapy is allowed and provided instructions on holding the study 
drugs for patients who require such therapy.

Section 6.3.2: Several changes have been made to match recent updates to prohibited 
concomitant therapy for patients receiving INC280 treatment.

Table 7-1: Visit schedule was updated to reflect additional biopsies and blood collections 
for new analysis added with this amendment.

Section 7.1.1: Text updated to clarify the molecular pre-screening sample requirement and 
the analysis expected to be performed on that sample.

Table 7-2: Frequency of imaging related assessments was reduced starting with Cycle 13.

Table 7-11: Updated most of the table to reflect additional biomarker samples collections 
and the planned analysis.

Section 7.2.4.1: Biomarker tumor assessment section updated to reflect additional 
assessments and time points added with this amendment.

Section 7.2.4.2: Inserted text related to additional blood sample collection for cytokine 
assessments at various time-points.




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Amendment 3
Amendment rationale
The primary purpose of this amendment is to implement changes that were introduced with two 
Urgent Safety Measures (USMs) that were issued on December 17, 2015 and January-28, 2016. 
The first USM was issued after a fatal case of toxic epidermal necrolysis (TEN) occurred in a 
patient in Group 1 (EGF816 plus nivolumab). Although TEN is reported as a rare adverse event 
associated with nivolumab and is listed within the informed consent form for this study, 
Novartis could not exclude the possibility that this adverse event was related to the combination 
of EGF816 and nivolumab. Novartis therefore instituted a temporary halt to enrollment into 
Group 1 (EGF816 plus nivolumab), effective December 10, 2015, to allow for a thorough 
review of available data. Novartis also issued an USM to provide guidance on the re-consent 
and management of ongoing patients in Group 1 (EGF816 plus nivolumab), and to provide 
updated skin toxicity management guidelines for Group 1 patients.
The second USM was issued after a fatal case of pneumonitis occurred in a patient in Group 1. 
Pneumonitis is an expected adverse event associated with nivolumab monotherapy. According 
to the U.S. Prescribing Information, pneumonitis, including interstitial lung disease, was 
reported in 3.4% of patients treated with single-agent nivolumab in a phase 3 study of metastatic 
non-squamous NSCLC. The fatal case occurring in Group 1 of this study (CEGF816X2201C) 
was the second case of pneumonitis in 18 patients treated in this group; in addition, a case of 
interstitial lung disease was also reported in another patient in this group. 
Pneumonitis/interstitial lung disease is a rare adverse event associated with EGF816 
monotherapy, having been reported in 2 patients of 146 treated with the single agent as of 
January 19, 2016. These data suggest that the rate of pneumonitis may be higher for EGF816 
in combination with nivolumab than for nivolumab alone.
To minimize the risk to patients participating in the CEGF816X2201C study, the following 
changes have been made to the protocol:

Halt of enrollment to Group 1 (EGF816 plus nivolumab).

Permanent discontinuation of nivolumab for all ongoing patients in Group 1 (EGF816 plus 
nivolumab). Ongoing patients in Group 1 may remain on EGF816 as a single agent after 
re-consent of the patient.

Addition of a provision that if at any time during the study Novartis determines that a 
lower dose level of EGF816 or INC280 should be explored, enrollment to the ongoing 
higher dose cohort may be stopped and ongoing patients may have their dose of EGF816 
or INC280 reduced.

Altering the dose-modification table (Table 6-2) to refer to a separate section (Section 
6.2.1.1) for separate skin toxicity management guidelines for patients in Groups 1 and 2.

Moving Appendix 6 to Section 6.2.1.1 and reflecting the recommendation that all rashes 
in Group 1 patients should be considered possibly related to EGF816 and nivolumab, and 
that skin toxicity grade-specific actions should be taken with both drugs as defined in 
Table 6-4. Separate guidance for non-maculopapular rashes was also removed.


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
Changing Table 14-12 to Table 6-4 and providing grade-specific skin toxicity 
management guidelines appropriate to the presumption that all rashes are attributable to 
both EGF816 and nivolumab.
Changes to the protocol
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
List of abbreviations
Abbreviations added for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Section 1.2.3.2.2 Clinical Safety – Added descriptions of the case of TEN and pneumonitis, and 
the rationales for their possible attribution to the combination of EGF816 and nivolumab.
Section 4.1 Description of Study Design –
Added the statements that, as of Amendment 3, enrollment to Group 1 has been halted and 
ongoing patients in Group 1 must be discontinued from nivolumab.
Added the provision that if at any time during the study Novartis determines that a lower dose 
level of EGF816 or INC280 should be explored, enrollment to the ongoing higher dose cohort 
may be stopped and Novartis may require the dose of EGF816 or INC280 to be reduced for any 
ongoing patients.
Table 6-2 Criteria for omission, delay, or discontinuation of Nivolumab, EGF816 and INC280
for patients receiving Nivolumab and EGF816 or Nivolumab and INC280 was updated
Created 6.2.1.1. Guidelines for prevention and management of rash/skin toxicities. Section 
6.2.2 deleted bullet “Patients who have not experienced a Grade 3 Nivolumab related skin AE 
may resume treatment in the presence of Grade 2 skin toxicity
Section 8.1.1 Added a statement permitting Novartis to centrally review any remaining clinical 
sample obtained from a patient as part of the evaluation of an adverse event.
Section 10.1.3 Per-Protocol Set, under bullet Group 1 patients, a sub-bullet “or have received 
agents targeting EGFR T790M” has been deleted. Under bullet Group 2 patients, 
“(adenocarcinoma)” has been deleted from the first bullet.
Section 14.6, Appendix 6 Guidelines for prevention and symptomatic care of rash/skin 
toxicities in Group 1 patients -

Moved to Section 6.2.1.1

Updated title to “Guidelines for prevention and management of rash/skin toxicities”

Added guidelines for education of patients on the importance of notifying investigators 
immediately if a skin rash occurs and on preventative care of the skin.

Added instructions for investigators to call Novartis if a patient develops a rash of Grade 2 
or higher

Added instructions to attribute all rashes in Group 1 patients to both EGF816 and 
nivolumab, and to refer to Table 6-4 for management of rashes and for actions to be taken 
with EGF816 in the event of rash


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
Table 14-11 Guidelines for prevention and symptomatic care of rash/skin toxicities, 
moved to Section 6.2.1.1 and changed the table number and title to “Table 6-3 Guidelines 
for prevention and symptomatic care of rash/skin toxicities for all patients”

Table 14-12 Management and dose modification for maculopapular rash moved to Section 
6.2.1.1 and changed the table number and title to “Table 6-4 Guidelines for dose 
modification and management related to rash for Group 1 patients”

Modified the table to include actions to be taken with EGF816 and nivolumab as well as 
additional management guidelines for each grade of rash

Removed Table 14-13 Management and dose modification for other rashes including 
acneiform rash as all rashes in Group 1 patients are to be managed similarly
Section 
14.7 
Appendix 
6 
Guidelines 
for 
the 
Management 
of 
Non-Infectious 
Pneumonitis/Insterstitial Lung Disease—This section is now Section 14.6. Modified the title to 
“Appending 6 Guidelines for EDG816 dose modification/ discontinuation in the context of non-
infectious pneumonitis/ interstitial lung disease. Added the statement that all patients should be 
educated on the importance of notifying the investigator immediately with any new respiratory 
symptoms. Removed two columns “Required investigations” and “Management of 
pneumonitis”.
IRB/IEC Approval
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 approval 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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Amendment 2
Amendment rationale
The primary purpose of this amendment is to address changes requested by Health Authorities. 
The changes include:

Clarifying the definition of “toxicity as independent of study drug” as it appears in the 
heading of the second column in Table 6-2 Criteria for interruption, omission, delay, re-
initiation and discontinuation of Nivolumab, EGF816 and INC280 for patients receiving 
Nivolumab and EGF816 or Nivolumab and INC280”

Modify the protocol guidelines for hepatotoxicity for cases meeting Hy’s Law criteria

Provide guidelines for dose modification or discontinuation for EGF816-related interstitial 
lung disease
In addition, the following changes have been made:

Update guidelines for dose modifications, dose interruptions and discontinuation of 
EGF816, INC280, and nivolumab due to hepatotoxicity associated with isolated elevations
of AST or ALT, or total bilirubin

Provide clarification to criteria for resuming nivolumab treatment after dose delay

Update list of prohibited concomitant medications to include live vaccines, for patients 
dosed with EGF816

Added additional guidance for managing EGF816-associated rash
Other sections of the protocol have been modified to provide further granularity and clarity.
Additionally, administrative and typographical errors have been corrected throughout the
document.
Changes to the protocol
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
List of abbreviations
Abbreviations added for laboratory tests and tuberculosis vaccine
Section 6.2.1 Dose modification and dose interruption for EGF816, INC280 and Nivolumab –
For either EGF816 or INC280 – Clarified text to allow a maximum of two dose interruptions 
per patient
Table 6-2 – Criteria for interruption, omission, delay, re-initiation and discontinuation of 
Nivolumab, EGF816 and INC280 for patients receiving Nivolumab and EGF816 or Nivolumab 
and INC280

Update table title to “Criteria for omission, delay, or discontinuation of Nivolumab, 
EGF816 and INC280 for patients receiving Nivolumab and EGF816 or Nivolumab and 
INC280”


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
Clarified table header to define toxicity during a cycle of therapy as “related to EGF816 or 
INC280” rather than “independent of study drug”

Clarified “Bilirubin” and “AST or ALT” sections as “Isolated Total Bilirubin elevation” 
and “Isolated AST or ALT elevation”

Added additional guidance for isolated total bilirubin and isolated AST or ALT elevation 
associated with EGF816, INC280, and nivolumab

Provided clarification and additional guidance for combined elevations of AST or ALT 
and total bilirubin toxicities associated with EGF816, INC280, and nivolumab

Additional clarifications and administrative updates as required
Section 6.2.2 Criteria to resume treatment with Nivolumab

Updated title to “Criteria to resume treatment with Nivolumab after Dose Delay”

Removed exception “patients with combined Grade 2 AST/ALT and total bilirubin values 
meeting discontinuation parameters should have treatment permanently discontinued”
Section 6.3.2 Prohibited concomitant therapy – Added “live vaccines (e.g., intranasal influenza, 
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines) 
should not be administered while a patient is dosed with EGF816 and for 30 days after the last 
dose of EGF816”
Appendix 2 Prohibited Concomitant Medications – Added live vaccines, e.g., intranasal 
influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a 
typhoid vaccines
Appendix 5 Management Algorithms – various administrative changes made
Appendix 6 Guidelines for prevention and symptomatic care of rash/skin toxicities – Updated 
to include adverse event management and action taken with study drug and dose modifications 
for EGF816-related maculopapular rash and other rashes including acneiform rash
Appendix 6 Guidelines for the management of non-infectious pneumonitis/interstitial lung 
disease – Updated to include action taken with study drug and dose modifications
Appendix 7 Guidelines for Viral Hepatitis testing and for ongoing and new patients – Provided 
clarification that eligible patients who are positive for HBsAb and negative for HBV-DNA 
should also have a history of Hepatitis B vaccination
IRB/IEC Approval
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 approval prior to 
implementation.


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Amendment 1
Amendment rationale
The primary purpose of this amendment is to address changes requested by Health Authorities. 
The changes include:

Providing additional guidelines for hepatic adverse event management for EGF816 and 
INC280 study medications.

Clarifying that in the United States, in the absence of an approved investigational drug 
exemption (IDE), assays for determination of cMet dysregulation will be performed only 
on archival samples.

Providing updated contraception guidance following nivolumab treatment, in alignment 
with guidelines provided in the nivolumab Investigator Brochure.

Adding simvastatin to the list of prohibited concomitant medication since simvastatin is a 
substrate of CYP3A4, CYP2C8 and OATP1B1.

Excluding patients with a history of allergy or hypersensitivity to nivolumab drug 
components.

Implementing HIV testing at screening for patients in Germany.
In addition, the following changes have been made:

Clarifying tests to be conducted at screening for Hepatitis B/C based on the Urgent Safety 
Measures issued on 8-Jul-2015 to all sites and investigators participating in the study 
CEGF816X2201C

Providing new clinical safety information for EGF816 and INC280.

Providing guidelines for prevention and symptomatic care of rash/skin toxicities and 
updating guidelines for skin toxicity management and dose modification.

Providing additional guidelines for monitoring and management of pneumonitis and 
interstitial lung disease.

Clarifying that samples collected from patients before withdrawal of consent can be 
retained and analyzed at future dates and results can be used for reporting purposes.

Clarifying that alternative dose cohorts may be opened after reviewing the data from the 
safety monitoring cohort during or/and at the end of the six week period after discussion 
and agreement between Novartis and investigators
Other sections of the protocol have been modified to provide further granularity and clarity.
Additionally, administrative and typographical errors have been corrected throughout the 
document.
Changes to the protocol
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.
List of abbreviations


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Abbreviations added for biological samples, withdrawal of consent and updated abbreviations 
for study treatment discontinuation.
Section 1.2.1.1 Clinical experience
Updated safety information for EGF816 based on new data from clinical trial CEGF816X2101.
Section 1.2.2.2.1 Clinical experience
Updated safety information for INC280 based on new data from clinical trial CINC280X2202.
Section 2.2 Rationale for the study design
Clarification added that alternative dose cohorts may be opened after reviewing the data from 
the safety monitoring cohort during or/and at the end of the six week period after discussion 
and agreement between Novartis and investigators
Section 4.1 Study design
Clarification added that if there are no safety concerns from the safety monitoring cohort and a 
lower dose is selected based on other ongoing studies, no additional safety monitoring cohort 
is needed and enrollment may proceed to reach the planned sample size at the selected lower 
dose. In addition, clarification added to state that based on emerging data, the safety-review 
meeting between Novartis and principal investigators may take place prior to completion of six 
weeks for study continuation to address potential safety concerns.
Molecular pre-screening – Clarification added that tumor tissue must be submitted at pre-
screening for determination and/or confirmation of protocol specific pre-requisite genetic 
alterations.
Section 5.2 Inclusion criteria –
Removed requirement of a mandatory pre-screening biopsy from criterion #6.
Section 5.3 Exclusion criteria - Modified criteria #19 and #20 to update contraception period 
for women of child bearing potential and for men who are sexually active with women of child 
bearing potential.
Added criterion #5 to state that patients with history of allergy or hypersensitivity to nivolumab 
study drug components will be excluded from the study
Section 6.2.1 Table 6-2

Added clarification for dose modification for hepatic adverse event management for 
EGF816 and INC280

Added clarification for dose modification for rash guidelines.
Section 6.3.2 Prohibited concomitant therapy.
Addition of Simvastatin, a substrate of CYP3A4, CYP2C8 and OATP1B1, as a prohibited 
medication for INC280/Nivolumab combination.
Section 7 Visit schedule and assessment.

Deleted blood sampling at cycle 6 for Nivolumab PK for consistency with Table 7-8 in 
Section 7.2.3.2.


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
Clarified that PK samples will be collected at disease progression for consistency with 
Tables 7-6 to 7-10

Added footnote to indicate that vital sign assessment is only required for patients at 
C2D14.

Added a footnote indicating that for United States (US) patients, only archival tumor 
sample will be used for determination/confirmation of cMet dysregulation.

Clarified that fresh biopsy will not be repeated at screening if performed at pre-screening.

Updated whole blood sampling for genetic analysis for consistency with text in Table 7-
11.

Added HIV testing at screening for patients in Germany.

Added Hepatitis B/C testing at screening to Table 7-1.

Edited/added footnotes accordingly.
Section 7.1.4.1 Added a section for withdrawal of consent - Text added to clarify that all 
samples/results collected from patients before withdrawal of consent can be retained and 
analyzed at future dates and results can be used for reporting purposes.
Section 7.1.4.2 Criteria for premature withdrawal updated for clarity.
Section 7.1.5 Follow up period
Added text to clarify that data collected should be added to Adverse Event CRF and 
concomitant medication CRF.
Section 7.1.6 Added a section for Lost to follow up
Added text to clarify that procedures for loss to follow up.
Section 7.2.2.5 Table 7-4 Local clinical laboratory parameters collection plan

Clarified tests to be conducted at screening for Hepatitis B/C based on the Urgent Safety 
Measures issued on 8-Jul-2015 to all sites and investigators participating in the study
CEGF816X2201C

Added HIV test at screening for patients in Germany.
Section 7.2.3.2 Pharmacokinetic and immunogenicity sampling schedule - Added a blood 
sampling timepoint to Table 7-8 for Nivolumab immunogenicity and pharmacokinetics.
Section 7.2.4 Biomarkers Table 7-11 - Updated to specify that cMet detection/confirmation of 
cMet dysregulation will be performed on archival tumor samples only for US patients.
Section 10 Statistical methods and data analysis
Added text to clarify that data from patients in safety monitoring cohorts treated at doses 
different from the respective selected dose will be analyzed as separate groups for safety and 
BOR.
Appendix 1 List of concomitant medications to be used with caution - Addition of P-gp 
substrate (dabigatran) and CYP2D substrate (perhexiline) and deletion of tizanidine.
Appendix 2 Prohibited Concomitant Medications - Addition of simvastatin to the list.


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Appendix 6 Guidelines for prevention and symptomatic care of rash/skin toxicities was added 
Appendix 7 Guidelines for management of non-infectious pneumonitis/interstitial lung disease 
was added.
Appendix 8 Guidelines for screening and monitoring for hepatitis B and C virus were added.
IRB/IEC Approval
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 approval 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
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Lung cancer is a major public health problem that accounts for 13% (1.6 million) of the total 
cancer cases and 18% (1.4 million) of cancer deaths (Jemal et al 2011). The American Cancer 
Society estimated 159,390 deaths from lung cancer in the United States for 2009 alone 
(Sangodkar et al 2010). In China, there were 497,908 new cases and 428,936 deaths in 2005, 
the highest for any malignant tumor (Wu et al 2007). Despite the identification of specific 
targets (1) progression on therapeutic agents designed to inhibit those targets occurs (e.g., 
EGFRT790M); (2) development of additional therapeutic agents that inhibit other targets is 
critical (e.g., cMet); and (3) development of combinations of targeted therapies in conjunction 
with immunotherapy is necessary.
Epidermal growth factor receptor (EGFR) has been proven to be a key therapeutic target for 
lung cancer. EGFR inhibitors, like erlotinib (Tarceva) and gefitinib (Iressa), have an established 
role in the treatment of non-small cell lung cancer (NCSLC). Importantly, clinical response is 
correlated with the presence of certain EGFR mutations, primarily exon 19 deletions and the 
L858R substitution, hereafter referred to as EGFR-mutant (Lynch 2004, Paez 2004, Mok 2009). 
For EGFR mutant NSCLC gefitinib or erlotinib is currently used as the first-line therapy world-
wide. However, despite the dramatic responses to such inhibitors, patients ultimately progress. 
In 50-60% of these cases, a secondary point mutation in EGFR occurs resulting in a threonine-
to-methionine amino acid change at position 790 of EGFR (T790M) causing resistance to 
gefitinib or erlotinib (Kobayashi 2005, Kosaka 2006). Third generation (i.e. irreversible; WT 
EGFR sparing; with relatively equal potency for activating EGFR mutations L858R, ex19del 
and acquired T790M) EGFR inhibitors are beginning to enter clinical development and are 
showing significant initial promise (e.g., CO-1686: 67% (6/9) (PRs) in T790M+ NSCLC 
patients (WCLC 2013), AZD9291: 50% (9/18) PRs in 18 T790M+ NSCLC patients (WCLC 
2013). However, it is likely that even third generation EGFR inhibitors may not be sufficient to 
achieve long-term disease control.
In human malignant disease, the cMet pathway is one of the most frequently dysregulated 
pathways. Increased activity of the cMet kinase triggers a highly diverse set of signaling 
cascades, resulting in pleiotropic effects on tumor cells. cMet mutations have been identified in 
primary tumors as well as metastatic lesions of several other cancers, including gastric, head 
and neck, liver, ovarian, non-small cell lung and thyroid cancers (Liu 2008, Lorenzato et al 
2002). Among them, splicing mutations deleting the juxtamembrane domain of the exon 14 
region was identified in primary resected non-small cell lung cancer (Onozato 2009), and was 
also shown to be functionally activating through stabilizing and delaying the internalization of 
the receptor (Kong-Beltran 2006). The existence of such mutations has been confirmed from 
the latest TCGA (The Cancer Genome Atlas) data, which suggested 4.3% cMet exon 14 
skipping mutations in 230 NSCLC adenocarcinoma samples (cbioportal.org/public-portal/, 
TCGA publication, Nature, in press for 2014). Using various biochemical, genetic and 
pharmaceutical approaches, specific downregulation of HGF or cMet expression or inhibition 
of cMet kinase activity in HGF/cMet driven tumor cells was demonstrated to significantly 
decrease cell proliferation, survival, migration and invasion in vitro, and reduce tumorigenic 


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and metastatic potential in vivo (Buchanan 2009, Burgess 2006, Tomioka 2001, Zou 2007). 
Despite these efforts, there are no cMet inhibitors or antagonists approved for the treatment of 
cancer. Currently, several cMet kinase inhibitors are being evaluated in clinical trials (Comoglio 
2008, Liu 2008). Despite promising early data, it is likely that cMet inhibitors as single agents 
will not be sufficient and thus, combination with other therapies needs to be pursued early.
In addition to its role within tumor cells, cMet signaling also plays a role in immune cells. 
Specifically, HGF/cMet signaling in monocytes has been demonstrated to shift their 
differentiation toward regulatory dendritic cells, which in turn inhibit T cell activation (Rutella 
2006). Therefore, inhibition of cMet in monocytes may result in enhanced anti-tumor T cell 
responses.
Cancer immunotherapy relies on the premise that tumors can be recognized as foreign rather 
than as self and can be effectively attacked by an activated immune system. An effective 
immune response in this setting is thought to rely on immune surveillance of tumor antigens 
expressed on cancer cells that ultimately results in an adaptive immune response and cancer cell 
death. Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer 
cells to evade immunosurveillance and escape effective innate and adaptive immune 
responses.(Jemal et al 2011, Pardoll et al 2007, Zitvogel et al 2006, Dunn et al 2002) Current 
immunotherapy efforts attempt to break the apparent tolerance of the immune system to tumor 
cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex 
process involving the integration of numerous positive as well as negative co-stimulatory 
signals in addition to antigen recognition by the T-cell receptor (TCR) (Jemal et al 2011), 
Zitvogel et al 2006, Dunn et al 2002). Collectively, these signals govern the balance between 
T-cell activation and tolerance. PD-1 is a member of the CD28 family of T-cell co-stimulatory 
receptors that also includes CD28, CTLA-4, ICOS, and BTLA.29. PD-1 signaling has been 
shown to inhibit CD-28-mediated upregulation of IL-2, IL-10, IL-13, interferon-g(IFN-g) and 
Bcl-xL. PD-1 expression also been noted to inhibit T cell activation, and expansion of 
previously activated cells. Evidence for a negative regulatory role of PD-1 comes from studies 
of PD-1 deficient mice, which develop a variety of autoimmune phenotypes (Sharpe et al 2007). 
These results suggest that the PD-1 blockade has the potential to activate anti-self T-cell 
responses, but these responses are variable and dependent upon various host genetic factors. 
Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of tolerance to self 
antigens.
In vitro, Nivolumab binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and inhibits the 
binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 1 nM). Nivolumab binds specifically to 
PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-4 and BTLA. 
Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement of both 
proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a CMV 
re-stimulation assay with human PBMC, the effect of nivolumab on antigen specific recall 
response indicates that Nivolumab augmented IFN-g secretion from CMV specific memory 
T cells in a dose-dependent manner versus isotype-matched control. In vivo blockade of PD-1 
by a murine analog of nivolumab enhances the anti-tumor immune response and result in tumor 
rejection in several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02) 
(Wolchok et al 2009). Several anti-PD1 compounds have already entered the clinic with 


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promising efficacy to date in lung cancer. In a Phase Ib (n=122) nonrandomized trial targeting 
pretreated advanced NSCLC patients, Nivolumab showed ORR=16.1%; mOS=9.6mo; 1yr 
OS=43%, and a 2yr OS=32% While in a chemotherapy naïve setting, Nivolumab in a Phase Ib 
showed mPFS 36.1weeks and 1yr OS=75%. Furthermore, Nivolumab has been combined safely 
with both cytotoxic platinum doublets at 5 or 10mg/kg as well as with erlotinib 150mg po qd 
without DLTs in safety determining cohorts (Getting et al 2014, Antonia et al 2014).
Despite these advancements in treatment, lung cancer remains a significant medical need. Both 
targeted therapies and immunotherapies show promise. This study is designed to test the 
hypothesis that a combined small molecule targeted-immunotherapy approach can provide 
synergistic benefit.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of EGF816
EGF816 is a targeted covalent irreversible EGFR inhibitor that selectively inhibits activating 
and acquired resistance mutants (L858R, ex19del and T790M), while sparing WT EGFR. 
EGF816 has shown significant efficacy in EGFR mutant (L858R, ex19del and T790M) cancer 
models (in vitro and in vivo) with no indication of WT EGFR inhibition at efficacious 
concentrations.
1.2.1.1
Non-clinical experience
1.2.1.1.1 Non-clinical pharmacokinetics and metabolism
EGF816 exhibited: moderate plasma clearance, a large volume of distribution and a short 
terminal half-life (~3 h) in rodents; a high clearance, a high volume of distribution and a 
relatively long terminal half-life (~13 h) in the dog. EGF816 showed high plasma protein 
binding. Following oral administration, EGF816 showed good oral bioavailability (>55%) in, 
rodent and dog. EGF816 is highly permeable across the Caco2 monolayer system. Given the 
high solubility of EGF816 observed across the pH range and in simulated intestinal fluid for 
both fasted and fed state, it is considered a preliminary biopharmaceutics classification system
(BCS) class I compound with low food effect risk. EGF816, showed almost complete recovery 
of radioactivity (97%) in rat. The predominant route of elimination was via fecal excretion with 
renal excretion a minor pathway. The predominant circulating component in rat plasma was the 
parent compound. The cross-species metabolism comparison in hepatocytes showed that the N-
demethylation pathway was more predominant in human than in dog and rat. The N-
demethylated metabolite (LMI258) showed similar pharmacological activity to EGF816 in vitro. 
The exposure of LMI258 was 3-9% and 20-40% of the parent exposure in rat and dog 4-week 
toxicology studies, respectively. EGF816 is primarily metabolized by CYP3A4. EGF816 
showed weak to moderate inhibition of CYP2D6 (Ki 3.3 µM, unbound) and CYP2C8 (IC50 ~11 
µM, unbound) whereas metabolite LMI258 showed relatively strong inhibition of CYP2D6 (Ki 
0.41 µM) and weak inhibition of CYP3A4 (IC50 12 µM) in vitro. EGF816 and LMI258 may 
increase the exposure of the substrates of these CYP isoforms if sufficiently high concentrations 
are reached in the clinic. EGF816 is a p-glycoprotein (P-gp) substrate with a Km value of 5.0 


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to 16 µM, and an inhibitor of breast cancer resistance protein (BCRP) with an estimated IC50
value of 4.0 µM.
For more information please refer to the current [EGF816 IB].
1.2.1.1.2 Pharmacology and toxicology
Non-clinical pharmacology
EGF816 is a potent third generation, irreversible EGFR mutant-selective inhibitor. It covalently 
links to Cys797 at ATP site of EGFR. In cell-based target modulation assays, EGF816 inhibits 
both oncogenic (L858R, ex19del) and TKI-resistance (L858R/T790M) lines with single digit 
nM potency and demonstrates good selectivity (~40-60 fold vs. the least active mutant line) 
over WT-EGFR cell lines. The potency and WT-selectivity of EGF816 was further confirmed 
in a receptor occupancy study using 14C-labeled EGF816. Profiling against several large panels 
of kinases indicates that EGF816 is highly selective. The confirmed off-target activities are 
mostly on kinases containing a similarly located cysteine as Cys797 in EGFR. EGF816 
demonstrated strong tumor regressions in several EGFR activating and resistant tumor models 
in vivo. These include HCC827 (ex19del), H3255 (L858R) and H1975 (L858R; T790M) that 
are representative of the relevant clinical settings. In all of the models EGF816 inhibited tumor 
growth in a dose-dependent manner and achieved regressions of established tumors at well 
tolerated doses. The HCC827 (ex19del activating mutation) mouse xenograft model was very 
sensitive to EGF816. Even at the lowest tested daily dose of 3 mg/kg, significant tumor 
regression was achieved. The effect was comparable to erlotinib at 60 mg/kg, a clinically 
relevant dose, which gave free plasma exposure similar to that observed at clinical efficacious 
dose. At doses of 10 mg/kg q.d. or above, EGF816 showed maximum regression similar to 
erlotinib at its maximum tolerated dose (MTD) of 120 mg/kg. EGF816 was very well tolerated, 
with no body weight loss observed up to 100 mg/kg, while erlotinib at 120 mg/kg showed 
significant body weight loss (~10%). In the H3255 (L858R) mouse xenograft model, EGF816 
was tested at 30 mg/kg and demonstrated strong tumor regression with no effect on body weight 
compared to vehicle. In the H1975 (L858R/T790M) mouse and rat xenograft models, 
significant tumor regression was achieved at doses ≥ 30 mg/kg. Importantly, EGF816 
demonstrated much improved tolerability with superior efficacy as compared to second-
generation irreversible pan-EGFR inhibitor afatinib. Dose-dependent inhibition of pEGFR and 
its down-stream pharmacodynamics (PD) markers were observed following single oral dose of 
EGF816 at several dose levels. Sustained inhibition of pEGFR relative to plasma PK was 
evident in either model, and is consistent with the irreversible binding mechanism of action. 
Targeted inhibition of WT EGFR in cells also inhibits dual specificity phosphatase 6 (DUSP6) 
(Vecchione et al 2011). In an effort to compare the in vivo WT EGFR selectivity of EGF816 
and afatinib, the DUSP6 gene expression was measured in the skin of treated animals. While 
afatinib caused significant DUSP6 inhibition, EGF816 had no effect at the efficacious doses.
For more information please refer to the current [EGF816 IB].
Toxicology
A series of preclinical toxicology studies were completed to support human clinical trials with 
EGF816, including safety pharmacology studies, genetic toxicology studies, general toxicology 


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studies, and photosensitization assessment. A 4-week GLP study in rats and a 4-week GLP 
study in beagle dogs were performed. Target organs in the rat included skin/eyelids 
(inflammation around hair follicles and in epidermis), lungs (foamy macrophages-
phospholipidosis), lymphoid organs (cell depletion), vagina (atrophy of epithelium), uterus 
(atrophy of endometrium), anal (sebaceous) glands (inflammation). The severely toxic dose to 
10% of animals (STD10) was 75 mg/kg/day. Target organs in the dog included cornea 
(epithelial thinning), and various glands throughout the organ system (atrophy). The highest 
non-severely toxic dose (HNSTD) was determined to be 20 mg/kg/day.
EGF816 showed a potential for phototoxicity in the 3T3 NRU in vitro assay. The Ames assay 
for EGF816 indicated that it was not a potential mutagen and the chromosomal aberration assay 
in human peripheral blood lymphocytes did not indicate the potential to cause chromosomal 
aberrations. An in vivo evaluation of the bone marrow for the presence of micronuclei was 
negative in rats. The IC50 for the hERG potassium channel is 6 µM.
For more information please refer to the current [EGF816 IB].
1.2.1.2
Clinical experience
CEGF816X2101 is the first-in-human Phase I/II study of single-agent oral EGF816. As of the 
data cut-off date (18-Dec-2015), in this study 148 patients have been treated with EGF816 
capsules or tablets at seven dose levels: 75 mg q.d. (N=7), 100 mg q.d. (N=29), 150 mg q.d. 
(N=64), 200 mg q.d. (N=8), 225 mg q.d. (N=24), 300 mg q.d. (N=5) and 350 mg q.d. (N=11). 
Eighty-four patients (56.8%) were still receiving treatment and 64 patients (43.2%) had 
discontinued treatment. Of these 64 patients, 53 (35.8%) discontinued treatment due to 
progressive disease, three (2.0%) discontinued treatment due to adverse events (AEs), and 3 
(2.0%) discontinued treatment due to death. Of the three patients who discontinued treatment 
due to AE, one patient at the 350 mg q.d. reported Grade 3 maculopapular rash, one patient at 
the 150 mg daily dose reported Grade 3 interstitial lung disease, and one patient at the 300 mg 
daily dose reported Grade 3 pulmonary edema. Of the three patients who discontinued treatment 
due to death, one patient died due to sepsis (considered not related to study treatment), one 
patient died due to hepatitis B virus (HBV) reactivation (considered related to study treatment), 
and one patient died due to pneumonia (considered not related to study treatment).
As of 18-Dec-2015, dose-limiting toxicities (DLT) were reported in five patients: one patient 
at the dose level of 150 mg capsule reported Grade 3 maculopapular rash that resulted in 
temporary treatment interruption, one patient at the dose level of 225 mg capsule reported Grade 
3 maculopapular rash that resulted in temporary treatment interruption, one patient at the dose 
level of 350 mg capsule reported Grade 3 acute kidney failure and Grade 3 maculopapular rash 
that resulted in temporary treatment interruption, one patient at the dose level of 350 mg capsule 
reported Grade 3 maculopapular rash that resulted in permanent discontinuation of treatment, 
and one patient at the dose level of 350 mg capsule reported Grade 3 enteritis and Grade 3 
dehydration that resulted in temporary treatment interruption.
The maximum tolerated dose (MTD) has not been determined for EGF816 as a single agent.
As of the data cutoff date of 18-Dec-2015, 142 patients (95.9%) who were treated with EGF816 
capsules or tablets experienced at least one AE of any grade, regardless of relationship to the 
study drug. The most frequent AEs (all CTCAE grades, >10% of patients) regardless of study 


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drug relationship at the seven dose levels were rash (group term) (56.1%), diarrhea (41.9%), 
maculopapular rash, pruritus (36.5%), fatigue (27.0%), stomatitis (27.0%), dry skin (24.3%), 
nausea (23.6%), cough (20.9%), decreased appetite (20.3%), vomiting (14.9%), constipation 
(14.2%), headache (12.8%), anemia (12.2%), paronychia (11.5%), pyrexia (11.5%), dyspnea 
(10.8%), edema peripheral (10.8%), back pain (10.1%), and upper respiratory tract infection 
(10.1%).
Seventy (47.3%) patients who were treated with EGF816 capsules or tablets at any dose 
experienced Grade 3 or Grade 4 AEs regardless of relationship to the study drug. Grade 3/4 
AEs occurring in ≥ 2% of patients were rash (grouped term) (15.5%), anemia (5.4%), 
pneumonia (5.4%), diarrhea (4.7%), fatigue (2.7%), dyspnea (2.7%), urticaria (2.7%), 
hypertension (2.7%), stomatitis (2.0%), decreased appetite (2.0%), hyperuricemia (2.0%), and 
seizure (2.0%).
As of the data cutoff date (18-Dec-2015), SAEs, regardless of study drug relationship, were 
reported in 48 patients (32.4%) who received at least one dose of single agent EGF816 capsules 
or tablets. Of these 48 patients, 15 experienced SAEs that were suspected to be related to study 
drug or study procedures: one patient at the 350 mg capsule daily dose was reported to have 
Grade 3 acute kidney injury that resulted in temporary drug interruption, one patient at the 
350 mg capsule daily dose was reported to have Grade 3 dehydration and enteritis that resulted 
in temporary drug interruption, one patient at the 225 mg capsule daily dose was reported to 
have Grade 3 hepatitis B reactivation and Grade 3 hepatic failure that resulted in permanent 
treatment discontinuation and death, one patient at the 225 mg capsule daily dose was reported 
to have Grade 3 purpura that resulted in temporary drug interruption, one patient at the 225 mg 
capsule daily dose was reported to have Grade 3 hepatitis B reactivation that resulted in 
temporary drug interruption, one patient at the 225 mg capsule daily dose was reported to have 
Grade 3 maculopapular rash that resulted in temporary drug interruption, one patient at the 
225 mg capsule daily dose was reported to have Grade 3 diarrhea that resulted in temporary 
drug interruption, two patients at the 150 mg capsule daily dose reported Grade 2 dyspnea that 
resulted in no action taken with study drug, one patient at the 150 mg capsule daily dose was 
reported to have Grade 1 acute renal failure that resulted in temporary drug interruption, one 
patient at the 150 mg capsule daily dose reported Grade 2 diarrhea that resulted in temporary 
drug interruption, one patient at the 150 mg capsule daily dose was reported to have Grade 3 
interstitial lung disease that resulted in temporary drug interruption, one patient at the 150 mg 
capsule daily dose was reported to have Grade 3 pneumothorax that was related to a study-
associated procedure that occurred after the patient had discontinued study drug, one patient at 
the 150 mg tablet daily dose was reported to have Grade 3 diarrhea that resulted in temporary 
drug interruption, and one patient at the 150 mg tablet daily dose was reported to have Grade 3 
upper gastrointestinal hemorrhage that resulted in temporary drug interruption and was reported 
to have Grade 3 anemia (the SAEs of gastrointestinal hemorrhage and anemia were updated to 
not suspected related to study treatment in the safety database, but have not been updated in the 
clinical database).
As of 18-Dec-2015, the outcome of SAEs suspected to be related to study treatment was 
recovered or recovering in 12 of 15 patients. One patient died due to hepatic failure secondary 
to HBV reactivation, one patient was reported as not recovered from Grade 3 maculopapular 
rash, and one patient was reported as not recovered from Grade 3 anemia.


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As of 18-Dec-2015, 2 SAEs of HBV reactivation have been reported in 2 patients participating 
in the CEGF816X2101 study. One case had a fatal outcome, and the second case was considered 
medically significant. The fatal case involved a patient who received EGF816 at 225 mg q.d., 
had a history of HBV infection and was not on antiviral treatment at study entry. The patient 
developed HBV reactivation during the study and died due to hepatic failure despite initiation
of antiviral treatment after HBV reactivation had been confirmed. The second patient also 
received EGF816 at 225 mg q.d., had a history of HBV and was not on antiviral treatment at 
the time of joining the study, HBV reactivation was detected after the patient had been on study 
for approximately 10 weeks. Antiviral treatment was immediately initiated, EGF816 was 
interrupted and the HBV infection was brought under control. The patient later resumed 
EGF816 at the same dose of 225 mg q.d. while continuing on antiviral medication. The viral 
reactivation in these two patients was likely due to immunosuppression related to EGF816. 
Reactivation of HBV and hepatitis C virus (HCV) has been reported with anticancer therapies 
that suppress the immune system.
It should be noted that the maculopapular rash associated with EGF816 treatment appeared to 
be different from the typical EGFR TKI-related rash (e.g., acneiform rash). Its onset was 
generally in the first 2-3 weeks of study treatment however it could be sporadic. The rash 
typically started on the trunk, spread out to the extremities, and in general spared the palms and 
soles. EGF816-associated rash was well managed with dose interruption and/or steroid and 
antihistamine treatments. In most cases, the rash resolved completely or almost completely 
within 1 week with drug interruption, and patients were able to restart study treatment, at the 
same dose or a reduced dose, without recurrence of the maculopapular rash
As of 02-February-2015, preliminary efficacy results showed an overall response rate (ORR) 
of 59.5% by Investigator assessment in 25 (11 confirmed and 14 awaiting confirmation) out of 
42 evaluable patients treated at all dose levels. Note: evaluable patients include those who were 
ongoing and had at least one post-baseline tumor assessment or who discontinued study 
treatment as of the data cut-off date. The antitumor activity of EGF816 is in line with the 
antitumor activity observed with other 3rd-generation EGFR TKIs including AZD9291and CO-
1686. Refer to Figure 1-1.
Please refer to the current Investigator’s Brochure [EGF816 IB] for more details.




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1.2.2.1.2 Non clinical drug metabolism and pharmacokinetics summary
INC280 was absorbed rapidly, and the absolute oral bioavailability (F%) was low to moderate 
(24-66%) in rats, dogs and monkeys. Single and multiple dose toxicokinetic studies in rats and 
monkeys showed that plasma INC280 maximum concentration (Cmax) and area under the 
concentration-time curve (AUC) increased with dose, although not always dose-proportional. 
INC280 plasma protein binding was moderate to high across species, and was 93.3% in humans. 
The in vitro blood-to-plasma ratio in humans was 1.7. INC280 was widely and rapidly 
distributed to all tissues following a single oral dose in rats. Melanin rich tissues, including eye 
choroid, uveal track and meibomium glands, appeared to have prolonged retention of the drug 
related materials. INC280 can penetrate across the blood-brain barrier in the rat with a brain-
to-blood ratio of approximately 0.1. In the rat, INC280 was mainly eliminated through biliary 
excretion via metabolism. INC280 is predominantly metabolized by cytochromes P450 (CYP) 
3A4 in human hepatic microsomes. INC280 showed inhibitory potency in vitro against 
CYP1A2, 2C8, 2C9, 2C19 and 3A4/5. INC280 also displayed inhibition of multidrug resistant 
1/Permeability glycoprotein (P-gp), MXR/breast cancer resistant protein (BCRP), organic anion 
transporting polypeptide (OATP) 1B1 and OATP1B3 mediated substrate efflux or uptake. 
Therefore, at clinical relevant doses, potential drug-drug interactions are possible due to 
inhibition of CYP1A2, 2C8, 2C9, 2C19 and 3A4/5 metabolic enzymes, and/or due to inhibition 
of P-gp, BCRP, and OATP1B1/1B3 transporters.
For more information, refer to current [INC280 IB].
1.2.2.1.3 Non clinical toxicology summary
A series of preclinical toxicology studies were completed to support human clinical trials with 
INC280, including safety pharmacology studies, genetic toxicology studies, general toxicology 
studies (single-and repeat-dose studies) in the mouse, rat, and monkey (in rats and monkeys up 
to 13-weeks in duration), embryofetal developmental toxicity studies, and photosensitization 
assessment. Safety pharmacology studies with INC280 indicated that INC280 had no 
significant effects on vital organ functions. Repeat dose toxicity studies conducted revealed the 
following target organs or systems: kidneys, pancreas, central nervous system (CNS), and 
potentially liver.
INC280 is not genotoxic. Studies on embryo-fetal development in rats and rabbits indicated that 
INC280 is teratogenic to both species, and the teratogenicity is consistent with the mechanism 
of action by cMet inhibition. INC280 should be considered potentially teratogenic to humans.
Additionally, INC280 has shown photosensitization potential in in vitro and in vivo assays.
For more information, refer to the current INC280 Investigator’s Brochure [INC280 IB].
1.2.2.2
Clinical experience
1.2.2.2.1 Clinical safety
As of 28-Sep-2017, a total of 1109 cancer patients and 158 non-cancer subjects have received 
INC280. A total of 622 patients with solid tumors have been treated with INC280 as a single 
agent, and 487 patients have been treated with INC280 in combination therapies. Treatment 
was with either the capsule formulation or tablets or both. Twenty-one clinical studies are 


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currently ongoing with INC280. A total of 19 patients have experienced 25 DLTs: 6 patients in 
single agent studies and 12 in combination studies. For more information, please refer to the 
current INC280 [Investigator’s Brochure].
Overall, the majority of the reported adverse events (AEs) are mild or moderate in severity. The 
most frequent AEs suspected to be related to INC280 of any grade reported in the largest single 
agent trial [CINC280A2201] (220 patients) were edema peripheral (77 patients, [35.0%]), 
nausea (69 patients, [31.4%]), vomiting (40 patients, [18.2%]), blood creatinine increased (39 
patients, [17.7%]), and fatigue (34 patients, [15.5%]), majority Grade 1/2. The most frequently 
occurring Grade 3/4 AEs suspected to be related to INC280 as a single agent included edema 
peripheral and lipase increased (each in 9 patients, [4.1%]), fatigue (8 patients, [3.6%]), alanine 
aminotransferase 
increased 
(7 
patients, 
[3.2%]), 
aspartate 
aminotransferase, 
hypophosphataemia, nausea  and vomiting (each in 3 patients, [1.4%]).
Caution is recommended when INC280 is administered in combination with other anticancer 
drugs with known risk of hepatotoxicity. One case of liver function test abnormal meeting Hy’s 
Law criteria for hepatotoxicity (PHHO2015CN003025) has been reported for a patient enrolled 
in the NSCLC combination study with gefitinib [CINC280X2202]. The event could not be 
attributed solely to either drug alone or to the combination. The patient experienced concurrent 
elevations of total bilirubin (TBIL) >2×ULN and ALT/AST >3×ULN with ALKP <2×ULN. 
The patient permanently discontinued both study drugs. Liver function tests improved after 
treatment discontinuation. 
As of the IB cut-off of 28-Sep-2017, one SAE (
) of interstitial lung 
disease (ILD) has been reported from INC280 single agent study [CINC280A2201]. A 
-year-
old 
 patient with prior chemo-radiotherapy developed interstitial lung disease (Grade 3) 
57 days after starting treatment with INC280. The investigator assessed the event ILD as related 
to both INC280 treatment and recent thoracic radiotherapy. Overall, from the single agent study 
[CINC280A2201] six non-serious cases were reported, of which two cases were  suspected by 
the investigator (outcome: both Grade 2 events and completely recovered) and one Grade 3 
SAE (
; fatal outcome; case described above) have been reported.
Nine ILD/pneumonitis cases were reported in INC280 combination studies with EGFR TKIs 
(erlotinib [n=1, fatal outcome], gefitinib [n=2, both complete recovery], EGF816 [n=6, four 
complete recovery, one resolving, and one fatal].
While the risk of pulmonary toxicity/interstitial lung disease (ILD) is a well established class 
effect for the EGFR TKIs, a casual role of the INC280 to events of pneumonitis cannot be 
elucidated at the current time.
Investigators are advised to carefully monitor patients receiving INC280 for signs and 
symptoms of pneumonitis.
The maximum tolerated dose (MTD) for INC280 capsules or tablets as single agent was not 
reached. The RP2D for INC280 as a single agent has been determined to be 600 mg BID in 
capsule formulation and 400 mg BID in tablet formulation.
For more information, refer to the current INC280 Investigator’s Brochure [INC280 IB].


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1.2.2.2.2 Clinical pharmacokinetics
As of 28-Sep-2016, INC280 (capsule and tablet) single agent steady state pharmacokinetic (PK) 
data are available from five clinical studies ([CINC280X2101T], [CINC280X2102], 
[CINC280X1101] [CINC280A2201] and [CINC280X2201]), and from four combination 
studies, 
INC280 
plus 
gefitinib 
([CINC280X2202]), 
INC280 
plus 
cetuximab 
([CINC280X2104]), INC280 plus EGF816 ([CINC280X2105C]) and INC280 plus BKM120 
(buparlisib) ([CINC280X2204]) After oral administration, INC280 was rapidly absorbed with 
the median time to reach maximum drug concentration (Tmax) ranging from 1 to 2 hours for 
tablets and from 1 to 4 hours for capsules. The elimination half-life estimated from 
[CINC280X1101] ranged from 3.5 to 6.3 hours across the cohorts. Accumulation in INC280 
exposure following repeated administration of 400 mg BID tablets is low, with geometric mean 
accumulation ratio of 1.4-fold in the single agent [CINC280A2201] study.  Steady state INC280 
exposure is expected to be reached by the third day of consecutive BID dosing. The mean 
plasma exposures (Cmax and AUC) for INC280 generally increased with dose up to 600 mg 
QD and 600 mg BID administration with capsule formulation. The mean plasma exposure 
increase is roughly dose proportional for INC280 tablet from 200 to 400 mg BID.
A relative bioavailability study, [CINC280X2103], was conducted to compare the INC280 
tablet to INC280 capsule. The outcome of this study showed that tablets provided higher 
systemic exposures (Cmax and AUC) and lower inter-subject variability following a single oral 
administration of 600 mg INC280 in healthy subjects. Tablet PK data are available in cancer 
patients at different doses (150 mg to 400 mg BID) in various INC280 studies. In the study 
[CINC280X2102], the INC280 MF tablet at 400 mg BID (N=8) provided comparable mean 
AUC0-12h,ss (1. 05-fold) and slightly higher Cmax,ss (1. 44-fold) compared with the INC280 
capsule at 600 mg BID (RP2D, N=45) in the limited subjects tested. In the ongoing phase 2 
[CINC280A2201] study with FMI tablet, the exposures (both Cmax and AUC) were 
comparable to what was observed in [CINC280X2102] study at 400 mg BID. Based on the 
tablet PK and safety data from these studies, the dosage of INC280 at 400 mg BID in tablet 
form has been declared as the RP2D for the single agent studies.
A study to evaluate the effect of INC280 on the PK of CYP3A4 substrate (midazolam) and 
CYP1A2 substrate (caffeine) in patients with MET dysregulated solid tumors was completed 
[INC280A2103]. Multiple doses of INC280 tablets at 400 mg BID did not lead to a clinically 
significant increase of CYP3A4 substrate (midazolam) exposure. However, AUC of CYP1A2 
substrate (caffeine) increased by 135%.
A study to evaluate the effect of INC280 on the PK of Pgp substrate (digoxin) and BCRP 
substrate (rosuvastatin) in patients with MET dysregulated solid tumors was completed 
[INC280A2105]. Multiple doses of INC280 tablets at 400 mg BID led to a 74% increase in 
digoxin Cmax and a 47% increase in AUC. Rosuvastatin Cmax and AUC increased 204% and 
108%, respectively.
A study to evaluate the effect of itraconazole (strong CYP3A4 inhibitor) and rifampicin (strong 
CYP3A4 inducer) on the single-dose pharmacokinetics of INC280 in healthy subjects was 
completed [INC280A2102]. When co-administered with itraconazole, INC280 AUC increased 
by approximately 40%. There was no change in Cmax. When co-administered with rifampicin, 
INC280 AUC and Cmax decreased by approximately 66% and 56%, respectively.


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Preliminary pharmacokinetics data from the ongoing study [CINC280A2108], in which 
INC280 tablet was administered with food in cancer patients, showed no food effect of high fat 
meal on INC280 exposure. Thus, INC280 can be taken with or without food.
INC280 displayed pH-dependent solubility in vitro. A study to evaluate the effect of a long 
acting proton pump inhibitor on the PK of a single dose of INC280 tablet was completed in 
healthy volunteers [CINC280A2101]. Daily treatment with 20 mg rabeprazole for 4 days 
resulted in a modest reduction in the extent of INC280 absorption with a 25.2% decrease in 
AUCinf and a 37.5% decrease in Cmax. The effect of food on the rate and extent of INC280 
exposure was assessed after a single oral dose administration of 600 mg INC280 tablet in 
healthy subjects ([CINC280X2107]). Compared to fasting conditions, a low fat meal increased 
AUCinf and Cmax by 1.20- and 1.11-fold, respectively; and a high fat meal increased AUCinf 
and Cmax by 1.46- and 1.15-fold, respectively. Preliminary pharmacokinetics data from the 
ongoing study [CINC280A2108] which INC280 tablet was administered with food in cancer 
patients, showed no positive food effect of high fat meal on INC280 exposure. While the data 
on the concurrent use of PPI and food have to be considered preliminary as they have been 
generated in a small cohort of patients of the study [CINC280A2108], the decrease in exposure 
imposes caution on the use of PPI when INC280 is taken without regard to food.
INC280 does not show a risk of QT prolongation. Preliminary analysis on 110 patients in study 
INC280A2201 showed that no patients had new post-baseline QTcF values greater than 500 
ms. Changes from baseline (ΔQTcF) greater than 60 ms were not observed and changes greater 
than 30 ms and below 60 ms were observed in 4 patients (4/110, 3.6%). The observed mean 
QTcF changes from baseline around Tmax (2 hours post-dose) were 5.21 ms on Cycle 1 Day 1 
and -0.54 ms on Cycle 1 Day 15. Based on the PK/QT analysis, the estimated mean ΔQTcF
(upper one-sided 95% CI) at mean steady state INC280 concentration 2 hours post-dose (4584 
ng/mL) was 0.11 ms (1.85 ms) at the recommended phase 2 dose of 400 mg BID with tablets. 
The upper one-sided 95% CIs for the estimated mean ΔQTcF at clinically relevant INC280 
concentrations are below the regulatory threshold of 10 ms.
For more information on the clinical studies and pharmacokinetics of INC280, refer to the 
current [INC280 IB].
1.2.3
Overview of Nivolumab
Nivolumab is a fully human, IgG4 (kappa) isotype mAb that binds PD-1 on activated immune 
cells and disrupts engagement of the receptor with its ligands PD-L1 (B7-H1/CD274) and PD-
L2 (B7-DC/CD273), thereby abrogating inhibitory signals and augmenting the host antitumor 
response.
1.2.3.1
Non-clinical experience
1.2.3.1.1 Non clinical pharmacokinetics, immunogenicity, and toxicity
Nivolumab was well tolerated in a 3-month intravenous (IV) repeat-dose (twice weekly) 
toxicology studies in monkeys at doses up to 50 mg/kg, with no effect on body weight and no 
clinical findings. Serum chemistry changes were limited to reversible 28% decrease of T3 in 
female monkey at 50 mg/kg dose. No T4 and TSH level changes observed. The highest tolerated 


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dose was 50 mg/kg twice weekly, which is at least 20 times greater than doses that demonstrated 
antitumor activity in humans (Wang et al 2014)
Pharmacokinetic study after single i.v. administration at 1 and 10 mg/kg in monkey showed that 
the concentration declined in a multi-phasic manner with Tmax observed within 0.5 hour. The 
apparent terminal half -life was 124-139 hours at 1 mg/kg and 261 hours at 10 mg/kg. Serum 
Nivolumab had a relative slow clearance with limited extra vascular distribution as 
demonstrated by a Vss value consistent with plasma volume.
Anti-Nivolumab antibody response were positive at day 28 at dose 1 and 10 mg/kg is some 
animals, but no substantial impact on PK and no adverse effects observed (Wang et al 2014)
1.2.3.2
Clinical experience
1.2.3.2.1 Clinical pharmacokinetics
Single dose pharmacokinetics (PK) of nivolumab was evaluated in subjects with multiple tumor 
types in CA209001, whereas multiple dose PK is being evaluated in subjects in CA209003. In 
addition, a preliminary population pharmacokinetic (PPK) model has been developed with data 
from 350 subjects from CA209001, CA209002, and CA209003.
The pharmacokinetics (PK) of Nivolumab was linear in the range of 0.1 to 10 mg/kg and both 
elimination and distribution of Nivolumab in the dose range studied appear to be independent 
of dose while end of infusion and minimum serum concentration (Cmin) after the first dose 
were approximately dose proportional. No differences in PK were observed across tumor types 
with every 2 week administration. The mean terminal elimination half-life of Nivolumab 
determined from a single dose in Nivolumab study is 17 to 25 days which is consistent with 
half-life of endogenous IgG4, indicating that the elimination mechanism of Nivolumab may be 
similar to IgG4.
A preliminary PK model was developed by nonlinear mixed effect modeling using data from 
350 adult subjects. Body weight normalized dosing showed approximately constant trough 
concentrations over a wide range of body weights (BW), and, therefore, confirms the 
appropriateness of this body weight adjustment of Nivolumab dose. The PK of Nivolumab was 
well characterized by a linear two compartment model with zero-order IV infusion and first-
order elimination. Typical CL and Vc estimates are: 0.0104 L/h and 4.56 L, with 52.8% and 
29.6% inter-individual variability. Baseline BW, sex, C-reactive protein, albumin, appear to 
have >20% effect on clearance (CL); BW and sex also appear to have a >20% effect on Vc BW 
normalized dosing produces relatively constant Nivolumab steady-state exposures across a 
wide BW range (40 to 150 kg).
1.2.3.2.2 Clinical safety
Please refer to the nivolumab (Opdivo®) prescribing information and the current nivolumab IB 
for clinical safety information. Nivolumab has been safely combined with both chemotherapy 
and erlotinib (Antonia et al 2014, Naiyer et al 2014).
On 
, Novartis received a serious adverse event report of a Grade 3 rash in a 
 year-old patient treated in Group 1 (EGF816 plus nivolumab) of CEGF816X2201C. Despite 
discontinuation of the study drugs and treatment with IV methylprednisolone and IV 




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clinical database review as of 19 Jan 2016, in the EGF816 single-agent study (CEGF816X2101) 
one case of interstitial lung disease and one case of pneumonitis (which was reported as a non-
serious adverse event) have been reported in 146 patients treated, and in the EGF816 plus 
nivolumab arm (Group 1) of CEGF816X2201C, one case of interstitial lung disease (which was 
reported as a non-serious adverse event) and two cases of pneumonitis, including the one 
described herein, have been reported in 18 patients treated. No cases of pneumonitis or 
interstitial lung disease have been reported in 4 patients treated in Group 2 (INC280 plus 
nivolumab). Based on these data the possibility cannot be excluded that the risk of 
pneumonitis/interstitial lung disease may be higher with the combination of EGF816 and 
nivolumab than with either drug alone.
One patient who received combination therapy of INC280 and PDR001 (a PD-1 inhibitor, i.e. 
the same drug class as Nivolumab) in the Novartis study CPDR001J2201, experienced Grade 1 
myocarditis and hepatitis (serious) approximately two months after initiation of therapy. The 
subject was treated with corticosteroids. At the time of reporting, hepatitis has fully recovered 
and myocarditis was ongoing.
2
Rationale
2.1
Study rationale and purpose
Currently approved EGFR TKIs are effective in activated EGFR mutant NSCLC (Section 1.1), 
however nearly all patients develop resistance. cMet positive NSCLC patients progressing on 
chemotherapy fare prognostically worse than their non-cMet positive counterparts. Inhibition 
of cMet in cMet positive NSCLC cells may inhibit their growth, while inhibition of cMet in 
immune cells may enhance anti-tumor immunity. Harnessing the immune system to treat 
patients with non-small cell lung cancer (NSCLC) represents a novel and exciting new 
treatment approach. The anti-PD-1 antibody Nivolumab has demonstrated response rates of up 
to 20% in patients with NSCLC and has been safely combined with several small molecules as 
well as cytotoxic chemotherapies.
In order to explore the hypothesis that concurrent treatment with an immune checkpoint 
inhibitor along with a targeted therapy is safe and may result in durable and sustained responses, 
Nivolumab will be combined with either the third generation EGFR TKI, EGF816, in EGFR 
T790M NSCLC patients who have developed resistance to EGFR TKI treatment or with the 
highly selective and potent cMet inhibitor, INC280, in cMet positive (EGFR wild type) patients 
who progressed on chemotherapy.
2.2
Rationale for the study design
This study is a phase II, multicenter, open-label study of EGF816 in combination with 
Nivolumab in adult patients with EGFR mutated non-small cell lung cancer and of INC280 in 
combination with Nivolumab in adult patients with EGFRwt non-small cell lung cancer. This 
study is designed to target patients with NSCLC progressing on standard of care (e.g., erlotinib 
or gefitinib for EGFR-mutant NSCLC or platinum doublet chemotherapy for EGFR wt 
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This study is designed to include a safety monitoring cohort consisting of a minimum of six (6) 
T790M positive NSCLC patients and a minimum of 6 EGFR wt NSCLC patients. The safety 
monitoring cohort will be used to assess the safety profiles during the first six weeks and ensure 
that the observed exposures (PK) of the combinations are in range of those observed for the 
single agents at efficacious dosages of EGF816 with Nivolumab or of INC280 with Nivolumab. 
Enrollment of additional patients at the ongoing dose level will be put on hold until the decision
for study continuation is made after reviewing the data from the safety monitoring cohort at the 
end of the six week period. At a joint meeting, Novartis and study investigators will use clinical 
and laboratory data obtained from the safety monitoring cohort to make an assessment on the 
safety of the combination dose for study (as per Section 8). Such data review and meeting may 
take place before the end of the six week period in case of potential safety concerns. If data 
from the safety monitoring cohort do not support study continuation with the initial doses or 
accumulating data from this study and/or other ongoing studies with these agents suggest that 
alternative lower doses should be explored then additional safety monitoring cohorts at 
alternative lower dose levels may be opened at any point in time following completion of 
accrual of the prior cohort after discussion and agreement between Novartis and investigators. 
However, the decision to resume enrollment at a given dose to reach the targeted enrollment in 
each treatment group, as specified in Section 5.1, must be based on assessment of data at the 
time when patients in the safety monitoring cohort at this given dose have completed six weeks 
of treatment or discontinued earlier.
The objectives of the study are to determine if the combination of EGF816 with nivolumab 
provides a clinically meaningful benefit over single agent EGF816 or single agent nivolumab 
observed in similar populations in historical and/or ongoing trials, and if the combination of 
INC280 with nivolumab provides clinically meaningful benefit over the single agent INC280 
or single agent nivolumab in similar populations observed in historical and/or ongoing trials.
2.3
Rationale for dose and regimen selection
In this study the selection of dosing regimen of INC280 and EGF816 is based on the currently 
available preclinical and clinical safety, efficacy, PK and PK/PD information for the 
investigational agents – EGF816, INC280 and Nivolumab.
Based on currently available non-clinical and clinical data, the provisional dose will be 400 
mg bid for INC280 (tablet formulation) and 150 mg qd on a continuous daily dose for 
EGF816 (capsule formulation). If prior to the first patient being treated on study, the data 
from ongoing single agent studies that are available support different EGF816 and/or INC280 
doses, Novartis and Investigators will meet via teleconference to review the available single 
agent data for EGF816 and INC280. (Section 4.1 and Section 10).
The dose and schedule of Nivolumab is 3 mg/kg every 2 weeks. This dose and schedule 
selection is based on results of safety, efficacy, and exposure-response analyses obtained from 
studies as described above. (Section 1.2.3) This dose and schedule of Nivolumab has been 
safely combined with other EGFR inhibitors (e.g., erlotinib) at registered doses as well as with 
other standard of care therapies (e.g., chemotherapies and ipilumumab) (Naiyer et al 2014, 
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2.4
Rationale for choice of combination drugs
This study is designed to:
1. explore if the combination of Nivolumab with the EGFR inhibitor, EGF816, will provide 
sustained clinical benefit to NSCLC patients whose tumors have become resistant to 
EGFR TKI treatment through acquiring T790M mutation by stimulating the host immune 
system and inhibiting EGFR T790M; and
2. explore if the combination of Nivolumab with the cMet inhibitor INC280 will provide 
sustained clinical benefit to NSCLC patients whose tumors are EGFR wt by stimulating 
the host immune system and inhibiting the cMet pathway in tumors and/or immune cells.
2.5
Rationale for maximum 2-year duration of Nivolumab treatment
The optimal duration of immunotherapy is an important question and continues to be 
investigated. Clinical trials across different tumors types in the Nivolumab development 
program indicate that most of the responses occur early, with a median time to response of 2-4 
months, and emerging data suggests that benefit can be maintained in the absence of continued 
treatment. 
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be
sufficient for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating 
the safety and clinical activity of Nivolumab in patients with previously treated advanced solid 
tumors (including 129 subjects with NSCLC), specified a maximum treatment duration of 2 
years. Among 16 subjects with non-small cell lung cancer (NSCLC) who discontinued 
Nivolumab after completing 2 years of treatment, 12 subjects were alive > 5 years and remained 
progression-free without any subsequent therapy. In this NSCLC cohort, the overall survival 
(OS) curve begins to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years 
(Brahmer et al 2017). These survival outcomes are similar to phase 3 studies in previously 
treated NSCLC, in which Nivolumab treatment was continued until progression or unacceptable 
toxicity (2 year OS rates of 23% and 29%, and 3 year OS rates of 16%-18% for squamous and 
non-squamous NSCLC respectively) (Felip et al 2017). Similar results have been reported in 
clinical studies of pembrolizumab, another PD-1 inhibitor. Keynote-010 was a randomized 
phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg every 3 weeks) versus docetaxel 
in subjects with previously treated, PD-L1-positive, advanced NSCLC which specified a 
maximum treatment duration of 2 years for pembrolizumab. OS was significantly longer with 
both Pembrolizumab 2 mg/kg (HR 0.72, p = 0.00017) and pembrolizumab 10 mg/kg (HR 0.60, 
p < 0.00001) compared to docetaxel, with an OS plateau developing beyond 2 years in both 
pembrolizumab arms. Among 690 patients who received pembrolizumab, 47 patients 
completed 2 years of pembrolizumab and stopped treatment. Most were able to maintain their 
response, including those with stable disease, with only 2 patients (4%) having confirmed 
progression after stopping at 2 years (Herbst et al 2016). Keynote-006 was a randomized phase 
3 study of pembrolizumab versus ipilimumab in patients with advanced melanoma, which also 
specified a maximum 2 year duration of pembrolizumab treatment. Of the 556 patients 
randomized to pembrolizumab, 104 (19%) of them completed 2 years of treatment. With a 
median follow-up of 9 months after completion of pembrolizumab, the estimated risk of 
progression or death was 9% in these patients (Robert et al 2017). Another recent analysis in a 


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melanoma study suggests the majority of patients who discontinue Nivolumab for toxicity 
maintain disease control in the absence of further treatment (Schadendorf et al 2016). 
In conclusion, these data suggest that there is minimal if any benefit derived from continuing 
checkpoint inhibitor immunotherapy treatment beyond 2 years in advanced tumors. Even 
though immunotherapy is well tolerated, patients will be at risk for additional toxicity with 
longer term treatment. Therefore, treatment will be given for a maximum of 2 years from the 
start of study treatment following the approval of protocol amendment 08.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4.
To estimate the clinical activity of Nivolumab in combination 
with EGF816 or INC280
6 month PFS rate using RECIST version1.1
(6mo PFS rate=6 cycles=168 days)
Secondary
Refer to Section 10.5.
To evaluate the preliminary antitumor activity of EGF816 
and Nivolumab and of INC280 and Nivolumab
ORR, DCR, other PFS measures, OS
To characterize the safety and tolerability of EGF816 and 
Nivolumab or of INC280 and Nivolumab
Safety, incidence and severity of AEs, including changes in 
hematology and chemistry values, vital signs and ECGs
Tolerability: Dose interruptions, reductions, and dose intensity
To evaluate PK of EGF816, INC280 and Nivolumab in the 
combination setting
PK parameters of Nivolumab,EGF816 and INC280 such as 
Cmax, AUC and Cmin


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4
Study design
4.1
Description of study design
This is a phase II, multi-center, open-label study of patients with advanced NSCLC.
Patients will be allocated based on their EGFR status to one of the two groups:

Group 1: EGFR-T790M NSCLC. As of December 17, 2015, enrollment to Group 1 has 
been halted.

Group 2: EGFR wild-type (wt) NSCLC. For the purpose of this protocol, EGFR wt is 
defined as negative for exon 19 deletions and for the L858R mutation in EGFR at a 
minimum; however, if more extensive EGFR mutation testing has been performed, the 
tumor must not harbor any known activating EGFR mutations in Exons 18-21 in order to 
be considered EGFR wt. Patients in Group 2 will be subdivided into two sub-groups:

Sub-group A: high cMet

Sub-group B: low cMet.
Based on group allocation, patients will be treated as follows:

Group 1: EGF816+nivolumab. As of January 28, 2016, nivolumab was required to be 
discontinued from all ongoing patients in Group 1. Ongoing patients who re-consent to 
remain on study will be treated with EGF816 as a single agent.

Group 2: INC280+nivolumab
A cycle will be defined as 28 days.
See Figure 4-1 for an overview of the study design
Figure 4-1
Study design
Please refer to Section 5 and Section 7.1 for further details. (*or other approved EGFR TKIs)


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Figure 4-2
Study visit flow
At least six patients of each group will constitute a safety monitoring cohort for that group. For 
each group, patients will be treated with either nivolumab 3mg/kg every two weeks and EGF816 
at 150mg qd or with nivolumab at 3mg/kg every two weeks and INC280 400mg bid. As part of 
the safety monitoring cohort, steady state PK profile for INC280 or EGF816 will be collected 
on Cycle 1 day 15, and trough samples for nivolumab will be collected on Cycle 1 Day 15.
When patients in the safety monitoring cohort have completed six weeks of treatment or 
discontinued earlier, Novartis and principal investigators will have a safety assessment meeting 
to review clinical, PK and laboratory data and decide on the dose for study continuation. Based 
on emerging data, this meeting may also take place earlier to address potential safety concerns. 
At this meeting, Novartis and the principal investigators must reach consensus as to whether 
the current doses in combination do not pose any additional safety concerns over those observed 
from the single agents. If safety concerns are noted in a given group following review of the 
data, a decision can be made to evaluate the next 6 patients at a lower dose level of EGF816 or 
INC280 with Nivolumab at 3mg/kg and repeat a medical review as part of another safety 
assessment meeting; or to terminate the respective treatment group. Alternatively, if no safety 
concerns are noted and data from other ongoing studies suggest that a higher dose of EGF816 
or INC280 may be more appropriate a decision can be made to evaluate the next 6 patients at a 
higher dose level of EGF816 or INC280 with Nivolumab at 3mg/kg and repeat a medical review 
as part of another safety assessment meeting. If applicable in the event that a higher dose is 
selected as the final dose, individual patients may be considered for treatment at a dose of 
EGF816 or INC280 that is higher than the dose to which they were initially assigned. In order 
for a patient to be treated at a higher dose of EGF816 or INC280, he or she must have received 
the lower dose for at least two cycles of therapy without a toxicity ≥ CTCAE grade 2 that is at 
least possibly related to the study drug. In addition, if there are no safety concerns but a lower 
dose is selected as the final dose based on data from other ongoing studies, no additional safety 
monitoring cohort is needed and enrollment may proceed to reach the planned sample size at 
the selected lower dose. Patients who were treated at the higher dose of EGF816 or INC280 
will remain at that dose if there are no safety concerns at the discretion of the treating 
investigator after discussion with Novartis. Novartis will prepare and circulate minutes from 
this meeting to each investigator for comments prior to finalization.
Once a dose is agreed upon after the safety monitoring cohort, enrollment will resume until the 
planned enrollment target as defined in Section 5.1, has been achieved in each treatment group.
However, if at any time during the study Novartis determines that a lower dose level of EGF816 
or INC280 should be explored, enrollment to the ongoing higher dose group may be stopped 
and Novartis may require the dose of EGF816 or INC280 to be reduced for any ongoing patients.
Detailed information on all patients will be collected and reported (see Section 10 for details).


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Molecular pre-screening
All patients must sign the molecular pre-screening consent to allow for the collection, and 
submission of tumor tissue to a Novartis designated central laboratory for determination and/or 
confirmation of protocol specific pre-requisite genetic alterations. Refer to Section 7.1 and 
Section 7.1.1 for further details.
Screening period
The screening period begins once the patient has signed the study informed consent. Patients 
will be evaluated against study inclusion and exclusion criteria and safety assessments 
(Table 7-1 and Section 7.1).
Treatment period
The treatment period will begin on Cycle 1 Day 1. The study treatment will be administered 
during 28-day cycles. Patients will be treated until unacceptable toxicity, progressive disease, 
treatment discontinuation at the discretion of the investigator, withdrawal of consent, or the 
patient is transferred to a Novartis roll-over study or an alternative treatment option that can 
continue to provide study treatment. Of note, eligible patients can only be transferred after the 
data cut-off for primary analysis. 
Following the approval of protocol amendment 08, the maximum treatment duration for 
Nivolumab cannot exceed 2 years. Patients who have received Nivolumab beyond 2 years will 
discontinue Nivolumab treatment and continue on EGF816/INC280 alone. Patients who have 
previously discontinued EGF816/INC280 and have been receiving Nivolumab alone beyond 2 
years will discontinue Nivolumab treatment, have an end of treatment visit and continue with 
the safety and survival follow-up as per Table 7-1b.
Follow up safety assessments
All patients must complete two safety follow-up assessments at 30 (±5) days and 100 (±7) days 
after last dose. Information relating to anti-neoplastic therapies taken since discontinuation of 
study treatment and AEs will be collected for 100 days after the last dose of study treatment.
For patients who transfer to a Novartis roll-over study or an alternative treatment option to 
continue provision of study treatment, an end of treatment visit will be conducted and follow-
up for safety, disease progression and survival will not be performed. 
Optional Novartis companion sample collection protocol
Patients may have tumor tissue and blood samples collected at baseline and at disease 
progression to study the mechanisms of drug treatment resistance. For sites that are participating 
in a Novartis optional companion sample collection protocol studying treatment resistance, the 
collection of these samples is guided by the companion sample collection protocol and informed 
consent once approved and open.
4.2
Timing of interim analyses and design adaptations
No formal interim analyses are planned for the study. Please refer to Section 10.7 in the protocol. 
Within each treatment group when patients in the safety monitoring cohort have completed six 


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weeks of treatment or discontinued earlier, a qualitative review of clinical, PK and laboratory 
data in a safety assessment meeting will take place (Section 2.2 and Section 4.1).
4.3
Definition of end of the study
End of study will occur after a minimum of 12 months has elapsed since last patient first 
treatment and when:

all patients have either discontinued study treatment and have completed 30-day and 
100-day safety follow up, or have been transferred to a Novartis roll-over study or 
alternative treatment option for continued access to study treatment

the study is terminated early.
Refer to Section 10 for details of timing of the primary analysis and final reporting of data.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.1 for a discontinued or withdrawn patient. 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 patient’s interests. The investigator will be responsible for 
informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
Adult 
patients 
with 
histologically 
or 
cytologically 
confirmed 
advanced 
and/or 
metastatic/unresectable NSCLC will be eligible to participate in this study.
The initial allocation of patients in the two groups will be based on EGFR and cMet status.
Group 1: will enroll at least 40 adult patients with advanced, recurrent or 
metastatic/unresectable EGFRT790M NSCLC progressing on standard of care (e.g., erlotinib, 
gefitinib or other approved EGFR TKI). As of December 17, 2015 enrollment to Group 1 has 
been halted.
Group 2: will enroll at least 50 adult patients, including at least 6 patients in the safety 
monitoring cohort of Group 2. Sub-group A will enroll approximately 20 high cMet and Sub-
group B will enroll approximately 30 low cMet patients.
The cMet status will be classified as high or low according to cMet expression assessed by 
immunohistochemistry (IHC), cMet gene amplification assessed by fluorescence in situ
hybridization (FISH), and cMet mutation status. Only IHC and FISH will be performed for pre-
screening, whereas mutation testing will be performed retrospectively for the purposes of 
analysis:
cMet high: if any one of the following criteria is satisfied:

IHC score = 3+ in at least 50% of tumor cells (regardless of gene copy number (GCN))


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
IHC score = 2+ in at least 50% of tumor cells and GCN ≥ 5

cMet exon 14 activating mutation positive
cMet low: if negative or unknown for cMet exon 14 activating mutation AND any one of the 
following criteria is satisfied

IHC score = 2+ in at least 50% of tumor cells and GCN < 5

IHC score = 2+ in less than 50% of tumor cells (regardless of GCN)

IHC score = 0 or 1+ (regardless of GCN)
The investigator or designee must ensure that only patients who meet all the inclusion and none 
of the exclusion criteria, as defined in Section 5.2 and Section 5.3 are offered treatment in the 
study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures
2. Patients (male or female) ≥ 18 years of age.
3. Presence of at least one measurable lesion according to RECIST v.1.1 as per Appendix 4.
4. ECOG performance status ≤ 2
5. Patients with histologically documented locally advanced, recurrent and/or metastatic 
NSCLC
6. Tumor tissue for determination and/or confirmation of genetic pre-requisites (i.e., EGFR 
T790M positivity post progression on EGFR TKI for Group 1; cMet status for Group 2) 
must be provided for analysis.
7. Group 1 patients
a. Patients with EGFR T790M NSCLC (adenocarcinoma)
b. Documented progression of disease according to RECIST v1.1 following primary 
standard of care (e.g. erlotinib, gefitinib)
8. Group 2 patients
a. Patients with EGFR wild-type NSCLC as defined in Section 4.1.
b. Documented progression of disease according to RECIST v1.1 following standard of 
care (e.g., platinum doublet).
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. For Group1: Patients who have received more than one prior line of EGFR TKI therapy
2. For Group 2: Previous treatment with a cMet inhibitor or HGF-targeting therapy
3. Patients with brain metastases. However, if radiation therapy and/or surgery has been 
completed and serial evaluation by CT (with contrast enhancement) or MRI over a 
minimum of one month demonstrates the disease to be stable and if the patient remains 
asymptomatic, then the patient with brain metastases may be enrolled. Such patients must 
have no need for treatment with steroids.


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4. Patients who require emergent use of systemic steroids, chronic use of prednisone (greater 
than 10mg or an equivalent steroid dose daily) or emergent surgery and/or radiotherapy.
5. History of allergy or hypersensitivity to Nivolumab components.
6. Any medical condition that would, in the investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures. Any severe, acute, or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study 
treatment administration or that may interfere with the interpretation of study results and, 
in the judgment of the investigator, would make the patient inappropriate for the study.
7. Patients with any known or suspected, current or past history of, autoimmune disease. 
Patients with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll
8. Patients with a condition requiring chronic systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 
days of treatment start. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
NOTE: Patients are permitted the use of topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption). Adrenal replacement steroid 
doses >10 mg daily prednisone are permitted. A brief (less than 3 weeks) course of 
corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
9. Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS)
10. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection.
Note: All patients will be screened for HBsAg, HBsAb, HBcAb, HC Ab and Hepatitis C 
RNA.  If a patient tests positive for any of the following: HBsAg, HBcAb or HC Ab or 
Hepatitis C RNA, then the patient should be excluded from the study.  If a patient tests 
positive only for HBsAb, HBV-DNA should be tested and if this test result is positive the 
patient should be excluded from the study.  Patients who test positive only for HBsAb and 
negative for HBV-DNA, and have a history of Hepatitis B vaccination, are eligible.  Please 
refer to Appendix 6 for further details.
11. Patients with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity
12. Patients with significant or uncontrolled cardiovascular disease (e.g., uncontrolled 
hypertension, peripheral vascular disease, congestive heart failure, cardiac arrhythmia, or 
acute coronary syndrome) within 6 months of starting study treatment or myocardial 
infarction within 12 months of starting study treatment.
13. Unable or unwilling to swallow tablets or capsules


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14. Unresolved toxicity greater than CTCAE grade 1 from previous anti-cancer therapy or 
radiotherapy (excluding neurotoxicity, alopecia, ototoxicity, lymphopenia), or incomplete 
recovery from previous surgery, unless agreed by Novartis and the Principal Investigator 
(PI) and documented
15. Prior therapy:
a. Patients who have been treated with prior PD-1 and PD-L1 agents
b. Patients who previously received agents targeting cMet and/or EGFR T790M. Note: 
Previous treatment with afatinib may be allowable after discussions between Novartis 
and Investigator.
c. Patients who have been treated with chemotherapy or biologic therapy or other 
investigational agent < 1 week prior to start of study treatment
d. Patients who have received radiotherapy to a large volume (including whole brain 
radiotherapy) < 2 weeks prior to starting study drug, and patients who have received 
radiotherapy to a small volume (including stereotactic radiotherapy to the CNS) < 1 
week prior to starting study drug.
e. Patients who have undergone major surgery < 2 weeks prior to starting study drug or 
who have not recovered from the surgical procedure
NOTE: exceptions to the above are possible, on a case by case basis, following discussion and 
mutual agreement between investigator and Novartis.
16. Patients with the following laboratory abnormalities:
a. Absolute Neutrophil Count (ANC) <1.5 x 109/L
b. Hemoglobin (Hgb) <9 g/dL
c. Platelets <100 x 109/L
d. Total bilirubin >1.5 x upper limit of normal (ULN). For patients with Gilbert’s 
syndrome total bilirubin >2.5 x upper limit of normal (ULN).
e. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 x ULN
f.
Serum creatinine >1.5 x ULN and/or measured or calculated creatinine clearance < 
75% LLN
g. For patients being screened for Group 2, asymptomatic serum amylase > CTCAE 
Grade 2 (1.5-2.0 x ULN). Patients with Grade 1 or Grade 2 serum amylase at the 
beginning of the study must be confirmed to have no signs or symptoms suggesting 
pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings 
of pancreas, etc.)
h. For patients being screened for Group 2: Serum lipase > ULN
17. Patients receiving treatment with medications that are known to be a) strong inhibitors 
of CYP3A4 (group 1 only) or strong inducers of CYP3A4 (for both Group 1 and 
Group 2), b) CYP3A4 or CYP1A2 substrates with narrow therapeutic index (for 
Group 2 only), and which cannot be discontinued for at least 1 week prior to the start 
of study treatment. Please refer to Appendix 2 for a list of prohibited concomitant 
medications
18. Pregnant or nursing (lactating) 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


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19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 23 weeks (30 days plus the time required for nivolumab to undergo 
five half-lives) after stopping investigational medication. Highly effective contraception 
methods include:
a. Total abstinence when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy, or tubal ligation at least six 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
c. Male sterilization (at least 6 months prior to screening). For female patients on the 
study the vasectomized male partner should be the sole partner for that patient.
d. Use of oral, injected or implanted 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.
NOTE: In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy) total hysterectomy, or tubal ligation at least six weeks ago. 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 not of child bearing potential.
20. Sexually active males unless they use a condom during intercourse while taking drug and 
for 31 weeks after the last dose of study treatment. Patients 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 drug via seminal fluid.
21. For Group 2: impairment of GI function or GI disease that may significantly alter the 
absorption of INC280 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
or malabsorption syndrome)
22. Patients with Long QT syndrome, family history of idiopathic sudden death or congenital 
long QT syndrome
23. Patients taking concomitant medication(s) with a “Known Risk of Torsades de Pointes” 
per www.qtdrugs.org that cannot be discontinued or replaced by safe alternative 
medication.
6
Treatment
6.1
Study treatment
The investigational drugs to be used in this study are EGF816, INC280 and Nivolumab.


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6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or Regimen
EGF816
Capsule for oral use
150 mg
Daily
INC280
Tablet for oral use
400 mg
Twice daily
Nivolumab
Solution for infusion
3mg/kg
Every two weeks
Instructions for administration of EGF816 and INC280
EGF816 will be administered orally on a daily schedule (QD) and INC280 will be administered 
bid. Both will be administered as a flat-fixed dose, not by body weight or surface area.
INC280 or EGF816 can be taken with or without food. The second (evening dose) for INC280 
should be taken 12 hours (+/-2 hours) apart from the first morning dose. Patients will self-
administer the study medication with a glass of water (approximately 250 mL; 8.5 ounces) at 
about the same time every day. Patients will consume another glass of water approximately two 
hours after each dosing. On the days when PK blood samples are to be collected (Section 7.2.3), 
patients will be instructed to hold their dose of study drugs and the administration of study drugs 
will be supervised by the study personnel, and the time of the meal before and after the dose 
need to be recorded on the eCRF.
During the entire duration of treatment with INC280, the patient is recommended to use 
precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective clothing, 
avoid sunbathing or using a sunlamp or tanning bed).
No food effect is anticipated for EGF816. Preliminary pharmacokinetics data from the ongoing 
study [CINC280A2108], in which INC280 tablet was administered with food in cancer patients,
showed no food effect of high fat meal on INC280 exposure. Thus, INC280 can be taken with 
or without food.
Patients in Group 1 must avoid consumption of grapefruit, grapefruit juice and grapefruit 
hybrids at least 7 days prior to the first dose of study treatment and during the entire study 
treatment period due to potential CYP3A interaction. For patients in Group 2, consumption of 
grapefruit, grapefruit juice and grapefruit hybrids is allowed with caution during the treatment 
period.
A missed dose is defined as any time point when a patient forgets to take INC280 or EGF816 
within 4 hours after the planned time of dosing or if a patient forgets to take his/her dose for 
that day. In such cases, the dose should be omitted and the patient should continue treatment 
with the next scheduled dose.
If vomiting occurs, no attempt should be made to replace the vomited dose. If any episodes of 
vomiting occurred within the first 4 hours of INC280 and EGF816 dosing on post dose PK 
sampling days, it must be noted in the Adverse Events CRF and the exact time of vomiting 
should be recorded on the appropriate Dosage Administration Record Case Report Form 
(eCRF).


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Instructions for administration Nivolumab
Patients should receive Nivolumab at a dose of 3 mg/kg as a 60-minute IV infusion every 2 
weeks, starting Day 1 of Cycle 1 for up to 2 years.
Following the approval of protocol amendment 08, patients who have received Nivolumab 
beyond 2 years will discontinue Nivolumab treatment and continue on EGF816/INC280 alone. 
Patients who have previously discontinued EGF816/INC280 and have been receiving 
Nivolumab alone, patients will discontinue Nivolumab treatment, have an end of treatment visit 
and continue with the safety and survival follow-up as per Table 7-1b.Dosing calculations 
should be based on the body weight assessed at baseline. It is not necessary to re-calculate 
subsequent doses if the patient weight is within 10% of the weight used to calculate the previous 
dose. All doses should be rounded to the nearest milligram.
There will be no dose escalations or reductions of Nivolumab allowed. Patients may be dosed 
no less than 12 days from the previous dose. There are no premedications recommended for 
Nivolumab on the first cycle.
Patients should be carefully monitored for infusion reactions during Nivolumab administration. 
If an acute infusion reaction is noted, patients should be managed according to Section 6.2.
Doses of Nivolumab may be interrupted, delayed, or discontinued depending on how well the 
patient tolerates the treatment.
General instructions
The investigator or responsible site personnel should instruct the patient to take the study drugs 
as per protocol (promote compliance). All dosages prescribed and dispensed to the patient and 
all dose changes and all missed doses during the study must be recorded on the Dosage 
Administration Record eCRF. Drug accountability must be performed on a regular basis. 
Patients will be instructed to return unused study drugs to the site at the end of each cycle. The 
site personnel will ensure that the appropriate dose of each study drug is administered at each 
visit and will provide the patient with the correct amount of drugs for subsequent dosing.
6.1.2
Sequence of drug administration
EGF816 and INC280 will be administered prior to Nivolumab and its pre-medication (if pre-
medication is necessary as per Table 6-7). The sequence will allow consistent time of daily 
dosing for EGF816 and INC280. A minimum of 1 hour must pass from the time of EGF816 or 
INC280 (morning dose) administration to the administration of Nivolumab (Figure 6-1).


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Figure 6-1
Sequence of drug administration (Group 1: EGF816 and Nivolumab; 
Group 2: INC280 (AM dose) and Nivolumab)
Note: 1On days in which Nivolumab is administered, INC280 (morning dose) should be 
withheld until arrival at the study center. The second (i.e. evening) INC280 dose may be taken 
outside the site center.
Pre-medications are not required for routine Nivolumab infusions but medications such as anti-
histamines (e.g., Benadryl or steroids per Table 6-7) may be administered to treat an existing 
infusion reaction or as pre-medication for a patient who has previously experienced an infusion 
reaction at the discretion of the investigator. All pre-medications, with reasons for use, will be 
recorded in the “Concomitant medications/Significant non-drug therapies” section of the eCRF.
6.1.3
Treatment duration
Patients may continue treatment with the study treatment until patient experiences unacceptable 
toxicity that precludes any further treatment, disease progression and/or treatment is 
discontinued at the discretion of the investigator or the patient. Patients may continue 
Nivolumab treatment for up to 2 years. Refer to Section 7.1.3 and Section 7.1.4.
Following the approval of protocol amendment 08, patients who have received Nivolumab 
beyond 2 years will discontinue Nivolumab treatment and continue on EGF816/INC280 alone. 
In patients who have previously discontinued EGF816/INC280 and have been receiving 
Nivolumab alone, patients will discontinue Nivolumab treatment, have an end of treatment visit 
and continue with the safety and survival follow-up as per Table 7-1b.
6.2
Dose modification and dose delay
6.2.1
Dose modification and dose interruption for EGF816, INC280 and 
Nivolumab
Guidelines for dose modifications, dose interruptions and discontinuation of each 
investigational agent within the combination may be different. In exceptional cases, after 
discussion with Novartis, patients may be allowed to continue treatment or resume treatment 
with just one of the investigational drugs. For purposes of this study, the term “discontinue 
study treatment” will refer to the discontinuation of both investigational agents; while the term 
“discontinue study drug” will refer specifically to the investigational agent being discussed.


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All dose modifications should be based on the worst preceding toxicity (CTCAE version 4.03). 
Specific criteria for interruption, re-initiation, dose reduction and/or discontinuation of EGF816, 
or INC280 or Nivolumab for patients receiving Nivolumab-EGF816 or Nivolumab-INC280 
combination are listed in Table 6-2.
All interruptions or modifications must be recorded on the Dosage Administration Record CRF.
Patients 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 should be consulted as deemed necessary. 
All patients must be followed up for adverse events and serious adverse events for up to 100 
days following the last doses of EGF816 or INC280 or Nivolumab – whichever may occur last 
in any given patient.
Prophylactic or supportive treatment for expected toxicities, including management of study-
drug induced adverse events will be as per institutional guidelines.
In case of study treatment interruption, the evaluation visit schedule should still be followed 
and assessments performed as per Table 7-1 and Table 7-1b.
For either EGF816 or INC280:
Each patient will be allowed two dose reductions to a minimum of 75 mg qd for EGF816 or to 
a minimum of 200mg bid of INC280. Dose reductions for EGF816 may only be multiples of 
25 mg (e.g., to doses of 100 mg or 75 mg) and for INC280 may only be multiples of 100 mg 
(e.g., to doses of 300 mg or 200 mg bid). If after interruption of treatment and resolution, 
treatment is resumed at the same dose following the criteria in Table 6-2, and if the same toxicity 
recurs with the same severity, next treatment re-initiation must resume at a lower dose 
irrespective of duration of toxicity. In addition, a patient must discontinue treatment if, after 
treatment is resumed at the minimum dose defined, the toxicity recurs with the same or worse 
severity unless specified otherwise in Table 6-2. Exceptions can be made on a case by case basis 
after discussion with Novartis and Investigator.
If a patient requires a dose interruption of either EGF816 or INC280 for > 21 days from the 
intended day of the next scheduled dose, due to toxicity attributed to EGF816 or INC280, 
respectively, then the patient must be discontinued from the study treatment unless otherwise 
specified in Table 6-2.
For Nivolumab:
There will be no dose reductions for Nivolumab.
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the patient with continued Nivolumab dosing 
may warrant interruption or discontinuation of Nivolumab dosing.
If a patient requires a dose interruption of Nivolumab for > 6 weeks from the intended day of 
the next scheduled dose, then the patient must be discontinued from the study treatment. 
Exceptions following discussion between Investigator and Novartis may be possible. Reasons 
for which exceptions may be possible include:


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a. Dosing delays to allow for prolonged steroid tapers to manage Nivolumab-related adverse 
events are allowed.
b. Dosing delays lasting > 6 weeks from the previous dose that occur for non-Nivolumab-
related reasons may be allowed.
All interruptions or modifications must be recorded on the Dosage Administration Record CRF.
In case of study treatment interruption, the evaluation visit schedule should still be followed 
and assessments performed as per Table 7-1 and Table 7-1b.
Table 6-2
Criteria for omission, delay, or discontinuation of Nivolumab, EGF816 
and INC280 for patients receiving Nivolumab and EGF816 or 
Nivolumab and INC280
Worst toxicity 
CTCAEa (unless 
otherwise 
specified)
Recommended dose modifications
for EGF816 or INC280
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO EGF816 OR INC280
Recommended dose modifications
for Nivolumab
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO NIVOLUMAB
Note: If a toxicity is suspected to be possibly related to both study drugs (EGF816 and nivolumab or 
INC280 and nivolumab), guidelines pertaining to both study drugs should be followed.
No toxicity
Maintain dose and schedule
Maintain dose and schedule
Neutropenia (ANC)
Grade 3 (ANC < 
1000 - 500/mm3)
Omit dose until resolved to ≤ Grade 2, 
then maintain dose
Dose delay for Nivolumab-related G3
See Section 6.2.4 on resuming Nivolumab
Grade 4 (ANC < 
500/mm3)
Omit dose until resolved to ≤ Grade 2, 
then reduce dose
Discontinue for Nivolumab related G4 > 7 
day duration
Thrombocytopenia
Grade 3 (PLT < 
50,000 -
25,000/mm3)
Omit dose until resolved to ≤ Grade 1, 
then:
If resolved in ≤ 7 days, maintain dose
If resolved in > 7 days, reduce dose
Dose delay for Nivolumab-related G3
See Section 6.2.4 on resuming Nivolumab
Discontinue for Nivolumab-related G3 > 7 
days or associated with bleeding
Grade 4 (PLT < 
25,000/mm3)
Omit dose until resolved to ≤ Grade 1, 
then reduce dose
Discontinue for Nivolumab-related G4
Febrile 
neutropenia
(ANC < 1.0 x 
109/L, fever ≥ 
38.5°C)
Omit dose until resolved, then reduce 
dose
Dose delay for Nivolumab-related G3
See Section 6.2.4 on resuming Nivolumab
Discontinue for Nivolumab-related G4
Lymphopenia
≤ Grade 3 (≥ 
200/mm3; ≥ 0.2 x 
109 /L)
Maintain dose and schedule
Maintain dose and schedule for 
Nivolumab-related ≤ G3
Grade 4 (< 
200/mm3;
< 0.2 x 109 /L)
Omit dose until resolved, then reduce 
dose
Dose delay for Nivolumab-related G4
Nivolumab-related G4 lymphopenia or 
leukopenia does not require 
discontinuation
See Section 6.2.4 on resuming Nivolumab


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Worst toxicity 
CTCAEa (unless 
otherwise 
specified)
Recommended dose modifications
for EGF816 or INC280
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO EGF816 OR INC280
Recommended dose modifications
for Nivolumab
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO NIVOLUMAB
Investigations 
(Renal)
Serum 
creatinine
Grade 2 (> 1.5 -
3.0 x ULN)
Omit dose until resolved to ≤ Grade 1 
or baseline, then maintain dose
Dose delay for Nivolumab-related ≥ G2
See Section 6.2.4 on resuming Nivolumab
Discontinue for Nivolumab-related G4
See “Renal Adverse Event Management 
Algorithm” for additional guidance on 
monitoring and management of any grade 
events. See Appendix 5.
Grade 3 (> 3.0 -
6.0 x ULN)
Omit dose until resolved to ≤ Grade 1 
or baseline, then reduce dose
Patients will be instructed to increase 
their fluid intake until resolution to ≤ 
Grade 1 or baseline.
Grade 4 (> 6.0 x 
ULN)
Discontinue patient from study 
treatment
Investigations (Hepatic)
Isolated Total Bilirubin elevationb
Grade 1 (> ULN 
– 1.5 X ULN)
Maintain dose level with LFTs 
monitored
Maintain dose level with LFTs monitored
Grade 2 (> 1.5 -
3.0 x ULN)
Omit dose until resolved to ≤ Grade 1, 
then:
If resolved in ≤ 7 days, maintain dose
If resolved in > 7 days, reduce dose
If baseline total bilirubin is within normal 
limits, delay dosing for ≥ Grade 2 toxicity
If baseline total bilirubin is within the 
Grade 1 toxicity range, delay dosing for ≥ 
Grade 3 toxicity
See Section 6.2.4 on resuming Nivolumab
Discontinue for:

Total bilirubin > 5X ULN
For all Grades See “Hepatic Adverse 
Event Management Algorithm” for 
additional guidance on monitoring and 
management of any grade events. See 
Appendix 5.
Grade 3 (> 3.0 -
10.0 x ULN)
Omit dose until resolved to ≤Grade 1, 
then:
If resolved in ≤7 days, reduce dose
If resolved in >7 days, discontinue 
patient from study drug
The patient should be monitored 
weekly (including LFTs (Liver 
Function Tests)), or more frequently if 
clinically indicated, until total bilirubin 
has resolved to baseline or stabilized 
over 4 weeks
Grade 4 (> 10.0 
x ULN)
Discontinue patient from study 
treatment
The patient should be monitored 
weekly (including LFTs), or more 
frequently if clinically indicated, until 
total bilirubin has resolved to baseline 
or stabilized over 4 weeks
Isolated AST or ALT elevation
Grade 2 (> 3.0 –
5.0 x ULN)
Maintain dose level
If baseline AST or ALT is within normal 
limits, delay dosing for ≥ Grade 2 toxicity


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Worst toxicity 
CTCAEa (unless 
otherwise 
specified)
Recommended dose modifications
for EGF816 or INC280
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO EGF816 OR INC280
Recommended dose modifications
for Nivolumab
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO NIVOLUMAB
Grade 3 (> 5.0 -
20.0 x ULN)
Omit dose until resolved to ≤ Grade 1 
(or ≤ Grade 2 if Grade 2 elevation at 
baseline, then:
If resolved in ≤ 7 days, maintain dose
If resolved in > 7 days, reduce dose.
See Appendix 6 for additional 
guidelines on further testing
If baseline AST or ALT is within the Grade 
1 toxicity range, delay dosing for ≥ Grade 
3 toxicity
See Section 6.2.4 on resuming Nivolumab
Discontinue for:

AST or ALT > 5 x ULN for > 2 weeks

AST or ALT >10 x ULN
See “Hepatic Adverse Event Management 
Algorithm” for additional guidance on 
monitoring and management of any grade 
events. See Appendix 5.
Grade 4 (> 20.0 
x ULN)
Discontinue patient from study drug
See Appendix 6 for additional 
guidelines on further testing
Combinedc elevations of AST or ALT and total bilirubine
AST or ALT > 
3.0 x ULN 
combined with 
total bilirubin > 
2.0 x ULN
For patients with normal baseline ALT 
or AST or total bilirubin value 
discontinue from study drug for:
AST or ALT > 3.0 x ULN 
combined with total bilirubin > 2.0 
x ULN without evidence of 
cholestasisd
OR
For patients with elevated baseline 
AST or ALT or total bilirubin value 
discontinue from study drug for:
[AST or ALT > 2.0 x baseline 
AND > 3.0 x ULN] OR [AST or 
ALT > 8.0 x ULN], combined with
[total bilirubin > 2.0 x baseline 
AND > 2.0 x ULN]
Repeat LFTsf as soon as possible, 
preferably within 48 hours from 
awareness of the abnormal results, 
then with weekly monitoring of LFTsf, 
or more frequently if clinically 
indicated, until AST, ALT, or bilirubin 
have resolved to baseline or 
stabilized over 4 weeks.
See Appendix 6 for additional 
guidelines on further testing
Discontinue patient from Nivolumab for:
Concurrent AST or ALT > 3x ULN and 
total bilirubin > 2x ULN without 
evidence of cholestasisd
Repeat LFTsf as soon as possible, 
preferably within 48 hours from 
awareness of the abnormal results, then 
with weekly monitoring of LFTsf, or more 
frequently if clinically indicated, until AST, 
ALT, or bilirubin have resolved to baseline 
or stabilized over 4 weeks.
See “Hepatic Adverse Event Management 
Algorithm” for additional guidance on 
monitoring and management of any grade 
events. See Appendix 5.
Asymptomatic amylase and/or lipase elevationg
Grade 2 (> 1.5 -
2.0 x ULN)
Maintain dose and schedule.
Maintain dose and schedule
Grade 3 (> 2.0 -
5.0 x ULN)
Omit dose until resolved to Grade ≤ 2,
If resolved in ≤ 14 days, maintain 
dose. If resolved in > 14 days, reduce 
dose.
Any Grade ≥3 Nivolumab-related isolated 
amylase or lipase abnormality that is not 
associated with symptoms or clinical 
manifestations of pancreatitis does not 


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Worst toxicity 
CTCAEa (unless 
otherwise 
specified)
Recommended dose modifications
for EGF816 or INC280
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO EGF816 OR INC280
Recommended dose modifications
for Nivolumab
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO NIVOLUMAB
Grade 4 (> 5.0 x 
ULN)
Discontinue patient from study 
treatment
require dose delay or discontinuation. The 
NVS Medical Monitor should be consulted 
for such amylase or lipase abnormalities.
Myotoxicity, excluding myocarditis
Grade 2
Omit dose until resolved to Grade ≤ 1. 
If resolved to ≤ Grade 1 in ≤ 7 days, 
maintain dose. If resolved in > 7 days, 
reduce dose.
Dose delay for any Grade ≥ 2 Nivolumab-
related myotoxicity and refer patient to a 
specialist for assessment and treatment
See Section 6.2.4 on resuming Nivolumab
Grade 3
Discontinue patient from study 
treatment
Discontinue for Grade 3 Nivolumab-
related myocarditis
Discontinue for Grade 3 Nivolumab-
related other myotoxicity lasting longer 
than 7 days
Grade 4
Discontinue patient from study 
treatment
Discontinue for Nivolumab-related Grade 
4 myotoxicity
Cardiac general, excluding myocarditis
Grade 2 or 3
Maintain dose and schedule.
Dose delay for any Grade ≥ 2 Nivolumab-
related adverse event
See Section 6.2.4 on resuming Nivolumab
Discontinue for any Grade 3 Nivolumab-
related adverse event lasting > 7 days
Grade 4
Discontinue patient from study 
treatment
Discontinue for any G4 Nivolumab-related 
adverse event
Myocarditis
Myocarditis 
Grade > 2
Mandatory: Permanently discontinue 
patient from study treatment
Discontinue for Nivolumab
Endocrine
Grade 2
Maintain dose and schedule
Dose delay for any Grade ≥ 2 Nivolumab-
related adverse event
See Section 6.2.4 on resuming Nivolumab
Grade 3
Omit dose until resolved to Grade ≤ 2,
If resolved in ≤ 14 days, maintain 
dose
If resolved in > 14 days, reduce dose
Grade 3 Nivolumab-related 
endocrinopathies adequately controlled 
with only physiologic hormone 


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Worst toxicity 
CTCAEa (unless 
otherwise 
specified)
Recommended dose modifications
for EGF816 or INC280
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO EGF816 OR INC280
Recommended dose modifications
for Nivolumab
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO NIVOLUMAB
Grade 4
Discontinue patient from study 
treatment
replacement do not require 
discontinuation
Grade 4 Nivolumab-related 
endocrinopathy adverse events, such as 
adrenal insufficiency, 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 
discontinuation after discussion with and 
approval from the NVS Medical Monitor.
See Section 6.2.4 on resuming Nivolumab
See “Endocrinopathy Management 
Algorithm” for additional guidance on 
monitoring and management of any grade 
events. See Appendix 5.
Diarrhea/Colitish
Grade 1
Maintain dose level but initiate anti-
diarrhea treatment per institutional 
standard
Dose delay for any Grade ≥ 2 Nivolumab-
related adverse event
See Section 6.2.4 on resuming Nivolumab
Discontinue for any Grade 3 Nivolumab-
related adverse event lasting > 7 days, or 
any G4 Nivolumab-related adverse event
See “GI Adverse Event Management 
Algorithm” for additional guidance on 
monitoring and management of any grade 
events. See Section 6.2.4.
Grade 2
Omit dose until resolved to ≤ grade 1 
and initiate anti-diarrhea treatment, 
then maintain dose
If diarrhea returns as ≥ grade 2, then 
omit dose until resolved to ≤ grade 1, 
then reduce dose
Grade 3
Omit dose until resolved to ≤ grade 1, 
then reduce dose
Grade 4
Discontinue patient from study 
treatment
Vomiting
Grade 1 (despite 
standard anti-
emetics)
Maintain dose level
Dose delay for Nivolumab-related 
Grade 3
See Section 6.2.4 on resuming Nivolumab
Discontinue for Nivolumab-related 
Grade 4
Grade 2 (despite 
standard anti-
emetics)
Omit dose until resolved to ≤ grade 1, 
then maintain dose level.
If vomiting returns as ≥ grade 2, then 
omit dose until resolved to ≤ grade 1, 
then ↓1 dose level.
Grade 3 (despite 
standard anti-
emetics)
Omit dose until resolved to ≤ grade 1, 
then ↓1 dose level


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Worst toxicity 
CTCAEa (unless 
otherwise 
specified)
Recommended dose modifications
for EGF816 or INC280
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO EGF816 OR INC280
Recommended dose modifications
for Nivolumab
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO NIVOLUMAB
Grade 4 (despite 
standard anti-
emetics)
Omit dose until resolved to ≤ grade 1, 
then ↓1 dose level
Nausea
Grade 1 or 2 
(despite 
standard anti-
emetics)
Maintain dose level
Dose delay for Nivolumab-related 
Grade 3
See Section 6.2.4 on resuming Nivolumab
Discontinue for Nivolumab-related 
Grade 4
Grade 3 (despite 
standard anti-
emetics)
Omit dose until resolved to ≤ grade 1, 
then ↓1 dose level
Skin See Section 6.2.2.1 for Skin Toxicity Management Guidelines
Peripheral edema (General disorders and administration site conditions)
Grade 1 or 2
Conservative measures such as leg 
elevation, compression stockings, and 
dietary salt modification. Consider 
supportive medications as clinically 
indicated.
Dose delay for Nivolumab-related 
Grade 3
See Section 6.2.4 on resuming Nivolumab
Discontinue for Nivolumab-related 
Grade 4
Grade 3
Discontinue dose until resolved to ≤ 
Grade 1, then ↓1 dose level
Grade 4
Discontinue INC280
Fatigue/Asthenia
Grade 3
Omit dose until resolved to ≤ grade 1, 
then :
If resolved in ≤ 7 days, maintain dose
If resolved in > 7 days, reduce dose
Grade 2 Nivolumab-related fatigue does 
not require Nivolumab delay.
Dose delay for any Grade ≥ 3 Nivolumab-
related adverse event
See Section 6.2.4 on resuming Nivolumab
Discontinue for any Grade 3 Nivolumab-
related adverse event lasting > 7 days, or 
any G4 Nivolumab-related adverse event
Grade 4
Omit dose until resolved to ≤ grade 1, 
then :
If resolved in ≤ 7 days, maintain dose
If resolved in > 7 days, reduce dose
Any Neurological toxicity
Grade 2
Omit dose until resolved to ≤ grade 1
Dose delay for any Grade ≥ 2 Nivolumab-
related adverse event
See Section 6.2.4 on resuming treatment
Discontinue for any Grade 3 Nivolumab-
related adverse event lasting > 7 days, or 
any G4 Nivolumab-related adverse event
See “Neurological Adverse Event 
Management Algorithm” for additional 
guidance on monitoring and management 
of any grade events. See Appendix 5.
Grade 3 or 4
Omit dose.
Neurological assessments must be 
repeated at least twice a week until 
resolution to < CTCAE grade 1. 
Unscheduled MRI and gadolinium 
enhanced T1 imaging may also be 
conducted to evaluate patients for 
intramyelinic edema like lesions, brain 
metastases and other unanticipated 
CNS occurrences. An EEG may be 
performed to monitor for physiological 
changes in brain activity.


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Worst toxicity 
CTCAEa (unless 
otherwise 
specified)
Recommended dose modifications
for EGF816 or INC280
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO EGF816 OR INC280
Recommended dose modifications
for Nivolumab
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO NIVOLUMAB
Ocular
Grade 2
Omit dose until resolved to ≤ grade 1, 
then :
If resolved in ≤ 7 days, maintain dose
If resolved in > 7 days, reduce dose
Dose delay for any Grade ≥ 2 Nivolumab-
related adverse event
See Section 6.2.4 on resuming Nivolumab
Discontinue for any Grade 2 Nivolumab-
related uveitis, eye pain or blurred vision 
that does not respond to topical therapy 
and does not improve to Grade 1 severity 
within the re-treatment period OR requires 
systemic treatment
Grade 3 Nivolumab-related uveitis of any 
duration requires discontinuation
Discontinue for any Grade 3 Nivolumab-
related adverse event lasting > 7 days, or 
any G4 Nivolumab-related adverse event
Grade 3
Discontinue patient from study 
treatment
Grade 4
Discontinue patient from study 
treatment
Pulmonary toxicity other than ILD/Pneumonitis
Grade 2
Omit dose until resolved to ≤ grade 1, 
then :
If resolved in ≤ 7 days, maintain dose
If resolved in > 7 days, reduce dose
Dose delay for any Grade ≥ 2 Nivolumab-
related adverse event
See Section 6.2.4 on resuming Nivolumab
Grade ≥3 Nivolumab-related pneumonitis 
of any duration requires discontinuation
Discontinue for any Grade 3 Nivolumab-
related pulmonary adverse event other 
than pneumonitis lasting > 7 days, or any 
G4 Nivolumab related pulmonary adverse 
event other than pneumonitis
See “Pulmonary Adverse Event 
Management Algorithm” for additional 
guidance on monitoring and management 
of any grade events. See Appendix 5.
Grade 3
Omit dose until resolved to ≤ grade 1, 
then :
If resolved in ≤ 7 days, maintain dose
If resolved in > 7 days, reduce dose
Grade 4
Discontinue patient from study drug
ILD like events/Pneumonitis
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. In addition, withhold INC280
for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and 
fever and during diagnostic workup for pneumonitis/ILD to exclude alternative causes such as, but not 
limited to infections, lymphangitic carcinomatosis, cardiogenic edema, or pulmonary hemorrhage.  
Any grade pneumonitis/interstitial lung disease should be considered possibly related to BOTH study 
drugs (nivolumab and EGF816 or nivolumab and INC280).  
For the follow-up and management of ILD like events/pneumonitis, also refer to Appendix 5, 
Pulmonary Adverse Event Management Algorithm.


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Worst toxicity 
CTCAEa (unless 
otherwise 
specified)
Recommended dose modifications
for EGF816 or INC280
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO EGF816 OR INC280
Recommended dose modifications
for Nivolumab
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO NIVOLUMAB
Grade 1
Asymptomatic, 
radiographic 
findings only
Continue EGF816 at same dose 
level. 
Interrupt INC280 during diagnostic 
workup for ILD/Pneumonitis. Exclude 
infections and other etiologies.
In presence of diagnosis of 
ILD/Pneumonitis after diagnostic 
workup, it is mandatory to 
permanently discontinue INC280.
Only in the absence of a diagnosis of 
ILD/Pneumonitis, INC280 may be 
restarted at the same dose.
If it recurs after resumption of study 
drug permanently discontinue 
INC280.
Consider delay of Nivolumab dosing.
Grade 2
Symptomatic, 
not interfering
with activity daily 
living (ADL)
Interrupt study drug dose during 
diagnostic workup for ILD until 
improvement to ≤ Grade 1. Exclude 
infections and other etiologies. 
In presence of diagnosis of 
ILD/Pneumonitis after diagnostic 
workup, it is mandatory to 
permanently discontinue study drug.
In the absence of a diagnosis of 
ILD/Pneumonitis, study drug may be 
restarted following guidelines:
if symptoms resolve to ≤ Grade 1 in ≤ 
7 days reduce study drug by 1 dose 
level. 
If symptoms fail to resolve within 7 
days or recur after resumption of 
study drug at decreased dose, 
permanently discontinue study drug.
Mandatory: Delay Nivolumab dosing 
during diagnostic work up for ILD until 
improvement to ≤ Grade 1. Exclude 
infections and other etiologies.
See Section 6.2.4 on resuming 
Nivolumab.
See “Pulmonary Adverse Event 
Management Algorithm” for additional 
guidance on monitoring and management 
in Appendix 5.


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Worst toxicity 
CTCAEa (unless 
otherwise 
specified)
Recommended dose modifications
for EGF816 or INC280
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO EGF816 OR INC280
Recommended dose modifications
for Nivolumab
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO NIVOLUMAB
Grade 3
Symptomatic,
interfering with 
ADL; O2
indicated and 
Grade 4 Life-
threatening;
ventilatory 
support indicated
Permanently discontinue study drug.
Permanently discontinue Nivolumab. 
Hypersensitivity
As per Non-laboratory AE guidance
See Table 6-7 for treatment of Nivolumab-
related infusion reactions
Grade >/= 3 Nivolumab-related 
bronchospasm, hypersensitivity reaction, 
or infusion reaction of any duration 
requires discontinuation
Other Non-laboratory adverse events
Grade 1 or 2
Maintain dose and schedule.
Dose delay for any Grade ≥ 2 Nivolumab-
related adverse event
See Section 6.2.4 on resuming Nivolumab
Discontinue for any Grade 3 Nivolumab-
related adverse event lasting > 7 days, or 
any G4 Nvolumab-related adverse event
Grade 3
If ongoing at time of next scheduled 
drug – omit scheduled dose
If resolved to ≤ grade 1 and prior to 
scheduled dose; may proceed with 
scheduled dose
Grade 4
Discontinue patient from study 
treatment
Other laboratory adverse events
As per Non-laboratory AE guidance 
above
Grade 2 or 3 Nivolumab-related 
laboratory abnormalities other than 
specified above do not require a 
Nivolumab delay.
Dose delay for any Grade ≥ 3 Nivolumab-
related adverse event
See Section 6.2.4 on resuming Nivolumab
All dose modifications should be based on the worst preceding toxicity.
a Common Toxicity Criteria for Adverse Events (CTCAE Version v4.03)
b If total bilirubin > 3.0 x 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 ↓1 dose level and continue treatment at the discretion of the 
investigator.
c “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST 
increase to the defined threshold
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. discontinue treatment at the 


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Worst toxicity 
CTCAEa (unless 
otherwise 
specified)
Recommended dose modifications
for EGF816 or INC280
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO EGF816 OR INC280
Recommended dose modifications
for Nivolumab
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO NIVOLUMAB
situation when omit dose is needed for one parameter and 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 x ULN and R value <2] in patients without bone 
metastasis, or elevation of ALP liver fraction in patients 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
e For toxicity defined as related to EGF816 or INC280; 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. discontinue treatment at the situation when omit dose is needed for one parameter 
and discontinue treatment is required for another parameter). After all elevations resolve to the defined 
thresholds that allow treatment re-initiation, restart the treatment either at the same dose or at one 
dose lower if meeting a criterion for dose reduction.
f LFTs include albumin, ALT, AST, GGT, total bilirubin (fractionated (direct and indirect) if total 
bilirubin >2.0 x ULN), alkaline phosphatase (fractionated (quantification of isoforms) if alkaline 
phosphatase > 2.0 x ULN) and GGT. For isolated elevations of any grade of alkaline phosphatase 
and/or gamma-glutamyl transpeptidase (GGT), maintain dose level.
g 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 of amylase and/or lipase. If asymptomatic Grade 
3 elevations of lipase and/or amylase occur again at the reduced dose, patients will be discontinued 
permanently from study drug.
h antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or 
overt diarrhea
6.2.2
Follow-up for toxicities
In case of isolated elevations in total bilirubin, AST or ALT, or ILD/Pneumonitis additional 
follow-up evaluations are recommended as outlined in Table 6-3:


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Table 6-3
Follow-up evaluations for selected toxicities
TOXICITY
FOLLOW-UP EVALUATION
HEPATIC
Isolated total bilirubin elevation
CTCAE Grade 1
Monitor LFTs per protocol or more frequently if clinically indicated
CTCAE Grade 2
Weekly monitoring of LFTs, or more frequently if clinically indicated, until 
resolved to ≤ 1.5 x ULN
CTCAE Grade 3
Weekly monitoring of LFTs, or more frequently if clinically indicated, until 
resolved to ≤ 1.5 x ULN. If resolved in > 7 days, after discontinuing the 
patient from INC280 permanently, the patient should be monitored 
weekly (including LFTs), or more frequently if clinically indicated, until 
total bilirubin have resolved to baseline or stabilization over 4 weeks
CTCAE Grade 4
After discontinuing the patient from INC280 permanently, the patient 
should be monitored weekly (including LFTs), or more frequently if 
clinically indicated, until total bilirubin have resolved to baseline or 
stabilization over 4 week
Isolated AST/ALT elevation
CTCAE Grade 2
For patients with baseline value ≤ 3.0 
x ULN
Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; if abnormal lab values are confirmed 
upon the repeat test, then monitor LFTs weekly, or more frequently if 
clinically indicated, until resolved to ≤ 3.0 x ULN
For patients with baseline value > 3.0 
- 5.0 x ULN
Monitor LFTs per protocol or more frequently if clinically indicated
CTCAE Grade 3 -For elevation > 5.0 -
10.0 x ULN:
For patients with baseline value ≤ 3.0 
x ULN
Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to ≤ 3.0 x ULN
For patients with baseline value > 3.0 
- 5.0 x ULN:
Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; if abnormal lab values are confirmed 
upon the repeat test, then monitor LFTs, weekly, or more frequently if 
clinically indicated, until resolved to ≤ 5.0 x ULN
CTCAE Grade 3
For AST/ALT elevation > 10.0 - 20.0 x 
ULN:
Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to ≤ baseline
CTCAE Grade 4
Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to baseline or stabilization 
over 4 weeks.
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
ILD/Pneumonitis
CTCAE Grade 1
CT scan (high-resolution with lung windows) recommended, with serial 
imaging to monitor for resolution or progression- re-image at least every 
3 weeks
Monitor for symptoms every 2-3 days - Clinical evaluation and laboratory 
work-up for infection
Monitoring of oxygenation via pulse oximetry recommended
Consultation of pulmonologist recommended


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TOXICITY
FOLLOW-UP EVALUATION
CTCAE Grade 2
CT scan (high-resolution with lung windows)
•
Monitor symptoms daily, consider hospitalization
•
Clinical evaluation and laboratory work up for infection
•
Consult pulmonologist
•
Pulmonary function tests a - if normal at baseline, repeat every 8 
weeks 
•
Bronchoscopy with biopsy and/or BAL recommended c
Symptomatic therapy including corticosteroids if clinically indicated (1 to 
2 mg/kg/day prednisone or equivalent as clinically indicated) b
CTCAE Grade 3 and Grade 4
CT scan (high-resolution with lung windows)
Clinical evaluation and laboratory work-up for infection
Consult pulmonologist
Pulmonary function tests a-if < normal, repeat every 8 weeks until ≥ 
normal
Bronchoscopy with biopsy and/or BAL if possible c
Treat with IV steroids (methylprednisolone 125 mg) as indicated. When 
symptoms improve to ≤ Grade 1, a high dose oral steroid (prednisone 1 
to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours) b.
If IV steroids followed by high dose oral steroids does not reduce initial 
symptoms within 48 to 72 hours, consider non-corticosteroid 
immunosuppressive medication
*Note: this table refers only to the evaluation schedule to monitor selected toxicities. Refer to Table 6-2 for dose 
modifications required for applicable toxicities
a PFT (Pulmonary function tests) to include: diffusing capacity corrected for hemoglobin (DLCO); spirometry; 
resting oxygen saturation
Guideline for significant deterioration in lung function: Decrease in spirometry and/or DLCO of 30% and/or O2
saturation ≤88% at rest on room air.
b Duration and dose of course of corticosteroids will vary according to circumstances but should be as limited as 
possible. Consider tapering dosage at end.
c If bronchoscopy is performed, bronchoalveolar lavage (BAL) should be done where possible to exclude alveolar 
hemorrhage, opportunistic infections, cell count + determination lymphocyte CD4/8 count where possible.
6.2.2.1
Guidelines for prevention and management of rash/skin toxicities
For all patients, guidelines for the prevention and symptomatic management of skin toxicities 
are provided in Table 6-4. Additional guidelines for the management of rash/skin toxicities 
specific to Group 1 and Group 2 patients are provided below.


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Table 6-4
Guidelines for prevention and symptomatic care of rash/skin toxicities 
for all patients
Type of care
Action
Prevention/Prophylaxis
Starting from Da
y 1 for all patients

Avoid unnecessary exposure to sunlight

Apply broad-spectrum sunscreen with SPF≥15 at least twice daily

Use thick, alcohol-free emollient cream (e.g. glycerine and 
cetomacrogol cream) on dry areas of the body at least twice daily
Symptomatic care*

Pruritic lesions: cool compresses and oral antihistamine therapies

Desquamation: thick, alcohol-free emollient cream and mild soap

Paronychia: antiseptic bath and topical antibiotics; if no 
improvement, consult dermatologist

Infected lesions: appropriate topical or systemic antibiotics
*Patients who develop rash/skin toxicities should be evaluated by a qualified physician and receive 
symptomatic and supportive care management.
Group 1 patients
Rash, particularly maculopapular rash or rash pruritic, is an adverse event frequently observed 
following treatment with EGF816. Rash is also a common adverse event associated with 
nivolumab. Patients must be closely monitored for any signs/symptoms related to rash/skin 
toxicities. Recommended guidelines for management and dose modification of rash/skin 
toxicities are provided in Table 6-4 and Table 6-5. These guidelines constitute guidance to the 
Investigator and may be supplemented or modified on a case-by-case basis after discussion with 
Novartis. In addition:
1. Educate all patients on the importance of notifying the investigator immediately (e.g., by 
telephone) if a rash appears. Investigators are to contact Novartis if a patient develops a 
grade 2 or higher rash.
2. Educate all patients on the guidelines for prevention of rash/skin toxicity (see Table 6-4).
3. All rashes occurring on study for patients receiving the combination are to be considered 
possibly related to both EGF816 and nivolumab, even after the discontinuation of 
nivolumab (due to its long half-life).
4. For all rashes, institute interventions related to rash as outlined in Table 6-4 and Table 6-5.


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Table 6-5
Guidelines for dose modification and management related to rash for 
Group 1 patients1
Note: For any grade Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, permanently 
discontinue EGF816.
CTCAE 
Grade
Actions
Grade 1

Continue EGF816 at same dose level

See “Skin Adverse Event Management Algorithm” (Section 14.5) for actions to be 
taken if rash persists more than 1-2 weeks

Initiate appropriate symptomatic care, if not already instituted (refer to Table 6-4)

Use mild-strength topical steroid (e.g. 1% hydrocortisone cream) on affected areas

Re-assess after 1 week

If systemic steroids are instituted based on nivolumab guidelines (Section 14.5), 
follow the nivolumab guidelines for the systemic steroid course.
Grade 2

Interrupt EGF816 until recovered to ≤ Grade 1. Once rash has recovered to ≤ Grade 
1, restart EGF816 at one level reduced from the previous dose level2

See “Skin Adverse Event Management Algorithm” (Section 14.5) for follow-up actions 
if rash persists > 1-2 weeks or recurs.

Initiate appropriate symptomatic care, if not already instituted (refer to Table 6-4)

Use moderate-strength topical steroid (e.g. 2.5% hydrocortisone cream or 0.5% 
fluticasone cream) on affected areas PLUS low-dose oral steroid (e.g. prednisone 
5mg-10mg PO QD for 1 week) with taper. If systemic steroids are instituted based on 
nivolumab guidelines (Section 14.5), follow the nivolumab guidelines for the systemic 
steroid course.

Re-assess after 1 week
Grade 3

Interrupt EGF816 until rash recovers to ≤ Grade 1. Once recovers to ≤ Grade 1, 
restart EGF816 at one level reduced from the previous dose level2.

If no recovery to ≤ Grade 2 within 3 weeks, permanently discontinue EGF816

Initiate appropriate symptomatic care, if not already instituted (Refer to Table 6-4)

Start systemic steroids and follow additional instructions per nivolumab guidelines 
(See Section 14.5, “Skin Adverse Event Management Algorithm”)

Consult dermatologist
If re-initiating EGF816 after Grade 3 rash:

Oral antihistamine therapies (e.g. levocetirizine 5mg QD, desloratadine 5mg QD, or 
fexofenadine 180 mg QD) should be given concurrently with EGF816 for 4 weeks 
when restarting treatment.

Patients who develop more than 1 episode of Grade ≥ 3 rash will be permanently 
discontinued from EGF816
Grade 4

Permanently discontinue EGF816

Initiate appropriate symptomatic care, if not already instituted (Refer to Table 6-4)

Follow instructions for systemic steroid treatment in nivolumab guidelines (See 
Section 14.5, “Skin Adverse Event Management Algorithm”)

Consult dermatologist


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Note: For any grade Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, permanently 
discontinue EGF816.
CTCAE 
Grade
Actions
1 For all grades of rash, consider skin biopsy for pathologic evaluation.
2 A maximum of 2 dose reductions is allowed. Patients who require further dose decrease after 2 dose 
reductions should be discontinued from study drug. Escalation by one level to previous dose level 
may be considered if no rash is evident after 4 weeks of uninterrupted study drug at the reduced dose 
level. Re-escalation can only be done once.
Group 2 patients
The guidelines in Table 6-6 apply to patients in Group 2.


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Table 6-6
Criteria for omission, delay, or discontinuation of Nivolumab and 
INC280 for skin toxicity for patients receiving Nivolumab and INC280
Worst toxicity CTCAEa
(unless otherwise 
specified)
Recommended dose 
modifications
for INC280
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO INC280
Recommended dose 
modifications
for Nivolumab
During a cycle of therapy
TOXICITY DEFINED AS
RELATED TO NIVOLUMAB
Note: For any grade Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, permanently 
discontinue INC280 and nivolumab.
Grade 1
Maintain dose level of INC280. 
Consider initiating institutional 
standard and/or local practice 
guidelines to treat skin toxicity 
therapy (such as antihistamines, 
topical corticosteroids and low-dose 
systemic corticosteroids per 
institutional standard).
Dose delay for any Grade ≥ 3 
Nivolumab-related adverse event
See Section 6.2.4 on resuming 
Nivolumab
Discontinue for or any Grade 3 
Nivolumab-related adverse event 
lasting > 7 days, or any G4 
Nivolumab-related adverse event
See “Skin Adverse Event 
Management Algorithm” (Appendix 
5) for additional guidance on 
monitoring and management of any 
grade events.
Grade 2
Maintain dose level of INC280, but 
initiate/intensify appropriate skin 
toxicity therapy (such as 
antihistamines, topical 
corticosteroids and low-dose 
systemic corticosteroids per 
institutional standard). If no 
recovery or worsened within 1 
week, interrupt study drug until 
recovery to ≤ Grade 1. Once rash 
has recovered to ≤ Grade 1, then 
restart at reduced dose.
Grade 3, despite skin 
toxicity therapy
Omit INC280 until resolved to 
Grade ≤ 1, and then:
initiate/intensify appropriate skin 
toxicity therapy (such as 
antihistamines, topical 
corticosteroids and low-dose 
systemic corticosteroids).
Resume at reduced dose.
If no recovery to ≤ Grade 2 within 3 
weeks, permanently discontinue 
study treatment.
Patients who develop more than 1 
episode of Grade ≥3 rash will be 
permanently discontinued from 
study treatment.
Grade 4, despite skin 
toxicity therapy
Discontinue patient from study 
treatment.
All dose modifications should be based on the worst preceding toxicity.
a Common Toxicity Criteria for Adverse Events (CTCAE Version v4.03)


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6.2.3
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients 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 the absence of cholestasis, these patients should be immediately discontinued from study
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.

Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.

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.

Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g., biliary 
tract) may be warranted.

Obtain PK sample, as close as possible to last dose of study drug.

Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
6.2.4
Criteria to resume treatment with Nivolumab after dose delay
Subjects may resume treatment with Nivolumab when the Nivolumab-related AE(s) resolve(s) 
to Grade ≤ 1 or baseline, with the following exceptions:

Patients may resume treatment in the presence of Grade 2 fatigue

Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in 
the presence of Grade 2 AST/ALT OR total bilirubin


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
Nivolumab-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline 
before treatment is resumed. Patients with persistent Grade 1 pneumonitis after 
completion of a steroid taper over at least 1 month may be eligible for retreatment if 
discussed with and approved by Novartis.

Nivolumab-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with Novartis
Dose delay of Nivolumab which results in treatment interruption of > 6 weeks require treatment 
discontinuation, with exceptions as noted above. There will be no dose reductions for 
Nivolumab.
6.2.5
Treatment of Nivolumab-related infusion reactions and other immune-
related AEs
Since Nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to Novartis and reported as an SAE if it 
meets the criteria. Infusion reactions should be graded according to NCI CTCAE (Version 4.03) 
guidelines.
Additionally, immuno-oncology (I-O) agents are associated with AEs that can differ in severity 
and duration than AEs caused by other therapeutic classes. Nivolumab is considered an 
immuno-oncology agent in this protocol. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management Algorithms have 
been developed to assist investigators in assessing and managing the following groups of AEs: 
Gastrointestinal; Renal; Pulmonary; Hepatic; Endocrinopathy; Skin; Neurological; and 
Myocarditis. Management Algorithms can be found in the Nivolumab IB and Appendix 5.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:


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Table 6-7
Guidelines for treatment for Nivolumab induced infusion reactions
Grade
Recommended Intervention
For Grade 1 symptoms: (mild reaction; infusion 
interruption not indicated; intervention not 
indicated):
Remain at bedside and monitor patient until 
recovery from symptoms. The following 
prophylactic premedications are recommended 
for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or acetaminophen/paracetamol 
325 to 1000 mg at least 30 minutes before 
additional Nivolumab administrations
For Grade 2 symptoms: (moderate reaction 
required therapy or infusion interruption but 
responds promptly to symptomatic treatment (eg, 
antihistamines, non-steroidal anti inflamatory 
drugs, narcotics, corticosteroids, bronchodilators, 
IV fluids); prophylactic medications indicated for < 
24 hours):
Stop the Nivolumab infusion, begin an IV infusion 
of normal saline, and treat the patient with 
diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg; 
remain at bedside and monitor patient until 
resolution of symptoms. Corticosteroid and/or 
bronchodilator therapy may also be administered 
as appropriate. If the infusion is interrupted, then 
restart the infusion at 50% of the original infusion 
rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate 
may be increased to 100% of the original infusion 
rate. Monitor patient closely. If symptoms recur, 
then no further Nivolumab will be administered at 
that visit. For future infusions, the following 
prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before 
Nivolumab infusions. If necessary, corticosteroids 
(up to 25 mg of SoluCortef or equivalent) may be 
used.
For Grade 3 or 4 symptoms: (severe reaction, 
Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for 
other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates].
Grade 4: Life threatening; pressor or ventilatory 
support indicated):
Immediately discontinue infusion of Nivolumab. 
Begin an IV infusion of normal saline and treat the 
patient as follows: Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of 
a 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV 
with methylprednisolone 100 mg IV (or 
equivalent), as needed. Patient should be 
monitored until the Investigator is comfortable that 
the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should 
follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and 
monitor patient until recovery of the symptoms
In case of late-occurring hypersensitivity 
symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after 
treatment)
Symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).


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6.3
Concomitant medications
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g. such as anti-emetics, anti-diarrhea) and safety of the patient are allowed except as 
specifically prohibited in Section 6.3.2. The patient must be told to notify the investigational 
site about any new medications he/she takes after the start of the study drug combination. All 
medications (other than study drug combination) and significant non-drug therapies (including 
physical therapy, herbal/natural medications and blood transfusions) administered during the 
study must be listed on the Concomitant Medications or the Surgical and Medical Procedures 
CRF
Steroids
Patients are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Systemic corticosteroids ≤ 10 mg daily 
prednisone equivalent are allowed (higher doses to treat a drug-related immune-mediated AE 
must be tapered to 10 mg or lower before resuming nivolumab). Adrenal replacement steroid 
doses > 10 mg daily prednisone are permitted. A brief (less than 3 weeks) course of 
corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune 
conditions (e.g., delayed-type hypersensitivity reaction caused by a contact allergen) is 
permitted.
6.3.1
Permitted concomitant therapy requiring caution and/or action
INC280 is a moderate CYP1A2 inhibitor. Co-administration of INC280 increased the sensitive 
CYP1A2 probe substrate (caffeine) AUC by 135%. The dose of CYP1A2 substrates with 
narrow therapeutic index may need to be reduced when used concurrently with INC280, as 
INC280 may increase their exposure. Consult the product information of the concomitant drug 
for dose adjustment.
Co-administration of INC280 increased Pgp substrate (digoxin) exposure (AUC and Cmax by 
47% and 74%, respectively) and BCRP substrate (rosuvastatin) exposure (AUC and Cmax by 
108% and 204%, respectively). Monitor patients closely for symptoms of increased exposure 
to Pgp or BCRP substrates. Consult the concomitant Pgp or BCRP substrate product 
information when considering dose adjustment.
Co-administration of INC280 with a strong CYP3A4 inhibitor (itraconazole) increased INC280 
AUC by 40%. There was no change in INC280 Cmax. Exercise caution when using a strong 
CYP3A4 inhibitor concurrently with INC280. 
While the data on the concurrent use of PPI and food have to be considered preliminary as they 
have been generated in a small cohort of patients of the study [CINC280A2108], the decrease 
in exposure imposes caution on the use of PPI when INC280 is taken with no regards of food.
Short acting gastric acid modulators containing aluminum hydroxide and magnesium hydroxide, 
or calcium carbonate can be taken. However, it is recommended that these drugs be taken at 
least 3 hours before or 3 hours after administration of INC280. H2 receptor antagonists should 
be avoided. If patients are using H2 receptor antagonists during the course of this study, patients 
should not take H2 receptor antagonists for at least 2 hours after administration of INC280. In 


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addition, the next scheduled dose of INC280 should be administered at least 8 hours after taking 
H2 receptor antagonists.
INC280 is a weak to moderate inhibitor of CYP2C8, CYP2C9 and CYP2C19 in vitro. 
Substrates of CYP2C8, CYP2C9 and CYP2C19 with a narrow therapeutic window should be 
administered with caution for patients treated with INC280.
EGF816 is a moderate to weak inhibitor for CYP2D6 and CYP2C8. The sensitive substrates 
for these CYP isoforms, should be administered with caution for EGF816 and Nivolumab 
combination.
EGF816 is a P-gp substrate and a moderate inhibitor of BCRP and human multidrug and toxin 
extrusion (MATE; 1 and 2K) transporters. Caution should be exercised when potent P-gp 
inhibitors, BCRP and MATE substrates are concurrently used in the EGF816/Nivolumab 
combination.
INC280 displayed inhibition of P-gp, BCRP, MATE, OATP1B1 and OATP1B3. Sensitive 
substrates for P-gp, BCRP, MATE and OATP transporters should also be administered with 
caution for INC280/Nivolumab combinations.
Localized palliative non-invasive therapy, such as radiotherapy, is allowed for the treatment of 
symptomatic bone or CNS lesions. EGF816 should be interrupted at least 5 days prior to such 
therapy if medically safe to delay local therapy, and may be resumed ≥3 days after completion 
of therapy if all AEs related to the intervention have resolved to ≤ Grade 1. INC280 should be 
interrupted at least 2 days prior to such therapy if medically safe to delay local therapy, and 
may be resumed ≥3 days after completion of therapy if all AEs related to the intervention have 
resolved to ≤ Grade 1. No washout period is required for nivolumab prior to local therapy; 
nivolumab may be resumed ≥ 2 weeks after completion of local therapy if all AEs related to the 
intervention have resolved to ≤ Grade 1.
Please refer to Table 14-1 for a full list of concomitant medications to be used with caution.
6.3.2
Prohibited concomitant therapy
EGF816 is mainly metabolized by CYP3A4, therefore strong inhibitors and strong inducers of 
CYP3A4 (Table 14-2) should not be used concomitantly with EGF816. Co-administration of 
INC280 with a strong CYP3A4 inducer (rifampicin) decreased INC280 AUC by 66% and Cmax 
by 56%. Concurrent use of strong CYP3A4 inducers is prohibited for patients treated with 
INC280 as decreased INC280 exposure may lead to reduced efficacy.
For INC280, drugs with known risk of causing TdP are prohibited (Table 14-2). Study treatment 
must be interrupted as long as the patient requires therapy with QT prolonging agent.
Immunosuppressive agents and immunosuppressive doses of systemic corticosteroids (except 
as stated above) are prohibited, except when utilized to treat a drug-related adverse event.
Live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow 
fever, varicella, and TY21a typhoid vaccines) should not be administered while a patient is 
dosed with EGF816 and for 30 days after the last dose of EGF816.
Concomitant antineoplastic therapy (including radiotherapy and surgery) or other 
investigational treatment is prohibited except as described in Section 6.3.1.


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6.4
Patient numbering, treatment assignment, or randomization
6.4.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each patient is numbered uniquely across the entire database. Upon 
signing the informed consent form, the patient is assigned to the next sequential Subject No. 
available to the investigator through the Oracle Clinical RDC interface.
Once assigned, the Subject No. must not be reused for any other patient and the Subject No. for 
that individual must not be changed, even if the patient is re-screened.
6.4.2
Treatment assignment or randomization
The assignment of the patient to the treatment groups will be coordinated by Novartis. No 
randomization will be performed for this study.
6.5
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient and/or administered 
to the patient by authorized site personnel only. All dosage prescribed to the patient and all dose 
changes during the study must be recorded on the Dosage Administration Record eCRF.
6.5.1
Study drug packaging and labeling
The study medication packaging has a 2-part label. Site personnel will add the patient number 
on the label. Immediately before dispensing the package to the patient, site personnel will detach 
the outer part of the label from the packaging and affix it to the source document (Drug Label 
Form) for that patient’s unique patient number.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug but will not supply information about 
the patient. EGF816 and INC280 will be supplied by Novartis. EGF816 25 mg, 50 mg, and 100 
mg capsules will be packaged in high density polyethylene (HDPE) bottles. INC280 50 mg, 
150 mg, and 200 mg tablets will be packaged in HDPE bottles. Nivolumab will be supplied in 
vials as a solution for infusion. Instructions for preparation and dispensation for Nivolumab are 
described in the Nivolumab Investigator Brochure.
6.5.2
Study drug supply and storage
Study treatments must be received by designated personnel 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, the study treatment should be stored according to 
the instructions specified on the drug labels and in the [Investigator’s Brochure].


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6.5.3
Study drug compliance and accountability
6.5.3.1
Study drug compliance
At the day of a scheduled visit to the clinic, the patient will take either EGF816 or INC280 
according to the assigned treatment group and will be given a Nivolumab infusion, at the clinic 
under the supervision if the Investigator or his designee. For all other study days, the patient 
will take EGF816 or INC280 at home depending on the assigned treatment group.
The time of dose administrations on days when PK blood samples are drawn must be recorded 
in the Dosage Administration Record eCRF.
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.
6.5.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and 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.
6.5.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 and Table 7-1b list all of the assessments and indicates with an “X”, the visits when 
they are performed. All data obtained from these assessments must be supported in the patient’s 
source documentation.
No CRF will be used as a source document.
For all visits, with the exception of PK sampling, there is a +/- 3 days window on assessments 
to take into account scheduling over public or religious holidays, if not explicitly stated 
otherwise. For PK sampling, time windows are defined in Section 7.2.3. Should there be a need 
to modify the PK schedule due to dose interruptions, please contact Novartis to discuss 
sampling schedules.


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Disease progression and overall survival follow-up visits have a +/- 7 days window.
For imaging assessments, a +/- 7 days window is allowed, except for the first post baseline 
assessment and for confirmatory scans (+7 days window only permitted). All screening 
assessments, including baseline imaging assessments, must be completed within 28 days before 
the first dose. Laboratory assessments performed as part of the screening evaluations and within 
72 hours of the first dose of study treatment, are not required to be repeated on the first dosing 
day.
Molecular pre-screening assessments can be performed any time prior to the initiation of 
screening.
PK samples will be collected according to Table 7-6, Table 7-7, Table 7-8, Table 7-9, and 
Table 7-10.
Biomarker sampling will be conducted as outlined in Table 7-11.
All assessments should be performed as outlined in Table 7-1 and as clinically indicated.
Following the approval of protocol amendment 8, the ongoing patients will follow a reduced 
schedule of safety assessments as specified in Table 7-1b. The assessment schedule specified 
in Table 7-1 will become obsolete. Other assessments may be performed at the discretion of 
investigator as per the standard of care at site.  


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Table 7-1
Visit evaluation schedule
Screening 
Phase
Treatment Phase
Follow-Up
Category
Protocol Section
Molecular Pre-
screening
Screening
Cycle 1
Cycle 2
Subsequent cycles
EoT
30 day safety F/U
100-day Safety F/U
(end of study)
Disease progression 
F/U
Survival (every 12 
weeks)
Day of Cycle
-28 
to 1
1
8
15
22
1
14
15
22
1
15
Obtain Molecular Pre-screening 
Informed Consent (if applicable)
D
7.1.1.
X
Obtain Informed Consent
D
7.1.2.
X
Demography
D
7.1.2.3.
X
X
Inclusion/exclusion criteria
D
5.2/5.3.
X
Medical history/Current medical 
conditions
D
7.1.2.3.
X
Diagnosis and extent of cancer
D
7.1.2.3.
X
Prior antineoplastic therapies
D
7.1.2.3.
X
Smoking history
D
7.1.2.3.
X
Prior/concomitant medications
D
7.1.2.3.
CONTINUOUSLY
Antineoplastic therapies since 
discontinuation of study 
treatment
D
7.1.5.
X
X
X
X
X
Physical examination
S
7.2.2.1.
X
X
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2.
X
X
X
X
X
X1
X
X
X
X
X
X
X
Pulse Oximetry
D
7.2.2.2.
X
X
X
X
X
X
X
X
X
Height
D
7.2.2.3.
X


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Screening 
Phase
Treatment Phase
Follow-Up
Category
Protocol Section
Molecular Pre-
screening
Screening
Cycle 1
Cycle 2
Subsequent cycles
EoT
30 day safety F/U
100-day Safety F/U
(end of study)
Disease progression 
F/U
Survival (every 12 
weeks)
Day of Cycle
-28 
to 1
1
8
15
22
1
14
15
22
1
15
Weight
D
7.2.2.3.
X
X
X
X
X
X
X
X
X
X
Performance status
D
7.2.2.4.
X
X
X
X
X
X
X
HIV testing8
D
7.2.2.5.2.
X8
Hepatitis B and C testing
D
7.2.2.5.2.
X
Hematology
D
7.2.2.5.1.
X
X
X
X
X1
X
X2
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5.2.
X
X
X
X
X1
X
X2
X
X
X
X
X
X
X
Coagulation
D
7.2.2.5.3.
X
Serum Pregnancy Test
D
7.2.2.5.4.
X
X
X
X
X
X
Urine Pregnancy Test9
S
X
Tumor evaluation as per 
RECIST v1.1 CT/MRI
D
7.2.1
/7.1.5.
X
End of every 2 cycles, 
Q8 wks up to C12, then 
end of every 12 wks 
from C13 to C24, then 
every 24 weeks to C36, 
then every 52 weeks 
from C37.
X
X
ECG
D
7.2.2.6.
X
X
X
X
X
X
AEs
D
8.1.
X
X
Continuously
Collection of archival or newly 
obtained tumor sample
D
7.1.1.
7.2.4.
X


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Screening 
Phase
Treatment Phase
Follow-Up
Category
Protocol Section
Molecular Pre-
screening
Screening
Cycle 1
Cycle 2
Subsequent cycles
EoT
30 day safety F/U
100-day Safety F/U
(end of study)
Disease progression 
F/U
Survival (every 12 
weeks)
Day of Cycle
-28 
to 1
1
8
15
22
1
14
15
22
1
15
Collection of newly obtained 
tumor sample
D
7.1.1.
7.2.4.
X6
X (C3D1)
X (C5D1-optional)
X (C7D1-optional)
X optional
Companion3 Sample protocol 
Assessments (consent, 
inclusion, exclusion, sample 
collection, biopsy related 
serious adverse events)
D
7.2.4.
X
X
X (upon disease progression)
X
Nivolumab dosing (every 2 
weeks)
D
6.1.1.
X
X
X
X
X
X
EGF816 Dosing
D
6.1.1.
Continuously
INC280 Dosing
D
6.1.1.
Continuously
EGF816 and INC280 PK blood 
sampling (Safety monitoring 
cohort only)
D
7.2.3.2.
X4
X4
X
X
X (cycles 4,6, 8 & 
upon disease 
progression)


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Screening 
Phase
Treatment Phase
Follow-Up
Category
Protocol Section
Molecular Pre-
screening
Screening
Cycle 1
Cycle 2
Subsequent cycles
EoT
30 day safety F/U
100-day Safety F/U
(end of study)
Disease progression 
F/U
Survival (every 12 
weeks)
Day of Cycle
-28 
to 1
1
8
15
22
1
14
15
22
1
15
Nivolumab PK blood sampling 
(All patients)
D
7.2.3.2.
X
X
X
X (cycles 4, 8) 
then every 8th
cycle after C8D1& 
upon disease 
progression
X
X
Meal Record
D
7.2.3.1.
X
X (cycles 4,6, 8)
EGF816 and INC280 PK blood 
sampling (After safety 
monitoring cohort)
D
7.2.3.2.
X
X
X (cycles 4,6, 8 & 
upon disease 
progression)
Survival contact (telephone call)
D
7.1.5.
X


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Screening 
Phase
Treatment Phase
Follow-Up
Category
Protocol Section
Molecular Pre-
screening
Screening
Cycle 1
Cycle 2
Subsequent cycles
EoT
30 day safety F/U
100-day Safety F/U
(end of study)
Disease progression 
F/U
Survival (every 12 
weeks)
Day of Cycle
-28 
to 1
1
8
15
22
1
14
15
22
1
15
1.
For patients in safety monitoring cohort only
2.
For patients in safety monitoring cohort, hematology and chemistry assessments will be performed on C2D14 instead of Cycle 2 D15.
3.
Mandatory if participating in the Companion Sample Collection, unless medically unsafe or infeasible. See companion sample collection protocol for further 
information
4.
For EGF816 only
5.
For US patients cMet detection/confirmation of cMet dysregulation will be performed on archival tumor sample only
6.
Sample will not be collected if a newly obtained tumor sample has already been obtained at pre-screening for the purpose of 
. An archival sample 
may be submitted instead of a newly obtained tumor sample after documented discussion with Novartis, if it was recently obtained and there has been no intervening 
systemic anti-neoplastic therapy.
7.
Collect at screening or anytime thereafter.
8.
HIV testing will be done at screening for patients in Germany
9.
Monthly urine pregnancy tests should be performed after the 30 day safety follow up visit and should continue until approximately 23 weeks after discontinuation of 
the study treatment. Urine pregnancy test results should remain with the patient records and do not need to be included in the  clinical database.


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Table 7-1b
Visit evaluation schedule (effective after protocol amendment 08 is approved)
Follow Up
Category
Day 1 of every other cycle (every 
8 weeks)
EoT
30-day 
safety F/U
100-day 
Safety F/U
(end of 
study)
Disease 
progression 
F/U
Survival 
(every 12 
weeks)
Physical examination
S
X
X
Vital signs
D
X
X
Hematology
D
X (on Day 1 of EVERY cycle 
during the first 13 cycles)
X
Chemistry
D
X (on Day 1 of EVERY cycle 
during the first 13 cycles)
X
Serum pregnancy test
D
X (on Day 1 of EVERY cycle)
X
X
Urine pregnancy test
S
X
Tumor evaluation as per 
RECIST v1.1 CT/ MRI
D
Every 8 weeks up to C12, then 
every 12 weeks from C13 to C24, 
then every 24 weeks from C25 to 
C36, then every 52 weeks from 
C37 onwards until 12 months has 
elapsed since last patient first 
treatment
X
X (every 12 
weeks with ±
7 days 
window, until 
12 months 
has elapsed 
since last 
patient first
treatment)
ECG
S
X
X
Adverse event
D
Continuous
Concomitant medications
D
Continuous
New antineoplastic therapy 
since discontinuation of study 
treatment 
X
X


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Follow Up
Category
Day 1 of every other cycle (every 
8 weeks)
EoT
30-day 
safety F/U
100-day 
Safety F/U
(end of 
study)
Disease 
progression 
F/U
Survival 
(every 12 
weeks)
Collection of newly obtained 
tumor sample
D
X 
(optional)
EGF816/ INC280 dosing
D
Continuous
Nivolumab dosing 
D
Continuous
(every 2 weeks on Day 1 & Day 15 
of every cycle for up to 2 years)
Survival contact (telephone 
contact)
D
X


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7.1.1
Molecular pre-screening
An archival or a newly obtained tumor sample will be submitted to a Novartis-designated 
central laboratory for molecular pre-screening. This sample will be used to detect the T790M 
mutation in the EGFR gene for Group 1 patients, and to determine cMet status by IHC and 
FISH for Group 2 patients (for US patients, cMet testing will be performed on an archival tumor 
sample only). Only those patients whose tumors are EGFR T790M-mutated will be eligible to 
screen for Group 1. To be eligible for Group 2, cMet IHC and FISH status must be successfully 
determined centrally, and documentation of EGFR wt status must be available (local mutation 
testing for EGFR is preferred, but central testing can be performed if local results are not 
available). Results of central pre-screening analysis will be communicated back to the 
investigator.
Upon positive determination that the sample submitted contains the required EGFR T790M 
mutation and that cMet molecular status has been determined, the patient may sign the study’s 
main Informed Consent to begin screening procedures.
Additionally for all patients enrolled into this study, a newly obtained tumor sample or a 
recently-obtained archival tumor sample will be collected for 
 analyses as outlined 
in Table 7-11.
7.1.2
Screening
The IRB/IEC study approved informed consent form (ICF) must be signed and dated before 
any screening procedure is performed. Procedures which are part of the clinical routine during 
the initial diagnostic work-up of the patient may be obtained before obtaining the ICF. A copy 
of the ICF must be given to the patient or to the person signing the form. The investigator or his 
designee must record the date when the study informed consent was signed in the medical 
records of the patient.
Patients will be evaluated against study inclusion and exclusion criteria and safety assessments. 
For details please refer to Table 7-1.
Screening assessments must be done within 28 days prior to the first dose of the study 
medication with the exception of the pregnancy test, which must be performed within 72 hours 
of the first dose. Clinical and radiological tumor assessment by RECIST v1.1 (Appendix 4) 
should be conducted within 1 week (7 days) prior to the first dose of study treatment; however 
tumor assessments up to 4 weeks (28 days) prior to the first dose will be acceptable. The tumor 
assessment during the screening phase will be used to determine future responses and/or 
progression.
7.1.2.1
Enrollment process
When the patient is considered eligible, the investigator or clinical site should complete the 
Patient Registration Form and send it to Novartis.
After the patient signs the study Informed Consent form, the investigator or clinical site should 
determine patient eligibility. The investigator or site staff should complete patient registration 


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form and send it to Novartis. The allocation of patients to treatment groups will be handled by 
Novartis.
7.1.2.2
Information to be collected on screening failures
Patients who signed a molecular pre-screening ICF but are considered ineligible after molecular 
pre-screening, as well as patients who are found not eligible after signing the main study consent 
will be considered as screening failures, and data will be handled in the same manner.
The reason for molecular pre-screening failure or screening failure will be entered on the 
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details). For molecular pre-screening failures, only SAEs possibly related to a study 
procedure will be reported.
7.1.2.3
Patient demographics and other baseline characteristics
Data to be collected will include general patient demographics, relevant medical history and 
current medical conditions, diagnosis and extent of tumor, details of prior anti-neoplastic 
treatments and any other assessments that are done for the purpose of determining eligibility 
for inclusion in the study. All medications and significant non-drug therapies (including herbal 
medicines, physical therapy and blood transfusions) taken within 4 weeks prior to first dose of 
study drug must be recorded on the eCRF. Smoking history will be recorded on the eCRF at 
screening
7.1.3
Treatment period
A treatment cycle is defined as 28 days (4 calendar weeks) for the purposes of scheduling 
procedures and evaluations. Please refer to Table 7-1 and Table 7-1b for details of the timing 
of required assessments and Section 7.1 for visit windows.
During the treatment period, the patient is obliged to follow the investigators instructions with 
regards to contraception, concomitant medications and dosing regimen.
There is no fixed treatment duration.
Patients will be treated until patient experiences unacceptable toxicity, progressive disease 
and/or treatment is discontinued at the discretion of the investigator or withdrawal of consent
as described in Section 7.1.4.2, or the patient is transferred to a Novartis roll-over study or an 
alternative treatment option that can continue to provide study treatments.
Following the approval of protocol amendment 08, the maximum treatment duration for 
Nivolumab cannot exceed 2 years. Afterwards, patients who have received Nivolumab beyond 
2 years will discontinue Nivolumab treatment and continue on EGF816/INC280 alone. In 
patients who have previously discontinued EGF816/INC280 and have been receiving 
Nivolumab alone, patients will discontinue Nivolumab treatment, have an end of treatment visit 
and continue with the safety and survival follow-up as per Table 7-1b.


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7.1.4
End of treatment visit including study completion and premature 
withdrawal
At the time patients discontinue study treatment, a visit should be scheduled as soon as possible, 
and within 14 days of the last dose of study drugs or within 14 days of the decision to 
permanently discontinue study treatment, at which time all of the assessments listed for the End 
of Treatment (EOT) visit will be performed. For purposes of this study, the term “discontinue 
study treatment” will refer to the discontinuation of both investigational agents. Patients who 
meet the criteria for exceptional cases and/or a discontinuation criteria that applies to only one 
of the investigational agents will not be scheduled to undergo an EOT until all investigational 
agents are discontinued.
If the decision to withdraw the patient occurs at a regularly scheduled visit, that visit may 
become the EOT visit rather than having the patient return for an additional visit.
An End of Treatment Phase Disposition CRF page should be completed, giving the date and 
reason for stopping the study treatment.
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit but do not formally withdraw consent, will be assessed via safety 
evaluations as outlined in Table 7-1 and Table 7-1b during the 100 days following the last dose 
of study treatment. Patients should return for 30-day safety follow-up (see Section 7.1.5), 
disease progression follow-up (if applicable), 100-day safety follow-up, survival follow-up 
assessments at the visits according to Table 7-1 and Table 7-1b and should not be considered 
withdrawn from the study.
If a study withdrawal occurs, or if the patient fails to return for visits, the Investigator must 
make every effort (e.g. telephone, email, letter) to determine the primary reason for a patient’s 
premature withdrawal from the study, and record this information on the End of Treatment 
Disposition CRF page.
If a patient discontinues study treatment, but continues study assessments (i.e. enters post-
treatment follow-up phase), the patient remains on study until such time as he/she completes 
protocol criteria for ending study assessments (i.e. ending post-treatment follow-up phase). At 
that time (ending post-treatment follow-up phase), the reason for study completion should be 
recorded on the End of Post Treatment Phase Disposition CRF page.
In exceptional cases patients may remain on study treatment or re-initiate study treatment even 
after meeting a criterion for premature patient withdrawal if a clear benefit to the patient can be 
documented and there is agreement between Investigator and Novartis.
Patients who transfer into a Novartis roll-over study or an alternative treatment option to 
continue provision of study treatment will perform the end of treatment procedures. 
7.1.4.1
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient:

Does not want to participate in the study any longer, and 

Does not allow further collection of personal data


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In this situation, the investigator should make a reasonable effort (e.g. telephone, email, letter) 
to understand the primary reason for patient’s decision to withdraw his/her consent and record 
this information.
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 patient are not allowed unless safety findings require 
communication or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a patient’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
7.1.4.2
Criteria for premature patient withdrawal
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator must make every effort 
(e.g. telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information in the patient’s chart and on the appropriate CRF pages. They may be considered 
withdrawn if they state an intention to withdraw, fail to return for visits, or become lost to 
follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being.
Patients may be withdrawn from the study if any of the following occur:

AE

Lost to follow-up

Physician decision

Progressive disease

Protocol deviation

Study terminated by the sponsor

Patient withdrew consent
Patients will be withdrawn from the study if any of the following occur:

Pregnancy


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
Death
Patients who discontinue study treatment should NOT be considered withdrawn from the study. 
They should return for the assessments indicated in Section 7.1.4.2. If they fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, email, letter) should be 
made to contact them as specified in Section 7.1.6.
7.1.4.3
Replacement policy
No replacements will be needed.
7.1.5
Follow up period
100-day safety follow-up period
All patients must have safety evaluations as per Table 7-1 and Table 7-1b for 100 days after the 
last dose of investigational drug(s), even if a new anti-cancer therapy is initiated.
Hematological and chemistry assessments should be done in person at 30-day and 100-day 
follow up visits as per Table 7-1. Following the approval of protocol amendment 08, it is not 
required to perform these assessments as per Table 7-1b.  
All patients will be followed for AEs for 100 days after the last dose of the study drug.
Information related to AEs (including concomitant medications taken for ongoing AEs) and 
ongoing anti-neoplastic treatments will be collected for 100 days after last dose of study drug. 
All AEs suspected to be related to study treatment should be followed up weekly, or as clinically 
indicated, until resolution or stabilization. Data collected should be added to the Adverse Events 
CRF and the Concomitant Medications CRF.
Patients lost to follow up should be recorded as such on the CRF. For patients who are lost to 
follow-up, the investigator 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.
Disease progression follow up
All patients enrolled in the study who discontinue study treatment for any reason other than 
disease progression will have a tumor assessment every 12 weeks (± 7 days) as detailed in 
Table 7-1 and Table 7-1b, until disease progression or the initiation of subsequent anticancer 
therapies, death, or 12 months has elapsed from last patient first treatment, whichever occurs 
first. Any newly started antineoplastic therapies during the follow-up period must be recorded 
on the antineoplastic therapy since discontinuation eCRF.
Survival follow-up period
All patients enrolled in the study will be followed by phone call for survival every 12 weeks for 
one year after discontinuation of treatment until death, lost to follow up, consent withdrawal,
or end of study (see Section 4.3), whichever occurs first. Newly started antineoplastic therapies 
during this follow-up period must be recorded on the Antineoplastic therapy eCRF since 
discontinuation.


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For patients who transfer to a Novartis roll-over study or an alternative treatment option to 
continue provision of study treatment, the follow-up for safety, disease progression and survival 
will not be performed.  
7.1.6
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Tumor response will be determined locally according to Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 (Appendix 4). The local investigator’s assessment will be used for the 
primary endpoint analysis and for treatment decision making.
CT/MRI scans will be performed at baseline within 28 days (preferably 7 days) before start of 
treatment and subsequently every 8 weeks up to cycle 12, every 12 weeks (as per regional and/or 
institutional standards) from Cycle 13 to Cycle 24, every 24 weeks from Cycle 25 to Cycle 36, 
and every 52 weeks from Cycle 37, until progression of disease. For patients who enter the 
follow-up period after completing 13 or more cycles of therapy, radiological assessment will 
be performed every 12 weeks. Following the approval of protocol amendment 08 and after 12 
months has elapsed since last patient first treatment, no efficacy assessment will be performed 
on the still ongoing patients and patients in disease progression follow-up. If there is an event 
of unconfirmed PR at this time point, an additional radiological assessment will be performed 
to confirm the response. See Table 7-2 for details. If the prior tumor evaluation was done within 
28 days of EOT or objective evidence of progressive disease has already been documented, then 
tumor evaluations do not need to be repeated at EOT. Depending on regulatory requirements 
the EOT scan may be performed within an extended time frame but not later than 8 weeks from 
the last CT/MRI scan.
Disease progression follow-up should be performed as described in Section 7.1.5. After baseline, 
all assessments should be performed within ±7 days of the scheduled day of assessment. 
Imaging evaluations subsequent to an off-schedule confirmatory scan should be performed 
according to the original assessment schedule. The same method of assessment and the same 
technique should be used to characterize each individual and reported lesion at baseline and 
during follow up.
If at baseline a patient has a medical contraindication to CT i.v. contrast or develops a 
contraindication during the trial, a non-contrast CT of chest plus contrast-enhanced MRI of 
abdomen is acceptable.


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Patients with clinical evidence of bone metastases must have a whole body bone scan at baseline 
per local institutional practice (e.g., Tc99m bone scan, NaF positron emission tomography (PET) 
or whole body bone MRI). Lesions identified on the whole body bone scan at baseline, which 
are not visible on the chest and abdomen CT (or MRI) scan should be imaged at baseline and 
followed at subsequent scheduled visits using localized CT, MRI or X-ray. After baseline, 
whole body bone scans need not be repeated, unless clinically indicated.
Skin lesions present at baseline should be documented using color photography, including a 
ruler, so that the size of the lesion(s) can be determined from the photograph. Skin photographs 
should be continued at subsequent tumor assessments for any lesions that were photographed 
at screening.
Baseline brain CT or MRI will be mandated for all patients prior to study treatment. Subsequent 
brain scans should only be conducted if brain lesions are documented at baseline for eligible 
patients or in patients that develop symptoms indicative of brain metastases.
All CRs and PRs must be confirmed by a second assessment not earlier than 4 weeks after the 
criteria for response are first met.
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.
PET/CT may be used only if the CT is of similar diagnostic quality as a CT performed without 
PET, including the utilization of oral and intravenous contrast media.
All patients discontinuing from the study for PD must have their disease progression 
documented by radiologic evaluation. In cases of clinically-evident disease progression, all 
efforts should be made to perform a radiologic evaluation. Following the approval of protocol 
amendment 08 and after 12 months has elapsed since last patient first treatment, CT/MRI scans 
for routine disease monitoring purposes may be performed following local standard of care
outside the setting of this study. 
Patients with symptoms of rapidly progressing disease without radiological evidence will be 
classified as progression only when clear evidence of clinical deterioration is documented 
and/or patient discontinued due to ‘Disease progression’ or death due to study indication.
All radiological assessments obtained for patients will be centrally collected and subjected to 
quality checks by an imaging CRO selected by Novartis. The site manual provided by the 
designated imaging CRO will provide further details regarding image collection.


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Table 7-2
Imaging or disease assessment collection plan
Procedure
Screening/Baseline
During Treatment/Follow-up*
CT or MRI
with contrast enhancement
(Chest and Abdomen)
Mandated
Mandated, every 8 weeks
(±7 days) up to cycle 12
Every 12 weeks (±7 days) from Cycle 13 Day 
1 to Cycle 24, every 24 weeks (±7 days) from 
Cycle 25 to Cycle 36, every 52 weeks (±7 
days) from Cycle 37; every 12 weeks (+/- 7 
days) during follow up for patients 
discontinuing for reasons other than disease 
progression.
Whole body bone scan
If clinically indicated
If clinically indicated
Brain CT or MRI
Mandated
If brain lesions at screening
every 8 weeks (±7 days) up to cycle 12.
Every 12 weeks (±7 days) from Cycle 13 Day 
1 to Cycle 24, every 24 weeks (±7 days) from 
Cycle 25 to Cycle 36, every 52 weeks (±7 
days) from Cycle 37; every 12 weeks (+/- 7 
days) during follow up for patients 
discontinuing for reasons other than disease 
progression.
Bone X-ray, CT or MRI
(bone lesions only)
If lesions on bone scan 
that are not visible on 
the chest and abdomen 
CT/MRI
If bone lesions at screening
every 8 weeks (±7 days) up to cycle 12.
Every 12 weeks (±7 days) from Cycle 13 Day 
1 to Cycle 24, every 24 weeks (±7 days) from 
Cycle 25 to Cycle 36, every 52 weeks (±7 
days) from Cycle 37; every 12 weeks (+/- 7 
days) during follow up for patients 
discontinuing for reasons other than disease 
progression.
Skin color photography 
(skin lesions only)
Mandated if skin lesions 
at screening
If skin lesions at screening
every 8 weeks (±7 days) up to cycle 12.
Every 12 weeks (±7 days) from Cycle 13 Day 
1; every 12 weeks (+/- 7 days) during follow 
up for patients discontinuing for reasons 
other than disease progression.
CT or MRI of other tumor 
sites (e.g., pelvis)
If clinically indicated
If lesions identified at screening every 8 
weeks (±7 days) up to cycle 12.
Every 12 weeks (±7 days) from Cycle 13 Day 
1 to Cycle 24, every 24 weeks (±7 days) from 
Cycle 25 to Cycle 36, every 52 weeks (±7 
days) from Cycle 37; every 12 weeks (+/- 7 
days) during follow up for patients 
discontinuing for reasons other than disease 
progression.
* Following the approval of protocol amendment 08, no efficacy assessment will be performed on the 
still ongoing patients and patients in disease progression follow-up after 12 months has elapsed since 
last patient first treatment.
CT: Chest, abdomen and pelvis CT. The preferred radiologic technique is CT with intravenous 
(i.v.) contrast. However, if CT assessments require additional regulatory approval in a country, 


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MRI is allowed for chest, abdomen and pelvis. If a patient is known to have a contraindication 
to CT contrast media or develops a contraindication during the trial, a non-contrast CT of the 
chest (MRI is not recommended due to respiratory artifacts) plus a contrast-enhanced MRI (if 
possible) of the abdomen and pelvis should be performed.
Bone scintigraphy: If bone metastases are suspected/clinically indicated, a whole body bone 
scan per institutional standard of care. Localized CT, MRI or X-rays should be acquired for all 
skeletal lesions identified on bone scan, which are not visible on the chest, abdomen and pelvis 
CT/MRI/X-ray. These lesions, which are not visible on chest, abdomen and pelvis CT/MRI/X-
ray, should be evaluated with same frequency as chest, abdomen, pelvis CT/MRI/X-ray.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing the procedures listed below as well as collecting of the 
adverse events at every visit. For details on AE collection and reporting, refer to Section 8.
7.2.2.1
Physical examination
A complete physical examination that evaluates all major organ systems will be performed at 
screening/baseline. Subsequent physical exams may be limited and should be focused on sites 
of disease to explore clinical signs and symptoms.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF
7.2.2.2
Vital signs
Vital signs (body temperature, pulse rate, blood pressure, pulse oximetry) must be performed 
before dosing and as indicated in Table 7-1 and Table 7-1b as per institutional standards.
Vital signs should be assessed on the scheduled day, even if study treatment is being withheld. 
More frequent examinations may be performed at the discretion of the Investigator and if 
medically indicated.
7.2.2.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured as indicated in Table 7-1.
Height information will be collected at screening only. Following the approval of protocol 
amendment 08, it is not required to collect weight information as per Table 7-1b. 
7.2.2.4
Performance status
ECOG performance status will be assessed according to Table 7-1 and Table 7-3. Following 
the approval of protocol amendment 08, it is not required to collect ECOG performance status
as per Table 7-1b.


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Table 7-3
ECOG performance status
Grade
ECOG 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
7.2.2.5
Laboratory evaluations
All laboratory parameters assessed for safety purposes will be evaluated locally, at the site. 
Refer to Table 7-4 and Table 7-4b for a summary of the parameters to be evaluated according 
to Table 7-1 and Table 7-1b.
Unscheduled assessment can be performed if clinically indicated.
Novartis will be provided with a copy of the site’s local laboratory certification and tabulation 
of the normal ranges for each parameter required at study start and should be kept up to date on 
an ongoing basis. In addition, if at any time a patient has laboratory parameters obtained from 
a different outside laboratory, Novartis must be provided with a copy of the certification and a 
tabulation of the normal ranges for that laboratory.
Table 7-4
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, hemoglobin, platelets, white blood cells (WBC), WBC morphology 
with differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils)
Chemistry
Albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), amylase, lipase, 
calcium, chloride, magnesium, potassium, creatinine, creatine kinase, direct 
bilirubin, indirect bilirubin, total bilirubin, blood urea nitrogen (BUN) or urea, uric 
acid, glucose, Thyroid functions tests (freeT3, freeT4, TSH), Hepatitis B (HBsAg, 
HBsAb, and HBcAb; if HBsAb positive; Hep B DNA needs to be performed) at 
screening and Hepatitis C (HC Ab and HC-RNA) at screening only. Please see 
Appendix 6 for additional guidelines), HIV test (screening only for patients in 
Germany)
Coagulation
Prothrombin time (PT) or international normalized ratio (INR)
Table 7-4b
Local clinical laboratory parameters collection plan (effective after 
protocol amendment 08 is approved)
Test Category
Test Name
Hematology
Hematocrit, hemoglobin, platelets, white blood cells (WBC)
Chemistry
Albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), amylase, lipase, 
creatinine, total bilirubin, thyroid functions tests (freeT4 & TSH)


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7.2.2.5.1 Hematology
Hematology panel outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1. Following the approval of protocol amendment 08, please follow the assessment plan
in Table 7-1b and Table 7-4b. 
7.2.2.5.2 Clinical chemistry
Clinical chemistry panel outlined in Table 7-4 will be performed as per the assessment schedule 
in Table 7-1. Following the approval of protocol amendment 08, please follow the assessment 
plan in Table 7-1b and Table 7-4b.
7.2.2.5.3 Coagulation
Coagulation panel outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1 and Table 7-1b.
7.2.2.5.4 Pregnancy and assessments of fertility
Serum pregnancy test will be performed at screening, C1D1, at day 1 of subsequent cycles, at 
the end of treatment visit and at the 30-day safety follow up visit. Monthly urine pregnancy 
tests should be performed thereafter until approximately 23 weeks after discontinuation of the 
study medication. Urine pregnancy test results should remain with the patient records and do 
not need to be included into the clinical database.
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed as per the assessment schedule in Table 7-1, 
Table 7-1b and Table 7-5.
Table 7-5
Central ECG collection plan
Cycles
Day
Time Point
Screening a
-28 to -1
Anytime
Cycle 1
1
Pre-dose
Cycle 1
15
Pre-dose
Cycle 1b
15
3 hr post dose (+/- 30 min)
Cycle 2 and afterwards
1
Pre-dose
EOT
-
Anytime
Unscheduled
Anytime
a. A single standard 12 lead ECG will be performed at screening. Triplicate ECGs will be done at all 
other time points.
b. This time point is only needed for safety monitoring cohort patients following EGF816 or INC280
Note: If both ECG and PK sample are scheduled at the same time, the PK sample should be taken 
immediately within 1 hour) after ECG assessment
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
CRF page. Each ECG tracing should be labeled with the study number, patient initials (where 




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Table 7-6
Schedule of blood collection for EGF816 (QD), PK for patients 
participating in the safety monitoring cohort
Cycle
Day
Scheduled time (hours)
Dose reference ID
Sample number
1
1
Pre-C1D1 dose a
1
1
1
8
Pre-C1D8 dose a
2/102
2
1
15
0 hr/ Pre- C1D15 dose a
3/103
3
1
15
1 hr (±10 minutes)
3
4
1
15
3 hr (±15 minutes)
3
5
1
15
6 hr (±1 hr)
3
6
1
15
8 hr (±2 hr)
3
7
2
1
0 hr /Pre-C2D1 dose a
4/104
8
4
1
0 hr /pre-C4D1 dose a
5/105
9
6
1
0 hr/ pre-C6D1 dose a
6/106
10
8
1
0 hr/ pre-C8D1 dose a
7/107
11
Unscheduled and at the 
time of progression b
1001+
a. Take samples immediately prior to the administration of EGF816
b. Unscheduled blood samples will be uniquely, sequentially numbered 1001, 1002,
Table 7-7
Schedule of blood collection for INC280 (BID) PK for patients 
participating in the safety monitoring cohort
Cycle
Day
Scheduled time (hours)
Dose reference ID
Sample number
1
15
0 hr / pre-C1D15 AM dose a
21/211
201
1
15
1 hr (±10 minutes)
21
202
1
15
3 hr (±15 minutes)
21
203
1
15
6 hr (±1 hr)
21
204
1
15
8 hr (±2 hr)
21
205
2
1
0 hr / pre-C2D1 AM dose a
22/221
206
4
1
0 hr / pre-C4D1 AM dose a
23/231
207
6
1
0 hr / pre-C6D1 AM dose a
24/241
208
8
1
0 hr / pre-C8D1 AM dose a
25/251
209
NA
NA
Unscheduled and at the time 
of progression b
--
2001+ b
a.
Take samples immediately prior to the administration of INC280
b.
Unscheduled blood samples will be uniquely, sequentially numbered 2001, 2002,


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Table 7-8
Schedule of blood collection for Nivolumab (1 hour infusion) PK and 
immunogenicity for all patients
Cycle
Day
Scheduled 
time (hours) c
Description
Dose 
reference ID
Sample 
number
1
1
0 hr
Preinfusion a
40
400
1
15
0 hr
Preinfusion a
40/41
401
2
1
0 hr
Preinfusion a
41/42
402
4
1
0 hr
Preinfusion a
43/431
403
8
1
0 hr
Preinfusion a
44/441
404
Every 8th Cycle after
C8D1 until
discontinuation of study
treatment (2 follow up 
visits up to 100 days 
from end of treatment)
1
0 hr
Preinfusion a
45 e/451
405 d
NA
NA
Unscheduled and 
at the time of 
progression b
--
4001+ b
a.
Take samples within 60 min before the 1hr infusion begins
b.
Unscheduled blood samples will be uniquely, sequentially numbered 4001, 4002,
c.
Time is relative to the beginning of the infusion
d.
Sample number will be labeled sequentially from 405, 406, ….until the 2 follow-up visit samples 
are collected (samples for the follow-up visit can be collected anytime during the visit)
e.
Dose reference ID will be labeled sequentially from 45, 46, ….until the 2 follow-up visit samples 
are collected (samples for the follow-up visit can be collected anytime during the visit)
Table 7-9
Schedule of blood collection for EGF816 (QD) PK for patients NOT 
participating in the safety monitoring cohort
Cycle
Day
Scheduled time (hours)
Dose reference ID
Sample number
1
15
0 hr/ Pre- C1D15 dose a
3/103
3
2
1
0 hr /Pre-C2D1 dose a
4/104
8
4
1
0 hr /pre-C4D1 dose a
5/105
9
6
1
0 hr/ pre-C6D1 dose a
6/106
10
8
1
0 hr/ pre-C8D1 dose a
7/107
11
Unscheduled and at the time of 
progression b
1001+
a. Take samples immediately prior to the administration of EGF816
b. Unscheduled blood samples will be uniquely, sequentially numbered 1001, 1002,


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Table 7-10
Schedule of blood collection for INC280 (BID) PK for patients NOT 
participating in the safety monitoring cohort
Cycle
Day
Scheduled time (hours)
Dose reference ID
Sample number
1
15
0 hr / pre-C1D15 AM dose a
21/211
201
2
1
0 hr / pre-C2D1 AM dose a
22/221
206
4
1
0 hr / pre-C4D1 AM dose a
23/231
207
6
1
0 hr / pre-C6D1 AM dose a
24/241
208
8
1
0 hr / pre-C8D1 AM dose a
25/251
209
NA
NA
Unscheduled and at the time 
of progression b
--
2001+ b
Take samples immediately prior to the administration of INC280
Unscheduled blood samples will be uniquely, sequentially numbered 2001, 2002,
7.2.3.3
Analytical method
INC280 and EGF816 concentrations in human plasma will be determined with a validated 
liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. Nivolumab
concentrations in human serum will be determined with a validated ELISA assay. Any results 
below the lower limit of quantification (LLOQ) and any missing samples will be labeled 
accordingly.
7.2.4
Biomarkers
The biomarker collections for this study are summarized in Table 7-11.
While the goal of the biomarkers is to provide supportive data for the clinical study, there may
be circumstances when a decision is made to stop a collection, or not perform or discontinue an 
analysis due to either practical or strategic reasons (e.g., inadequate sample number, issues
related to the quality of the sample or issues related to the assay that preclude analysis,
impossibility to perform correlative analyses, etc.). Therefore, depending on the results obtained 
during the study, sample collection and analysis may be omitted at the discretion of Novartis.








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2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, 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 Appendix 4, should not be reported as a serious 
adverse event.
Adverse events separate from the progression of malignancy (example, 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.
If a clinical sample is obtained as part of the evaluation of an adverse event that is suspected to 
be treatment-related (e.g., skin biopsy for rash), Novartis may request that the remaining clinical 
sample be submitted for central evaluation to gain further understanding of that adverse event, 
or other safety findings associated with that adverse event.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 


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investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

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 patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event

Serious adverse events considered by the investigator to be possibly related to a biopsy 
procedure will be indicated as such in the AE CRF.
8.2.2
Reporting
For patients with unknown EGFR and/or cMet statuses and who sign the molecular pre-
screening ICF, SAE collection will start upon signing the molecular pre-screening ICF. SAEs 
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). Serious adverse events 
considered to be possibly related to a biopsy procedure will be indicated as such in the Adverse 
Event eCRF. SAEs will be followed until resolution or until clinically relevant improvement or 
stabilization. If the main ICF is not signed (molecular screen failure), SAE collection ends 30-
days after the last study related procedure.
For patients with known EGFR and/or cMet statuses who sign the main study ICF, SAE 
collection starts at time of main study informed consent whether the patient is a screen failure 
or not.


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To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 100 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 100 days period (or 5 half-lives, whichever is longer) should 
only be reported to Novartis if the investigator suspects a causal relationship to the study 
treatment. Recurrent episodes, complications, or progression of the initial SAE must be reported 
as follow-up to the original episode within 24 hours of the investigator receiving the follow-up 
information. An SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours Novartis. Detailed instructions 
regarding the submission process and requirements for signatures are to be found in the 
investigator folder provided to each site.
A copy of the SAE data submitted must be kept with the case report form documentation at the 
study site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Chief 
Medical Office and Patient Safety (CMO&PS) 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 drug 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 in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment or 
within 23 weeks of discontinuing study treatment must be reported to Novartis within 24 hours 
of learning of its occurrence. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary 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 on a Clinical Trial Pregnancy Form and reported by the
investigator to the oncology Chief Medical Office and Patient Safety (CMO&PS). Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 


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possible relationship to the investigational treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Outcomes of pregnancies in female partners of any males who took study treatment in this study, 
occurring while the male partner is on study treatment or within 31 weeks of discontinuing 
study treatment, should be collected. The newborn will be followed up to three months after 
delivery date. Consent to report information regarding these pregnancy outcomes should be 
obtained from the mother.
8.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.5
Data Monitoring Committee
A Data Monitoring Committee (DMC) will not be in place for this trial. However, measures are 
put in place for monitoring the safety of the patients participating in the study, and Novartis will 
convene a joint teleconference with the participating Investigators to ensure a prompt review of 
safety data and constant monitoring for emerging safety signals by participating study sites and 
Novartis Personnel. As for any other study conducted by Novartis, any SUSAR and/or new 
safety signals will be promptly communicated to all participating investigators and Health 
Authorities.
When patients in the safety monitoring cohort have completed six weeks of treatment or 
discontinued earlier, Novartis and investigators will have a safety assessment meeting to 
qualitatively review clinical, PK and laboratory data and to decide on the appropriate dose for 
study continuation (Section 2.2 and Section 4.1).
Individual patient data will be reviewed on an ongoing basis and aggregate safety data and the 
primary endpoint will be monitored quarterly by the study team across the duration of the trial. 
The data review and analysis will be based on the available investigator reported data in the 
clinical database at the respective time.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following:

What protected health information (PHI) will be collected from patients in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research patient to revoke their authorization for use of their PHI.


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In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the patient 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the 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 


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have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff.
Blood and tumor samples for PK and biomarkers will be collected by sites and sent to a Central 
laboratory for processing. The Laboratory results will be sent electronically to Novartis. 
Radiological and photography data will be acquired by the sites and interpreted locally. Imaging 
data will be centrally collected and checked for quality by an imaging CRO designated by 
Novartis and may undergo independent review according to the Novartis guideline. Details 
regarding all CRO procedures including collection and shipment of data will be described in 
the manual provided by the respective CRO.
If a patient enrolls on a companion sample collection study to evaluate the mechanisms of 
resistance, data required for the companion sample collection study are collected in the clinical 
trial database for the treatment protocol. A description of the data to be collected for the study 
of resistance is provided in the companion sample collection protocol.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
9.4
Database management and quality control
For studies using eCRFs, 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 is 
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 
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.
Biomarker and PK samples will be processed centrally and the results will be sent electronically 
to Novartis (or a designated CRO).
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
Study data will be analyzed by Novartis and/or designated contract research organization 
(CRO). Any data analysis carried out independently by the investigator must be submitted to 
Novartis before publication or presentation.
Study data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, 
pharmacokinetics and pharmacodynamics measurements. Categorical data will be presented as 
contingency tables (frequencies and percentages). For continuous data summary statistics 
including mean, standard deviation, median, minimum, and maximum will be presented. In 
addition, individual listings of all raw data captured in the clinical database will be presented 


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by treatment group and patient. All data from participating centers in this protocol will be 
combined, so that an adequate number of patients will be available for analysis.
Data from patients in safety monitoring cohorts treated at doses different from the respective 
selected dose will be analyzed as separate groups for safety and BOR.
Sub-group A and sub-group B in Group 2 will be considered as separate treatment groups. 
Including Group 1 there will be total 3 treatment groups for all analyses. For analyses of safety 
and pharmacokinetics additional information with sub-group A and sub-group B in Group 2 
pooled will also be presented.
The primary analysis will be conducted after a minimum of 12 months has elapsed since last 
patient first treatment. This analysis will consist of the results related to the primary and 
secondary endpoints, and will include all the available data. Any additional data collected after 
the data cutoff date for the primary analysis will be further summarized and reported in a final 
study report once the end of study is reached as defined in Section 4.3.
10.1
Analysis sets
The following analysis sets which will be derived prior to database lock will be used.
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who have received at least one dose of 
INC280, EGF816 or Nivolumab. Patients will be analyzed according to the planned treatment 
they have been assigned to. The FAS will be used for all listings of raw data.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of INC280, EGF816 or 
Nivolumab and have at least one valid post-baseline safety assessment. Please note that the 
statement that a patient had no AEs (on the AE eCRF page) constitutes a safety assessment. 
Patients will be analyzed according to the study treatment (regimen) they actually received. A 
precise definition of “actually received” will be added in the Reporting and Analysis Plan (RAP).
10.1.3
Per-Protocol Set
All major protocol deviations leading to exclusion from the PPS are listed below:

Patients without written informed consent prior to any screening procedures

Patients without presence of at least one measurable lesion according to RECIST v.1.1 as 
per Appendix 4.

Patients who have been treated with prior PD-1 and PD-L1 agents

Group 1 patients

without EGFR T790M NSCLC (adenocarcinoma);

or without documented progression of disease according to RECIST v1.1 following 
primary standard of care (e.g. erlotinib, gefitinib);

or have received more than one prior line of EGFR TKI therapy.


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
Group 2 patients

without EGFR wild-type NSCLC;

or without documented progression of disease according to RECIST v1.1 following 
primary standard of care (e.g. platinum doublet);

or had previous treatment with a cMet inhibitor or HGF-targeting therapy.
Patients will be classified according to treatment received.
The PPS will be used in the sensitivity analysis of the primary endpoint (see Section 10.4). If 
the PPS and the FAS are identical, then analyses described by the PPS below will not be 
performed.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data (including disease characteristics) will be summarized 
descriptively by treatment group for the FAS. For patients from Germany HIV test results will 
be listed by treatment group.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
10.3.1
Study treatment
Duration of exposure to study treatment in days, as well as actual total doses, actual dose 
intensities, and relative dose intensities of both study drugs will be summarized using 
descriptive statistics by treatment group for the safety set.
10.3.2
Concomitant medications
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized by treatment group for the safety set by ATC 
(Anatomical therapeutic chemical classification system) term.
10.3.3
Compliance
Compliance to the study treatment within each treatment group will be assessed by the number 
of dose reductions, number of dose interruptions and percent of days received planned dose for 
both study drugs separately in summary tables by treatment group for the safety set
10.4
Primary objective
The primary objective is to estimate the clinical activity of Nivolumab in combination with 
EGF816 or INC280 (Table 3-1).
10.4.1
Variable
The primary efficacy variable is PFS rate assessed at 6 months (more precisely after 6 cycles = 
168 days as specified in Table 3-1) following either Nivolumab and EGF816 treatment or 
Nivolumab and INC280 treatment. CT/MRI assessments will be used for efficacy assessments 
of anti-tumor activity on study. PFS will be defined as per RECIST v1.1 (see Appendix 4).


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The primary analysis will be performed after 12 months has elapsed from last patient first 
treatment.
10.4.2
Statistical hypothesis, model, and method of analysis
For each treatment group a Bayesian design will be used (see Appendix 3 for details). PFS will 
be modeled using a Weibull distribution. Assuming a weakly informative prior distribution for 
the PFS rate at 6 months, the distribution will be updated with all available data from patients 
treated at the confirmed dose in the FAS. The PFS rate at 6 months will be estimated from the 
posterior distribution. Inferential summaries (e.g., mean, median, standard deviation, 95% 
credible intervals, and interval probabilities) based on the posterior distribution will also be 
presented.
The primary Bayesian analysis of ORR will only be performed for the final selected dose levels. 
Other secondary analyses of activity will be performed for all treatment groups as described in 
Section 10.5.2.
Group 1: Nivolumab and EGF816
For PFS rate at 6 months the indifference point is set at 70% and the inferential intervals are 
given below:

[0, 55%) unacceptable anti-tumor activity

[55%, 70%) limited anti-tumor activity

[70%, 85%) moderate anti-tumor activity

[85%, 100%] strong anti-tumor activity
If the estimated PFS rate at 6 months is equal to or greater than 70% and the posterior risk of 
being in the unacceptable anti-tumor activity interval [0, 55%) is lower than 5%, then 
preliminary anti-tumor activity of the study treatment will be declared. Posterior summaries for 
the 4 inferential intervals above will also be assessed.
Group 2: Nivolumab and INC280
Sub-group A: EGFR wild-type high cMet
For PFS rate at 6 months the indifference point is set at 50% and the inferential intervals are 
given below:

[0, 35%) unacceptable anti-tumor activity

[35%, 50%) limited anti-tumor activity

[50%, 65%) moderate anti-tumor activity

[65%, 100%] strong anti-tumor activity
If the estimated PFS rate at 6 months is equal to or greater than 50% and the posterior risk of 
being in the unacceptable anti-tumor activity interval [0, 35%) is lower than 5%, then 
preliminary anti-tumor activity of the study treatment will be declared. Posterior summaries for 
the 4 inferential intervals above will also be assessed.
Sub-group B: EGFR wild-type low cMet


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For PFS rate at 6 months the indifference point is set at 40% and the inferential intervals are 
given below:

[0, 25%) unacceptable anti-tumor activity

[25%, 40%) limited anti-tumor activity

[40%, 55%) moderate anti-tumor activity

[55%, 100%] strong anti-tumor activity
If the estimated PFS rate at 6 months is equal to or greater than 40% and the posterior risk of 
being in the unacceptable anti-tumor activity interval [0, 25%) is lower than 5%, then 
preliminary anti-tumor activity of the study treatment will be declared. Posterior summaries for 
the 4 inferential intervals above will also be assessed.
10.4.3
Handling of missing values/censoring/discontinuations
The PFS time of patients who have not died or progressed at time of the primary analysis will 
be censored at the last adequate tumor assessment. For patients who initiate a new antineoplastic 
therapy without experiencing disease progression under study treatment, their PFS time will be 
censored at time of initiating the new antineoplastic therapy.
10.4.4
Supportive analyses
For each group the primary analysis of PFS rate at 6 months will be repeated using PPS, if PPS 
is different from FAS. In addition, the PFS rate at 6 months and the corresponding 95% 
confidence interval will be presented using Kaplan-Meier estimate.
Additional supportive 
 analyses will be conducted to support the primary 
objective if appropriate and details of the analyses will be defined in the Reporting and Analysis 
Plan (RAP).
10.5
Secondary objectives
Please refer to Table 3-1 for secondary objectives
10.5.1
Safety objectives
10.5.1.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used if not otherwise specified. All listings and 
tables will be presented by treatment group. Sub-group A and sub-group B in Group 2 will be 
considered as separate treatment groups. In addition, results with sub-group A and sub-group B 
in Group 2 pooled will also be presented.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 100 days after last dose 
of study medication
3. post-treatment period: starting at day 101 after last dose of study medication


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10.5.1.2 Adverse events (AEs)
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged.
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and/or preferred term, severity (based on CTCAE grades), 
relation to study treatment by treatment group.
Deaths reportable as serious adverse events (SAEs) and non-fatal SAEs will be listed by patient 
and tabulated by treatment group.
10.5.1.3 Laboratory abnormalities
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 the study’s biostatistical and reporting team will grade laboratory data 
accordingly. For laboratory tests covered by CTCAE, a 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, results will be graded by the low/normal/high classifications 
based on laboratory normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:

frequency table for newly occurring on-treatment grades 3 or 4 (see below for details)

shift tables using CTCAE grades to compare baseline to the worst on-treatment value

for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value

listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.
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 might 
be specified in the MAP and/or RAP.
10.5.1.4 Other safety data
ECG

shift table baseline to worst on-treatment result for overall assessments

listing of ECG evaluations for all patients with at least one abnormality.
Vital signs

shift table baseline to worst on-treatment result

table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points.






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
If the true PFS rate at 6 months is low at 55%, the probability to wrongly declare success 
is low at 0.02;

If the true PFS rate at 6 months is moderate at 75%, the probability to correctly declare 
success is high at 0.81;

If the true PFS rate at 6 months is high at 85%, the probability to correctly declare success 
is very high at 1.
Such operating characteristics are satisfactory.
Group 2: Nivolumab and INC280
Sub-group A: High cMet
With a sample size of 20 patients, including potentially 15% drop-outs and loss to follow-up 
per patient-year prior to cut-off for primary CSR:

If the true PFS rate at 6 months is low at 35%, the probability to wrongly declare success 
is low at 0.05;

If the true PFS rate at 6 months is moderate at 55%, the probability to correctly declare 
success is high at 0.73;

If the true PFS rate at 6 months is high at 65%, the probability to correctly declare success 
is very high at 0.95.
Such operating characteristics are satisfactory.
Sub-group B: Low cMet
With a sample size of 30 patients, including potentially 15% drop-outs and loss to follow-up 
per patient-year prior to cut-off for primary CSR:

If the true PFS rate at 6 months is low at 25%, the probability to wrongly declare success 
is low at 0.02;

If the true PFS rate at 6 months is moderate at 45%, the probability to correctly declare 
success is high at 0.80;

If the true PFS rate at 6 months is high at 55%, the probability to correctly declare success 
is very high at 0.98.
Such operating characteristics are satisfactory.
10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 




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11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov before study start. 
In addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., LPLV), those for interventional clinical trials involving 
pediatric patients within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 


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and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
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/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
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/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 


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approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
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 (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.


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13
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14
Appendices
Table 14-1 and Table 14-2 present concomitant medications by mechanism of interaction. Some 
drugs are, as they have an interaction potential through several mechanisms, presented in both 
tables.  If a medication is listed in both Table 14-1 and Table 14-2, the more stringent practice 
shall be applied (that is, the medication shall be prohibited as in Table 14-2).
14.1
Appendix 1: List of concomitant medications to be used with 
caution
Table 14-1
Permitted concomitant medications requiring caution
Mechanism of Interaction
Drug Name
Strong CYP3A4 inhibitor**
clarithromycin, telithromycin, troleandomycin, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, 
itraconazole, ketoconazole, posaconazole, voriconazole, 
boceprevir, telaprevir, cobicistat, conivaptan, 
elvitegravir, mibefradil, nefazodone, grapefruit, 
grapefruit juice, grapefruit hybrids, danoprevir/ritonavir, 
eltegravir/ritonavir
Moderate CYP3A4 inhibitor*
Amprenavir, aprepitant, atazanavir, casopitant, 
cimetidine, ciprofloxacin, crizotinib, cyclosporin, 
darunavir/ritonavir, diltiazem, dronedarone, 
erythromycin, fluconazole, fosamprenavir, imatinib, 
lomitapide, netupitant, nilotinib, schisandra 
sphenanthera, tofisopam, verapamil
Moderate CYP3A4 inducer***
bosentan, efavirenz, etravirine, genistein, lersivirine, 
lopinavir, modafinil, nafcillin, semagacestat, talviraline,
thioridazine tipranavir
CYP1A2 substrate with NTI**
theophylline, tizanidine
CYP2C9 substrate with NTI**
Phenytoin, warfarin
CYP2C19 substrate with NTI**
(S)-mephenytoin
Sensitive CYP2C8 substrate***
Repaglinide
Sensitive CYP2D6 substrate*
atomoxetine, bosentan, desipramine, doxepin, 
efavirenz, etravirine, encainide, genistein, 
methoxyphenamine, modafinil, nibivolol, nafcillin, 
nefazodone, perhexiline, perphenazine, risperidone, 
tolterodine, traxoprodil, trimipramine, tropisetron,
[talviraline], vernakalant


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Mechanism of Interaction
Drug Name
Sensitive CYP3A4 substrate**
vanafil, aronedarone, bosutinib, ebastine, brotizolam, 
ibrutinib, midazolam, triazolam, felodipine, nisoldipine, 
brecanavir, capravirine, darunavir, atorvastatin, 
lovastatin, simvastatin, everolimus, lurasidone, 
perospirone, quetiapine, levomethadyl, budesonide, 
fluticasone, sildenafil, vardenafil, aprepitant, casopitant,
alpha-dihydroergocryptine, aplaviroc, buspirone, 
darifenacin, eletriptan, eplerenone, lumefantrine, 
maraviroc, ridaforolimus, ticagrelor, tolvaptan, vicriviroc, 
alfentanil, almorexant, atazanavir, conivaptan, 
danoprevir, dasatinib, elvitegravir, ibrutinib, indinavir, 
ivacaftor, lomitapide, lopinavir, midostaurin, neratinib, 
saquinavir, simeprevir, ticagrelor, terfenadine, tilidine, 
tipranavir, voclosporin
P-gp inhibitor*
alogliptin, amiodarone, azithromycin, canaglifozin, 
captopril, carvedilol,  conivaptan, cremophor RH40, 
curcumin, diltiazem, dronedarone, elacridar, 
erythromycin, felodipine, fluvoxamine, ginko, indinavir, 
indinavir/ritonavir, itraconazole, ketoconazole, lapatinib, 
lopinavir/ritonavir, mibefradil, milk thisle, mirabegron, 
nelfinavir, nifedipine, nitredipine, paroxetine, 
propafenone, quercetin, quinidine, ranolazine, rifampin, 
ritonavir, sequinavir/ritonavir, schisandra chinesis 
extract, simepravir, St. John’s wort extract, talinolol, 
telaprevir, telmisartan, ticagrelor, tipranavir/ritonavir, 
tolvaptan, valspodar, vandetanib, verapamil, voclosporin
P-gp inducer*
avasimibe, carbamazepine, efavirenz, genistein,
phenytoin, quercetin, rifampin, St. John’s Wort extract
P-gp substrates**
Aliskiren, ambrisentan, atorvastatin, atorvastatin acid, 
azithromycin, cerivastatin, CP-481,715, cyclosporine, 
dabigatran, docetaxel, domperidone, doxorubicin, 
fentanyl, lapatinib, linezolid, loperamide, maraviroc, 
nevirapine, paclitaxel, proguanil, quinidine, ranolazine, 
ritonavir, saquinavir, simvastatin, sirolimus, sofosbuvir, 
tacrolimus, ticagrelor, voclosporin, colchicine, digoxin, 
everolimus, fexofenadine, , afatinib, alfuzosin, alogliptin, 
apixaban, apremilast, aprepitant, boceprevir, bosentan, 
carvedilol, carvedilol, caspofungin, ceritinib, citalopram, 
doxepin, eribulin, fluvastatin, fosamprenavir, gatifloxacin, 
idelalisib, iloperidone, indacaterol, irbesartan, 
lacosamide, levetiracetam, levofloxacin, linagliptin, 
losartan, maraviroc, mirabegron, moxifloxacin, 
naloxegol, nateglinide, nintedanib, olodaterol, 
pantoprazole, paroxetine, pazopanib, posaconazole, 
pravastatin, quinine, riociguat, risperidone, rivaroxaban, 
silodosin, simeprevir, sitagliptin, sorafenib, telaprevir, 
tenofovir, tipranavir, tolvaptan, topotecan, umeclidinium, 
valsartan, vardenafil, vincristine, voriconazole.
P-gp substrate with NTI**
cyclosporine, digoxin, fentanyl, paclitaxel, phenytoin, 
quinidine, sirolimus, tacrolimus


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Mechanism of Interaction
Drug Name
BCRP substrate***
atorvastatin daunorubicin, doxorubicin,
hematoporphyrin, imatinib, methotrexate, mitoxantrone, 
pitavastatin, rosuvastatin, SN-38 (irinotecan), 
ethinylestradiol, simvastatin, sulfasalazine, sofosbuvir, 
topotecan, sulfasalazine
MATE substrate*
metformin, tenfovir
OATP substrates**
Atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, 
rosuvastatin, simvastatin acid, pitavastatin, pravastatin, 
repaglinide, valsartan, olmesartan, telmisartan
**Proton pump inhibitor
Omeprazole, pantoprazole, lansoprazole, 
esomeprazole, rabeprazole, dexlansoprazole
**Short acting gastric acid modulator and 
H2 receptor antagonist
Antacids containing aluminum hydroxide and 
magnesium hydroxide, or calcium carbonate  cimetidine,
famotidine, nizatidine, ranitidine
Source: Adapted from Oncology Clinical Pharmacology Drug-Drug Interaction Database (v06 2016) 
which was compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table and 
supplemented with the FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, 
Data Analysis, and Implications for Dosing and Labeling (February 2012), and the University of 
Washington’s Drug Interaction Database.
The lists provided may not be exhaustive.
Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-
administered with a known potent inhibitor.
* Applies to patients receiving EGF816 treatment
** Applies to patients receiving INC280 treatment
*** Applies to patients receiving either EGF816 or INC280 treatment


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14.2
Appendix 2: Prohibited concomitant medications
Table 14-2
Prohibited concomitant medication
Mechanism of Interaction
Drug Name
Strong CYP3A4 inhibitor*
clarithromycin, telithromycin, troleandomycin
indinavir, lopinavir, nelfinavir, ritonavir saquinavir, tipranavir/ ritonavir, 
itraconazole, ketoconazole, posaconazole, voriconazole
boceprevir, telaprevir, danoprevir, cobicistat, conivaptan, mibefradil, 
nefazodone, grapefruit juice, grapefruit, grapefruit hybrids, 
danoprevir/ritonavir, eltegravir/ritonavir, indinavir/ritonavir, 
lopinavir/ritonavir (HIV), saquinavir/ritonavir
Strong CYP3A4 inducer***
avasimibe, carbamazepine, enzalutamide, mitotane, phenobarbital, 
phenytoin, rifabutin, rifampin, St. John's wort, enzalutamide
Live vaccines*
e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, 
yellow fever, varicella, and TY21a typhoid vaccines
Medications with a known risk 
to prolong the QT interval 
and/or known to cause 
Torsades de Pointe**
amiodarone, anagrelide, arsenic trioxide, astemizole (off US mkt), 
azithromycin, bepridil (off US mkt), chloroquine, chlorpromazine, 
cisapride (off US mkt), citalopram, clarithromycin, cocaine, 
disopyramide, dofetilide, domperidone (not on US mkt), dronedarone, 
droperidol, erythromycin, escitalopram, flecainide, grepafloxacin (off 
market worldwide), halofantrine, haloperidol, ibutilide, levofloxacin, 
levomethadyl (off US mkt), mesoridazine (off US mkt), methadone, 
moxifloxacin, ondansetron, pentamidine, pimozide, probucol (off US 
mkt), procainamide (oral off US mkt), quinidine, sevoflurane, sotalol, 
sparfloxacin (off US mkt), sulpiride (not on US mkt), terfenadine (off 
US mkt), thioridazine, vandetanib
For a comprehensive list of drugs, refer to www.qtdrugs.org
Immunosuppressive agents and Immunosuppressive doses of systemic corticosteroids (except when 
utilized to treat a drug related adverse event or as stated below) are prohibited.
Patients are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg daily 
prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (eg, 
contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity 
reaction caused by a contact allergen) is permitted.
Source: Adapted from Oncology Clinical Pharmacology Drug-Drug Interaction Database (v06 2016, 
which was compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table, FDA 
Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and Implications 
for Dosing and Labeling (February 2012), and the University of Washington’s Drug Interaction 
Database. The lists provided may not be exhaustive.
Drugs between brackets are not marketed in US
NTI: narrow therapeutic index
NA, not available
* Applies to patients receiving EGF816 treatment
** Applies to patients receiving INC280 treatment
*** Applies to patients receiving either EGF816 or INC280 treatment


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14.3
Appendix 3: Bayesian study design set-up, posterior analysis 
and operating characteristics
All calculations below consider 1 month with 28 days, i.e. cycle duration.
14.3.1
Statistical model
For each treatment group a Bayesian design will be used to estimate PFS rate at 6 months and 
to provide inferential statements based on the uncertainty of this quantity. PFS time will be
modeled using a Weibull distribution, which is a flexible distribution allowing for time varying 
hazard rate. The Weibull probability density function is given by
where γ is a shape parameter and λ a scale parameter. The corresponding survival function is
and the median PFS can be calculated as
14.3.2
Prior specifications
For each treatment group it is assumed that the prior distribution of γ is an exponential 
distribution with a specified rate and that the prior distribution of the natural log of λ, ln(λ), is 
a normal distribution with specified mean and standard deviation. The prior distribution of PFS 
rate at 6 months is estimated by simulations with the following steps:
1. Draw 100000 random samples of γ from the specified exponential distribution and 100000 
random samples of ln(λ) from the specified normal distribution.
2. Calculate PFS rates at 6 months using equation [2] with x=6 and the 100000 pairs of γ and 
λ.
3. Calculate mean of the 100000 PFS rates at 6 months, proportion of values in the 
unacceptable activity interval, and proportion of values equal to or greater than the 
indifference point, i.e. clinically relevant activity.
The rate for γ prior distribution and the mean and standard deviation for ln(λ) prior distribution 
are chosen to give a prior distribution of PFS rate at 6 months that has a mean close to the 
respective indifference point and is reasonably non-informative with a nontrivial probability for 
unacceptable activity in the left tail and a nontrivial probability for clinically relevant activity 
in the right tail. The selected prior parameter values and the resulting prior distributions of PFS 
rate at 6 months are summarized in Table 14-3 below.


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Table 14-3
Specifications for prior distributions
Group
Prior parameter
Prior distribution of PFS rate at 6 months
Rate for
γ
Mean for
ln(λ)
SD for
ln(λ)
Mean
Prob.
unacceptable
activity
Prob.
clin. relevant 
activity
1)
Nivolumab
& EGF816
0.5
3
1
69%
0.33
in [0%, 55%)
0.54
in [70%, 100%]
2)
Nivolumab
& INC280 
(Sub-group A)
2.0
3
2.25
50%
0.25
in [0%, 35%)
0.43
in [50%, 100%]
3)
Nivolumab
& INC280 
(Sub-group B)
5
2.3
5
40%
0.24
in [0%, 25%)
0.43
in [40%, 100%]
14.3.3
Operating characteristics
The posterior distribution of PFS rate at 6 months is not recognizable and an analytical solution 
does not exist. The operating characteristics for the Bayesian analysis described above are 
obtained by performing extensive simulations
14.3.3.1 Generating hypothetical datasets
Let ni and ai denote the sample size and average accrual rate per month of treatment group i. 
The values of ni and ai are specified below:
Treatment group (i)
Sample size (ni)
Average accrual rate (ai)
Group 1
40
6.5
Group 2 Sub-group A
20
1.0
Group 2 Sub-group B
30
2.0
For each patient within a treatment group the following variables are calculated:

Accrual waiting time: It is assumed that the accrual waiting time of Cycle 1 Day 1 
between two consecutive patients follows an exponential distribution with a rate of ai. The 
accrual waiting time is in unit of month and set to 0 for the first patient.

Accrual calendar time: This is the cumulative sum of the accrual waiting times. The origin 
is set to 0 at Cycle 1 Day 1 of the first patient. The interval from the origin to Cycle 1 Day 
1 of the last patient is accrual duration.

End of study calendar time (EOS): It is set at Cycle 1 Day 1 of the last patient plus 6 
months. This is also the study duration.

PFS time: It is assumed that the PFS time in unit of month follows an exponential 
distribution with a rate of -ln(specified true PFS rate at 6 months) / 6. The origin is Cycle 
1 Day 1 of each patient.

PFS calendar time: This is the sum of accrual calendar time and PFS time. The origin is 
Cycle 1 Day 1 of the first patient.

Censoring time: The risk of censoring not due to cut-off for primary CSR is set at 0.15 per 
patient-year (i.e. 365 days). It is assumed that the censoring time in unit of month follows 


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an exponential distribution with a rate of -ln(1 - 0.15) / (365/28) 0.012. The origin is 
Cycle 1 Day 1 of each patient.

Censoring calendar time: This is the sum of accrual calendar time and censoring time. The 
origin is Cycle 1 Day 1 of the first patient.

Event indicator: If the PFS time is smaller than the censoring time and PFS calendar time 
is smaller than EOS, then the PFS event is observed; otherwise PFS is censored.

Observation time: For a PFS event the observation time is the respective PFS time. For a 
censored case the observation time is the respective censoring time if censoring calendar 
time is smaller than EOS, or equals (EOS - accrual calendar time) otherwise. The origin is 
Cycle 1 Day 1 of each patient.
For each treatment group several possible values for true PFS rate at 6 months are specified. 
For each scenario with one of the specified values for true PFS rate at 6 months the hypothetical 
PFS dataset is generated by the following steps:
1. Set accrual waiting time to 0 for the first patient. Generate a random sample of accrual 
waiting times for the remaining ni – 1 patients from an exponential distribution with the 
rate of ai.
2. Generate a random sample of ni PFS times from an exponential distribution with the rate 
of -ln(specified true PFS rate at 6 months) / 6.
3. Generate a random sample of ni censoring times from an exponential distribution with the 
rate of -ln(1 -0.15) / (365/28).
4. Calculate accrual calendar time, EOS, PFS calendar time and censoring calendar time to 
determine event indicator and observation time for each patient.
The steps 1-4 above are repeated to generate a total of 1000 hypothetical datasets for each 
scenario.
14.3.3.2 Posterior analysis
Primary endpoint
Given the prior distributions and parameter values specified in Section 14.3.2 above, the 
corresponding posterior distributions of γ and ln(λ) for each of the 1000 hypothetical datasets 
are obtained by performing extensive MCMC simulations using R and WinBUGS software 
packages, with 5000 iterations for each of 4 chains. For each pair of posterior values of γ and 
ln(λ) the PFS rate at 6 months is calculated using equation [2] with x=6. The calculated PFS 
rates at 6 months from the iterations form the posterior distribution for the primary endpoint. 
The mean, median, standard deviation and 95% credible intervals for PFS rates at 6 months will 
be calculated from this posterior distribution. The posterior mean is taken as the estimated PFS 
rate at 6 months. The posterior risk of being in a specific interval is calculated as the proportion 
of calculated PFS rate at 6 months in that specific interval.
For Group 1: If the estimated PFS rate at 6 months is equal to or greater than 70% and the
posterior risk of being in the unacceptable anti-tumor activity interval [0, 55%) is lower than 
0.05, then preliminary anti-tumor activity of the study treatment will be declared, i.e. success. 
The operating characteristics in terms of probability of success among 1000 hypothetical 


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datasets for the above-mentioned Bayesian study design under different true PFS rates at 6 
months are summarized in Table 14-4 below. Such operating characteristics are satisfactory.
Table 14-4
Operating characteristics of Group 1 Bayesian study design
True PFS rate at 6 months
55%
70%
75%
80%
85%
Probability of success
0.02
0.53
0.81
0.96
1
In Sub-group A if the estimated PFS rate at 6 months is equal to or greater than 50% and the 
posterior risk of being in the unacceptable anti-tumor activity interval [0, 35%) is lower than 
0.05, then preliminary anti-tumor activity of the study treatment will be declared, i.e. success. 
In Sub-group B if the estimated PFS rate at 6 months is equal to or greater than 40% and the 
posterior risk of being in the unacceptable anti-tumor activity interval [0, 25%) is lower than 
0.05, then preliminary anti-tumor activity of the study treatment will be declared, i.e. success.
The operating characteristics in terms of probability of success among 1000 hypothetical 
datasets for the above-mentioned Bayesian study design under different true PFS rates at 6 
months are summarized in Table 14-5 below. Such operating characteristics are satisfactory.
Table 14-5
Operating characteristics of Group 2 Bayesian study design
Sub-group A:
True PFS rate at 6 months
35%
50%
55%
60%
65%
Probability of success
0.05
0.50
0.73
0.87
0.95
Sub-group B:
True PFS rate at 6 months
25%
40%
45%
50%
55%
Probability of success
0.02
0.59
0.80
0.93
0.98
Secondary endpoints
The MCMC simulations for the primary endpoint will be used also for analysis of two 
secondary endpoints: PFS rate at 3 months and median PFS time.

PFS rate at 3 months: For each pair of posterior values of γ and ln(λ) the PFS rate at 3 
months is calculated using equation [2] with x=3. The calculated PFS rates at 3 months 
from the iterations form the posterior distribution for this secondary endpoint. The mean, 
median, standard deviation and 95% credible intervals for PFS rates at 3 months will be 
calculated from this posterior distribution.

Median PFS time: For each pair of posterior values of γ and ln(λ) the median PFS time is 
calculated using equation [3]. The calculated median PFS times from the iterations form 
the posterior distribution for this secondary endpoint. The mean, median, standard 
deviation and 95% credible intervals for median PFS time will be calculated from this 
posterior distribution.


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14.4
Appendix 4: Guidelines for response, duration of overall 
response, TTF, TT, progression-free survival and overall survival 
(based on RECIST 1.1)
Harmonization of Efficacy Analysis of Solid Tumor Studies
Document type:
TA Specific Guideline
Document status:
Version 3.1: 29-Nov-2011
Version 3:0: 19-Oct-2009
Version 2:0: 18-Jan-2007
Version 1:0: 13-Dec-2002
Release date:
29-Nov-2011


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List of Contributors
Authors (Version 3.1):
Authors (Version 3):
Authors (Version 2):
Authors (Version 1):


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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
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
UNK
Unknown


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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 
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 2 and the definition of best response in 
Section 3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions and 
rules for determination of best response. Section 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 4 of this 
guideline describes data handling and programming rules. This section is to be referred to in 
the RAP (Reporting and Analysis Plan) to provide further details needed for programming.
2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.
2.1
Definitions
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 patients without measurable disease see Section 3.2.8.
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 5mm 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.


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
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 
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 patient, 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.
2.1.2 Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient 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 patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 3.2.8.
2.2
Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v) 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 patients, 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 patient is 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.


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
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 change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. 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 the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan).

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.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. US 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 must 
normalize for a patient 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 


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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.
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 CRF 
(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 2.1.1.

Nodal target: See Section 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 
documented on eCRF.
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 


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for the target (Table 14-6) and non-target lesions (Table 14-7) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 14-8) as well as the presence or absence of new lesions.
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.
2.4.1.1
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.
2.4.1.2
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.
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.


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2.4.2 Determination of target lesion response
Table 14-6
Response criteria for target lesions
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 a 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 an 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.
Methodology change See Section 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 three 
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 CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-6 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at 
or after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.

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 


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remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
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.


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2.4.3 Determination of non-target lesion response
Table 14-7
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 lesions 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 a 
different method than baseline.
1.
Although a clear progression of non-target lesions only is exceptional, in such circumstances, 
the opinion of the treating physician does prevail and the progression status should be 
confirmed later on by the review panel (or study chair).
Notes on non-target lesion response

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 any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

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 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.
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 CRF 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 


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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 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 2.5).

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). See Section 2.2.
2.5
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 14-8.
Table 14-8
Overall lesion response at 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
SD1, 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 2.4.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.
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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3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
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) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).


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
PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
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)
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.


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Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients 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 patients with a best overall response of CR or 
PR or SD.
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 patients 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 patients 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. Patients 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, 
patients 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).
3.2
Time to event variables
The protocol should state which of the following variables is used in that study.
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.
3.2.2 Overall survival
All patients 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”).


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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.
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 patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
3.2.4 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 drug. In some protocols, time to treatment 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 patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
3.2.5 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 


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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 patients 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 patients 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.
Duration of stable disease (CR/PR/SD): For patients 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.
3.2.6 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 3.2.5. 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. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients 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 patients 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 patients 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.


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3.2.7 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.
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 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 
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
Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
3.2.8 Handling of patients with non-measurable disease only at baseline
It is possible that patients 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.
It is recommended that any patients 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 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 14-9.
Table 14-9
Overall lesion response at each assessment: patients 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
Yes or No
PD
Any
Yes
PD
1 As defined in Section 2.4.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients 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 patients 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 patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.


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3.2.9 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 3.2.7, and using the draft FDA guideline on endpoints 
(Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 2005) as a 
reference, the following analyses can be considered:
Table 14-10
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
No baseline assessment
(1) Date of randomization/start of 
treatment3
Censored
B
Progression at or before next 
scheduled assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly 
one missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or 
more missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. clinical 
progression based on investigator 
claim
(1) N/A
(2) Date of discontinuation (visit date at 
which clinical progression was 
determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP 
and 
duration of 
response)
1.
=Definitions can be found in Section 3.2.7.
2.
=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 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.


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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 patients 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.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case.
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 Table 14-10 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.
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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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).
4.2
End of treatment phase completion
Patients 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 patients 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.
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

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)
4.3
End of post-treatment follow-up (study phase 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.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy


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
Protocol deviation

Technical problems

Subject/guardian decision

Death

New therapy for study indication

Progressive disease

Study terminated by the sponsor
4.4
Medical validation of programmed overall lesion response
As RECIST 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), these UNK 
assessments may be re-evaluated by clinicians 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 patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
4.5
Programming rules
The following should be used for programming of efficacy results:
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.
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, 
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assessment date is calculated as outlined in Section 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.
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.
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)’.
4.5.5 Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
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 14-10)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 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 


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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 patients 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.
5
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791.
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47.
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465.
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005.
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 S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16.


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14.5
Appendix 5: Management algorithms
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Novartis Medical Monitor. The guidance applies to all immuno-oncology 
(I-O) agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into 
account when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used.


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14.6
Appendix 6: Guidelines for viral hepatitis testing for ongoing and 
new patients
For all ongoing patients:
HBV testing
Screen all patients with HBV serologic markers: HBsAg, HBsAb, and HBcAb. If positive for 
either HBsAg and/or HBcAb, the patient should be discontinued/excluded from the study as 
required by the current protocol, and Novartis should be notified immediately. If positive only 
for HBsAb, HBV-DNA should be tested and if this returns positive the patient should be 
discontinued/excluded from the study as required by the current protocol, and Novartis should 
be notified immediately. Patients who are positive only for HBsAb and negative for HBV-DNA 
may continue on the protocol. Patients who screen negative for these serologic markers will 
continue on protocol.
HCV testing
Screen all patients with hepatitis C antibodies HC Ab and Hepatitis C RNA. If positive for 
either or both, the patient should be discontinued/excluded from the study as required by the 
current protocol, and Novartis should be notified immediately.
For all new patients:
HBV testing, treatment and monitoring
Screen all patients with HBV serologic markers: HBsAg, HBsAb, and HBcAb. If positive for 
either HBsAg and/or HBcAb, the patient should be excluded from the study as required by the 
current protocol, and Novartis should be notified immediately. If positive only for HBsAb, 
HBV-DNA should be tested and if this returns positive the patient should be excluded from the 
study as required by the current protocol, and Novartis should be notified immediately. Patients 
who are positive only for HBsAb and negative for HBV-DNA, and have a history of Hepatitis 
B vaccination, are eligible. Patients who screen negative for these serologic markers remain 
eligible.
HCV testing
Screen all patients with hepatitis C antibodies HC Ab and Hepatitis C RNA. If positive for 
either or both, the patient should be excluded from the study.
LFT monitoring and subsequent testing guidelines for all patients
LFTs should be monitored for all patients as per protocol, or more frequently if clinically 
indicated. At any time during the study, if ALT > 5 x ULN in patients with baseline ALT ≤ 3 x 
ULN, or if ALT > 8 x ULN in patients with baseline ALT > 3 x ULN but ≤ 5 x ULN: 
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1. Perform test(s) for viral hepatitis infection or reactivation: all patients should be screened 
with viral hepatitis panel (HA Ab-IgM, HBsAg, HBcAb-IgM, HBV-DNA, HCV Ab, and 
HCV-RNA).
2. If any of the above tests indicate new viral infection or viral reactivation, immediately 
interrupt EGF816 treatment, consult a physician with expertise in managing viral hepatitis 
and contact Novartis for further discussion
3. Perform other relevant tests/procedures as clinically indicated
4. Follow the dosing modification for ALT elevation according to guidelines in the current 
protocol