A Phase 2, Open-Label, Multicenter Study of the Combination of RMC-4630 and Sotorasib for Non-Small Cell Lung Cancer Subjects With KRASG12C Mutation After Failure of Prior Standard Therapies
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Sponsor: Revolution Medicines, Inc.

 
TITLE PAGE 
Protocol Title:  
A Phase 2, Open-Label, Multicenter Study of the Combination of 
RMC-4630 and Sotorasib for Non-Small Cell Lung Cancer 
Subjects with KRASG12C Mutation After Failure of Prior Standard 
Therapies 
Protocol Number:  
RMC-4630-03 
EudraCT Number: 
2021-003254-23 
Compound Number:  
RMC-4630 
Study Phase:  
Phase 2 
Short Title:  
Combination Study of RMC-4630 and Sotorasib for Non-Small 
Cell Lung Cancer Subjects with KRASG12C Mutation After Failure 
of Prior Standard Therapies 
Sponsor Name:  
Revolution Medicines, Inc. 
Legal Registered 
Address: 
700 Saginaw Drive 
Redwood City, CA 94063 
Regulatory Agency 
Identifying Number(s):  IND 138359 
Version/Date:  
V5.0 / 06 September 2023 
 
 
 

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SPONSOR SIGNATORY 
SPONSOR SIGNATORY 
 
Chief Medical Officer, Clinical and Medical Affairs 
 
Date 
 
Sponsor Medical Monitor Name and Contact Information: 
 
Revolution Medicines, Inc. 
 
18-Sep-2023 | 10:11:35 PDT

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PROTOCOL SIGNATORY, PRINCIPAL INVESTIGATOR  
 
Title: 
A Phase 2, Open-Label, Multicenter Study of the Combination of 
RMC-4630 and Sotorasib for Non-Small Cell Lung Cancer 
Subjects with KRASG12C Mutation After Failure of Prior Standard 
Therapies 
Protocol No.: 
RMC-4630-03 
EudraCT Number: 
2021-003254-23 
Version No. / Date: 
V5.0 / 06 September 2023  
Compound ID: 
RMC-4630 
Phase: 
2 
Sponsor: 
Revolution Medicines, Inc. 
Regulatory Agency 
Identifying No.: 
IND 138359 
I agree to conduct the study in accordance with the current protocol. 
Principal Investigator’s Name (Print) 
Principal Investigator’s Signature 
Site Number 
Date (DD/Month/YYYY) 
 

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SUMMARY OF CHANGES  
 
Summary of Changes Since Version 4.0 
Version 5.0 
Amendment Date 
06 September 2023 
Global 
Protocol Amendment Summary and Rationale: 
This table describes the changes incorporated in Version 5.0 of the protocol. The primary reasons for this 
amendment are to: 
• 
Add an Extended-Use phase to the protocol for subjects experiencing continued clinical benefit from 
study treatment  
• 
Align all countries with a single amendment 
In this amendment, minor grammatical, editorial, formatting, and administrative changes not affecting the 
conduct of the study are included for clarification and administrative purposes only. 
Sections 
Affected 
Changes 
Rationale 
Section 1.1.3 
Added a brief description of the Extended-Use phase 
to the Overall Design. 
To include the rationale for the 
Extended-Use phase of the protocol 
and clarify that LTFU subjects will not 
be followed in the Extended-Use 
phase. 
Section 1.1.4, 
Section 4.1.1 
Added the Extended-Use phase to the duration of 
treatment. 
To clarify that treatment may continue 
after the EOS for subjects benefitting 
from study treatment. 
Section 1.1.4, 
Section 4.1.3 
Added duration of Extended-Use phase. 
To provide the length of the Extended-
Use phase. 
Section 1.2 
(Figure 1) 
Added a footnote to Figure 1 that schema refers to 
main protocol only. 
Clarification of assessment differences 
between main protocol and Extended-
Use phase. 
Section 1.3 
(Table 1) 
• 
Added text to distinguish assessments for the main 
protocol from assessments for the Extended-Use 
phase. 
• 
Added columns to the SoA for assessments during 
the Extended-Use phase and added footnotes for 
assessments to be performed as clinically indicated 
and according to local standards of care. 
• 
Added a footnote to LTFU. 
• 
To clarify assessments not being 
performed during the Extended-
Use phase. 
• 
To describe the assessments to be 
performed during the Extended-
Use phase. 
• 
To clarify that LTFU subjects will 
not be followed in the Extended-
Use phase.  
Section 1.3 
(Table 2) 
Added a row for the Extended-Use phase. 
To clarify that PK and biomarker 
sampling will not be performed during 
the Extended-Use phase. 
Section 2.2.2.3  Added hepatotoxicity and QT prolongation if co-
administered with drugs known to prolong QT to 
potential risks.  
Update to potential risks. 
Section 2.2.2.4 Added prohibition of medications known to prolong 
QT. 
Update to steps to minimize risk. 
Section 2.2.2.5 Section was deleted. 
COVID-19 pandemic assessments no 
longer being performed. 

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Summary of Changes Since Version 4.0 
Version 5.0 
Amendment Date 
06 September 2023 
Global 
Section 4.1.2, 
Section 7.1, 
Section 7.2 
Removed LTFU from the Extended-Use phase of the 
study. 
To clarify that LTFU subjects will not 
be followed in the Extended-Use 
phase. 
Section 4.1.4, 
Section 8.2 
Added eligibility for the Extended-use phase and a 
reference to SoA for Extended-Use phase assessments. 
To clarify assessments during the 
Extended-Use phase. 
Section 4.4 
Added the LSLV date (EOS) and the Extended-Use 
phase. 
To clarify EOS and Extended-Use 
phase. 
Section 6.1 
Added Extended-Use phase to study treatment 
description. 
To describe study treatment 
administration during the 
Extended-Use phase. 
Section 8.1 
Table 1, 
[footnote 25, 
footnote 27] 
Added text that tumor imaging in the Extended-Use 
phase is not required per protocol and that subjects in 
the Extended-Use phase will be managed according to 
local standards of care. 
To clarify assessments and subject 
management during the Extended-Use 
phase. 
 
Section 8.2.2 
Added to record vital signs in the medical record 
during the Extended-Use phase. 
 
Clarification for recording of 
assessments. 
Table 1, 
[footnote 15], 
Section 8.3.1,  
Section 8.3.3, 
Section 8.3.4 
Added AE/SAE reporting during the Extended-Use 
phase. 
To clarify AE/SAE reporting changes 
during the Extended-Use phase. 
Section 8.3.5  
Added that pregnancy reporting will continue during 
the Extended-Use phase using the SAE report form. 
Clarification of pregnancy reporting. 
Section 8.5, 
Section 8.6 
Added that there will not be PK sample collection for 
treatment of overdose. 
To clarify assessment differences 
between main protocol and 
Extended-Use phase. 
Section 8.8 
Added clarification regarding biomarker sample 
collection. 
To clarify assessment differences 
between main protocol and 
Extended-Use phase. 
Appendix 5 
Added text that use and analysis of tumor DNA refers 
to the main protocol only. 
To clarify assessment differences 
between main protocol and 
Extended-Use phase. 
Abbreviations: AE = adverse event; CRFs = case report forms; EOS = end of study; LTFU = long term follow up;  
LSLV = last subject last visit; SoA = Schedule of Activities; SAE = serious adverse event. 

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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SPONSOR SIGNATORY ...............................................................................................................2 
SPONSOR SIGNATORY ...............................................................................................................2 
PROTOCOL SIGNATORY, PRINCIPAL INVESTIGATOR .......................................................3 
SUMMARY OF CHANGES ...........................................................................................................4 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
1.1. 
Synopsis for Protocol RMC-4630-03 .........................................................................11 
1.1.1. 
Rationale .....................................................................................................................11 
1.1.2. 
Objectives and Endpoints ...........................................................................................13 
1.1.3. 
Overall Design ............................................................................................................14 
1.1.4. 
Duration of Therapy ...................................................................................................15 
1.2. 
Schemas ......................................................................................................................16 
1.3. 
Schedule of Activities (SoA) ......................................................................................17 
2. 
INTRODUCTION ......................................................................................................26 
2.1. 
Background .................................................................................................................26 
2.1.1. 
RMC-4630 ..................................................................................................................26 
2.1.2. 
Sotorasib .....................................................................................................................28 
2.1.3. 
RMC-4630 and Sotorasib Combination .....................................................................29 
2.2. 
Benefit/Risk Assessment ............................................................................................30 
2.2.1. 
Overview and Potential Benefit ..................................................................................30 
2.2.1.1. 
RMC-4630 ..................................................................................................................30 
2.2.1.2. 
Sotorasib .....................................................................................................................30 
2.2.1.3. 
Rationale for RMC-4630 in Combination with Sotorasib in Protocol 
RMC-4630-03 .............................................................................................................30 
2.2.2. 
Important Risks ...........................................................................................................31 
2.2.2.1. 
Identified and Potential Risks of RMC-4630 .............................................................31 
2.2.2.2. 
Potential Risks of Sotorasib ........................................................................................33 
2.2.2.3. 
Potential Risks of RMC-4630 and Sotorasib Combination ........................................33 
2.2.2.4. 
Steps to Minimize Risk ...............................................................................................34 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................35 
4. 
STUDY DESIGN .......................................................................................................36 
4.1. 
Overall Study Design ..................................................................................................36 

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4.1.1. 
Duration of Treatment ................................................................................................36 
4.1.2. 
Long-Term Follow-Up Period ....................................................................................37 
4.1.3. 
Duration of the Study ..................................................................................................37 
4.1.4. 
Intervention After the End of the Study .....................................................................37 
4.2. 
Scientific Rationale for Study Design ........................................................................37 
4.3. 
Dose Justification ........................................................................................................37 
4.3.1. 
RMC-4630 ..................................................................................................................37 
4.3.2. 
Sotorasib .....................................................................................................................38 
4.4. 
EOS Definition ...........................................................................................................38 
5. 
STUDY POPULATION .............................................................................................39 
5.1. 
Inclusion Criteria ........................................................................................................39 
5.2. 
Exclusion Criteria .......................................................................................................40 
5.3. 
Lifestyle Considerations .............................................................................................43 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................43 
5.4. 
Screen Failures ............................................................................................................43 
6. 
STUDY TREATMENT ..............................................................................................44 
6.1. 
Study Treatments Administered: RMC-4630 and Sotorasib ......................................44 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................45 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................45 
6.4. 
Study Treatment Compliance .....................................................................................46 
6.4.1. 
Compliance Instructions .............................................................................................46 
6.4.2. 
Missed Dose ................................................................................................................46 
6.5. 
Permitted Concomitant Therapy .................................................................................46 
6.6. 
Prohibited Concomitant Therapy ................................................................................47 
6.7. 
Dose Modification ......................................................................................................47 
6.7.1. 
Supportive Care Guidelines for Selected Expected Toxicities ...................................52 
6.7.2. 
Management of Rash ..................................................................................................53 
6.7.3. 
Management of Diarrhea ............................................................................................53 
6.7.4. 
Management of Ophthalmologic Complications ........................................................53 
6.7.5. 
Management of Hypertension .....................................................................................54 
6.7.6. 
Management of Liver Function Abnormalities and Hepatotoxicity ...........................54 
6.7.7. 
Management of Hemorrhage ......................................................................................55 
6.7.8. 
Management of Fatigue ..............................................................................................55 

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6.7.9. 
Pneumonitis ................................................................................................................55 
6.7.10. 
Management of Fluid Retention/Overload Events .....................................................55 
7. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................56 
7.1. 
Discontinuation of Study Treatment ...........................................................................56 
7.2. 
Subject Discontinuation/Withdrawal from the Study .................................................57 
7.3. 
Lost to Follow-Up.......................................................................................................57 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................58 
8.1. 
Efficacy Assessments .................................................................................................58 
8.2. 
Safety Assessments .....................................................................................................59 
8.2.1. 
Physical Examinations ................................................................................................59 
8.2.2. 
Vital Signs ..................................................................................................................60 
8.2.3. 
Weight and Height ......................................................................................................60 
8.2.4. 
Electrocardiograms .....................................................................................................60 
8.2.5. 
Echocardiograms/Multigated Acquisition Scans ........................................................60 
8.2.6. 
Clinical Safety Laboratory Assessments ....................................................................61 
8.2.7. 
ECOG Performance Status .........................................................................................61 
8.2.8. 
Ophthalmologic Examinations ...................................................................................61 
8.3. 
Adverse Events and Serious Adverse Events .............................................................61 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................62 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................62 
8.3.3. 
Follow-Up of AEs and SAEs ......................................................................................62 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................63 
8.3.5. 
Pregnancy ...................................................................................................................63 
8.3.6. 
Committees .................................................................................................................64 
8.3.6.1. 
Dose Committee .........................................................................................................64 
8.3.6.2. 
ISMC...........................................................................................................................64 
8.4. 
Dose Limiting Toxicity Criteria .................................................................................64 
8.5. 
Treatment of Overdose ...............................................................................................65 
8.6. 
Pharmacokinetics ........................................................................................................66 
8.7. 
Tumor Genetics ..........................................................................................................67 
8.8. 
Other Biomarkers ........................................................................................................67 
9. 
STATISTICAL CONSIDERATIONS .......................................................................68 

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9.1. 
Statistical Hypotheses .................................................................................................68 
9.2. 
Sample Size Determination ........................................................................................68 
9.3. 
Populations for Analyses ............................................................................................68 
9.4. 
Statistical Analyses .....................................................................................................69 
9.4.1. 
Efficacy Analyses .......................................................................................................69 
9.4.2. 
Safety Analyses ..........................................................................................................70 
9.4.3. 
Pharmacokinetic Analyses ..........................................................................................71 
9.4.4. 
Other Analyses ............................................................................................................71 
10. 
REFERENCES ...........................................................................................................72 
APPENDIX 1. REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS ..................................................................................................74 
APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS AND REVIEW AND 
ASSESSMENT OF POTENTIAL HY’S LAW CASES ............................................78 
APPENDIX 3. ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................81 
APPENDIX 4. CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION ...............................................................................85 
APPENDIX 5. GENETICS .........................................................................................................88 
APPENDIX 6. RESPONSE EVALUATION CRITERIA IN SOLID TUMOURS 
(RECIST V1.1) ...........................................................................................................89 
APPENDIX 7. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS SCALE .........................................................................99 
APPENDIX 8. LIST OF PROHIBITED MEDICATIONS WHILE RECEIVING 
TREATMENT ..........................................................................................................100 
APPENDIX 9. POTENTIAL GENETIC MODIFIERS FOR ENROLLMENT INTO 
DOSE EXPANSION ................................................................................................102 
APPENDIX 10. CONTINGENCY MEASURES FOR A REGIONAL OR 
NATIONAL EMERGENCY THAT IS DECLARED BY A 
GOVERNMENTAL AGENCY ...............................................................................103 
APPENDIX 11. MODIFIED TOXICITY PROBABILITY INTERVAL-2 (MTPI-2) 
DESIGN DETAILS ..................................................................................................104 
APPENDIX 12. ABBREVIATIONS ........................................................................................105 
 
 
 

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LIST OF TABLES 
Table 1: 
Schedule of Activities for Protocol RMC-4630-03 ....................................................18 
Table 2: 
PK and ctDNA Biomarker Sampling .........................................................................25 
Table 3: 
Objectives and Endpoints ...........................................................................................35 
Table 4: 
Study Treatment Administered: RMC-4630 and Sotorasib ........................................44 
Table 5: 
Dose Reduction Guidelines with RMC-4630 and Sotorasib ......................................48 
Table 6: 
Dose Modification Guidelines for RMC-4630 and Sotorasib ....................................49 
Table 7: 
General Dose Modification Guidelines with RMC-4630 and Sotorasib for 
All Other AEs .............................................................................................................52 
Table 8: 
Population Definitions ................................................................................................69 
Table 9: 
Stopping Boundary by Number of Subjects ...............................................................71 
Table 10: Operating Characteristics of Stopping Rules ..............................................................71 
 
LIST OF FIGURES 
Figure 1: 
RMC-4630-03 Study Schema .....................................................................................16 
Figure 2: 
The RAS Signaling Pathway Demonstrating the Convergence Nodal 
Position of SHP2 in the Pathway ................................................................................26 
 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis for Protocol RMC-4630-03 
Protocol Title: A Phase 2, Open-Label, Multicenter Study of the Combination of RMC-4630 
and Sotorasib for Non-Small Cell Lung Cancer (NSCLC) Subjects with KRASG12C Mutation 
After Failure of Prior Standard Therapies 
Short Title: Combination Study of RMC-4630 and Sotorasib for NSCLC Subjects with 
KRASG12C Mutation After Failure of Prior Standard Therapies 
1.1.1. 
Rationale 
The RAS signaling pathway is frequently dysregulated in human cancers, typically as a result of 
genomic alterations that lead to hyperactivation (Dhillon, 2007). These alterations can occur at 
3 levels: upstream of RAS in receptor tyrosine kinases (RTKs), directly within mediators of the 
RAS catalytic cycle (RAS isoforms and RAS-GTPase activating proteins [GAPs], such as 
neurofibromin 1 [NF1]), or in downstream effector kinases, such as BRAF or MEK 
(TCGA Network, 2014).  
Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is a positive upstream 
regulator of RAS activation. Thus, SHPs presents a suitable therapeutic target for patients whose 
tumors harbor oncogenic mutations that remain dependent on active RAS cycling between 
guanosine triphosphate (GTP)- and guanosine diphosphate (GDP)-bound states. Examples of these 
include subsets of Kirsten rat sarcoma viral oncogene homolog (KRAS)G12, mutations in NF1 
predicted to result in loss of function (NF1LOF) mutations, Class 3 type mutations in BRAF 
(Nichols, 2017; Nichols 2018), or amplification of wild-type KRAS (Wong, 2018). Preclinical 
studies demonstrated that daily oral (PO) administration of a SHP2 inhibitor alone (at the 
maximum tolerated dose [MTD]) achieved tumor cytostasis in cell-line-derived xenograft (CDX) 
and patient-derived xenograft (PDX) models harboring these mutations, and in some instances, 
tumor regressions (Nichols, 2017; Nichols, 2018; Wong, 2018).  
The KRAS p.G12C mutation has been identified as an oncogenic driver in several types of solid 
tumors including NSCLC, colorectal cancer (CRC), and other solid tumors. However, effective 
targeted therapies for KRAS-mutant cancers remain an unmet clinical need. Two inhibitors, 
sotorasib and adagrasib, are currently in clinical trials in subjects with advanced KRASG12C 
mutated solid tumors (NCT03600883 [sotorasib] and NCT03785249, NCT04685135, 
NCT04330664, and NCT04613596 [adagrasib]). Data reported from these early clinical trials 
have shown favorable safety profiles and some promising monotherapy responses in patients 
with NSCLC (Canon, 2019; Hallin, 2020; Hong, 2020, Jänne, 2020; Johnson, 2020; Li, 2021 ). 
On 28 May 2021, the United States (US) Food and Drug Administration (FDA) granted 
accelerated approval to sotorasib (LUMAKRAS™) for adult patients with KRASG12C‑mutated 
locally advanced or metastatic NSCLC who have received at least one prior systemic therapy. 
The European Medicines Agency (EMA) recently granted conditional approval on 12 November 
2021 of LUMYKRAS® (sotorasib) in patients with KRASG12C-mutated advanced NSCLC. Based 
on Amgen’s public release announcement on 09 January 2022, the European Commission (EC) 
has granted conditional marketing authorization for LUMYKRAS® (sotorasib). The approval was 
based on CodeBreaK 100, a multicenter, single-arm, open label clinical trial (NCT03600883) 
that included subjects with locally advanced or metastatic NSCLC with KRASG12C mutations. 

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Efficacy was evaluated in 124 subjects whose disease had progressed on or after at least one 
prior systemic therapy. Subjects received sotorasib 
 PO once daily (QD) until disease 
progression or unacceptable toxicity. The main efficacy outcome measures were objective 
response rate (ORR), according to Response Evaluation Criteria in Solid Tumours, Version 1.1 
(RECIST v1.1), as evaluated by blinded independent central review and response duration. The 
ORR was 36% (95% confidence interval [CI]: 28%, 45%) with a median response duration of 
10 months (range 1.3+, 11.1). The most common adverse reactions (≥ 20% of subjects) were 
diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common 
laboratory abnormalities (≥ 25% of subjects) were decreased lymphocytes, decreased 
hemoglobin, increased aspartate aminotransferase (AST), increased alanine aminotransferase 
(ALT), decreased calcium, increased alkaline phosphatase (ALP), increased urine protein, and 
decreased sodium. The recommended sotorasib dose is 
 PO QD with or without food. 
The Sponsor notes that data readout from a post-marketing study of sotorasib dose optimization 
in patients with advanced NSCLC who have received one prior therapy (see NCT03600883 
found on ClinicalTrials.gov) is imminent at the time of this protocol amendment. If supported by 
the data, at the Sponsor’s discretion, new subjects enrolling on this trial may be treated at the 
lower sotorasib dose of 
 in combination with RMC-4630 (see Table 4 and Table 5). 
Subjects currently enrolled at 
 in combination with RMC-4630 may continue at their 
current dose or dose reduce based on discussion with the Sponsor Medical Monitor. Subjects 
developing toxicities at sotorasib 
 may dose reduce to sotorasib 
or 
discontinue treatment. 
Despite encouraging early clinical data in monotherapy, not all second- or third-line treatments 
for NSCLC patients with KRASG12C-mutated tumors are effective. (Hong, 2020) has reported an 
objective response rate (ORR) to sotorasib of 32%, and (Jänne, 2020) has reported an ORR to 
adagrasib of 45%. Therefore, improvements in therapy are needed for patients with KRASG12C 
NSCLC after failure of prior standard therapies. In addition, biomarkers, such as comutation of 
STK11/LKB1 and/or KEAP1, appear to delineate subpopulations that are relatively less 
responsive to standard-of-care NSCLC therapy (Singh, 2021); these comutations also may 
influence the response rate to sotorasib monotherapy (Li, 2021). 
Preclinical data demonstrates that the potency of KRASG12C inhibitor treatment can be modulated 
by upstream RTK activation (Lito, 2016), which occurs as an adaptive response to inhibition of 
KRASG12C OFF state with either sotorasib or adagrasib. Concurrent inhibition of RTK signaling 
can optimize the RAS signaling pathway in KRASG12C tumors (Lito, 2016; Canon, 2019). The 
addition of a SHP2 inhibitor like RMC-4630 to KRASG12COFF state inhibitors improves tumor 
responses in preclinical models (Hallin, 2020; Liu, 2018), and can also abrogate KRAS signaling, 
eliminate residual or bypass upstream RTK activity, and thereby potentially lead to greater 
combinatorial efficacy and deeper, more durable responses. Phase 1b clinical trials combining 
KRASG12COFF-state inhibitors with SHP2 inhibitors are currently ongoing, but the data are not 
yet available. 
RMC-4630 and sotorasib combination therapy is being tested in an ongoing Amgen-sponsored 
Phase 1b platform Study (CodeBreaK 101 [NCT04185883], Subprotocol C, hereafter referred to 
as CodeBreaK 101C). CodeBreaK 101C was initiated in May 2020 and is currently dosing 
subjects at RMC-4630 
 twic
) on 
 
of each week in 
a 21-day cycle (ie, Days 1, 2, 8, 9, 15, and 16 of each 21-day cycle). The study has tested and 
cleared lower dose levels of RMC-4630, which include both 
 of each week in a 

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21-day cycle (ie, Days 1, 2, 8, 9, 15, and 16 of each 21-day cycle) and 
 on Day 1 
and Day 4 (D1D4) of each week in a 21-day cycle (ie, Days 1, 4, 8, 11, 15, and 19 of each 
21-day cycle) in combination with of sotorasib QD.  
This protocol (RMC-4630-03) is a Phase 2 study designed to complement the ongoing 
CodeBreaK 101C study and will further characterize the efficacy, safety, pharmacokinetics (PK), 
and tolerability of RMC-4630 and sotorasib combination therapy for subjects with KRASG12C 
mutant locally advanced or metastatic NSCLC who have received at least one prior systemic 
therapy.  
Emerging clinical data from sotorasib monotherapy and adagrasib monotherapy suggest that 
KRASG12C-mutated NSCLC could represent a heterogenous population defined by comutations 
such as STK11 and KEAP1 (Li, 2021; Jänne, 2020). Preclinical data suggest SHP2 resistance in 
select tumors including those harboring BRAF Class 1 and 2 and neuroblastoma RAS viral 
oncogene homolog (NRAS) mutations (Nichols, 2018). Leveraging these learnings, this study 
will prospectively define analysis of subpopulations of KRASG12C-mutated NSCLC without or 
with detectable comutations that might influence the outcome to sotorasib (eg, STK11, KEAP1) 
and/or RMC-4630 (eg, BRAF, NRAS).  
1.1.2. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the antitumor effects of RMC-4630 and 
sotorasib in locally advanced or metastatic NSCLC 
subjects with KRASG12C mutation with and without co-
existing genetic aberrations in specific genes such as 
STK11/LKB1, KEAP1, and PIK3CA (see detailed list in 
Appendix 9) after failure of prior standard therapy 
ORR as assessed per RECIST v1.1 
Secondary 
• 
To characterize the safety, tolerability, and PK of 
RMC-4630 in combination with sotorasib for 
subjects with KRASG12C mutant NSCLC after 
failure of prior standard therapy 
• 
To further characterize efficacy of RMC-4630 in 
combination with sotorasib as assessed by DOR, 
DCR, PFS, and OS in subjects with KRASG12C 
mutant locally advanced or metastatic NSCLC 
after failure of prior standard therapy 
• 
Incidence, nature, and severity of TEAEs, SAEs, 
clinically significant changes in laboratory tests, 
ECGs, and vital signs 
• 
Trough and approximate peak concentrations of 
RMC-4630 and sotorasib 
• 
DOR, DCR, and PFS as assessed per 
RECIST v1.1, and OS 
 
Exploratory 
• 
To explore PK relationships with safety and/or 
efficacy endpoints  
• 
To investigate potential biomarkers by 
biochemical and/or genetic analysis of blood 
and/or tumor tissue samples 
 
• 
Sotorasib and RMC-4630 exposure/safety and 
exposure/efficacy relationships  
• 
Quantification of biomarker expression (protein, 
RNA, and DNA levels) as appropriate in ctDNA 
and archival tumor tissues (or fresh, if archival 
tumor is not available). 
Abbreviations: ctDNA = circulating tumor deoxyribonucleic acid; DCR = disease control rate; DOR = duration of response; 
DNA = deoxyribonucleic acid; ECG = electrocardiogram; KEAP1 = Kelch-like ECH-associated protein 1; KRASG12C = 
KRAS with a mutation at codon 12, which encodes glycine (G) to cysteine (C); NSCLC =  non–small-cell lung cancer; 
LKB1 = liver kinase B1; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PIK3CA = 
phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha; PK = pharmacokinetic(s); RECIST v1.1 = 

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Response Evaluation Criteria in Solid Tumours, Version 1.1; RNA = ribonucleic acid; SAE = serious adverse event; STK11 = 
serine/threonine kinase 11; TEAE = treatment-emergent adverse event. 
1.1.3. 
Overall Design  
This is a phase 2 multicenter, open-label study evaluating the efficacy, safety, tolerability, and 
pharmacokinetics (PK) of RMC-4630 in combination with sotorasib in subjects with KRASG12C 
mutant locally advanced or metastatic NSCLC after failure of prior standard therapy. The overall 
study schema is illustrated in Figure 1. The study will be conducted at approximately 
clinical 
sites globally and is expected to enroll up to approximately 
subjects. 
Prior to enrollment, all subjects will undergo screening to determine study eligibility. Eligibility 
will be assessed based on inclusion and exclusion criteria (Sections 5.1 and 5.2, respectively) and 
prior/local genomic testing reports from a tumor biopsy or plasma sample. Information on the 
presence of any genotypic aberrations in the tumor will be collected for all subjects based on 
prior/local genomic testing reports. Mutation testing results for all subjects must have been 
obtained in a Clinical Laboratory Improvement Amendments (CLIA)/College of American 
Pathologists (CAP) certified laboratory and collected preferably within 3 years of the subject’s 
study enrollment. See Appendix 9 for details of genotypic mutations required for enrollment. 
Subjects may remain in the study, regardless of the results of central laboratory testing, unless 
other exclusionary criteria are met, or the subject withdraws consent.  
This Phase 2 study will have a safety run-in period where RMC-4630 will be administered at a 
starting dose of 
 on 
 of each week in a 21-day cycle (ie, Days 1, 2, 8, 9, 15, and 16 
of each 21-day cycle) and sotorasib 
 QD in a 21-day cycle. Subjects will be evaluated for 
dose -limiting toxicities (DLTs) (Section 8.4). The decision to escalate the RMC-4630 dose to 
 on 
 of each week in a 21-day cycle (ie, Days 1, 2, 8, 9, 15, and 16 of each 21-day 
cycle) will be guided by a modified toxicity probability interval 2 (mTPI-2) algorithm (see 
Appendix 11) and made by the Dose Committee. After completion of the safety run-in (DLT 
clearance) of both dose levels, additional subjects may be enrolled into one or both dose cohorts 
for the purpose of dose optimization before selecting the final expansion dose. Expansion may 
commence as soon as the expansion dose has been selected from either CodeBreaK 101C or this 
study, whichever occurs first. The Sponsor may proceed directly to dose expansion without 
completing the safety run-in period. The combination dose for expansion will be determined by 
the Sponsor after taking into consideration the totality of available data from CodeBreaK 101C 
and the cumulative data from this study. The Sponsor notes that data readout from a post-
marketing study of sotorasib dose optimization in patients with advanced NSCLC who have 
received one prior therapy (NCT03600883) is imminent at the time of this protocol amendment. 
If supported by the data, at the Sponsor’s discretion, new subjects enrolling on this trial may be 
treated at a lower sotorasib dose of 
 in combination with RMC-4630 (see Table 4  and 
Table 5). Subjects currently enrolled at sotorasib dose of 
 in combination with 
RMC-4630 may continue at their current dose of sotorasib or dose reduce based on discussion 
with the Sponsor Medical Monitor. Subjects developing toxicities at sotorasib 240 mg QD may 
dose reduce to sotorasib 
 or discontinue treatment. 
The study will enroll a total of approximately 
 globally. Subjects will be categorized 
into 1 of 2 cohorts.  

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• Cohort 1 will be the primary cohort of this study and will consist of KRASG12C 
NSCLC subjects without potential genetic aberrations in specific genes, such as 
STK11/LKB1, KEAP1, and PIK3CA (see detailed list in Appendix 9). 
• Cohort 2 will consist of KRASG12C NSCLC subjects with co-existing genetic 
aberrations in specific genes, such as STK11/LKB1, KEAP1, and PIK3CA (see 
detailed list in Appendix 9). Additional details of the sample size and statistical 
considerations are provided in Section 9. 
Subjects may remain on study drug until disease progression per RECIST v1.1, unacceptable 
toxicity, or other criteria for withdrawal are met, whichever occurs first. The End-of-Study 
(EOS) is defined as the date of the last visit of the last subject in the study (ie, last subject, last 
visit [LSLV]) or 12 months after the last subject is enrolled, whichever occurs first. Subjects 
benefitting from administration of RMC-4630 and sotorasib may continue to receive study 
treatment until disease progression or unacceptable toxicity as part of an Extended-Use phase of 
the protocol. 
Upon permanent discontinuation of study treatment for any reason, including for subjects in the 
Extended-Use Phase, an end-of-treatment (EOT) visit should be completed within 30 days after 
the last dose of study treatment or before any new antitumor treatment is started. 
Following the EOT visit, subjects will be considered to have completed the study. Survival 
follow up will be discontinued for subjects currently in LTFU. 
1.1.4. 
Duration of Therapy 
Subjects will be permitted to remain on study treatment until disease progression per 
RECIST v1.1, unacceptable toxicity, or other criteria for withdrawal are met (see Section 7.1, 
whichever comes first. Subjects will return to the clinical site for an EOT visit within 30 days 
after their last dose of study treatment. Subjects who are benefitting from study treatment at the 
time of the EOS may continue treatment in the Extended-Use phase of the study, which will be 
conducted through June 2024. 

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1.2. 
Schemas  
Figure 1: 
RMC-4630-03 Study Schema 
 
Abbreviations: ctDNA = circulating tumor deoxyribonucleic acid; 
 of each week in a 21-day cycle (ie, Days 1, 2, 8, 9, 15, and 16 of each 21-day cycle); 
KRASG12C = KRAS with a mutation at codon 12, which encodes glycine (G) to cysteine (C); mTPI-2 = modified toxicity probability interval-2; QD = once daily.  
Note: The study schema refers the main protocol only. 
¥ Eligibility for study entry will be based on existing genomic reports from a qualified or validated test. Retrospective ctDNA may identify comutation(s) that may shift subjects 
from Cohort 1 to Cohort 2. 
∑ The starting dose is 
 on 
 of each week in a 21-day cycle (ie, Days 1, 2, 8, 9, 15, and 16 of each 21-day cycle) and escalation to 
 of each week in a 
21-day cycle (ie, Days 1, 2, 8, 9, 15, and 16 of each 21-day cycle) will be guided by an mTPI-2 algorithm (Appendix 11) and made by the Dose Committee.  
At the Sponsor’s discretion, new subjects enrolling on this trial may be treated at the lower sotorasib dose of 
 in combination with RMC-4630 instead of 
 in 
combination with RMC-4630 (see Table 4 and Table 5). 
§ Expansion in this study may commence as soon as the expansion dose has been selected from either CodeBreaK 101C or RMC-4630-03, whichever occurs first. The Sponsor 
may proceed directly to dose expansion without completing the safety run-in period. The combination dose for expansion in this study will be determined by the Sponsor after 
taking into consideration the totality of available data from both CodeBreaK 101C and cumulative data from this study. After completion of the safety run-in (DLT clearance) of 
both dose levels, additional subjects may be enrolled into one or both dose levels for the purpose of dose optimization to inform final expansion dose selection. 

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1.3. 
Schedule of Activities (SoA)  
Weekends and national holidays do not count towards visit windows and will not be considered protocol deviations. 
For subjects continuing study treatment beyond Cycle 2, the clinic visits are reduced to D1 of each cycle. If clinically indicated, 
subjects can be seen at any time in the clinic for an unscheduled visit. The SoA is presented in Table 1.   
Note that assessments from Screening through LTFU are for the main protocol only. Assessments performed during the Extended-Use 
phase will occur as clinically indicated, unless specified otherwise. 
 
 

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Table 1: 
Schedule of Activities for Protocol RMC-4630-03 
Screening1 
Treatment 
EOT/ 
EOS2 
LTFU3 
Extended
-Use4  
Extended
-Use 
EOT/ 
EOS2 
Cycle/Day 
Cycle 1  
(21-Days) 
Cycle 2 
(21-Days) 
Cycle 3 
(21-Days) 
D1 of  
Every 
Cycle  
(After C3) 
D1 of  
Every 
Other Cycle  
(After C3) 
 
 
Day 
-28 
to 1 
-14 to 
1 
1 
8 
(±1D) 
15 
(±1D) 
1 
(±1D) 
15 
(±1D) 
1 (±1D) 
1 (±1D) 
1 (±1D) 
(+30D) 
(±14D) 
After 
Main 
EOS 
(+30D) 
General and Safety Assessments 
 
 
Informed5 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Demographics6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical/
Cancer History7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of 
KRASG12C 
Mutation8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
Physical 
Examination9  
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Limited Physical 
Examination10  
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
Vital Signs11 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Body Weight and 
Height12 
 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
12-Lead ECG13 
 
X 
X 
 
X 
 
 
X 
 
X 
X 
 
X  
X 
 
 

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Table 1: 
Schedule of Activities for Protocol RMC-4630-03 (Continued) 
Screening1 
Treatment 
EOT/ 
EOS2 
LTFU33 
Extended
-Use34 
Extended
- Use 
EOT/ 
EOS2 
Cycle/Day 
Cycle 1  
(21-Days) 
Cycle 2 
(21-Days) 
Cycle 3 
(21-Days
) 
D1 of  
Every 
Cycle  
(After C3) 
D1 of 
Every Other 
Cycle  
(After C3) 
 
 
Day 
-28 
to 1 
-14 to 
1 
1 
8 
(±1D) 
15 
(±1D) 
1 
(±1D) 
15 
(±1D) 
1 (±1D) 
1 (±1D) 
1 (±1D) 
(+30D) 
(±14D) 
After 
Main 
EOS 
(+30D) 
ECHO/MUGA14 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
ECOG PS15 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X  
X 
Ophthalmologic 
Examination16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events17 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Concomitant 
Medications18 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Assessment and 
Documentation of 
Study Treatment 
Compliance19  
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
  
X 
X 
Hematology 
Panel20 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Serum Chemistry 
Panel21 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Coagulation Tests 
(PT, INR, and 
aPTT or PTT)22  
 
X 
X 
 
 
 
 
X 
 
X 
X 
 
X 
X 
Urinalysis23  
 
X 
X 
 
 
 
 
X 
 
 
X 
 
X  
X 
 
 

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Table 1: 
Schedule of Activities for Protocol RMC-4630-03 (Continued) 
Screening1 
Treatment 
EOT/ 
EOS2 
LTFU33 
Extended
-Use 34 
Extended
-Use 
EOT/ 
EOS2 
Cycle/Day 
Cycle 1  
(21-Days) 
Cycle 2 
(21-Days) 
Cycle 3 
(21-Days) 
D1 of  
Every 
Cycle  
(After C3) 
D1 of  
Every 
Other Cycle  
(After C3) 
 
 
Day 
-28 to 
1 
-14 to 
1 
1 
8 
(±1D) 
15 
(±1D) 
1 
(±1D) 
15 
(±1D) 
1 (±1D) 
1 (±1D) 
1 (±1D) 
(+30D) 
(±14D) 
After 
Main 
EOS 
(+30D) 
Pregnancy 
Test (FSH and 
Estradiol, if 
needed)24  
 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
 
X 
Hepatitis B 
and C Virus 
Tests25  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK (Total 
and MM 
Isoenzymes)26  
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
CT Scan27  
X 
 
 
 
 
 
 
X 
(±1 week) 
 
X 
(every 2 
cycles then 
every 4 
cycles 
[±1 week]  
starting at 
C9) 
X 
 
  
 
Brain MRI28 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
RECIST v1.1 
Tumor 
Response 
Assessment29  
 
 
 
 
 
 
 
X 
(±1 week) 
 
X 
(every 2 
cycles then 
every 4 
cycles 
[±1 week]  
starting at 
C9) 
X 
 
 
X 
Study Treatment Administration 
RMC-463030  
 
 
<-
 
 
 
X 
 
Sotorasib31 
 
 
<----------------------------------------------- Dosed QD-----------------------------------------> 
 
 
X  
 

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Table 1: 
Schedule of Activities for Protocol RMC-4630-03 (Continued) 
Screening1 
Treatment 
EOT/ 
EOS2 
LTFU33 
Extended
-Use34 
Extended
- Use 
EOT/ 
EOS2 
Cycle/Day 
Cycle 1  
(21-Days) 
Cycle 2 
(21-Days) 
Cycle 3 
(21-Days) 
D1 of  
Every 
Cycle  
(After C3) 
D1 of  
Every 
Other Cycle  
(After C3) 
 
 
Day 
-28 to 
1 
-14 to 
1 
1 
8 
(±1D) 
15 
(±1D) 
1 
(±1D) 
15 
(±1D) 
1 (±1D) 
1 (±1D) 
1 (±1D) 
(+30D) 
(±14D) 
After 
Main 
EOS 
(+30D) 
PK and Biomarker Assessment 
 
 
PK 
Sampling32 
 
 
See Table 2  
 
 
 
 
Blood for 
ctDNA 
biomarker33 
 
 
See Table 2   
X 
 
 
 
Archival 
tumor tissue 
(FFPE) for 
solid tumors or 
fresh-tissue 
biopsy34 
X 
 
 
 
 
 
 
Long-Term Follow-up 
 
 
Telephone 
contact for 
survival 
status3 
 
 
Only completed after EOT 
 
X 
 
 
1 Screening window is 14 days, unless otherwise specified. Informed consent and subject demographics, medical history, smoking status, documentation of 
tumor genotypic mutations, screening hepatitis tests, CT/MRI scan, ECHO/MUGA, and ophthalmic examination may be obtained 28 days before C1D1. 
2 Subjects who discontinue study treatment should complete the EOT visit within 30 days of last dose of study treatment. Subjects who wish to withdraw from 
treatment should be encouraged to complete the EOT assessments. If a subject chooses to withdraw from the study completely, record the reason for 
withdrawal on the appropriate page(s) of the eCRF. Subjects who are on treatment at the main EOS and are deriving clinical benefit from RMC 4630 and 
sotorasib will be considered for enrollment in a separate Extended-Use phase. These subjects should enter the Extended-Use phase without interruption of 
treatment and should complete main EOT assessments to receive treatment on Day 1 of the Extended-Use phase. EOT/EOS for the Extended-Use phase will be 
performed within 30 days of the last dose in the Extended-Use phase. 
3 After termination of treatment, subjects in the main study will remain on study for survival follow-up. Survival follow up will be discontinued for subjects 
currently in LTFU at the time of the initiation of the Extended-Use phase. 
4 Assessments performed during the Extended-Use phase will occur as clinically indicated, unless specified otherwise. 

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5 Obtain written informed consent from the subjects before any protocol required procedures and assessments are performed. Standard of care evaluations 
performed as part of the subject’s routine treatment prior to signing consent may be used if they were done in the timeframe required for screening. 
6 Demographic information includes the following: age, gender, race, and ethnicity. 
7 Prior cancer history includes: (i) date of diagnosis, (ii) staging, (iii) all previous therapies (ie, chemotherapy, immunotherapy, biologic or targeted agents, 
experimental therapies, radiotherapy, and surgery), (iv) previous therapy details (ie, regimen, start and stop dates), (v) best response for each regimen, (vi) date 
of relapse or disease progression, and (vii) any molecular characterization of tumor (eg, PD-L1 expression). 
8 Documentation of KRASG12 NSCLC in a prior genomic report within 3 years of study enrollment. Please see Appendix 9 for a detailed list of genetic 
aberrations, which may be allowed for subjects enrolling in Cohort 2 of the dose expansion portion of the study.  
9 Complete physical examination should be performed during screening, C2D1, and at EOT. The examination should include an evaluation of the HEENT, 
dermatologic, cardiovascular, respiratory, GI (including assessments of liver and spleen), musculoskeletal, neurological, and lymphatic systems. A 
symptom/AE-directed physical examination should be performed as indicated by subject presentation or reported symptoms or AEs. New or worsened 
abnormalities should be recorded as AEs, if appropriate. 
10 Limited physical examination should be performed on C1D1, C1D8, C1D15, C2D15 and C3D1 and D1 of each subsequent cycle and should include evaluation 
of HEENT, dermatologic, cardiovascular, respiratory, and GI systems. A symptom/AE-directed physical examination should be performed as indicated by 
subject presentation or reported symptoms or AEs. New or worsened abnormalities should be recorded as AEs, if appropriate. 
11 Vital signs include the following: temperature, blood pressure preferably in seated position, pulse rate, pulse oximetry, and respiratory rate. Vital signs should 
be taken prior to administration of study treatment. 
12  Height and Weight should be measured during screening for the purposes of documentation. Only weight is measured at the remaining timepoints, and weight 
may be measured and recorded at other time points if clinically indicated at the investigator’s discretion. Abnormalities including >10% weight change, should 
be recorded as AEs, if appropriate. 
13  ECGs should be performed on all subjects in the supine position. A single ECG may be performed at Screening, but the average of triplicate readings for 
assessing QTc interval may be used at Screening to determine eligibility. Triplicate ECGs should be performed at C1D1 and C1D15 pre-dose and again 
approximately 2-4 hours post-dose. Then a single pre dose ECG should be obtained on D1 of every 2 cycles starting at C3 (eg, C3D1, C5D1, etc) and at EOT. 
During the Extended-Use phase, ECGs will be performed according to local standards of care. 
14 ECHO is the preferred methodology to measure LVEF. MUGA may be used if ECHO is not available or not technically feasible. However, the same 
methodology should be used throughout the study. Assessments should be performed during screening, on C2D1 (+7 days), EOT, and if clinically indicated at 
any point. If a subject does not complete 2 cycles of study treatment, the EOT assessment of LVEF is not required unless clinical signs or symptoms warrant an 
examination. All subjects who require dose reduction of study treatment due to decrease in LVEF should have ECHO at the end of each cycle for 2 more cycles 
and then if clinically indicated to ensure that subject is not experiencing a decrease in LVEF even with a reduced dose. 
15 ECOG PS to be assessed at screening, C1D1, C1D15, and D1 of each subsequent cycle beginning at C2, and at EOT. During the Extended-Use phase, ECOG 
PS will be assessed according to local standards of care. 
16 Ophthalmic examination if clinically indicated, including full fundoscopic examination and optical coherence tomography should be performed by an 
ophthalmologist. Additional examinations should be performed as clinically indicated. 
17 Monitor and record AEs and SAEs throughout the main study. Record all AEs, regardless of relationship to study treatment, that occur after initiation of first 
study treatment until EOT. All AEs and SAEs will be collected from the start of treatment until 30 days after the last dose, or upon initiation of alternative 
cancer treatment, whichever occurs first. After this period, investigators should report only SAEs that are thought to be related to RMC 4630 and/or sotorasib. 
After informed consent, but prior to initiation of study treatment, only SAEs caused by a protocol mandated intervention will be collected (eg, SAEs related to 
invasive procedures such as biopsies or medication washout). All SAEs that occur should be reported to the Sponsor or designee within 24 hours of investigator 
awareness. All AEs (regardless of relationship to study treatment) and SAEs determined not to be study- treatment related (ie, not related and unlikely related) 

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will be followed through the last study visit and be noted as “continuing” if not resolved at this visit. Any SAE that is determined to be study treatment related 
(possibly, probably, or definitely related) will be followed to resolution or stabilization, until it is determined to be irreversible by the investigator, the subject is 
lost to follow up, or it has been determined that the study treatment is not the cause of the AE/SAE. AE/SAE reporting will end after the subject initiates 
alternative cancer treatment. During the Extended-Use phase of the study, only SAEs (irrespective of causality) and related AEs will be reported in the EDC. 
All SAEs will also be reported on the SAE Report Form. 
18 Record all concomitant medications including any prescription medications, over the counter preparations, and transfusions received by subject from 7 days 
preceding C1D1 through EOT. During the Extended-Use phase, concomitant medications given for SAEs only will be recorded. 
19 Subjects should be instructed to bring their pills and diary to every clinic visit, or to submit diary information at that time. 
20 Hematology includes the following: RBC count, hemoglobin, hematocrit, MCV, MCH, % reticulocytes, platelet count, WBC count, and differential 
(neutrophils, bands [if available], lymphocytes, monocytes, eosinophils, basophils, other cells). NOTE: Testing must be performed and reviewed before dosing 
on C1D1. If hematology samples are obtained within the previous 72 hours as part of screening, then re-testing on C1D1 is not required. For subsequent visits 
after C1D1, samples may be obtained up to 72 hours prior to the visit. During the Extended-Use phase, hematology testing will be performed according to local 
standards of care. 
21 Serum chemistry includes the following: sodium, potassium, chloride, bicarbonate/carbon dioxide, BUN, creatinine, glucose (non-fasting), albumin, total 
protein, calcium, magnesium, phosphorus, uric acid, lipase, GGT, ALT, AST, total and direct bilirubin, and ALP. NOTE: Perform tests and review results 
before dosing on C1D1. If chemistry samples were obtained within the previous 72 hours as part of screening, then re-testing on C1D1 is not required. Plasma 
is permitted. For subsequent visits after C1D1, samples may be obtained up to 72 hours prior to the visit. During the Extended-Use phase, serum chemistry 
testing will be performed according to local standards of care. 
22 Coagulation studies to include PT, INR and aPTT/PTT during screening, C1D1, C3D1, every other subsequent cycle after C3D1, and EOT. Additional testing 
may be performed if clinically indicated. If coagulation samples were obtained within the previous 72 hours as part of screening, then re-testing on C1D1 is not 
required. For subsequent visits after C1D1, samples may be obtained up to 72 hours prior to the visit.” During the Extended-Use phase, coagulation testing will 
be performed according to local standards of care. 
23 Urinalysis includes the following: appearance, pH, specific gravity, glucose, protein/albumin, blood, ketones, bilirubin, nitrites, urobilinogen, and leukocyte 
esterase. In addition, a microscopic examination for casts, crystals, and cells may be performed if feasible and clinically indicated. If urinalysis samples were 
obtained within the previous 72 hours as part of screening, then re-testing on C1D1 is not required. For subsequent visits after C1D1, samples may be obtained 
up to 72 hours prior to the visit. During the Extended-Use phase, urinalysis will be performed according to local standards of care. 
24 For females of childbearing potential (including tubal ligation), perform a blood pregnancy test at screening and a urine/blood pregnancy test pre-dose within 
72-hours of D1 of each cycle, as well as at the EOT. A positive urine pregnancy test must be confirmed with a blood test. For all other women, documentation 
of non-childbearing potential must be present in the medical history. Perform FSH and estradiol tests as needed, in women of non-childbearing potential only. 
25 Hepatitis serology includes HBsAg, HBcAb, and HCV antibody. Additional testing (eg, hepatitis B viral load, HBsAb, hepatitis B core IgM antibody) may be 
required if results are inconclusive or positive for surface antigen/core antibody. 
26 CPK levels should be obtained within 72-hours of C1D1, C1D15, and D1 of each cycle, EOT and if clinically indicated. 
27 Tumor imaging should be performed at screening and every 2 cycles starting from Cycle 3 (ie, every 6 weeks [±1 week]) up to Cycle 9, every 4 cycles (ie, 
every 12 weeks [±1 week]) thereafter and EOT. Tumor assessments should include CT scans (with contrast) or MRI of the chest and abdomen (depending on 
primary tumor type, site of metastasis, and investigator assessment). At the investigator’s discretion, the imaging studies may be repeated at any time if disease 
progression is suspected. Additional studies, such as PET scans or bone scans to confirm presence of new lesions, should be performed if clinically indicated. 
Every effort should be taken to repeat the same modality used at screening throughout the study and to ensure all anatomy imaged at screening is again imaged 
at follow up scans for any given subject. Please note that the window for CT/MRI and tumor assessments is ± 7 days. Radiographic response (CR and PR) 
requires confirmation by a repeat scan at least 4 weeks after the first documentation of response and may be delayed until the next scheduled scan to avoid 

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unnecessary procedures. An EOT scan is not needed if it was already performed at the time of disease progression and the subject discontinued study treatment 
due to disease progression. In the Extended-Use phase, tumor imaging is not required per protocol. If required, imaging should be performed according to local 
standards of care. 
28 Required within 4 weeks of C1D1 for subjects with previous history of brain metastases or suspected brain metastasis to establish stable disease. 
29 Measurable disease is required for each subject. All measurable disease must be documented at screening and reassessed at each subsequent tumor evaluation. 
Response assessments will be assessed by the investigator, based on physical examinations and CT scans or MRI using RECIST v1.1 (Appendix 6). As part of 
tumor assessment, physical examinations should include all areas of tumor involvement that are amenable to examination including biopsy sites, lymph nodes, 
and bone tenderness, if applicable. Scans should be performed every 2 cycles until Cycle 9, and every 4 cycles thereafter. During the Extended-Use phase, 
tumor imaging is not required per protocol. Response assessments will be performed according to local standards of care and may be reported in the eCRF at 
the end of the extended use phase, if available. 
30 RMC 4630 BIW dosing should be administered PO on D1 and D2. During clinic visit days in C1, as well as D1 of subsequent cycles, RMC 4630 should be 
administered in the clinic in order to comply with blood PK, ctDNA, or ECG assessment timepoints. 
31 Initially, subjects will be dosed sotorasib 960 mg QD PO. If supported by the data from a post-marketing study of sotorasib dose optimization in patients with 
advanced NSCLC who have received 1 prior therapy, at the Sponsor’s discretion, new subjects enrolling on this trial may be treated at sotorasib 240 mg QD in 
combination with RMC-4630. Subjects currently enrolled at 960 mg may continue at their current dose or dose reduce based on discussion with the Sponsor’s 
Medical Monitor. Subjects developing toxicities at sotorasib 240 mg QD in combination with RMC-4630 may dose reduce to sotorasib 120 mg QD in 
combination with RMC-4630 or discontinue treatment. During clinic visit days in C1, as well as D1 of subsequent cycles, sotorasib should be administered in 
the clinic in order to comply with blood PK, ctDNA, and ECG assessment timepoints. 
32 Blood samples (3 mL/sample) for RMC 4630 and sotorasib PK analyses will be obtained at the timepoints listed in Table 2. 
33 Blood samples (10 mL/sample) for ctDNA will be obtained at the timepoints listed in Table 2. 
34 For all subjects, archival tumor tissue collected preferably within 3 years should be submitted between screening and EOT. FFPE tissue blocks with sufficient 
specimen to allow sectioning for 21 × 4 micron slides are preferred. Alternatively, one H&E-stained slide with a 20 × 4 micron freshly cut specimen (with 
minimum 30% viable tumor volume) can be provided. Pretreatment fresh biopsies will be mandatory for subjects who do not have available archival tissue 
preferably from within 3 years, unless the investigator determines that the tumor site is not amenable to biopsy or poses a significant risk to subject safety. The 
Sponsor will evaluate this requirement on a case-by-case basis. The pre-treatment biopsy should not be collected until the subject is determined to be eligible 
for the study by the Sponsor. Any tumor site amenable to biopsy (excisional or needle [4 cores × 18 gauge or <18 gauge needle]) is acceptable, except for bone 
metastases. Acceptance of needle biopsy cores from >18-gauge needles will be evaluated by the Sponsor on a case-by-case basis and may require additional 
cores.  
Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; aPTT = activated partial thromboplastin 
time; BIW = twice weekly; BUN = blood urea nitrogen; C = cycle; C1D1 (CxDx, etc) = Cycle 1 Day 1, etc; CPK = creatine phosphokinase; CR = complete response; 
CT = computed tomography; ctDNA = circulating tumor deoxyribonucleic acid; D = day; ECG = electrocardiogram; eCRF = electronic Case Report Form; ECHO = 
echocardiogram; ECOG = Eastern Cooperative Oncology Group; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EOS = End-of-Study; EOT = End-of-
Treatment; FFPE = formalin fixed paraffin embedded; FSH = follicle-stimulating hormone; GGT = gamma-glutamyl transferase; GI = gastrointestinal; HBcAb = hepatitis B core 
antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; H&E = hematoxylin and eosin; HEENT = head, eyes, ears, nose, and throat; INR = international 
normalized ratio; KRASG12C = KRAS with a mutation at codon 12, which encodes glycine (G) to cysteine (C); LVEF = left ventricular ejection fraction; MCH = mean corpuscular 
hemoglobin; MM = striated muscle; MRI = magnetic resonance imaging; MUGA = multigated acquisition; MCV = mean corpuscular volume; NSCLC =  non–small-cell lung 
cancer; OCT = optical coherence tomography; PD-L1 = Programmed death-ligand 1; PET = positron emission tomography; PK =pharmacokinetics(s); PO = oral(ly); PR = partial 
response; PT = prothrombin time; PTT = partial thromboplastin time; QD = once daily; RBC = red blood cell; QTc = corrected QT interval; RECIST v1.1 = Response Evaluation 
Criteria in Solid Tumours, Version 1.1; SAE = serious adverse event; SOC = standard-of-care; WBC = white blood cell. 

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Table 2: 
PK and 
 Sampling 
Cycle/EOT 
Study Day 
PK  
Time Points 
  
Time Points 
Collection-Time Window 
C1 
 
NA 
 
NA 
 
Predose 
 
Within 1 hour before dose 
2 hours postdose 
-- 
2 hours ±10 minutes after dose 
C2, C3, C4 
 
Predose 
  
Within 1 hour before dose 
Every 3 cycles (C7, C10, C13, C16) afterward up to C16 
 
Predose 
NA 
Within 1 hour before dose 
EOT 
NA 
X 
Any time during visit 
Extended-
Use 
NA 
NA 
NA 
Abbreviations: C = cycle; 
; EOT = End-of-Treatment; NA = not applicable; 
PK = pharmacokinetic(s).  
Note: On any days that a PK specimen is collected, the subject should be administered study drug in the clinic.  

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2.
INTRODUCTION
2.1. 
Background 
2.1.1. 
RMC-4630 
SHP2 is a non-receptor protein tyrosine phosphatase and scaffold protein that functions 
downstream of multiple RTKs, integrating cell surface growth factor signals to promote RAS 
activation Figure 2. RMC-4630 was designed as a potent and selective SHP2 allosteric inhibitor 
that suppresses RAS activation and the proliferation in cancers that, distinct from those 
dependent on oncogenic RTKs, are driven by nucleotide cycling oncogenic point mutations 
(eg, KRASG12C) and wild-type amplification of KRAS and other RAS-GTP dependent 
downstream mutations, eg, NF1LOF, or RAS-GTP dependent oncogenic BRAF Class 3 
(Wong, 2018; Fedele, 2018). 
Figure 2: 
The RAS Signaling Pathway Demonstrating the Convergence Nodal Position 
of SHP2 in the Pathway 
SHP2 is a convergent node for RTK to RAS signaling and regulator of RAS-GTP loading. SHP2 
inhibition modulates RTK signal transduction as well as RAS signaling pathway hyperactivation 
driven by specific oncoproteins. Preclinical studies demonstrated that daily PO administration of 
RMC-4630 alone achieved dose-dependent tumor cytostasis, and in some instances, tumor 
reductions, in multiple CDX models bearing RAS signaling pathway activating mutations of 
interest: NSCLC NCI-H358 KRASG12C, pancreatic ductal adenocarcinoma (PDAC) MIA PaCa-2 
KRASG12C, NSCLC NCI-H2122 KRASG12C, NSCLC NCI-H1838 NF1LOF, and melanoma 
MeWo NF1LOF (Nichols, 2017; Nichols, 2018). RMC-4630 also significantly inhibited tumor 
growth in 2 PDX models of NSCLC in athymic nude mice: LUN#023 bearing BRAF Class 3 
(BRAFD594N) and LUN#037, which carries BRAFN581D, a known Class 3 variant position 
(see current RMC-4630 Investigator’s Brochure [IB]). 
RMC-4630 is a potent, selective, and orally bioavailable SHP2 allosteric inhibitor that is being 
developed for patients with tumors harboring certain activating genotypic aberrations in the RAS 
signaling pathway. In this study (Protocol RMC-4630-03), RMC-4630 will be studied in 
combination with sotorasib, a KRASG12C inhibitor, in locally advanced or metastatic NSCLC 

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subjects with KRASG12C mutation after failure of prior standard therapy to determine the efficacy, 
safety, tolerability and PK profile of the combination. 
Preclinical data demonstrate that the potency of KRASG12C inhibitor treatment can be modulated 
by upstream RTK activation (Lito, 2016), which occurs as an adaptive response to inhibition of 
KRASG12COFF state with either sotorasib or adagrasib. Concurrent inhibition of RTK signaling 
can optimize RAS pathway signaling in KRASG12C tumors (Lito, 2016; Canon, 2019). The 
addition of a SHP2 inhibitor like RMC-4630 to KRASG12COFF state inhibitors improves tumor 
responses in preclinical models (Hallin, 2020; Liu 2018) can also abrogate KRAS signaling, 
eliminate residual or bypass upstream RTK activity, and thereby lead to greater combinatorial 
efficacy as well as deeper and more durable responses.  
Most patients with mutations/rearrangements that confer hyperactivation of the RAS signaling 
pathway have a poor prognosis. RMC-4630 is currently being studied in the clinic as a 
monotherapy and in combination with several agents, including cobimetinib (MEK inhibitor), 
pembrolizumab (checkpoint inhibitor), osimertinib (RTK inhibitor), and sotorasib 
(KRASG12COFF state inhibitor). A first-in-human, Phase 1 dose-escalation and expansion study 
(RMC-4630-01; NCT03634982) established a recommended phase 2 dose (RP2D) and schedule 
(RP2DS) of 
 on a 
schedule on 23 October 2020. As of 16November 2020, 
subjects had been treated with RMC-4630 monotherapy. The median age reported for this 
subject population is 63 years (range: 24.0 to 86.0 years), median prior systemic therapies is 
3 (range: 0 to 11) with 69% having received 3 or more prior systemic therapies. A majority 
(61.5% [64/104]) of enrolled subjects have an Eastern Cooperative Oncology Group (ECOG) 
score of 1. 
 
 
 
 
 
 Median treatment duration 
 
(range: 0 to 15.6 months). 
 
 
 
 
 
. Therefore, the clinical activity observed 
in KRASG12C mutant NSCLC is encouraging and warrants further exploration in combination 
studies with KRASG12COFF state inhibitors. As mentioned above, there is an ongoing study of 
RMC-4630 and sotorasib, which is also evaluating the safety and efficacy of this combination 
and is sponsored by Amgen.  
RMC-4630 has been extensively evaluated in nonclinical studies to characterize its safety 
profile; the results of these studies support entry into clinical study. The following potential risks 
are based on emerging clinical data from the RMC-4630-01 (monotherapy) and RMC-4630-02 
(combination) clinical trials: edema, diarrhea, anemia, and thrombocytopenia.  
 
More detailed information about the expected 

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benefits and risks and expected AEs of RMC-4630, based on clinical and preclinical data and 
drug class are in the current RMC-4630 IB, as well as in Section 2.2.1. 
In summary, the preclinical and clinical findings reveal potential therapeutic approaches that use 
a potent SHP2 inhibitor in combination with another in-pathway inhibitor to counteract the 
evolution of resistance in tumors harboring alterations in the RAS signaling pathway. 
Additionally, the combination of SHP2 inhibition with sotorasib has the potential to provide 
therapeutic benefit in tumors driven by oncogenic mutations insensitive to either agent alone.  
2.1.2. 
Sotorasib 
Sotorasib (AMG 510) is a small molecule that specifically and irreversibly inhibits KRASG12C 
through a unique interaction with the P2 pocket-bound state (OFF state) by a mechanism similar 
to that described for other KRASG12C inhibitors (Lito, 2016). Preclinical studies showed that 
sotorasib inhibited nearly all detectable phosphorylation of extracellular signal-regulated kinase 
(ERK), a key downstream effector of KRAS, leading to durable complete tumor regression in 
mice bearing KRAS p.G12C tumors (Canon, 2019). 
In a Phase 1 trial of sotorasib, subjects with advanced solid tumors (59 with NSCLC, 42 with 
CRC and 28 with other tumors) harboring the KRASG12C mutation received sotorasib QD 
(Hong, 2020). The subjects had received a median of 3 (range: 0 to 11) previous lines of 
anticancer therapies for metastatic disease. Objective response was assessed according to 
RECIST v1.1. Sotorasib showed encouraging anticancer activity. In the subgroup of subjects 
with NSCLC, 32.2% (19 subjects) had a confirmed objective response (CR or PR) and 88.1% 
(52 subjects) had disease control (objective response or stable disease [SD]); the median 
progression-free survival [PFS] was 6.3 months (range: 0.0+ to 14.9; + indicates that the value 
includes subject data that were censored at data cutoff). No dose-limiting toxic effects or 
treatment-related deaths were observed. Grade 3 or 4 treatment-related toxic effects occurred in 
11.6% of the subjects. 
On 28 May 2021, the US FDA granted accelerated approval to sotorasib for adult patients with 
KRASG12C mutated locally advanced or metastatic NSCLC who have received at least one prior 
systemic therapy. The approval was based on CodeBreaK 100, a multicenter, single-arm, open 
label clinical trial (NCT03600883) that included subjects with locally advanced or metastatic 
NSCLC with KRASG12C mutations. Efficacy was evaluated in 
ith at least one 
measurable lesion at baseline with disease progression after receiving an immune checkpoint 
inhibitor and/or platinum-based chemotherapy. Subjects received sotorasib 960 mg QD until 
disease progression or unacceptable toxicity. The major efficacy outcome measures were ORR 
according to RECIST v1.1, as evaluated by blinded independent central review and response 
duration (DOR). The ORR was 36% (95% CI: 28%, 45%) with a median response duration of 
10 months (range 1.3+, 11.1). In a pooled Phase 1 and Phase 2 dataset of Amgen 
Study 20170543 for NSCLC at 960 mg (N=204), the most common adverse reactions (≥ 20% of 
subjects) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The 
most common laboratory abnormalities (≥ 25% of subjects) were decreased lymphocytes, 
decreased hemoglobin, increased AST, increased ALT, decreased calcium, increased ALP, 
increased urine protein, and decreased sodium. Serious adverse reactions occurred in 50% of 
subjects treated with sotorasib. Serious adverse reactions in ≥ 2% of subjects were pneumonia 
(8%), hepatotoxicity (3.4%), and diarrhea (2%). Fatal adverse reactions occurred in 3.4% of 

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subjects who received sotorasib due to respiratory failure (0.8%), pneumonitis (0.4%), cardiac 
arrest (0.4%), cardiac failure (0.4%), gastric ulcer (0.4%), and pneumonia (0.4%). 
More detail regarding the potential risks, warning and precautions can be found in the current 
Sotorasib IB and in Section 2.2.1 
2.1.3. 
RMC-4630 and Sotorasib Combination 
Most patients with mutations/rearrangements that confer hyperactivation of the RAS signaling 
pathway have a poor prognosis. RMC-4630 is currently being studied in the clinic as a 
monotherapy and in combination with several agents, including cobimetinib (MEK inhibitor), 
pembrolizumab (checkpoint inhibitor), osimertinib (RTK inhibitor), and sotorasib 
(KRASG12COFF state inhibitor).  
The efficacy, safety, tolerability, and PK of the RMC-4630 and sotorasib combination in subjects 
with advanced solid tumors with KRAS p.G12C mutation is being evaluated in an ongoing 
Amgen-sponsored Phase 1b platform study (CodeBreaK 101C [NCT04185883]). 
CodeBreaK 101C was initiated in May 2020 and is currently dosing subjects with RMC-4630 at 
 of each week in a 21-day cycle (ie, Days 1, 2, 8, 9, 15, and 16 of each 
21-day cycle), after dose level review and clearance of two lower dose levels (RMC-4630 
 of each week in a 21-day cycle (ie, Days 1, 4, 8, 11, 15, and 19 of each 
21-day cycle) and 
 on
 of each week in a 21-day cycle.  
This protocol (RMC-4630-03) is designed to complement ongoing CodeBreaK 101C and will 
further characterize the efficacy, safety, tolerability, and PK of RMC-4630 and sotorasib 
combination therapy for subjects with KRASG12C mutant locally advanced or metastatic NSCLC 
after failure of prior standard therapy. Early data (n=27) from CodeBreaK 101c with a median 
follow up of 5.8 months, show that combination of RMC-4630 and sotorasib appears to be safe 
and well tolerated. The most common study-treatment-related AEs of any grade in >10% of the 
population were edema (30%), diarrhoea (26%), dry mouth (11%), and fatigue (11%). Four 
subjects had treatment-related AEs leading to discontinuation of one or both study drugs and 
12 subjects had a treatment-related AE leading to dose modification of one or both study drugs. 
Based on the PK profile, there were no drug-drug interactions between the study drugs. Among 
the subjects with NSCLC (n=11), the overall response rate was 27% overall and 50% in the sub-
population of subjects who were KRASG12C inhibitor naïve (n=6). Durable partial responses were 
observed in 2 subjects who were KRASG12C inhibitor naïve and received 200 mg of RMC-4630 
with 960 mg of sotorasib (Falchook, 2022). 
Emerging clinical data from sotorasib monotherapy and adagrasib monotherapy suggest that 
KRASG12C-mutated NSCLC could represent a heterogenous population defined by comutations 
such as STK11 and KEAP1 (Li, 2021; Jänne, 2020). Preclinical data suggest SHP2 resistance in 
select tumors including those harboring BRAF Class 1 and 2 and NRAS mutations 
(Nichols, 2018). Leveraging these learnings, this study will prospectively define analysis of 
sub-populations KRASG12C-mutated NSCLC without and with detectable comutations that might 
influence the outcome to sotorasib (eg, STK11, KEAP1) and/or RMC-4630 (eg, BRAF, NRAS).  
More detailed information about the expected benefits and risks and expected AEs of 
RMC-4630, based on clinical and preclinical data and class of drugs are in the current 
RMC-4630 IB, as well as in Section 2.2.1. 

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The combination of SHP2 inhibition together with KRASG12COFF state inhibition provides a 
potentially novel targeted treatment for patients with KRASG12C mutant NSCLC with relapsed or 
refractory solid tumors harboring mutations resulting in hyperactivation of the RAS signaling 
pathway.  
More detailed information regarding the known and expected benefits, risks, and AEs of 
sotorasib is provide in the current Sotorasib IB. 
2.2. 
Benefit/Risk Assessment 
2.2.1. 
Overview and Potential Benefit 
2.2.1.1. 
RMC-4630 
RMC-4630 (also known as SAR442720 or RMC-0694630) is a potent, selective, orally 
bioavailable allosteric inhibitor of SHP2, a protein tyrosine phosphatase functioning downstream 
of multiple RTKs as a convergent node in RAS signaling. RMC-4630 is being developed 
primarily to combine with RAS inhibitors to treat RAS-addicted tumors. SHP2 also plays a vital 
role in promoting antitumor immunity and enhancing T-cells cytotoxic function. The current 
focus is to combine RMC-4630 with KRASG12C inhibitors as well as programmed cell death 
protein 1 (PD-1) inhibitors.  
The current clinical development program for RMC-4630 comprises a Phase 1 monotherapy 
study RMC-4630-01 (NCT03634982) conducted by Revolution Medicines, a Phase 1b/2 
combination study RMC-4630-02 (SHP2 inhibitor + mitogen activated protein kinase inhibitor; 
SHP2 inhibitor + epidermal growth factor RTK inhibitor; NCT03989115) also conducted by 
Revolution Medicines, and an Amgen sponsored Phase 1b study (CodeBreaK 101C; 
NCT04185883) evaluating RMC-4630 in combination with sotorasib in subjects with advanced 
solid tumors with KRASG12C mutation are ongoing. Sanofi is conducting a Phase 1/2 combination 
study TCD16210 (SHP2 inhibitor + programmed cell death-1 receptor inhibitor; NCT04418661). 
Please refer to the current RMC-4630 IB for a summary of the clinical development program. 
In a Phase 1 monotherapy study, RMC-4630 demonstrated acceptable tolerability with an 
intermittent dosing schedule (Day 1 and Day 2 of each week) and single agent activity in 
subjects with KRASG12C NSCLC. Tumor and blood-based immune-oncology biomarkers 
demonstrated preliminary evidence of anti-tumor immune activation, supporting an immune-
mediated mechanism of action for SHP2 in addition to modulation of RTK signal transduction.   
2.2.1.2. 
Sotorasib 
Sotorasib (AMG 510) is a small molecule that specifically and irreversibly inhibits KRASG12C 
through a unique interaction with the P2 pocket-bound state (OFF state) by a mechanism similar 
to that described for other KRASG12C inhibitors. Sotorasib is the first approved targeted therapy 
for tumors with KRAS mutation indicated for the treatment of adult patients with KRASG12C 
mutated locally advanced or metastatic NSCLC, marketed as LUMAKRAS™ or LUMYKRAS® 
in several countries.  
2.2.1.3. 
Rationale for RMC-4630 in Combination with Sotorasib in Protocol 
RMC-4630-03 
Most patients with mutations/rearrangements that confer hyperactivation of the RAS signaling 
pathway have a poor prognosis. Recent advances in the treatment paradigm for RAS mutant 

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NSCLC include several first-in-class irreversible inhibitors of KRASG12C (eg, sotorasib 
[AMG 510]) which have demonstrated a favorable safety profile along with early promising 
anti-tumor activity in subjects with advanced NSCLC harboring a KRASG12C. Recently, both 
(Canon, 2019; Hallin, 2020) have interrogated cellular mechanisms that limit the therapeutic 
response to these KRASG12C inhibitors, as a means to identify key vulnerabilities that can be 
co-targeted in combination with other therapeutic agents. Multiple lines of evidence indicate that 
baseline RTK activation, as well as adaptive resistance mechanisms that increase signaling flux 
downstream of RTKs, can limit therapeutic response to KRASG12 inhibitors. Clustered regularly 
interspaced short palindromic repeats (CRISPR) based drug-anchored screens and combination 
experiments in vitro and in vivo have identified SHP2 as an important RAS/MAPK pathway 
node that can be co-targeted to enhance KRASG12C inhibitor activity and abrogate RTK-mediated 
adaptive resistance mechanisms.  
Furthermore, nonclinical data demonstrates that the potency of KRASG12C inhibitors can be 
modulated by upstream RTK activation and concurrent inhibition of RTK signaling can lead to 
maximal KRASG12C inhibition. Tumor development in mutant KRAS driven murine models of 
NSCLC can be inhibited by genetic deletion of Ptpn11, the gene encoding SHP2, confirming the 
role of SHP2 as an important RAS/MAPK pathway node that can be co-targeted to enhance 
KRASG12C inhibitor activity and abrogate potential resistance via RTK activation. These 
published studies suggest that the addition of a SHP2 inhibitor like RMC-4630 to a targeted 
therapy against mutant KRASG12C may completely inhibit KRAS signaling, eliminate residual or 
bypass upstream RTK activity, and thereby promoting deeper and more durable responses.  
This combination is also being tested in advanced KRASG12C mutant solid tumors including 
locally advanced or metastatic NSCLC in an ongoing Phase 1b study sponsored by Amgen 
(CodeBreaK 101C) within the US. The study consists of two parts, Part 1 dose exploration and 
Part 2 dose expansion. CodeBreaK 101C has tested and cleared all dose levels of RMC-4630, 
which include 
 of each week in a 21-day cycle, 
1D2 of 
each week in a 21-day cycle, and 
 of each week in a 21-day cycle in 
combination with 
 of sotorasib QD. 
2.2.2. 
Important Risks 
2.2.2.1. 
Identified and Potential Risks of RMC-4630 
RMC-4630 is currently being evaluated as monotherapy and in multiple combination studies. 
The Phase 1, first-in-human study in adult subjects with relapsed/refractory solid tumors 
(NCT03634982) has established a RP2DS of 
 of each week in a 21-day 
cycle. The toxicity profile of RMC-4630 in humans is emerging and is provided in detail in the 
current RMC-4630 IB. Dose modification guidance for selected toxicities is provided in 
Section 6.7 and supportive care guidelines are provided in Section 6.7.1.  
 
 
 
 
 
 Safety data, as of 17 July 2022, 
are summarized below.  

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 of subjects in study RMC-4630-01.
 
The median time to 
first onset of a
 
 
 
 
 
 
 
As of 17-Jul-2022, a total of 
 across the clinical development program had a reported 
event (irrespective of attribution to study drug(s)) consistent with 
 which 
include  
with an
 and 1 subject with an event of interstitial lung 
disease. Of the 
 with an event, 1
 received RMC-4630 monotherapy, while the 
remaining 
 received RMC-4630 in combination therapy (4 subjects with cobimetinib, 
2 subjects with osimertinib, and 2 subjects with pembrolizumab). A total of 7 subjects had an 
event which was 
 which included
 with a 
 (1 subject 
who received RMC-4630 with cobimetinib and 1 subject who received RMC-4630 with 
osimertinib). 
In addition to the risks described above, thromboembolic events are being monitored. As of 
 
 
 
 
 
 
for subjects with 
 
 

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Because full cytochrome P-450 (CYP) isoform phenotyping studies for RMC-4630 have not 
been completed, RMC-4630 remains a putative substrate of CYP3A4; precautions should be 
taken with co-administration of strong CYP3A4 inducers or inhibitors. These agents are 
contraindicated in this trial (see Appendix 8).  
Based on published on-target effects from other small-molecule inhibitors of the RAS signaling 
pathway, including inhibitors of RTKs, and/or nonclinical toxicology studies with RMC-4630, 
the following toxicities (listed alphabetically) are possible: 
 
 
 
. In general, toxicities are dose dependent and, in the 
case of MEK inhibitors, may also increase in frequency and severity with dosing duration.  
In addition, the following toxicities listed alphabetically have been reported during clinical 
studies of more than one inhibitor of the RAS signaling pathway and it is not known whether 
they are on target toxicities: alopecia, conduction abnormalities, embryofetal toxicity, 
hand-foot-mouth syndrome, hyperglycemia, hypopigmentation, hypothyroidism, interstitial lung 
disease (ILD), left ventricular dysfunction/cardiomyopathy, neurotoxicity, and pleural effusions. 
Additional supporting data from nonclinical studies are provided in the current RMC-4630 IB. 
2.2.2.2. 
Potential Risks of Sotorasib  
Based on non-clinical toxicity studies of sotorasib, the key safety information of sotorasib 
includes renal toxicity, anemia, leukocytosis, thyroid abnormalities, and splenomegaly. Based on 
clinical study data, the key risks to be monitored include increases to AST and ALT, and 
ILD/pneumonitis. Adverse drug reactions with the use of sotorasib include diarrhea, nausea, 
fatigue, vomiting, abdominal pain, increased liver enzymes, and pneumonitis. Clinical signs and 
symptoms of potential toxicities, along with safety laboratories, will be monitored during the 
study to ensure the subjects’ safety. More detailed information about the safety profile and risks 
of sotorasib, including the most recent information on adverse drug reactions based on the 
ongoing clinical program, may be found in the current version of the Sotorasib IB.  
2.2.2.3. 
Potential Risks of RMC-4630 and Sotorasib Combination  
As sotorasib impacts signaling in the RAS-MAPK signaling pathway, it is possible that 
overlapping toxicities with RMC-4630 will be observed. The clinical study design builds in 
safeguards which minimize potential toxicities to subjects. 
The combination of RMC-4630 and sotorasib has been previously administered in humans in an 
ongoing study conducted by Amgen (CodeBreaK 101C; NCT04185883). As stated above, 
CodeBreaK 101C is a Phase 1b study evaluating the safety, tolerability, pharmacokinetics, and 
efficacy of RMC-4630 in combination with sotorasib in subjects with previously treated 
KRASG12C mutant advanced solid tumors. The combination of RMC-4630 and sotorasib has 
shown acceptable safety and tolerability to date, with no new safety signals. The risk of 
synergistic toxicity is anticipated to be low because sotorasib is highly selective for the 
KRASG12C mutation, which has not been found in normal tissue. In general, if potential toxicities 
do occur, they are predicted to be dose and duration dependent, monitorable, and reversible. The 
nonclinical toxicity findings identified with RMC-4630 repeated daily dosing is largely similar to 
those described for sotorasib. When RMC-4630 and sotorasib are administered in combination, 
AEs (eg, diarrhea, hematological effects, renal effects, pneumonitis, hepatotoxicity, and QT 

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prolongation if co-administered with drugs known to prolong the QT interval) may increase in 
frequency and severity with duration of therapy and/or manifest at a lower individual dose of 
each treatment. Given the potential for overlapping toxicities in the combination therapy, 
subjects will be monitored by routine safety parameters as described in Section 2.2.2.4. 
The potential of drug‑drug interaction is low for RMC-4630 and sotorasib. 
For more information, please see the risks associated with sotorasib (AMG 510) summarized in 
the current Sotorasib IB (Section 7) and the risks associated with RMC-4630 summarized in the 
current RMC-4630 IB (Section 7). 
2.2.2.4. 
Steps to Minimize Risk 
The RMC-4630-03 study will incorporate the following safety monitoring and risks mitigation 
strategies: 
• Safety measures to minimize risks to subjects have been incorporated in the design of 
the study and eligibility criteria to specifically exclude subjects who may be at 
increased risk of specific toxicities 
• Medications known to prolong QT are prohibited during study drug administration 
• Guidance for investigators to follow institutional guidelines/standard of care with 
respect to implementation of prophylaxis for specific toxicities (eg, antibacterials for 
infections) to minimize risk to subjects 
• The study will include a safety run-in period that will evaluate DLTs and clear a 
combination dose by the Dose Committee as guided by the mTPI-2 algorithm (see 
Appendix 11) 
• In addition to DLT criteria, dose modifications after the DLT window have been 
included in order to reduce the risk of toxicity while continuing to provide subjects a 
potential treatment opportunity 
• Safety monitoring (consisting of AE assessments, physical examinations, vital signs 
measurements, electrocardiograms [ECGs], clinical laboratory tests, 
ECOG performance status [PS], and echocardiogram [ECHO]/multigated acquisition 
[MUGA] scans), will occur at regular intervals throughout the study 
• As a precaution, subjects receiving strong CYP3A4 inhibitors (see Appendix 8) 
and/or inducers are excluded, until further data become available 
• Invasive measures in this study are limited to venipuncture (all study subjects) and 
tumor biopsies in subjects, when feasible. The primary purpose of the pretreatment 
biopsies is to assess tumor biology and explore predictive biomarkers (Hirsch, 2003) 
(see Section 8.7). 
• An Internal Safety Monitoring Committee (ISMC) will be used to monitor the safety 
of RMC-4630 and sotorasib combination therapy throughout the study. The ISMC is 
RMC-4630-program specific and will review emergent safety data at regular intervals 
for all subjects during the trial in conjunction with data from other active RMC-4630 
clinical trials. Additional details are provided in Section 8.3.6.2. 

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3. 
OBJECTIVES AND ENDPOINTS  
The study objectives and endpoints are provided in Table 3. 
Table 3: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the antitumor effects of RMC-4630 and 
sotorasib in locally advanced or metastatic NSCLC 
subjects with KRASG12C mutation with and without 
co-existing genetic aberrations in specific genes such 
as STK11/LKB1, KEAP1, and PIK3CA (see detailed list 
in Appendix 9) after failure of prior standard therapy 
ORR as assessed per RECIST v1.1 
Secondary 
• 
To characterize the safety, tolerability, and PK of 
RMC-4630 in combination with sotorasib for 
subjects with KRASG12C mutant NSCLC after 
failure of prior standard therapy  
• 
To further characterize efficacy of RMC-4630 in 
combination with sotorasib as assessed by DOR, 
DCR, PFS, and OS in subjects with KRASG12C 
mutant locally advanced or metastatic NSCLC 
after failure of prior standard therapy 
• 
Incidence, nature, and severity of TEAEs, SAEs, 
clinically significant changes in laboratory tests, 
ECGs, and vital signs 
• 
Trough and approximate peak concentrations of 
RMC-4630 and sotorasib 
• 
DOR, DCR, and PFS as assessed per 
RECIST v1.1, and OS 
 
Exploratory 
• 
To explore PK relationships with safety and/or 
efficacy endpoints  
• 
To investigate potential biomarkers by 
biochemical and/or genetic analysis of blood 
and/or tumor tissue samples 
 
• 
Sotorasib and RMC-4630 exposure/safety and 
exposure/efficacy relationships  
• 
Quantification of biomarker expression (protein, 
RNA, and DNA levels) as appropriate in ctDNA 
and archival tumor tissues (or fresh, if archival 
tumor is not available).  
Abbreviations: ctDNA = circulating tumor deoxyribonucleic acid; DCR = disease control rate; DNA = deoxyribonucleic acid; 
DOR = duration of response; ECG = electrocardiogram; KRASG12C = KRAS with a mutation at codon 12, which encodes glycine 
(G) to cysteine (C); NSCLC =  non–small-cell lung cancer; ORR = objective response rate; OS = overall survival; PFS = 
progression-free survival; PK = pharmacokinetic(s); RECIST v1.1 = Response Evaluation Criteria in Solid Tumours, 
Version 1.1; RNA = ribonucleic acid; SAE = serious adverse event; TEAE = treatment-emergent adverse event. 

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4. 
STUDY DESIGN 
4.1. 
Overall Study Design  
This is a Phase 2 multicenter, open-label study evaluating the efficacy, safety, tolerability, and 
PK of RMC-4630 in combination with sotorasib in subjects with KRASG12C mutant locally 
advanced or metastatic NSCLC who have received at least one prior systemic therapy. The 
overall study design schema is shown in Figure 1. The study will be conducted at approximately 
40 clinical sites globally and is expected to enroll up to approximately 
.  
Prior to enrollment, all subjects will undergo screening to determine study eligibility. The 
presence of KRASG12C mutation is required for enrollment. Eligibility will be assessed based on 
prior/local genomic testing using a clinically validated or qualified assay of tumor samples. 
Circulating tumor deoxyribonucleic acid (ctDNA) mutational analysis using a clinically qualified 
or validated test may also be used for enrollment.  
Mutation testing results for all subjects must have occurred in a CLIA-/CAP-certified laboratory 
and collected preferably within 3 years of study enrollment. All local tumor genotyping analyses 
will be confirmed by central testing when the tumor tissue is provided. A fresh biopsy will not be 
used to determine eligibility.  
This Phase 2 study will have a safety run-in period where RMC-4630 will be administered at a 
starting dose of 
 of each week in a 21-day cycle and sotorasib 
 QD 
in a 21-day cycle. Subjects will be evaluated for DLTs (see Section 8.4). The decision to escalate 
the RMC-4630 dose to 
 of each week in a 21-day cycle will be guided by 
a modified toxicity probability interval 2 (mTPI-2) algorithm (see Appendix 11) and made by the 
Dose Committee. After completion of the safety run-in (DLT clearance) of both dose levels, 
additional subjects may be enrolled into one or both dose levels for the purpose of dose 
optimization before selecting the final expansion dose. Expansion may commence as soon as the 
expansion dose has been selected from either CodeBreaK 101C or this study, whichever occurs 
first. The Sponsor may proceed directly to dose expansion without completing the safety run-in 
period. The combination dose for expansion will be determined by the Sponsor after taking into 
consideration the totality of available data from CodeBreaK 101C and the cumulative data from 
this study. The study will enroll a total of approximately 
 globally. Subjects will be 
categorized into one of two cohorts:  
• Cohort 1 will be the primary cohort of this study and will consist of KRASG12C 
NSCLC subjects without potential genetic aberrations in specific genes, such as 
STK11/LKB1, KEAP1, and PIK3CA (see detailed list in Appendix 9). 
• Cohort 2 will consist of KRASG12C NSCLC subjects with co-existing genetic 
aberrations in specific genes, such as STK11/LKB1, KEAP1, and PIK3CA (see 
detailed list in Appendix 9).  
4.1.1. 
Duration of Treatment 
Subjects will be permitted to remain on study treatment until disease progression per 
RECIST v1.1, unacceptable toxicity, or other criteria for withdrawal are met (see Section 7.1, 
whichever occurs first. Subjects who discontinue treatment will return to the clinical site for an 
EOT visit within 30 days after last dose of study treatment. Subjects who are benefitting from 

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study treatment at the time of the EOS may continue treatment in the Extended-Use phase of the 
study. 
4.1.2. 
Long-Term Follow-Up Period 
For subjects in the main study who discontinue treatment and do not withdraw consent, there will 
be a LTFU period for clinical evaluation of disease status and survival.  Survival follow up will 
be discontinued for subjects currently in LTFU at the time of the initiation of the Extended-Use 
phase. See Section 7.2 for details. 
4.1.3. 
Duration of the Study 
The main study duration is approximately 2 years. The Extended-Use phase will be conducted 
through June 2024. 
4.1.4. 
Intervention After the End of the Study 
Subjects who are on treatment at the EOS and are deriving clinical benefit from RMC-4630 and 
sotorasib may be considered for enrollment in a separate Extended-Use phase of the study. These 
subjects should enter the separate Extended-Use phase without interruption of treatment and 
should complete EOT assessments listed in the SoA (Table 1) prior to treatment on Day 1 of the 
Extended-Use phase. Assessments outlined in the SoA are to be followed during the 
Extended-Use phase of the study.  
4.2. 
Scientific Rationale for Study Design 
This is a Phase 2 study designed to characterize the efficacy, safety, tolerability, and PK of 
RMC-4630 and sotorasib combination therapy in subjects with KRASG12C mutant locally 
advanced or metastatic NSCLC after failure of prior standard therapy. The PK (trough and 
approximate peak concentrations) and efficacy (ORR, DOR, and PFS assessed per 
RECIST v1.1) endpoints in this study are commonly used for PK modeling and characterization 
of exposure/safety and exposure/efficacy relationships for the target population of subjects with 
KRASG12C mutant NSCLC. 
4.3. 
Dose Justification  
4.3.1. 
RMC-4630 
RMC-4630 is being studied in the clinic as a monotherapy in Study RMC-4630-01 
(NCT03634982), and in various other combination studies. RMC-4630 has been tested at various 
dose levels and schedules including daily dosing, intermittent dosing schedule on 
 and 
 As of 16 November 2020, 
 have been treated with RMC-4630 
monotherapy; the RP2DS was determined to be 
 of each week in a 21-day 
cycle. At this dose level, the plasma concentrations of RMC-4630 were above those predicted to 
be clinically active, based on preclinical models. The Cmax reached, and often exceeded, the 
apoptotic threshold (75% effective concentration [EC75]), defined as plasma concentrations that 
were associated with induction of tumor regressions or cell death in preclinical models. Trough 
concentrations at the end of each week were close to the 50% effective concentration (EC50) for 
RAS signaling pathway inhibition in tumors, which was predicted to be sufficient to permit 
normal tissue recovery and therefore contribute to tolerability. 
Furthermore, RMC-4630 and sotorasib combination is being tested in an ongoing 
Amgen-sponsored Phase 1b platform (CodeBreaK 101C). CodeBreaK 101C was initiated in May 

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2020 and is currently dosing subjects at RMC-4630
 
 of each week in a 
21-day cycle and 
of each week in a 21-day cycle). This Phase 2 study 
(RMC-4630-03) will have a safety run-in period in which RMC-4630 will be administered at 
 of each week in a 21-day cycle as the starting dose with the option of 
escalating to RMC-4630 
 of each week in a 21-day cycle if tolerated per 
modified toxicity probability interval 2 (m-TPI2). 
4.3.2. 
Sotorasib 
The FDA-approved dose for sotorasib monotherapy in patients with KRASG12C mutated locally 
advanced or metastatic NSCLC is 960 mg QD administered PO. Therefore, the same dose will 
be used for this study. The Sponsor notes that the US FDA expressed concerns regarding the 
validity of 960 mg to be the optimal dose of sotorasib due to the following reasons (CDER 
application #214665Orig1s000 sotorasib; https://www.accessdata.fda.gov/drugsatfda_docs/ 
nda/2021/214665Orig1s000MultidisciplineR.pdf [accessed 28 May 2021]): 1) No relationship 
between dose and drug exposure at steady-state, 2) no evidence of dose-response relationship, 
3) gastrointestinal toxicities are lower at the lower doses tested in dose escalation, 4) preclinical 
data suggest that the minimal effective dose is 
 daily, and 5) the labeled dose 
requires patients to take eight tablets at a time, which is a pill-burden on patients. Upon approval 
of LUMAKRAS, the US FDA has requested that Amgen compare their approved 960 mg dose 
with a 240 mg dose, as one of their postmarketing requirements. Data readout from a 
postmarketing study of sotorasib dose optimization in patients with advanced NSCLC who have 
received one prior therapy (see https://clinicaltrials.gov/ct2/show/NCT03600883) is imminent at 
the time of this protocol amendment. If supported by the data, at the Sponsor’s discretion and 
after discussion with the Dose Committee, new subjects enrolling on this trial may be treated at 
the lower sotorasib dose of 240 mg in combination with RMC-4630 (see Table 4 and Table 5). 
Subjects currently enrolled at 960 mg may continue at their current dose or dose reduce based on 
discussion with the Sponsor’s Medical Monitor. Subjects developing toxicities at sotorasib 
240 mg QD may dose reduce to sotorasib 120 mg QD or discontinue treatment. 
4.4. 
EOS Definition 
The main study duration is approximately 2 years. The EOS is defined as the date of LSLV or 
12 months after the last subject receives the first dose of study treatment, whichever occurs first.  
Subjects who are benefitting from study treatment may continue receiving treatment through the 
Extended-Use phase of the study (Section 4.1.3). 

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
All subjects must meet ALL of the following inclusion criteria to be admitted into the study: 
1. Subject must be ≥18 years of age at the time of signing the ICF. 
2. Subject is capable of giving signed informed consent, which includes compliance with 
the requirements and restrictions listed in the ICF and in this protocol.  
3. Subject must have pathologically documented, locally advanced or metastatic KRASG12C 
NSCLC (not amenable to curative surgery) that has progressed on prior standard 
therapies (no more than 3 prior lines of therapies are allowed), as follows: 
a. Subject with actionable oncogenic driver mutations (eg, epidermal growth factor 
receptor (EGFR), anaplastic lymphoma kinase [ALK], and reactive oxygen species 
proto-oncogene 1 [ROS1]) must have received standard-of-care anticancer 
treatments, including approved drugs for oncogenic drivers in their tumor type.  
b. Subject’s tumor must harbor a KRASG12C mutation assessed by a 
CLIA-/CAP-certified laboratory or equivalent per region. 
c. Subjects with locally advanced KRASG12C NSCLC must have received prior radio-
chemotherapy followed by immunotherapy (applicable only in France) 
4. Subject must have measurable disease per RECIST v1.1, criteria. 
5. Subject must have a life expectancy of at least 3 months. 
6. The subject’s ECOG PS of 0 to 1 with no deterioration in PS at 2 weeks prior to C1D1. 
Rescreening is required if PS is >1 for any reason prior to C1D1.  
7. Subject must have the ability to typically ingest and retain PO medications. 
8. Subject must have adequate hematological and biological function, as follows: 
a. Bone marrow function 
i. 
Absolute neutrophil count (ANC) ≥1.5 × 109/L without use of 
hematopoietic growth factors 
ii. 
Hemoglobin ≥9 g/dL; subject must not have received a red blood cell 
(RBC) transfusion within 28 days of Screening 
iii. 
Platelets ≥100 × 109/L; subject must not have received a platelet 
transfusion within 14 days of Screening 
b. Subject must have hepatic function as follows: 
i. 
AST and ALT ≤2.5 × upper limit of normal (ULN) 
ii. 
Bilirubin ≤1.5 × ULN (<2.0 × ULN for subject with documented Gilbert’s 
syndrome or <3.0 × ULN for subject for whom the indirect bilirubin level 
suggests an extrahepatic source of elevation) 

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c. Subject must have renal function as follows: 
Serum creatinine ≤1.5 × ULN and creatinine clearance (CrCl) of >50 mL/min 
(using the Cockcroft-Gault formula or 24-hour urine collection) 
d. Subject must have coagulation function as follows: 
Prothrombin time (PT)/international normalized ratio (INR) and activated 
partial thromboplastin time (aPTT)/partial thromboplastin time (PTT) 
<1.3 × ULN, or within target range if taking prophylactic anticoagulant(s) 
9. Female subject is eligible to participate if she meets the following criteria: 
a. Is not a woman of childbearing potential (WOCBP), OR 
b. Is a WOCBP and using a contraceptive method that is highly effective (ie, with a 
failure rate of <1% per year), preferably with low user dependency, during the 
treatment period and for at least 2 months after the last dose of study treatment and 
agree not to donate eggs (ie, ova and oocytes) for the purpose of reproduction during 
this period. The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study treatment. Hormonal contraception 
efficacy may potentially be decreased due to interaction with sotorasib; therefore, 
male condoms must be used in addition to any hormonal-based contraception 
methods. 
10. Male subject is eligible to participate if he agrees to the following during the treatment 
period and for ≥3 months after the last dose of study treatment: 
a. Refrains from donating sperm (any donation of sperm should be conducted prior to 
study start) 
b. PLUS, either: 
c. Abstain from intercourse as his preferred and usual lifestyle (abstinent on a long-term 
and persistent basis) and agree to remain abstinent, OR 
d. Must agree to use a male condom AND should also be advised of the benefit for a 
nonpregnant female partner to use a highly effective method of contraception as a 
condom may break or leak 
11. Subject must provide unstained, archived, tumor tissue samples collected preferably 
within the past 3 years. Subjects who do not have archived tissue available are required to 
undergo a tumor biopsy. Subjects who neither have archival tumor tissue samples nor can 
provide fresh pretreatment biopsies may still be eligible to participate in the study with 
approval from the Sponsor Medical Monitor. 
5.2. 
Exclusion Criteria  
If a subject meets ANY of the following criteria, he or she will be excluded from study 
participation: 
1. Subject has primary central nervous system (CNS) tumor(s) 
2. Subject has known or suspected leptomeningeal or brain metastases or spinal cord 
compression. However, subjects who were previously treated for these conditions who 
have had stable CNS disease (no evidence of clinical and radiographic disease 
progression and asymptomatic in the absence of corticosteroids or anti-convulsant 

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therapy) are eligible to participate in the study, as long as SD is documented by a brain 
magnetic resonance imaging (MRI) performed within 28 days of C1D1. 
3. Subject who has any of the following cardiac abnormalities:  
a. Medically uncontrolled hypertension (≥160 mmHg systolic blood pressure 
or ≥100 mm Hg diastolic blood pressure) 
b. Congestive heart failure Class ≥2, as defined by the New York Heart Association 
c. Acute coronary syndrome (including unstable angina, coronary artery stenting, or 
angioplasty, bypass grafting within prior 6 months); myocardial infarction within 
6 months of informed consent. 
d. History or evidence of current, uncontrolled, clinically significant, unstable 
arrhythmias 
i. 
Subject with medically controlled atrial fibrillation >1 month prior to 
Study Day 1 is eligible. 
ii. 
Subject who has a pacemaker in place to control atrial arrhythmias is a 
candidate for the study. 
e. History of congenital long QT syndrome or prolonged corrected QT interval (QTc) 
>470 msec for females and > 450 msec for males using Fridericia’s formula (unless a 
pacemaker is in place) or uncorrectable abnormalities in serum electrolytes 
(ie, sodium, potassium, calcium, magnesium, phosphorus): 
i. 
Subject may use average of triplicate readings for assessing QTc interval. 
ii. 
Subject with an implantable defibrillator is not eligible to participate in the 
study. 
f. Current cardiomyopathy or history within in the past 12 months prior to informed 
consent. 
g. Baseline left ventricular ejection fraction (LVEF) below the institutional lower limit 
of normal (LLN) or <50%, whichever is lower. 
4. Any prior history of (or active) ILD or pneumonitis, or prior thoracic radiotherapy within 
2 months of enrollment. 
5. Subject has a history of or ongoing retinal pigment epithelial detachment (RPED), central 
serous retinopathy, or retinal vein occlusion (RVO), or predisposing factors to RPED or 
RVO (eg, uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, 
hyperviscosity, or hypercoagulability syndromes; see Section 8.2.8 for details).  
6. Former exclusion criterion is withdrawn. 
7. Subject has of Grade ≥2 proteinuria. 
8. Subject has a history of cerebrovascular accident or transient ischemic attack within 
previous 6 months of signing the informed consent form (ICF). 
9. Subject has a known activating SHP2 mutation (eg, Noonan syndrome). 
10. Subject has an active autoimmune disease requiring systemic treatment (ie, with use of 
disease modifying agents, non-physiologic doses of corticosteroids, or 

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immunosuppressive drugs) within the past 2 years of signing the ICF; includes current 
autoimmune sequelae or previous Grade >2 autoimmune sequelae from checkpoint 
inhibitors or other immunomodulatory treatments that require systemic therapy. Subject 
with autoimmune endocrine disorder on hormonal supplementation may be enrolled, 
even if Grade >2 upon initial presentation, if approved by the Medical Monitor. 
11. Subject has known human immunodeficiency virus (HIV) infection. 
12. Subject has an active/chronic hepatitis B or C virus infection. 
13. Subject has a known impairment of gastrointestinal (GI) function that may significantly 
alter the absorption of RMC-4630 (eg, uncontrolled nausea and vomiting, diarrhea, 
malabsorption syndrome, inflammatory bowel disease, gastrectomy, or small bowel 
resection). 
14. Subject has a history of severe allergic reactions to any of the study treatment 
components. 
15. Subject has major surgical procedures ≤28 days or non-study-related minor procedures 
≤7 days prior to Cycle 1 Day 1 (C1D1); in all cases, the subject must be sufficiently 
recovered and stable before treatment administration. 
16. Subject has any other unstable or clinically significant concurrent medical condition 
(including, but not limited to substance abuse, uncontrolled intercurrent illness such as 
active infection, arterial thrombosis, or symptomatic pulmonary embolism) that would, in 
the opinion of the investigator, jeopardize the safety of a subject, impact their expected 
survival through the end of the study participation, and/or impact their ability to comply 
with the protocol. Any subject who had a pulmonary embolism within 3 months of C1D1 
will also be excluded.  
17. Subject has had prior therapy with one or both of the following agents, meets criteria for 
exclusion: 
a. KRASG12C inhibitor  
b. SHP2 inhibitor  
18. Subject has had treatment with chemotherapy or biologics/monoclonal antibodies 
<21 days or 5 half-lives (whichever is shorter) before C1D1. 
19. Subject has had treatment with non-thoracic radiation therapy <14 days before C1D1. 
20. Subject has had treatment with tyrosine kinase inhibitor (TKI), hormonal therapy 
(except megesterol acetate) <7 days before C1D1. 
21. Subject has had treatment with immunotherapy (eg, checkpoint inhibitors) 14 to 21 days 
before C1D1, depending on cycle length of drug. 
22. Subject has had treatment with all other anticancer treatments including investigational 
agents that do not fit in the above categories <21 days before C1D1. 
23. Use of proton pump inhibitors (PPIs) within 3 days or H2 receptor antagonists (H2-
blockers) within 1 day prior to study intervention. Subjects using an antacid or other acid 
reducing agent must have a 24-hour wash out period prior to initiation of study treatment. 

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24. Subject has had consumption of strong CYP3A4 inducers or inhibitors within 7 days 
prior to initiation of study treatment and requires treatment with strong CYP3A4 inducers 
or inhibitors. 
25. Subject has had consumption of strong P-glycoprotein (P-gp) inhibitors (eg, cyclosporine, 
tacrolimus) within 7 days prior to initiation of study treatment and requires treatment 
with a strong P-gp inhibitor. 
26. Use of known CYP3A4 and P-gp sensitive substrates (with a narrow therapeutic 
window), within 14 days or 5 half-lives of the drug prior to study day 1 that was not 
reviewed and approved by the principal investigator. 
27. Subject has had clinically significant reversible toxicities from prior cancer therapy that 
have not recovered to Grade 1 or baseline, except for alopecia. 
Subject with Grade ≤2 neuropathies due to prior treatment will be allowed on study. 
Subject with other Grades ≤2 clinical nonsignificant toxicities, may be allowed on 
study after discussion with Medical Monitor. 
28. Female who is pregnant or breastfeeding. 
29. Unwillingness or inability to comply with the protocol. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
Subjects should refrain from consumption of grapefruit or grapefruit-containing products, or 
Seville oranges from 7 days before the start of study treatment until after the final dose. 
Fasting (except water) 1 hour prior to and 1 hour after each RMC-4630 dose is required. Fasting 
is NOT required for sotorasib; however, on days when both medications are taken together, 
fasting is requisite due to the requirements of RMC-4630. Sotorasib tablets should be swallowed 
whole, with or without food. 
5.4. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently able to receive treatment in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (ie, screen failure) may be 
rescreened within 5 days of the initial screening date of screen failure. Rescreened subjects 
should be assigned the same subject number as for the initial screening. Only hematology, 
chemistry, and coagulation tests may need to be repeated if outside the screening window. Other 
clinical testing will not need to be repeated if outside screening window (ie, within 5 days).  

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6. 
STUDY TREATMENT 
6.1. 
Study Treatments Administered: RMC-4630 and Sotorasib 
The study treatment for this protocol is combination therapy of the investigational drug product 
RMC-4630 and the marketed product sotorasib. 
RMC-4630 
 will be administered PO on
 of each week in a 21-day 
cycle (ie, Days 1, 2, 8, 9, 15, and 16 of each 21-day cycle). RMC-4630 capsules should not be 
crushed or chewed. 
Sotorasib 
 mg will be administered PO QD per instructions provided in the current 
Sotorasib IB. At the Sponsor’s discretion, new subjects enrolling on this trial may be treated at 
sotorasib 240 mg in combination with RMC-4630 (see Table 4). Subjects currently enrolled at 
sotorasib 960 mg may continue at their current dose or dose reduce based on discussion with the 
Sponsor Medical Monitor. Subjects developing toxicities at sotorasib 
 may dose 
reduce to sotorasib 
 or discontinue treatment. 
For the main protocol, the subject should administer the study treatment at approximately the 
same time every day except for clinic visit days as listed in the SoA (Table 1). On these clinic 
visits, the subject should await instruction from the study staff to coordinate with the timing of 
PK and/or biomarker sampling. 
Subjects deriving benefit from treatment who enter the Extended-Use phase of the study should 
continue treatment without interruption. 
Table 4: 
Study Treatment Administered: RMC-4630 and Sotorasib 
Component Name 
Drug Product Information 
Treatment Name 
RMC-4630 and sotorasib combination therapy 
Type 
Drugs 
Dose Formulation 
RMC-4630: PIC drug product 
Sotorasib: tablet 
Unit Dose Strengths 
RMC-4630: 
g 
Sotorasib: 120 mg 
Dosage Levels 
RMC-4630:  
 for a treatment 
cycle of 21 days 
Sotorasib: 
QD  
Route of Administration 
PO with water after 1 hour fast; no food or drink (other than water) 
allowed for 1 hour after administration for RMC-4630 alone or 
RMC-4630 in combination with sotorasib. 
PO; no restrictions on food for sotorasib when taken alone. 
Investigational Product 
RMC-4630 in combination with 
Sotorasib IMP to be supplied for all sites unlabeled drug product 
sourced from Amgen 
 

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Table 4: 
Study Treatment Administered: RMC-4630 and Sotorasib (Continued) 
Component Name 
Drug Product Information 
Sourcing 
RMC-4630: Manufactured and provided centrally by the Sponsor 
through the third party CMO 
Sotorasib: IMP (unlabeled drug product supplied by Amgen) to be 
provided by Sponsor 
Packaging and Labeling 
RMC-4630: Study treatment (PIC drug products) is packaged in 8-
count HDPE bottles with open label. 
Sotorasib: IMP (unlabeled drug product supplied by Amgen) to be 
provided for all sites 
Current/Former Name(s) or 
Alias 
RMC-4630, RMC-0694630 
Sotorasib: AMG 510 
Abbreviations: CMO = contract manufacturing organization; HDPE = high-density polyethylene; IMP = investigational 
medicinal product; PIC = powder-in-capsule; PO = oral(ly); QD = daily; US = United States. 
6.2. 
Preparation/Handling/Storage/Accountability 
RMC-4630 (powder in capsule [PIC] drug products: 20 mg and 100 mg, respectively) are 
packaged in high density-polyethylene (HDPE) bottles with open labeling and are shipped and 
stored below 30°C (86°F) but they are not to be frozen.  
Clinical sotorasib 120 mg tablets are yellow, oblong-shaped, film-coated, debossed with “AMG” 
on one side and “120” on the opposite side. Sotorasib tablets are packaged in 120-count HDPE 
bottles. 
Sotorasib is stored at 20°C to 25°C (68°F to 77°F). Excursions permitted from 15°C to 30°C 
(59°F to 86°F). 
The sotorasib tablets supplied by Amgen will be clinically labeled and QP released as IMP and 
distributed to the site by the Sponsor. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only subjects enrolled in the study may receive RMC-4630 and sotorasib as a combination and 
only authorized site staff may supply study treatment to the subjects.  
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the study Pharmacy and Investigational Product Administration Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label, nonrandomized study. In order to minimize bias, subjects will be assigned 
sequentially as they are enrolled into the study using the inclusion and exclusion criteria outlined 
in Section 5.1 and Section 5.2, respectively. Enrollment will be confirmed by the Sponsor 
Medical Monitor after review of all supporting documentation for eligibility criteria. Subjects 

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will be assigned a screening number at the time of signing the ICF. If a subject is a screen 
failure, the number will not be reassigned. 
For Italy only, the eligibility form will not be used to allow the Sponsor or contract research 
organization (CRO) to make any medical decisions for the subject. Instead, it will be used for 
Sponsor and CRO to confirm that the subject’s eligibility check has been fully completed (eg, no 
inclusion/exclusion criteria are missing, and all of the screening procedures have been 
completed), with the intention to ensure subject safety and data integrity.  
6.4. 
Study Treatment Compliance 
6.4.1. 
Compliance Instructions 
Dosing instructions will be provided to the subject, and subject compliance with study treatment 
will be reviewed at each visit. Compliance will be assessed by counting returned RMC-4630 
capsules, in conjunction with subject diary information and subject questioning. Subject 
compliance for sotorasib administration will only be assessed by reviewing subjects’ diaries and 
questions asked during clinic visits. The investigator should follow the guidance provided in 
Section 8.5 if a subject is suspected to have taken greater than the assigned dosage.  
6.4.2. 
Missed Dose 
RMC-4630:  If a subject misses a Day 1 (D1) dose of RMC-4630, it should be taken as soon as 
the missed dose is discovered. The D2 dose should then follow 24-hours after. If the subject 
misses D2 dose, it should be taken as soon as the missed dose is discovered, provided there is at 
least a 24-hour gap between D1 dose and D2 dose. If the gap between D1 and D2 dose is more 
than 48 hours, the D2 dose should not be administered and should be recorded as an omission. 
The subject should not administer more than the recommended dose. 
Sotorasib: If a dose of sotorasib is missed, or if vomiting occurs when the dose is taken, the 
subject should resume dosing with the next scheduled dose. 
6.5. 
Permitted Concomitant Therapy 
Supportive care (eg, antiemetics, analgesics, blood transfusions, hematopoietic growth factor 
support) may be used at the investigator’s discretion and in accordance with institutional 
procedures. Localized radiotherapy used for palliative purposes may be considered after 
discussion with the Medical Monitor. Anticoagulation with low-dose aspirin, low-molecular 
weight heparin (LMWH), and direct Factor-Xa inhibitors are allowed. Contraceptives are also 
allowed throughout the study (see Section 5.1). 
If an acid reducing agent cannot be avoided, administer sotorasib and RMC-4630 either 4 hours 
before or 10 hours after a local antacid.  
Avoid coadministration with CYP3A4 substrates for which minimal concentration changes may 
lead to therapeutic failures of the substrate. If coadministration cannot be avoided, adjust the 
substrate dosage in accordance with the current Sotorasib IB. 
Avoid coadministration with P-gp substrates for which minimal concentration changes may lead 
to serious toxicities. If coadministration cannot be avoided, decrease the substrate dosage in 
accordance with the current Sotorasib IB. 

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A local antacid (eg, calcium carbonate, sodium bicarbonate, or bismuth subsalicylate-containing 
agents such as Tums, Alka-Seltzer, Pepto-Bismol, etc.) may be permitted after discussion with 
the Sponsor Medical Monitor if RMC-4630 is administered either 4 hours before or 10 hours 
after the local antacid. 
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, that the subject is receiving at the time of enrollment or receives 
during the study, must be recorded along with the following: 
• Reason for use 
• Dates of administration, including start and end dates 
• Dosage information, including dose and frequency 
• Route of administration 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.6. 
Prohibited Concomitant Therapy 
In addition to prohibited medications/foods listed in the Exclusion Criteria (Section 5.2), a 
complete list of prohibited medications during study treatment is provided in Appendix 8. 
The following medications are prohibited while on study treatment: 
• PPIs and H2-blockers  
• Medications known to prolong QTc interval  
• Anti-cancer therapy (except study treatment medications) 
• Strong CYP3A4 inhibitors and inducers  
• Strong P-gp inhibitors  
• Known CYP3A4 and P-gp sensitive substrates (with a narrow therapeutic index), that 
were not reviewed and approved by the principal investigator  
6.7. 
Dose Modification  
A 21-day cycle will be maintained, and dose interruption will be noted in the 21-day cycle 
schedule. Two types of dose modifications are allowed: dose interruption and dose level 
reduction. Any allowed dose modification and any deviation from the intended dose 
(missed doses or overdoses due to subject error) should be documented on the dose electronic 
Case Report Form (eCRF). 
In general, dose adjustments should be based on attribution to a particular treatment. Certain AEs 
are known to be associated with administration of sotorasib (see current Sotorasib IB), whereas 
others have been observed with the administration of RMC-4630 in clinical or preclinical studies 
(see current RMC-4630 IB). However, because both components of the study treatment affect 
the RAS signaling pathway, overlapping toxicities are likely to be observed.  
If RMC-4630 is discontinued due to toxicity, sotorasib monotherapy can be continued as it is the 
standard-of-care in this patient population. However, if sotorasib is discontinued due to toxicity 

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reasons, RMC-4630 continuation as monotherapy may be considered, provided that the subject 
per investigator discretion is clinically benefitting from treatment with no evidence of disease 
progression (and approval by the Sponsor’s Medical Monitor).  
Depending on the RMC-4630 starting-dose level, up to 2 dose-level reductions for 
 and 
one dose-level reduction for the 
 are permitted for upon discussion with the Sponsor 
Medical Monitor. Depending on the sotorasib starting-dose level, up to 2 dose-level reductions 
for 960 mg and one dose-level reduction for 240 mg are permitted upon discussion with the 
Sponsor’s Medical Monitor. Guidance for dose reduction for both components of the study 
treatment is presented in Table 5. If more than 2 dose reductions are required for either 
RMC-4630 or sotorasib 960 mg, or more than one dose reduction is required for sotorasib 
240 mg, administration must be discontinued for that component and treatment with the 
remaining single component (RMC-4630 or sotorasib) may be considered, depending on 
investigator assessment of clinical benefit and discussion with the Sponsor’s Medical Monitor. 
Dose modification guidelines for a subset of common AEs seen with RMC-4630 and/or sotorasib 
(per the current Sotorasib IB) are shown in Table 6. General guidance for dose modification is 
presented in Table 7. The investigator or treating physician should use his/her best medical 
judgement for management. 
When reducing dose, the dose of one or both agents (RMC-4630 and sotorasib) could be reduced 
depending on which may be causing the toxicity. 
Table 5: 
Dose Reduction Guidelines with RMC-4630 and Sotorasib 
Dose Level 
Treatment and Dosage 
RMC-4630  
(
 in a 21-Day 
Cycle) 
Sotorasib  
(QD) 
 1 (subject starting dose level)1 
 
960 mg 
240 mg 
-1 (dose reduction from starting 
dose for either component of 
study treatment if needed) 
 
480 mg 
120 mg 
-2 (dose reduction from starting 
dose for either component of 
study treatment if needed) 
 
240 mg 
NA 
Abbreviations: 
; NA = not applicable; QD = once daily. 
1 Starting dose level represents the subject’s assigned dose level at enrollment. For example, if the subject enrolled at the 
RMC-4630 140 mg dose level (default starting dose), they would dose reduce to 100 mg. A subject enrolled at the RMC-4630 
200 mg dose level would dose reduce to 140 mg, followed by reduction to 100 mg as necessary.  
 
 

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Table 6: 
Dose Modification Guidelines for RMC-4630 and Sotorasib 
 
 
 
AE 
Action 
Thrombocytopenia  Thrombocytopenia associated with clinically significant bleeding, at any 
level: Hold RMC-4630 and sotorasib and follow hemorrhage recommendations. 
Uncomplicated thrombocytopenia (without clinically significant bleeding):  
Grade 1-2: Continue treatment at current dose level for both components of 
study treatment and monitor closely. 
Grade 3-4: Manage per institutional guidelines and interrupt RMC-4630 dosing 
until the event recovers to Grade 1 or within normal limits or returns to 
baseline. If recovery occurs, resume RMC-4630 at one dose level lower. If 
Grade 3-4 events recur, hold dose until recovery to Grade 1 or within normal 
limits or returns to baseline and a second dose reduction may be considered. If 
the subject continues to experience high-grade thrombocytopenia, RMC-4630 
may be discontinued permanently and sotorasib monotherapy can be continued.  
Subjects on anticoagulant(s) 
Subjects receiving anticoagulant therapy should be monitored closely for 
evidence of treatment-emergent thrombocytopenia. Subjects who develop 
treatment-emergent thrombocytopenia may need to be managed more 
conservatively, due to increased risk of bleeding. 
Neutropenia/ 
Febrile 
Neutropenia/ 
Anemia/ 
Pancytopenia 
Assess for other causes. Hold concomitant medications associated with 
myelosuppression. 
Grade 3 neutropenia: Hold RMC-4630 if clinically indicated until the event 
recovers to Grade 1 or within normal limits or returns to baseline. If 
improvement occurs within 3 weeks, restart RMC-4630 at one dose level lower. 
If there is no improvement within 3 weeks, or upon recurrence of Grade 3 
neutropenia, additional dose reduction of RMC-4630 or permanent 
discontinuation of RMC-4630 can be considered. 
Grade 3 febrile neutropenia: Hold RMC-4630 and sotorasib until fever 
resolves and ANC recovers to Grade 1 or is within normal limits or returns to 
baseline. If improvement occurs within 2 weeks, restart RMC-4630 one dose 
level lower. If there is no improvement within 2 weeks, discontinue RMC-4630 
and sotorasib. 
Grade 3 anemia: Assess transfusion history. Transfuse per institutional 
guidelines. Hold RMC-4630 if clinically indicated until the event recovers to 
Grade 1 or within normal limits or returns to baseline. If improvement occurs 
within 4 weeks, restart RMC-4630 at the same dose level. If the AE re-occurs, 
consider dose reduction to one dose level lower for RMC-4630 after the AE 
resolves to Grade 1 or within normal limits or returns to baseline. If the AE 
does not improve within 4 weeks, consider discontinuation of RMC-4630. 
Grade 4 pancytopenia: Hold RMC-4630 and sotorasib until resolves to Grade 
1, within normal limits or returns to baseline. If improvement occurs within 4 
weeks, restart RMC 4630 and sotorasib one dose level lower. If there is no 
improvement within 4 weeks, discontinue both drugs. 

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Table 6: 
Dose Modification Guidelines for RMC-4630 and Sotorasib (Continued) 
AE 
Action 
Rash 
Grade 1-2 (tolerable): Administer supportive care and continue study treatment. 
Grade 3 or 4: Hold both components of study treatment until improvement to ≤ 
Grade 2.  
If there is improvement to ≤ Grade 2 within 3 weeks, then reduce RMC-4630 by 
1 dose level. If recurs, a second dose reduction for RMC-4630 and/or a dose 
reduction for sotorasib may be considered. If rash continues to occur with 2 dose 
reductions of RMC-4630 and/or 1 dose reduction of sotorasib, consider 
permanent discontinuation of RMC-4630. If Grade 3-4 rash does not improve 
within 3 weeks, permanently discontinue RMC-4630. 
Stevens Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN): Any 
grade, permanently discontinue both components of study treatment 
Ocular symptoms 
For neurosensory retinal detachment and other ocular events: 
Grade 3 or 4 – Hold RMC-4630 until the AE recovers to normal or Grade 1 and 
re-start RMC-4630 at one dose level lower. For recurrence of a Grade 3 AE, 
dose interrupt until the AE recovers to normal or Grade 1 and consider a second 
dose reduction for RMC-4630. Permanently discontinue RMC-4630 if the Grade 
3 AE re-occurs after two dose reductions of RMC-4630. For recurrence of a 
Grade 4 AE, permanently discontinue RMC-4630. Discontinue RMC-4630 for 
any grade AE of retinal vein occlusion (RVO).  
Hemorrhage 
Rule out other causes. 
Grade 1-2: Continue both components of study treatment at the current doses 
and monitor closely for signs or symptoms of clinically significant bleeding. 
Grade 3: Hold RMC-4630 until resolution. If the event resolves within 3 weeks, 
consider restarting RMC-4630 at a lower dose. If not resolved within 3 weeks, 
permanently discontinue RMC-4630.  
Grade 4 or CNS hemorrhage: If hemorrhage is associated with 
thrombocytopenia or reduced platelet count from baseline, permanently 
discontinue RMC-4630. If not, hold RMC-4630 until resolution, and restart at a 
lower dose if resolves within 3 weeks. If not resolved within 3 weeks, 
permanently discontinue RMC-4630.  
Diarrhea/ Nausea/ 
Vomiting 
Grade 1-2: Maximal supportive care. Continue both components of study 
treatment at current doses and ongoing prophylaxis maybe considered upon 
investigator’s discretion after the first event 
Grade 3: Hold both components of study treatment (if receiving maximal 
supportive care) until the event recovers to Grade 1 or normal or returns to 
baseline. If improves within 3 weeks, then restart RMC-4630 and sotorasib at 1 
dose level lower. If not resolved within 3 weeks, permanently discontinue 
RMC-4630. If event recurs, hold both components of study treatment and 
consider a second dose reduction for both components of study treatment or 
permanent discontinuation of one or both components of study treatment 
depending on the clinical benefit. Note: Only one dose reduction is applicable 
for subjects starting dosing at 240 mg of sotorasib. 
Grade 4: Permanently discontinue RMC-4630 and sotorasib for Grade 4 
diarrhea or vomiting 

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Table 6: 
Dose Modification Guidelines for RMC-4630 and Sotorasib (Continued) 
Abbreviations: AE = adverse event; ANC = absolute neutrophil count; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; DILI = drug-induced liver injury; GGT = gamma-glutamyl transferase; ILD = interstitial lung disease; 
INR = international normalized ratio; PTT = partial thromboplastin time; SJS = Stevens-Johnson syndrome; TEN = toxic 
epidermal necrolysis; ULN = upper limit of normal. 
 
 
 
 
 
 
AE 
Action 
Liver function 
tests (AST, ALT, 
and/or total 
bilirubin) 
Grade 1: Continue both components of study treatment at current doses. 
Grade 2 AST or ALT with symptoms OR Grade 3 to 4 AST or ALT 
elevation: Rule out other causes such as metastatic liver disease, concomitant 
drugs, infection, hepatitis etc. Hold both RMC-4630 and sotorasib until the event 
recovers to Grade 1 or within normal limits or returns to baseline, then dose 
reduce RMC-4630 and sotorasib to one dose level lower. If AE does not improve 
or recurs, dose reduce another dose level. No dose modification is required for 
isolated elevations of GGT. Note: Only one dose reduction is applicable for 
subjects starting dosing at 240 mg of sotorasib. 
Both components of study treatment should be permanently discontinued for 
concurrent elevation of AST or ALT >3 × ULN AND total bilirubin >2 × ULN 
or INR >1.5 in the absence of cholestasis and other causes (eg, viral hepatitis, 
other pre-existing or acute liver disease, or another drug capable of the observed 
injury), which may indicate severe DILI (potential Hy’s law case). If liver injury 
is due to other causes such as viral hepatitis, acute liver disease, or another drug 
capable of liver injury, evaluate the extent of liver injury (eg, albumin level, 
PTT, INR, etc) and if considered to be severe, either consider continuing at a 
lower dose for both components of study treatment or discontinue one or both 
components of study treatment. 
Hypertension 
Grade 2: Treat according to institutional/provider guidelines in accordance with 
goal of reduction to Grade 1 or baseline. Continue RMC-4630 and sotorasib. 
Grade 3: Treat according to institutional guidelines with the goal of reducing 
blood pressure to Grade 1 or within normal limits or baseline. Consider holding 
RMC-4630. If there is improvement, restart RMC-4630 at the same dose level or 
one dose level lower per investigator judgement.   
Grade 4: Treat according to institutional guidelines. Permanently discontinue 
RMC-4630.  
ILD / pneumonitis  Any Grade  
Withhold RMC-4630 and sotorasib if ILD/pneumonitis is suspected.  
If diagnosis is confirmed, permanently discontinue sotorasib and RMC-4630.  

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Table 7: 
General Dose Modification Guidelines with RMC-4630 and Sotorasib for All 
Other AEs 
Severity Grade  
Action  
Grade 1  
Continue both components of study treatment at the current dose 
Grade 2  
May continue both components of study treatment without dose interruption and 
manage the toxicity using institutional guidelines.  
Dose interruption may be considered for one component of study treatment if the 
toxicity is a suspected toxicity of RMC-4630 and/or sotorasib, respectively.  
Upon recovery to baseline or Grade 1, treatment may be restarted at the same 
dose.  
If the toxicity re-occurs, consider a dose reduction for one of the components of 
study treatment if a causal relationship to the AE is suspected with RMC-4630 
and/or sotorasib, respectively.  
Grade 3 
Hold treatment with both components of study treatment until recovery to 
normal or baseline or Grade 1 and manage per institutional guidelines.  
Upon recovery, subject may start RMC-4630 and sotorasib at one dose level 
lower. If AE re-occurs after one dose reduction, consider a second dose 
reduction for one or both components of study treatment. Note: Only one dose 
reduction is applicable for subjects starting dosing at 240 mg of sotorasib. 
If permanent discontinuation of either component of study treatment is being 
considered in the setting of re-occurrence of the AEs, RMC-4630 should be 
discontinued prior to sotorasib.  
Grade 4 
Hold treatment with both components of study treatment until recovery to 
normal or baseline or Grade 1 and manage per institutional guidelines.  
Upon recovery, a causal relationship should be carefully evaluated with RMC-
4630 and permanent discontinuation of RMC-4630 considered for certain Grade 
4 AEs. If it decided to continue treatment with RMC-4630, it should be at a 
reduced dose level.  
Sotorasib may be continued at one dose level lower upon recovery.  
If event re-occurs after sotorasib dose reduction and RMC-4630 
reduction/discontinuation, consider permanent discontinuation of sotorasib.  
Abbreviations: AE = adverse event. 
6.7.1. 
Supportive Care Guidelines for Selected Expected Toxicities 
Dose modification guidelines for RMC-4630 and sotorasib are summarized in Table 6 and 
Table 7. Toxicities known from the administration of sotorasib can be found in the current 
Sotorasib IB. In general, AEs should be managed per institutional guidelines, if available, and 
should include evaluation for all potential underlying causes. Appropriate subspecialty 
consultation should be sought, as clinically indicated. The investigator or treating physician 
should use his/her best medical judgement for management. Guidelines for selected toxicities are 
summarized below. 

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6.7.2. 
Management of Rash 
For cutaneous changes suspicious of erythema multiforme or Stevens-Johnson syndrome (SJS), 
hold all study interventions, treat as per institutional guidelines, and consider dermatology 
consultation. 
For maculopapular rash or perifollicular eruptions, emollients alone may be used for Grade 1 
AEs. For Grade 2 AEs, addition of antihistamines and/or topical corticosteroids and/or oral 
minocycline or doxycycline may be considered. For Grade >2 events, oral steroids may be 
required. 
For dry skin, alcohol-free emollients and soap substitutes should be considered. For folliculitis or 
cysts, soap substitutes and topical or oral antibiotics are recommended. Consider surgical 
excision for symptomatic, uninfected cysts. For an erythema-nodosum type rash, emollients, 
topical steroids, and analgesics are recommended. In more severe cases, dermatologic 
evaluation, and systemic steroids and/or may be required. 
Consultation with a dermatologist should be considered as clinically indicated, including 
worsening or refractory symptoms, or rapidly growing lesions. 
6.7.3. 
Management of Diarrhea 
Evaluate for other or concomitant causes, including medications (eg, stool softeners, laxatives, 
antacids), infection, including Clostridium difficile, malabsorption/lactose intolerance, fecal 
impaction, and dietary supplements high in fiber. 
Premedication for management of diarrhea will be allowed after, but not before, the first dose of 
study treatment. Premedication should be administered as directed by the investigator. 
For Grade 1 or 2 diarrhea, dietary modifications should be considered, including cessation of 
lactose-containing products, eating small meals, and adequately hydrating. Consumption of the 
banana, rice, apples, and toast (BRAT) diet may be helpful. In addition, loperamide or codeine 
may be used or alternatives in refractory cases, such as octreotide and budesonide. 
For ≥ Grade 3 diarrhea, consider hospitalization for fluid and electrolyte replacement and 
antibiotics, particularly if accompanied by fever or Grades 3-4 neutropenia. 
Consultation with a gastroenterologist should be considered, particularly for severe or refractory 
cases. 
6.7.4. 
Management of Ophthalmologic Complications 
The causal relationship between a change in vision and the study treatment should be carefully 
explored and an ophthalmologist should be consulted. Immediate consultation should be sought 
for Grade >1 visual changes. Special attention should be given to macular findings (with optical 
coherence tomography [OCT] utilization) or retinal vein abnormalities (eg, RVO). If 
consultation cannot be obtained within 7 days of onset, interrupt all study interventions until the 
consultation has occurred.  
If RVO is diagnosed, permanently discontinue study treatment immediately and treat per 
institutional guidelines. If uveitis is diagnosed, withhold study treatment, and consider use of 
topical steroids until resolution. If central serous retinopathy or neurosensory retinal detachment 
is diagnosed, withhold all study interventions until symptoms resolve and retinal exam shows 
resolution.  

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There were no reported cases of retinopathy in RMC-4630-01. However, symptoms of 
retinopathy were observed in 6.7% (7/104) of subjects, of whom one experienced photopsia and 
6 experienced blurred vision. Therefore, subjects treated with RMC-4630 should be monitored 
for retinopathy. Symptoms include blurred vision, altered color perception, shadows, light 
sensitivity, metamorphopsia, and glare. Ophthalmic examination by best corrected visual acuity 
(BCVA), pinhole vision, and OCT are key (refer to Common Terminology Criteria for Adverse 
Events [CTCAE], v5.0, for grading; note that the grades are based on BCVA).  
The onset of retinopathy may occur very soon after dosing (eg, hours to weeks), and may also 
resolve spontaneously over time. For significant declines in visual acuity, dose hold according to 
Table 6 until improvement, then restart at the next lower dose level. Ophthalmology (eg, retinal 
specialist) consultation should be considered, if clinically indicated. 
6.7.5. 
Management of Hypertension 
Early identification and treatment of hypertension is recommended. Evaluate for other or 
concomitant causes. Assess renal function as well as urinalysis. For recurrent or persistent 
Grade 2 hypertension (systolic blood pressure 140-159 mm Hg or diastolic blood pressure 
90-99 mm Hg) treat according to institutional guidelines with the goal of therapy to reduce blood 
pressure to £ Grade 1. Hypertension associated with life-threatening consequences 
(eg, malignant hypertension, neurological deficits, hypertensive crisis), permanently discontinue 
study treatment. Provide supportive care per institutional guidelines. 
Cardiology or nephrology consultation should be considered, as clinically indicated. 
6.7.6. 
Management of Liver Function Abnormalities and Hepatotoxicity 
Monitor liver function tests (LFTs, which include ALT, AST, and total bilirubin) prior to the 
start of the study, weekly during Cycle 1, Day 1 and Day 15 during Cycle 2, Day 1 every Cycle 
starting at Cycle 3, and at EOT/EOS or as clinically indicated, with more frequent testing in 
subjects who develop transaminase and/or bilirubin elevations. Assess whether metastatic 
disease to the liver is contributing to liver function abnormalities and/or hepatotoxicity. Evaluate 
for infections or other causes of increased liver function abnormalities if appropriate. Consider 
imaging of the liver. Concomitant medications that may potentiate hepatotoxicity or metabolized 
by the liver should be held or reduced and the extent of liver injury should be evaluated 
(eg, albumin level, PTT, or INR).  
Concurrent elevation of AST or ALT >3 × ULN AND total bilirubin >2 × ULN or INR >1.5 in 
the absence of cholestasis and other causes (eg, viral hepatitis, other pre-existing or acute liver 
disease, or another drug capable of the observed injury), which may indicate severe drug-induced 
liver injury (DILI) (possible Hy’s law case). Study Treatment should be permanently 
discontinued.  
If liver injury is due to other causes such as viral hepatitis, acute liver disease, or another drug 
capable of liver injury, evaluate the extent of liver injury (eg, albumin level, PTT, INR, etc) and 
if considered to be severe, either consider a lower dose for both components of study treatment 
or discontinue one or both components of study treatment.  
Hepatology consultation should be considered, as clinically indicated. 

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6.7.7. 
Management of Hemorrhage 
Evaluate complete blood count (CBC) and coagulation laboratories. Transfuse blood products 
and correct coagulation abnormalities as per institutional guidelines. Hold all study interventions 
if hemorrhage associated with thrombocytopenia, reduced platelet count from baseline, or at the 
discretion of investigator. 
6.7.8. 
Management of Fatigue 
Other causes of fatigue should be evaluated (eg, infection, disease progression and 
hematological, electrolyte, and endocrine abnormalities). Dose-modification and/or low-dose 
corticosteroids may be considered. General guidelines from Table 7 can be used to manage 
fatigue as it may be an overlapping toxicity for both RMC-4630 and sotorasib.  
6.7.9. 
Pneumonitis 
Respiratory symptoms such as dyspnea, cough, shortness of breath, etc, should be investigated 
with a chest X-ray or chest computed tomography (CT) scan. Evaluate for possible infections 
and other causes of respiratory compromise including progressive pulmonary disease, cardiac 
dysfunction, or any environmental factors, etc.  
If the diagnosis of ILD or pneumonitis is confirmed, permanently discontinue sotorasib and 
RMC-4630. Initiate treatment per investigator judgement with corticosteroids and supportive 
care as per institutional guidelines.  
6.7.10. 
Management of Fluid Retention/Overload Events  
Evaluate for other or concomitant causes including medications. Treat according to institutional 
guidelines including the cessation of other medications known to be associated with the 
development of fluid retention/overload events, if clinically indicated. General guidelines from 
Table 7 can be used to manage fluid retention/overload events as it is considered to be an 
overlapping toxicity for both RMC-4630 and sotorasib.  
 

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7. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
In some instances, it may be necessary for a subject to permanently discontinue study treatment. 
Refer to the SoA (Table 1) for data to be collected at the time of discontinuation of study 
treatment. 
Subjects must stop study treatment, but continue to be monitored in the study, under the 
following circumstances: 
• Subject experiences a Grade 4 AE and is deemed by the investigator not to meet the 
criteria for withdrawal from the study (see Section 7.2). 
• Subject experiences prolonged QT interval corrected using Fridericia's formula 
(QTcF); prolonged QTcF is defined as >500 msec OR change from baseline 
>60 msec that does not resolve after excluding other causes. 
A subject must be discontinued from protocol-prescribed treatment if any of the following apply: 
• Documented disease progression, based on RECIST v1.1; in certain circumstances 
(eg, an isolated site of progression with responses at other sites that may be amenable 
to localized radiotherapy), subjects may be allowed to continue therapy during and 
after radiation with approval from Sponsor Medical Monitor. 
• Unacceptable toxicity  
• Subject’s request to withdraw from study treatment or withdraw of consent 
• Ineligibility 
• Unwillingness or inability to comply with study requirements 
• Initiation of alternative anticancer therapy 
• Investigator’s decision 
− Clinical need for concomitant or other ancillary therapy that is not permitted in 
the study 
− Unrelated intercurrent illness that, in the judgment of the investigator, will affect 
assessments of clinical status to a significant degree 
− Investigator believes that it is in the best interest of the subject to withdraw from 
the study 
• Pregnancy 
• Lost to follow-up 
• Sponsor’s decision to terminate the study 
Subjects who discontinue study treatment should complete the EOT visit, within 30 days after 
the last treatment dose. Subjects currently in LTFU should discontinue follow-up. See 
Section 7.2 for details on study discontinuation.  

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7.2. 
Subject Discontinuation/Withdrawal from the Study 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. These withdrawals are expected to be uncommon. 
A subject may be withdrawn from the study for any of the following reasons: 
• Subject’s withdrawal of consent for participation in the study  
• Sponsor’s decision to terminate the study 
• Subject is lost to follow-up  
• Death  
Upon permanent discontinuation of study treatment for any reason, including for subjects in the 
Extended-Use Phase, an end-of-treatment (EOT) visit should be completed within 30 days after 
the last dose of study treatment or before any new antitumor treatment is started. 
Following the EOT visit, subjects will be considered to have completed the study. Survival 
follow up will be discontinued for subjects currently in LTFU. 
If the subject withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a subject withdraws from the study, he/she may request in writing destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-Up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit 
schedule and determine whether or not the subject wishes to and/or should continue 
in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address, or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Study discontinuation at specific sites or of the study as a whole are described in 
Appendix 1 (Study and Site Closures). 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Table 1). Protocol 
waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue 
study treatment. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the subject’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be used for screening purposes 
provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• The maximum amount of blood collected from each subject over approximately 9 
months (13- to 14-cycle study duration), including any extra assessments that may be 
required, will not exceed 0.9 L. Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples. 
8.1. 
Efficacy Assessments 
Subjects will be assessed for response using RECIST v1.1 (see Appendix 6), as assessed by the 
investigator. All measurable disease must be documented at screening and reassessed at each 
subsequent tumor evaluation. Measurable disease is required for each subject (Inclusion 
Criterion 3 [Section 5.1]). Response assessments will be assessed by the investigator based on 
physical examination (including measurement of cutaneous lesions) and CT scans or MRI. 
Imaging should include chest and abdomen (depending on primary tumor type, site of metastasis 
and investigator assessment). At the investigator’s discretion, the imaging studies may be 
repeated at any time if disease progression is suspected. Additional studies, such as positron 
emission tomography (PET) or bone scans, should be performed if clinically indicated. Care 
should be taken to repeat the same modality used at screening throughout the study and to ensure 
all anatomy imaged at screening is again imaged at follow-up scans for any given subject. As 
part of the tumor assessment, physical examinations should include all areas of tumor 
involvement that are amenable to examination, including biopsy sites, lymph nodes, and bone 
tenderness, if applicable. 
All imaging studies should be evaluated by a local radiologist with expertise in the imaging 
modality. The investigator is responsible for determining the overall response at each timepoint. 
Radiological imaging and tumor assessments are required at screening and every 2 cycles 
starting from Cycle 3 (ie, every 6 weeks [±1 week]) up to Cycle 9, every 4 cycles (ie, every 
12 weeks [±1 week]) thereafter and EOT. Radiographic response (CR and PR) requires 

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confirmation by a repeat scan at least 4 weeks after the first documentation of response and may 
be delayed until the next scheduled scan to avoid unnecessary procedures.  
In the Extended-Use phase of the study, tumor imaging is not required per protocol. If required, 
imaging should be performed according to local standards of care and may be entered in the 
eCRF at the end of the extended use phase, if available. 
8.2. 
Safety Assessments 
Subjects will undergo the following safety assessments listed below and described in the 
following sections. Planned time points for all safety assessments are provided in the SoA 
(Table 1). Refer to the column on safety assessments for the Extended-Use phase of the study 
(Table 1) AEs, SAEs (Section 8.3) 
• Hematology, clinical chemistry, liver transaminases and bilirubin tests 
(Section 8.2.6), coagulation tests (PT, INR, and aPTT or PTT) and urinalysis. 
• Vital signs (Section 8.2.2) 
• Body weight and height (Section 8.2.3) 
• Physical examination (Section 8.2.1) 
• 12-lead ECGs (Section 8.2.4)  
• ECHO/MUGA scans (Section 8.2.5) 
• Ophthalmologic examinations (Section 8.2.8) 
• Concomitant medications/procedures 
• ECOG performance status (Section 8.2.7) 
The ISMC will review emergent safety data from the RMC-4630 program at regular intervals for 
all subjects during the trial in conjunction with data from other active RMC-4630 studies, 
described in Section 8.3.6. 
8.2.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
head, eyes, ears, nose, and throat (HEENT), dermatologic, cardiovascular, 
respiratory, GI (including assessments of liver and spleen), musculoskeletal, 
neurological, and lymphatic systems. Height and weight will also be measured and 
recorded. A symptom/AE directed physical examination should be performed as 
indicated by subject presentation or subject-reported symptoms or AEs. 
• A limited examination should include an evaluation of the HEENT, dermatologic, 
cardiovascular, respiratory, and GI systems. A symptom/AE directed physical 
examination should be performed as indicated by subject presentation or subject-
reported symptoms or AEs. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 

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8.2.2. 
Vital Signs 
Vital signs will be measured, preferably in a seated position, after an approximately 5-minute 
rest. Vital signs will include temperature, systolic and diastolic blood pressure, pulse rate, pulse 
oximetry, and respiratory rate. Results should be recorded on the appropriate eCRF. In the 
Extended-Use phase, vital signs results will be recorded in subject's medical record. 
8.2.3. 
Weight and Height 
Weight should be measured throughout the study as indicated in the SoA (Table 1). Coats and 
shoes should be removed prior to measurement. Height should be measured at screening, without 
shoes. 
8.2.4. 
Electrocardiograms 
The 12-lead ECGs will be obtained as outlined in the SoA (Table 1) for all subjects using an 
ECG machine that automatically calculates the heart rate and measures pulse rate, QRS, QT, and 
QTcF intervals. Refer to Section 7.1 for QTcF withdrawal criteria. Additional QTcF readings or 
continuous monitoring should be obtained to demonstrate improvement or resolution as per 
institutional guidelines. Subjects should be in the supine position after several minutes of 
inactivity before any study-related ECGs are conducted.  
The ECGs can be evaluated by the Investigator and/or by a local cardiologist for a final 
assessment, and these results should be recorded in the eCRF. An evaluation by a cardiologist 
will not be required for routine follow-up of ECGs and will be at the discretion of the Principal 
Investigator/Sub-Investigator. However, evaluation by a cardiologist will be required if the 
subject experiences a cardiac AE/SAE or if the subject experiences a QTc/QTcF prolongation. 
A single 12-lead ECG should be performed at Screening. The average of triplicate readings for 
assessing QTc interval may be used at Screening to determine eligibility. Triplicate 12-lead 
ECGs should be obtained on C1D1 and C1D15 predose and approximately 2 to 4 hours post-
dose. Then a single pre-dose ECG should be obtained on D1 of every 2 cycles starting at C3 
(eg, C3D1, C5D1, etc) and at EOT (see SoA [Table 1] for full schedule). 
8.2.5. 
Echocardiograms/Multigated Acquisition Scans 
All subjects must have their LVEF assessed by two-dimensional ECHO scan or MUGA scan as 
part of the screening procedure and as outlined in the SoA (Table 1). If a subject does not 
complete 2 cycles of study treatment, the EOT assessment for LVEF is not required, unless 
clinical signs or symptoms warrant additional imaging. 
ECHO is the preferred method since it can detect wall motion abnormalities. However, in 
situations where an ECHO machine is not readily available or is technically limited, a MUGA 
scan may be obtained to evaluate LVEF. The same methodology should be used throughout the 
study and, to the greatest extent possible, at the same institution/facility. 
The LVEF is to be calculated based on institutional guidelines and must be within institutional 
normal limits or 50%, whichever is lower, before a subject can enroll into the study. The LLN 
for the LVEF at the institution/facility should be recorded on the respective eCRF along with the 
LVEF result. 

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8.2.6. 
Clinical Safety Laboratory Assessments 
• Refer to Appendix 2 for the list of clinical laboratory tests to be performed and the 
SoA (Table 1) for the timing and frequency. 
• The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values. In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to 
be recorded as adverse events. However, laboratory value changes that require 
treatment or adjustment to current study therapy are considered adverse events. 
Where applicable, clinical sequelae (not the laboratory abnormality) are to be 
recorded as the adverse event. Refer to Appendix 2 for additional information 
pertaining to reporting of potential Hy’s Law cases. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study after the first dose of study treatment until EOT should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or Medical Monitor. 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified where possible, 
and the Sponsor notified. 
− All protocol required- laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA (Table 1). 
− If laboratory values from non–protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in subject 
management or are considered clinically significant by the investigator (eg, SAE, 
AE, or dose modification), then the results must be recorded in the eCRF. 
8.2.7. 
ECOG Performance Status 
ECOG performance status (Appendix 7) should be evaluated by the investigator by direct 
questioning of the subject at screening and at timepoints delineated in the SoA (Table 1). 
8.2.8. 
Ophthalmologic Examinations 
Ophthalmic examination if clinically indicated (ie, if subject is at high risk for RVO, RPED, 
and/or central serous retinopathy because of predisposing factors [uncontrolled glaucoma or 
ocular hypertension, uncontrolled diabetes mellitus, hyperviscosity, or hypercoagulability 
syndromes]), including full fundoscopic examination and OCT should be performed at Screening 
by an ophthalmologist as described in the SoA (Table 1). Additional examinations should be 
performed during study treatment as clinically indicated. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of AE and SAE can be found in Appendix 3. 
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative). 

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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
AEs that are serious, considered related to the study treatment or study procedures, or that caused 
the subject to discontinue the study treatment (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
Monitoring and recording of AEs and SAEs will be conducted throughout the study. After the 
signing of the ICF, but prior to initiation of study treatment, only SAEs caused by a 
protocol-mandated treatment will be collected (eg, SAEs related to invasive procedures, such as 
biopsies or medication washout). Any medical occurrence that begins before the start of study 
treatment but after obtaining informed consent, and which is not considered an SAE caused by a 
protocol-mandated treatment, will be recorded on the Medical History/Current Medical 
Conditions Section of the eCRF rather than the AE section. 
All AEs and SAEs will be collected from the start of treatment until 30 days after the last dose, 
or upon initiation of alternative cancer treatment, whichever occurs first. After this period, 
investigators should report only SAEs that are thought to be related to RMC-4630 and/or 
sotorasib. 
Any SAE that is determined to be study-treatment related (possibly, probably, or definitely 
related) will be followed to resolution or stabilization, until it is determined to be irreversible by 
the investigator, the subject is lost to follow-up, or it has been determined that the study 
treatment is not the cause of the AE/SAE, whichever occurs first. After this period, investigators 
should report only SAEs that are thought to be related to RMC-4630 and/or sotorasib.  
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of 
investigator awareness, as indicated in Appendix 3. The investigator will submit any updated 
SAE data to the Sponsor within 24 hours of it being available. During the Extended-Use phase of 
the study, only SAEs (irrespective of causality) and related AEs will be reported in the EDC. All 
SAEs will also be reported on the SAE Report Form.  
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken to not introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
8.3.3. 
Follow-Up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts through the last study visit. All AEs (regardless of relationship to 
study treatment) and SAEs determined not to be study-treatment related (ie, not related and 
unlikely related) will be followed through the last study visit and be noted as “continuing” if not 
resolved at this visit. 
All SAEs considered study-treatment related (possibly, probably, or definitely related) will be 
followed until resolution, stabilization, is determined to be irreversible by the investigator, the 
subject is lost to follow-up (as defined in Section 7.3), or it has been determined that the study 

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treatment is not the cause of the AE/SAE, whichever occurs first. The investigator will submit 
any updated SAE data to the Sponsor within 24 hours of it being available. During the 
Extended-Use phase of the study, only SAEs (irrespective of causality) and related AEs will be 
reported in the EDC. All SAEs will also be reported on the SAE Report Form. Reporting of 
AEs/SAEs will end after the subject initiates alternative cancer treatment.  
Further information on follow-up procedures is given in Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification (ie, within 24 hours of becoming aware of the event) by the 
investigator to the Sponsor of a SAE is essential so that legal obligations and ethical 
responsibilities toward the safety of subjects and the safety of a study treatment under 
clinical investigation are met. 
• The Sponsor has a legal responsibility to expeditiously notify both the local 
regulatory authority and other regulatory agencies about the safety of a study 
treatment under clinical investigation. The Sponsor will comply with country specific 
regulatory requirements relating to safety reporting to the regulatory authority, central 
IRBs/IECs, and investigators. 
• The Sponsor will prepare investigator safety reports for suspected unexpected serious 
adverse reactions (SUSARs), according to local regulatory and local IRB/IEC 
requirements and Sponsor policy, and forward them to investigators, as necessary 
within 7 calendar days for Fatal and Life-Threatening SUSARs and 15 calendar days 
for all other SUSARs. 
• An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the RMC-4630 IB and will notify the IRB/IEC, if 
appropriate, according to local requirements. 
• The Sponsor will regularly monitor reporting of SUSARs through compliance metrics 
and corrective and preventative actions to ensure that all recipients receive SUSAR 
reports in a timely manner. 
• During the Extended-Use phase of the study, only SAEs (irrespective of causality) 
and related AEs will be reported in the EDC. All SAEs will also be reported on the 
SAE Report Form. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female subjects and female partners of male subjects 
who become pregnant will be collected after the start of study treatment and will be 
followed to determine the outcome of the pregnancy.  
• If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 

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• Pregnancy reporting as detailed above will continue during the Extended-Use phase 
of the study and should be reported to Drug Safety on the SAE report form. 
8.3.6. 
Committees 
8.3.6.1. 
Dose Committee 
The Dose Committee is a study specific committee, composed of Sponsor representatives and 
investigators. Additional details regarding memberships, roles, and responsibilities are provided 
in the Dose Committee Charter.  
The Dose Committee will evaluate the safety data for the safety lead-in portion of the study. The 
combination dose for the expansion phase of the study will be decided by the Sponsor after 
taking into consideration the totality of data from both CodeBreaK 101C and the cumulative data 
from this study. The Sponsor may proceed directly to dose expansion in this study without 
completing the safety run-in period based on review of available data.  
8.3.6.2. 
ISMC 
The ISMC consists of representatives from the Sponsor and the designated CROs, as outlined in 
the ISMC Charter. The ISMC will review emergent safety data as per the ISMC charter from the 
RMC-4630 program after approximately every 3 months or after the first 6 subjects have 
completed 2 cycles in this study, whichever is earlier. The ISMC may also perform emergent ad 
hoc reviews of the safety data for all subjects during the study. Subsequently the committee will 
review data approximately every 3 months. The committee may adjust the timing of the review 
from the defined schedule, depending on the rate of enrollment. The committee will consist of 
the medical monitor, and a biostatistician. Relevant findings from the safety data reviews will be 
discussed with the study investigators. Based on the ongoing safety assessments, the committee 
may recommend changes in dosing regimen or other alterations to study procedures. The medical 
monitor may convene a meeting sooner should any concerns arise from review of data or from 
the investigators. 
8.4. 
Dose Limiting Toxicity Criteria 
Potential DLTs are defined as all AEs specified below that occur during the first cycle of study 
treatment and that are considered by the investigator to be related to RMC-4630 and/or sotorasib.  
DLT criteria are outlined below as follows: 
• An AE that results in permanent discontinuation of RMC-4630 or sotorasib  
• An AE that results in a delay of > 2 weeks in the start of Cycle 2 
• Febrile neutropenia 
• Grade 4 neutropenia of any duration 
• Grade 3 neutropenia lasting >7 days 
• Grade 3 thrombocytopenia with Grade ≥2 bleeding 
• Grade 4 thrombocytopenia 
• Grade 4 anemia 
• Grade ≥4 vomiting and diarrhea 

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• Grade 3 vomiting or diarrhea lasting >3 days despite optimal medical support 
• Grade ≥3 nausea lasting 3 days or more, despite optimal medical support 
• Grade ≥3 rash lasting 3 days or more despite optimal medical support 
• Grade 3 AST or ALT elevation lasting >5 days or Grade ≥4 AST or ALT elevation of 
any duration 
• Grade ≥3 bilirubin elevation 
• Grade ≥3 QTc prolongation 
• Retinal vein occlusion 
• Any other Grade ≥3 AE with the following exceptions:  
− Grade 3 Fatigue lasting 7 days or less 
− Asymptomatic Grade 3 electrolyte abnormalities that last <72 hours, are not 
clinically complicated, and resolve spontaneously or respond to medical 
interventions 
− Grade 3 amylase or lipase that is not associated with symptoms or clinical 
manifestations of pancreatitis 
− Other select laboratory abnormalities that do not appear to be clinically relevant 
or harmful to the subject and/or can be corrected with replacement or 
modifications (eg, Grade 3 lymphopenia, Grade 3 hypoalbuminemia) 
• Any subject meeting the criteria for a Hy’s Law case (ie, severe DILI) will be 
considered a DLT. A Hy’s Law case is defined as the following:  AST or ALT values 
of ≥3 × ULN, AND total bilirubin >2 × ULN or INR >1.5 in the absence of 
cholestasis and other causes (eg, viral hepatitis, other preexisting or acute liver 
disease, or another drug capable of the observed injury), to explain the observed liver 
related laboratory abnormalities. 
If a subject experiences a DLT during the DLT evaluation period during Cycle 1 of the safety 
run-in period, sotorasib and/or RMC-4630 treatment should be modified according to Table 6 
and Table 7. 
8.5. 
Treatment of Overdose 
For this study, any dose of RMC-4630 or sotorasib that is greater than the intended dose per 
administration or 2 administrations at the intended dose or more of sotorasib within <12 hours 
(QD dosing) or 2 administrations of RMC-4630 <12 hours apart (BIW D1, D2 dosing) will be 
considered an overdose. There is no clinical experience with an overdose of RMC-4630 in 
human clinical trials. No experiments have been performed to determine whether the effects of 
an overdose can be reversed, and there are no known antidotes.  
Revolution Medicines does not recommend specific treatment for an overdose. The individual 
should be monitored clinically, and supportive care should be undertaken as clinically indicated. 
In the event of an overdose, the investigator should:  

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1. Halt the dispensation and administration of the involved medication. The investigator 
may also hold the second medication based on his/her clinical judgement. 
2. Contact the Medical Monitor immediately. 
3. Closely monitor the subject for any AE/SAE, ECG, and laboratory abnormalities (blood 
glucose, liver function tests, creatinine, blood urea nitrogen (BUN), creatine 
phosphokinase (CPK), and complete blood count) until RMC-4630 and/or sotorasib can 
no longer be detected systemically. 
4. Obtain a plasma sample for PK analysis within 1 to 2 days from the date of the last dose 
of study intervention if requested by the Medical Monitor (determined on a case-by-case 
basis). Note, the PK sample collection applies to the main protocol only and not the 
Extended-Use phase. 
5. Document the quantity as well as the duration of the overdose in the eCRF. 
6. Decisions regarding resumption of study treatment will be made by the investigator in 
consultation with the Sponsor’s Medical Monitor based on clinical evaluation of the 
subject. 
8.6. 
Pharmacokinetics 
Plasma samples will be obtained for PK analysis of RMC-4630 and sotorasib as outlined in the 
SoA and (Table 2). Peripheral blood samples will be collected within C1 for sparse PK testing, 
and additional PK evaluations will continue to be obtained through C4 and every 3 cycles 
afterward up to Cycle 16. Note, PK sample collection applies to the main protocol only and not 
the Extended-Use phase. 
PK parameters (ie, approximate peak and trough concentrations) of RMC-4630 and sotorasib 
will be assessed for each evaluable subject: 
• Whole blood samples of approximately 3.0 mL will be drawn and processed into 
plasma for measurement of plasma RMC4630 and sotorasib concentrations as 
specified in the -SoA and Table 2. Instructions for the collection and handling of 
biological samples will be provided by the Sponsor. The actual date and time 
(24-hour clock) of each sample will be recorded. 
• Samples will be used to evaluate the PKs of RMC-4630 and sotorasib. Each plasma 
sample will be divided into 4 aliquots (2 each for primary and backup). Samples 
collected for analyses of plasma RMC-4630 and sotorasib concentrations may also be 
used for exploratory analysis, such as analysis of plasma RMC-4630 and sotorasib 
metabolites. 
Genetic analyses will not be performed on these plasma samples. Subject confidentiality must be 
maintained. Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team member and then 
archived in the Sponsor and site study files but will not constitute a protocol amendment. The 
IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the ICF. There will be no PK sample collection in the Extended-Use 
phase of the study. 

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8.7. 
Tumor Genetics 
Enrollment will be determined based on genotypic/histotypic strata mentioned in Section 5.1 
(Inclusion Criteria). Specific mutations are also defined in Appendix 9. Eligible mutations will 
be based on prior genotyping results using a clinically validated or qualified test. This test may 
have been performed on either tumor tissue or ctDNA samples. Sites must provide the Sponsor 
with the report. Archival tumor tissue will be collected for central laboratory testing. Details on 
processes for collection and shipment can be found in the laboratory manual. Fresh pretreatment 
biopsies will be mandatory for subjects who do not have available archival specimen tissue 
preferably from within 3 years, unless the investigator determines that the tumor site is not 
amenable to biopsy or poses a significant risk to the subject’s safety. Subjects who neither have 
archival tumor tissue samples nor can provide fresh pretreatment biopsies may still be eligible to 
participate in the study with agreement from the Sponsor Medical Monitor. The Sponsor will 
evaluate this requirement on a case-by-case basis. In the event of a discrepancy between the local 
and central testing results for the eligibility defining mutation, the subject will remain on study. 
For data analysis purposes, results from the central laboratory will supersede those of the local 
laboratory. 
Information regarding genetic research is provided in Appendix 5.  
8.8. 
Other Biomarkers 
Archival tumor samples will be collected for all subjects. These samples will be used to confirm 
mutations identified on the genomic report provided at enrollment. Archival samples will also be 
used to assess and evaluate potential markers of response to RMC-4630 and sotorasib 
combination therapy, including but not limited to deoxyribonucleic acid (DNA), ribonucleic acid 
(RNA), and protein expression. If tumor tissue allows, the remaining archival tumor samples 
may be stored for future development of companion diagnostic.  
Blood samples will be drawn as outlined in the SoA (Table 1) and Table 2 from every subject in 
order to extract and analyze ctDNA to assess and evaluate potential peripheral biomarkers of 
response to sotorasib and RMC-4630. Samples may be analyzed retrospectively. 
Note, biomarker sample collection applies to the main protocol only and not the Extended-Use 
phase. 

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9. 
STATISTICAL CONSIDERATIONS 
This is a Phase 2 multicenter, open-label study evaluating the efficacy, safety, tolerability, and 
PK of RMC-4630 in combination with sotorasib in subjects with KRASG12C mutant locally 
advanced or metastatic NSCLC after failure of prior standard therapy. Descriptive statistics will 
be used to summarize baseline demographic and disease characteristics, treatment 
administration, efficacy, and safety outcomes, and PK parameters. 
Descriptive summaries of discrete data will present the number of study subjects and the 
incidence as a frequency and as a percentage. Descriptive summaries of continuous data will 
present the group mean, standard deviation, median, minimum, maximum, and sample size. 
A final analysis will be performed at the EOS as defined in Section 4.4. 
9.1. 
Statistical Hypotheses 
No formal statistical hypothesis will be tested. 
9.2. 
Sample Size Determination 
Up to a total of 
cts will be enrolled into this study. Approximately 
jects will 
be enrolled during the safety run-in portion of the study. Initially, up to 
 will be 
enrolled and treated at the dose of 
 of each week in a 21-day cycle in 
combination with sotorasib at 960 mg QD. An additional 
 may be enrolled to receive 
RMC-4630 
 of each week in a 21-day cycle in combination with sotorasib 
at 960 mg QD, if a decision is made to increase the RMC-4630 dose from 
mg. 
After completion of the safety run-in (DLT clearance) of both dose levels, additional subjects 
may be enrolled for the purpose of dose optimization to inform the selection of the final 
expansion dose. Expansion may commence as soon as the final expansion dose has been 
selected. Approximately 
 will be enrolled for dose optimization and dose 
expansion. 
With a total sample size of 
, the probability of observing at least 1 AE with an 
incidence rate of 5% is at least 90%.  
The ORR will be reported by dose level pooling subjects from safety run-in and dose 
optimization (if applicable) and expansion. It’s anticipated that approximately 
ects 
will be treated at the final expansion dose depending on the actual number of subjects enrolled 
during safety run-in and/or dose optimization. For the final expansion dose, with 
 
 the lower bound of the one-sided 80% exact CI will be above 33.7% and 37.3% 
respectively if the observed response rate is 45%. 
The mutational status of each subject and, thus, placement into Cohort 1 or 2 (see Section 4.1) 
will be determined based on the historic genomic reports and later might be adjusted based on 
ctDNA analysis results collected at baseline. Therefore, the sample size for one or both cohorts 
will depend on the distribution of mutational status. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined in Table 8. 

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Table 8: 
Population Definitions 
Population 
Description 
Treated 
All subjects who take at least 1 dose of study treatment 
Evaluable 
DLT-evaluable: All subjects in the safety population who have received at least 80% of 
planned dose of sotorasib and at least 4 of 6 doses of RMC-4630 in Cycle 1 and have been 
observed for safety assessments for the full 21 days of the DLT evaluation period. Subjects 
who experience a DLT within the DLT period will be considered DLT evaluable regardless 
of the amount of study treatment received or completion of the observation period.  
Evaluable for efficacy: All subjects with measurable disease at baseline, who take at least 
1 dose of study treatment and (1) undergo 1 post-baseline response assessment or (2) who 
die or (3) had clinical progression prior to the first post-baseline response assessment. 
Abbreviations: DLT = dose-limiting toxicity. 
9.4. 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock. This section is 
a summary of the planned statistical analyses of the primary and secondary endpoints. 
9.4.1. 
Efficacy Analyses 
The statistical analysis plan will be developed and finalized before database lock. Below is a 
summary of the planned statistical analyses. 
Unless otherwise specified, efficacy analyses will be based on the efficacy-evaluable population 
and will be summarized by the initial combination dose level. Efficacy analyses will be 
presented for Cohort 1 and Cohort 2 separately, and for the overall study population.  
The primary efficacy endpoint is ORR, defined as the proportion of subjects who achieve a CR 
or PR per RECIST v1.1. The estimated proportion and the corresponding 95% two-sided exact 
CI using the Clopper-Pearson method will be derived for ORR. 
Secondary efficacy endpoints and analyses include the following: 
• DCR is defined as the proportion of subjects who achieve a CR or PR or SD per 
RECIST v1.1. DCR will be analyzed similarly as ORR. 
• DOR is defined as the interval from the first documentation of CR or PR to first 
documentation of definitive disease progression or death due to any cause, whichever 
occurs first. Subjects who are still alive and free from progression at the time of the 
data cutoff date, are lost to follow-up, have discontinued from the study, or have 
initiated subsequent anticancer therapy will be censored at the last adequate tumor 
assessment. Subjects who never achieve a response (PR or better) will be excluded 
from the analysis of DOR. 
• PFS is defined as the interval from the first dose of study treatment to documented 
disease progression per RECIST v1.1 or death due to any cause, whichever occurs 
first. Subjects who are still alive and free from progression at the time of the data 
cutoff date, are lost to follow-up, have discontinued from the study, or who have 
initiated subsequent anticancer therapy will be censored at the last adequate tumor 
assessment. PFS will be summarized for the all-treated population. 

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• Overall survival (OS) is defined as the interval from the first dose of study treatment 
to death due to any cause. Subjects who are not known to have died will be censored 
at the last known alive date. OS will be summarized on the all-treated population. 
The Kaplan-Meier method will be used to estimate DOR, PFS and OS curves and corresponding 
quartiles. The Kaplan-Meier median will be calculated with a two-sided 95% CI. 
9.4.2. 
Safety Analyses 
All DLT assessments will be performed on the DLT-evaluable population (see Section 8.4 for 
DLT assessment details). All other safety analyses will be performed on the Treated Population. 
Safety analyses will be descriptive in nature, and will include analyses of DLTs, AEs, SAEs, 
AEs leading to study treatment discontinuation and/or dose modification, clinical laboratory 
tests, vital signs, and ECGs. AEs will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. Unless otherwise specified, AEs will be summarized by 
primary MedDRA system organ classes and Preferred Term. Safety analyses will be summarized 
by the initial combination dose level. Safety analyses will be presented for each cohort separately 
and for the overall study population.  
During dose expansion after the final expansion dose has been selected, evaluation of all Grade 4 
or higher treatment-related adverse event rates will be conducted to assess if the unacceptable 
toxicity threshold has been reached. If this threshold is met, enrollment to dose expansion will be 
halted pending review of safety data. After reviewing the totality of data from both CodeBreaK 
101C and cumulative data from this study, one of the following actions may be taken: 
1. Terminate the study 
2. Amend the protocol to potentially improve the benefit/risk for subjects (eg, increase 
safety monitoring, modify dose/schedule, mandate premedication) 
3. Continue dose expansion without any changes 
The stopping rules use a Bayesian approach to pause the enrollment if the posterior probability is 
≥ 80% that the Grade 4 or higher treatment-related adverse event rate is greater than 20%. The 
stopping boundaries shown in Table 9 assume a prior distribution of Beta (0.4, 1.6). The 
operating characteristics with the pre-specified batch size of 10 new subjects are summarized in 
Table 10.  

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Table 9: 
Stopping Boundary by Number of Subjects 
Number of Subjects 
Treated 
Number of Subjects with Grade 4 or Higher Treatment-Related Adverse Events to 
Halt Enrollment 
10 
≥ 4 
20 
≥ 6 
30 
≥ 9 
40 
Expansion complete 
Table 10: 
Operating Characteristics of Stopping Rules 
True Grade 4 or Higher Treatment-
Related Adverse Event Rate 
Probability of Early Stopping of 
Dose Expansion 
Average Dose Expansion 
Sample Size 
0.1 
2.1% 
39 
0.15 
9.7% 
38 
0.2 
25.8% 
34 
0.25 
47.7% 
29 
0.3 
69.2% 
23 
9.4.3. 
Pharmacokinetic Analyses 
Concentrations of RMC-4630 and sotorasib will be summarized descriptively by timepoint. 
Concentrations of RMC-4630 may be used for population PK analysis and presented in a 
separate report. 
9.4.4. 
Other Analyses 
Additional efficacy and biomarker exploratory analyses will be described in the Statistical 
Analysis Plan (SAP) finalized before database lock. 

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10. 
REFERENCES 
Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives 
anti-tumour immunity. Nature 2019; 575: 217-23 
Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signaling pathways in cancer. Oncogene. 
2007;26(22):3279-90. doi:10.1038/sj.onc.121042. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
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doi:10.1016/j.ejca.2008.10.026. 
Falchook G, Li BT, Marrone KA, et al. OA03.03 Sotorasib in Combination with RMC-4630, a 
SHP2 Inhibitor, in KRAS p.G12C-Mutated NSCLC and Other Solid Tumors. Journal of 
Thoracic Oncology. 2022;17(9):S8. doi: 10.1016/j.jtho.2022.07.022 
Fedele C, Ran H, Diskin B, et al. SHP2 inhibition prevents adaptive resistance to MEK inhibitors 
in multiple cancer models. Cancer Discov. 2018;8 (10) 1237-1249. 
doi:10.1158/2159-8290. 
Guo W, Wang SJ, Yang S, et al. A Bayesian interval dose-finding design addressing Ockham’s 
razor: mTPI-2. Contemp Clin Trials. 2017;58:23-33 
Hallin J, Engstrom L, Hargis L, Calinisan A, Aranda R, Briere DM, et al. The KRASG12C 
inhibitor, MRTX849, provides insight toward therapeutic susceptibility of KRAS mutant 
cancers in mouse models and patients. Cancer Discov. 2020;10(1):54-71. 
Heuchel R, Berg A, Tallquist M, et al. Platelet derived growth factor ß receptor regulates 
interstitial fluid homeostasis through phosphatidylinositol-3’ kinase signaling. Proc Natl 
Acad Sci USA. 1999;96 : 11410-11415. doi:10.1073/pnas.96.20.11410 
Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Epidermal growth factor receptor in non-small-
cell lung carcinomas: Correlation between gene copy number and protein expression and 
impact on prognosis. J Clin Oncol. 2003;21:3798-807.  
doi:10.1200/JCO.2003.11.069. 
Hong DS, Fakih MG, Strickler JH, et al. KRASG12C Inhibition with Sotorasib in Advanced Solid 
Tumors. N Engl J Med 2020; Sep 24;383(13):1207-1217. doi: 10.1056/NEJMoa1917239. 
Jänne PA, Rybkin II, Spira AI, et al. KRYSTAL-1: Activity and Safety of Adagrasib 
(MRTX849) in Advanced/ Metastatic Non–Small-Cell Lung Cancer (NSCLC) Harboring 
KRAS G12C Mutation. European Journal of Cancer 2020;138S2: S1–S62. doi. 
org/10.1016/S0959-8049(20)31076-5. 
Johnson ML, Ou SH, Barve M, et al. KRYSTAL-1: Activity and Safety of Adagrasib 
(MRTX849) in Patients with Colorectal Cancer (CRC) and Other Solid Tumors 
Harboring a KRAS G12C Mutation. European Journal of Cancer 2020;138S2: S1–S62. 
doi.org/10.1016/S0959-8049(20)31077-7. 

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Li B, Skoulidis F, Falchook G, et al. CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib 
in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Presented at the 2020 World 
Conference on Lung Cancer Singapore (January 2021) 
Lito P, Solomon M, Li LS, Hansen R, Rosen N. Allele specific inhibitors inactivate mutant 
KRAS G12C by a trapping mechanism. Science. 2016;351(6273):604 8. 
doi:10.1126/science.aad6204 
Liu F, Yang X, Geng M, et al. Targeting ERK, an Achilles' Heel of the MAPK pathway, in 
cancer therapy. Acta Pharm Sinica B 2018;8(4):552-562. doi:10.1016/j/apsb.2018.01.008 
Singh A, Daemen A, Nickles D et al. NRF2 Activation Promotes Aggressive Lung Cancer and 
Associates with Poor Clinical Outcomes. Clin Cancer Res 2021;27:877–88. doi: 
10.1158/1078-0432.CCR-20-1985. 
Mazharian A, Mori J, Wang Y, et al. Megakaryocyte-specific deletion of the protein-tyrosine 
phosphatases Shpl and Shp2 causes abnormal megakaryocyte development, platelet 
production, and function. Blood. 2013 :121(20):4205-4219. doi:10.1182/blood-2012-08-
449272. 
Nichols RJ, Haderk F, Stahlhut C, et al. Efficacy of SHP2 phosphate inhibition in cancers with 
nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF and NF1 
loss. bioRxiv. 2017. doi:10.1101/188730. 
Nichols RJ, Haderk F, Stahlhut C, et al. RAS nucleotide cycling underlies the SHP2 phosphatase 
dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nature Cell Biology. 
2018;20(9):1064-1073. doi:10.1038/s41556-018-0169-1. 
Pietras K, Ostman A, Sjoquist M et al. Inhibition of platelet-derived growth factor receptors 
reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer 
Research. 2001;61:2929-2934. 
Singh A, Daemen A, Nickles D et al. NRF2 Activation Promotes Aggressive Lung Cancer and 
Associates with Poor Clinical Outcomes. Clin Cancer Res 2021;27:877–88. doi: 
10.1158/1078-0432.CCR-20-1985. 
The Cancer Genome Atlas (TCGA) Research Network. Comprehensive molecular profiling of 
lung adenocarcinoma. Nature. 2014;511(7511):543-50. doi:10.1038/nature13385. 
Wong GS, Zhou J, Liu JB, et al. Targeting wild-type KRAS-amplified gastroesophageal cancer 
through combined MEK and SHP2 inhibition. Nat Med. 2018;24(7):968-977. 
doi:10.1038/s41591-018-0022-x. 

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APPENDIX 1. REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, informed consent form (ICF), current RMC-4630 
Investigator’s Brochure (IB), and other relevant documents (eg, subject information, 
advertisements) must be submitted to an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) by the investigator and reviewed and approved by the IRB/IEC 
before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects. 
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of serious adverse events or other significant safety findings 
as required by IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulation (CFR), ICH guidelines, the IRB/IEC, 
and all other applicable local regulations 
Financial Disclosure 
Investigators and sub investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the study and for 1 year after 
study completion. 
Informed Consent Process 
• The investigator or his/her designated representative will explain the nature of the 
study to the subject and answer all questions regarding the study. 

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• Subjects must be informed that their participation is voluntary. Subjects will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center. 
• The medical record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign 
the ICF. 
• Per IRB/IEC requirements, subjects must be reconsented to the most current version 
of the ICF(s) during their participation in the study. 
• A copy of the ICF(s) must be provided to the subject.  
Subjects who are re-screened are not required to be re-consented; all re-screening should occur 
within 5 days of the initial date of the screen failure (see Section 5.4) 
The investigator or authorized designee will explain to each subject the objectives of the 
exploratory research. Any remaining mandatory samples may be used for optional exploratory 
research. Subjects will be told that they are free to refuse to participate and may withdraw their 
consent at any time and for any reason during the storage period.  
Data Protection 
• Subjects will be assigned a unique identifier by the Sponsor. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be 
transferred. 
• The subject must be informed that his/her personal study related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the subject. 
• The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
Dissemination of Clinical Study Data 
• The posting of company Sponsored clinical trial information and tabular study results 
on the United States (US) National Institute of Health (NIH) website 
(www.clinicaltrials.gov) and on other regional clinical trial registries in countries or 
regions where the clinical trial is conducted, will comply with local regulations. 
• Periodic safety reports will be submitted as required by regulation in the countries 
where the study is conducted. 

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Data Quality Assurance 
• All subject data relating to the study will be recorded on electronic Case Report Form 
(eCRF) unless transmitted to the Sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the Case Report Form (CRF). 
• The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• The investigator must permit study related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing methods, responsibilities, and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or 
onsite monitoring) are provided in the Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, contract research organizations [CROs]). 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for a period of 2 years following the date a 
marketing application is approved for RMC-4630 for the indication for which it is 
being investigated; or if no application is to be filed or if the application is not 
approved fur such indication, until 2 years after the investigation is discontinued and 
US Food and Drug Administration (FDA) is notified (ie, in accordance with 
21 CFR 312.62(c), unless local regulations or institutional policies require a longer 
retention period). No records may be destroyed during the retention period without 
the written approval of the Sponsor. No records may be transferred to another 
location or party without written notification to the Sponsor. 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the collected data. Source documents are filed at the investigator’s 
site. 
• Data entered on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 

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Study and Site Closures 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the investigator 
• Discontinuation of further study treatment development 
Publication Policy 
• The Sponsor will comply with the requirements for publication of study results, and 
the results of this study may be published or presented at scientific meetings. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement. The coordinating investigator agrees to submit all manuscripts or abstracts 
to the Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors (ICMJE) authorship requirements. 

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APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS AND 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S 
LAW CASES 
• The tests detailed in Table A2-1 will be performed by the local laboratory. 
• Protocol specific- requirements for inclusion or exclusion of subjects are detailed in 
Section 5.1 and Section 5.2 of the protocol, respectively. 
• Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• Pregnancy Testing: Refer to Section 5.1 for screening criteria, to Appendix 4 for 
women of childbearing potential (WOCBP) criteria, and to the Schedule of Activities 
(SoA; Table 1) for timepoints. 
• The results of each test must be entered into the electronic Case Report Form (eCRF). 
• Investigators must document their review of each laboratory safety report. 
Table A2-1 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
RBC Count 
RBC Indices: MCV, MCH, % Reticulocytes  
Hemoglobin 
WBC count with Differential: Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils, Bands (if available) 
Hematocrit 
Platelet count 
Clinical Chemistry 1 
Sodium 
Potassium 
Chloride 
Bicarbonate/Carbon 
Dioxide  
Blood urea nitrogen 
Creatinine 
Glucose (non-fasting) 
Total Protein 
Albumin 
Phosphorus 
Calcium 
Magnesium 
Uric Acid 
ALT/AST 
Total and direct 
bilirubin  
ALP 
Gamma-glutamyl 
transferase 
Lipase 
CPK isoenzymes 2 
Total and skeletal muscle (MM) component (not required for screening purposes) 
Coagulation Tests 
Prothrombin time/INR, aPTT or PTT 
Routine Urinalysis 
Appearance, specific gravity, pH, glucose, protein/albumin, blood, ketones, bilirubin, 
urobilinogen, nitrites, leukocyte esterase 
Microscopic examination (if blood or protein is abnormal) 

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Table A2-1 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Other Screening Tests 
Follicle stimulating hormone and estradiol (as needed in women of nonchildbearing 
potential only) 3 
Highly sensitive blood or urine hCG pregnancy test (as needed for women of 
childbearing potential) 4 
Serology 5: HBsAg, HBcAb, and hepatitis C virus antibody. Additional testing 
(eg, hepatitis B viral load, HBsAb, hepatitis B core IgM antibody) may be required if 
results are inconclusive or positive for surface antigen/core antibody.  
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; CPK = creatine phosphokinase; hCG = human chorionic gonadotropin; HBcAb = hepatitis B 
virus core antibody; HBsAg, hepatitis B virus surface antigen; IEC = Independent Ethics Committee; IRB, Institutional Review 
Board; INR, international normalized ratio; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; PTT = 
partial thromboplastin time; RBC = red blood cell; SAE = serious adverse event; ULN = upper limit of normal; WBC = white 
blood cell. 
1 Concurrent elevation of AST or ALT >3 × ULN AND total bilirubin >2 × ULN or INR >1.5 in the absence of cholestasis and 
other causes (eg, viral hepatitis, other pre-existing or acute liver disease, or another drug capable of the observed injury), which 
may indicate severe drug-induced liver injury (possible Hy’s law case). All events with the defined biochemical abnormalities 
must be reported as an SAE; and study medications should be permanently discontinued. 
2 Variations of CPK isoenzymes are acceptable (CK, CKMB, Troponin I) 
3 See Appendix 4. 
4 Local urine testing will be standard for the protocol unless blood testing is required by local regulation or IRB/IEC. For 
screening, a blood test is required. 
5 For Serology: 
• 
Negative HBsAg test is required at screening 
• 
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative 
hepatitis B virus (HBV) DNA test at screening. (The HBV DNA test must be performed for subjects who have a negative 
HBsAg test and a positive total HBcAb test.) 
• 
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV 
RNA test at screening. 
Review and Assessment of Potential Hy’s Law Cases 
The investigator is responsible for determining whether a subject meets potential Hy’s Law 
criteria at any point during the study. All sources of hepatic biochemistry laboratory data 
available to the investigator should be reviewed to identify potential Hy’s Law events; this 
includes samples taken at scheduled study visits and other visits, including central and all local 
laboratory evaluations, even if collected outside of the study visits. 
The following are the key components used to detect potential Hy’s Law cases: 
• Hepatocellular injury, indicated by 3-fold or greater elevations above the upper limit of 
normal (ULN) of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
• Elevation of serum total bilirubin to >2 × ULN (suggesting hepatic functional 
compromise), without initial findings of cholestasis (elevated serum alkaline phosphatase 
[ALP]) 
• No other reason can be found to explain the combination of increased aminotransferase(s) 
and total bilirubin, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or 
another drug capable of causing the observed injury 
Any potential Hy’s Law case (as described above) should be handled as a serious adverse event 
(see reporting requirements in Appendix 3) associated with the use of the drug and reported to 
the Sponsor promptly (ie, even before all other possible causes of liver injury have been 

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excluded). It should be promptly reported to the Sponsor before fully working up the subject to 
rule out other etiologies. The case should be reported with the seriousness criterion of medically 
significant selected, and should include all available information, especially that needed for 
evaluating the severity and likelihood that the drug caused the reaction and should initiate a close 
follow-up until complete resolution of the problem and completion of all attempts to obtain 
supplementary data. 

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APPENDIX 3. ADVERSE EVENTS: DEFINITIONS AND PROCEDURES 
FOR RECORDING, EVALUATING, FOLLOW-UP, AND 
REPORTING 
Definition of Adverse Event (AE) 
AE Definition 
• 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical study subject, temporally 
associated with the use of study treatment, whether or not considered related to the study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, electrocardiogram [ECG], radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease or laboratory value changes that require 
treatment or adjustment to current study therapy). 
• 
Exacerbation of a chronic or intermittent preexisting condition including either an increase in frequency 
and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a concomitant 
medication. Overdose per se will not be reported as an AE/serious adverse event (SAE) unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported 
regardless of sequelae. 
 
Events NOT Meeting the AE Definition 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being 
studied, unless more severe than expected for the subject’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the procedure is 
the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 
• 
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or detected at the start of 
the study that do not worsen. 

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Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE, even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death due 
to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life threatening 
The term 'life threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death 
at the time of the event. It does not refer to an event that hypothetically might have caused death if it had been 
more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during hospitalization are adverse events 
(AEs). If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from baseline is not 
considered an AE. 
d. 
Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance, such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), 
which may interfere with or prevent everyday life functions, but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs. 
f. 
Other situations 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations, such as important medical events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition. These events should usually be considered serious. 
Examples of such events include other invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
Potential Hy’s Law cases that meet the description outlined in Appendix 2 should be reported as SAE. 

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Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
• 
When an adverse event (AE)/serious adverse event (SAE) occurs, it is the responsibility of the investigator to 
review all documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) related to 
the event and report pertinent information. 
• 
The investigator will then record all relevant AE/SAE information in the electronic case report form (eCRF). 
Additionally, investigative sites should report SAEs within 24 hours of becoming aware of the event using 
the paper SAE report form. See section below on the reporting of SAEs. 
• 
It is not acceptable for the investigator to send photocopies of the subject’s medical records in lieu of 
completion of the AE/SAE Case Report Form (CRF) and SAE report form. Only pertinent information 
should be reported. 
• 
There may be instances when copies of medical records for certain cases are requested by the Sponsor or 
designee. In this case, all subject identifiers, with the exception that the subject number will be redacted on 
the copies of the medical records before submission to the Sponsor or designee. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
Assessment of Intensity 
The investigator will assess intensity (severity) for each AE and SAE reported during the study using the 
definitions found in the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5 
(NCI CTCAE v5) or later. The NCI CTCAE v5 displays Grades 1 through 5 with unique clinical descriptions of 
severity for each referenced AE. If a subject experiences any AE not listed in the NCI CTCAE v5, the following 
grading system should be used to assess severity: 
 
• 
Grade 1 (Mild) – experiences which are usually transient, requiring no special treatment, and not interfering 
with the subject’s daily activities 
• 
Grade 2 (Moderate) – experiences which introduce some level of inconvenience or concern to the subject, 
and that may interfere with daily activities, but are usually ameliorated by simple therapeutic measures 
• 
Grade 3 (Severe) – experiences that are unacceptable or intolerable, significantly interrupt the subject’s usual 
daily activity, and require systemic drug therapy or other treatment 
• 
Grade 4 (Life threatening) – experiences that cause the subject to be in danger of life-threatening 
consequences and urgent intervention is required 
• 
Grade 5 (Death) – experiences which result in subject death 
The terms “severe” and “serious” are not synonymous. An AE that is assessed as Grade 3 or 4 should not be 
confused with an SAE. Severity is a category utilized for rating the intensity of an event; and both AEs and 
SAEs can be assessed as Grade 3 or 4. An event is defined as serious when it meets at least 1 of the predefined 
seriousness, as described in the definition of an SAE, not only when it is rated as Grade 3 or 4. 

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Assessment of Causality 
• 
The investigator is obligated to assess the relationship between both study interventions/study treatment and 
each occurrence of each AE/SAE. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study treatment administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and applicable prescribing information in 
his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the investigator has minimal information to 
include in the initial report to the Sponsor or designee. However, it is very important that the investigator 
always makes an assessment of causality for every event before the initial transmission of the SAE 
data to the Sponsor or designee. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and send a SAE 
follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by the Sponsor or designee to elucidate the nature and/or 
causality of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
• 
If a subject dies during participation in the study or during a recognized follow-up period, the investigator 
will provide the Sponsor or designee with a copy of any postmortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The investigator will submit any updated SAE data within 24 hours of receipt of the information on an 
updated SAE report form to either the email or fax listed below. 
Reporting of SAES 
SAE Reporting to the Sponsor or Designee via Paper CRF 
• 
Investigative sites should report SAEs within 24 hours of becoming aware of the event to the Fortrea 
Pharmacovigilance department using the paper SAE report form and any supporting documentation either by 
email or fax.  
Email:  SAEIntake@fortrea.com 
Fax: 1 888 887 8097 
• 
In rare circumstances and in the absence of email or facsimile equipment, notification by telephone to the 
Medical Monitor is acceptable with a copy of the SAE report form sent to Fortrea when email and fax 
becomes available. 
• 
Contacts for SAE reporting and the SAE report form can be found in the Regulatory binder. 

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APPENDIX 4. CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal, unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study treatment, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with one of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should 
be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
− A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
A high follicle stimulating hormone (FSH) and estradiol level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH and estradiol 
measurement is required. 
− Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 

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Contraception Guidance 
CONTRACEPTIVES1 ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methods2 That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
• 
Implantable progestogen only hormone contraception associated with inhibition of ovulation 3 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)3 
• 
Bilateral tubal occlusion 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential (WOCBP) and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 
90 days.) 
Highly Effective Methods 3 That Are User Dependent Failure rate of <1% per year when used consistently and 
correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation 3 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulation 3 
• 
oral 
• 
injectable 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the subject.) 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method are NOT acceptable methods of contraception. Male condom and female condom 
should not be used together (due to risk of failure with friction). 
1 Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for 
those participating in clinical studies. Contraceptive requirements do not apply to subjects who are exclusively in same sex 
relationships. 
2 Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used 
consistently and correctly. 
3 Hormonal contraception efficacy may potentially be decreased due to interaction with sotorasib thus male condoms must be 
used in addition to hormonal contraception. 
COLLECTION OF PREGNANCY INFORMATION 
Male Subjects with Partners Who Become Pregnant 
• The investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this study. This 

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applies only to male subjects who receive RMC4630 and sotorasib under this 
protocol. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form provided in the regulatory binder and submit it to the Sponsor within 24 hours 
of learning of the partner’s pregnancy. The female partner will also be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Generally, the follow-up will be no longer 
than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Female Subjects Who Become Pregnant 
• The investigator will collect pregnancy information on any female subject who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
subject's pregnancy. 
• The subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the subject and the neonate, and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an adverse event (AE) or serious 
adverse event (SAE), any pregnancy complication or elective termination of a 
pregnancy will be reported as an AE or SAE. A spontaneous abortion is always 
considered to be an SAE and will be reported as such. Any poststudy pregnancy 
related SAE considered reasonably related to the study treatment by the investigator 
will be reported to the Sponsor pregnancy information on the appropriate form 
provided in the regulatory binder. While the investigator is not obligated to actively 
seek this information in former study subjects, he/she may learn of an SAE through 
spontaneous reporting. 
• Any female subject who becomes pregnant while participating in the study will 
discontinue study treatment and be withdrawn from the study. 

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APPENDIX 5. GENETICS 
Use and Analysis of Tumor DNA during the Main Protocol 
• Genetic variation in tumor tissue may impact a subject’s response to study treatment, 
susceptibility to, and severity and progression of disease. Variable response to study 
treatment may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) allow, blood and tumor tissue samples will be collected for DNA 
analysis from consenting subjects. 
• DNA samples from tumor tissue will be retrospectively analyzed to explore clinical 
activity in subjects with specific molecular abnormalities. In addition, predefined 
biomarkers for the sensitivity to SHP2 and/or MEK1/2, and EGFR will be evaluated. 
• DNA extracted from archival subject tumor tissue will be used to evaluate if a subject 
has specific tissue abnormalities in their DNA that may be sensitive to our RMC4630 
and sotorasib. This information will be used to confirm if a subject has the same 
mutations as their local genetic results (noncentralized testing laboratory) report. The 
local report is the basis for eligibility assessment. 
• Additional analyses may be conducted if it is hypothesized that this may help further 
understand the clinical data. 
• DNA and RNA from blood and archival tumor tissue will be used for research related 
to study treatment or non-small cell lung cancer (NSCLC) and/or other solid tumors. 
Genetic research will include biomarkers of sensitivity in blood, including but not 
limited to circulating tumor deoxyribonucleic acid (ctDNA). Whole exome and 
transcriptome studies, which will be conducted on archival tissue (or fresh if archival 
is not available) to explore if DNA and RNA can help identify potential biomarkers 
associated with response to RMC-4630 and sotorasib. 
• The results of genetic analyses may be reported in the clinical study report or in a 
separate study summary. 
The Sponsor will remove all subject identifiers from the subject samples to inhibit recognition or 
reidentification. The anonymized DNA samples will be stored in a secure storage space prior to 
testing for markers of drug sensitivity. All samples will be processed and analyzed for the 
purposes of this study and the output will be anonymized subject data, which may be applied for 
future research. 
Subject sample retention will not exceed 10 years after the final study results have been reported 
as per local requirements. 

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APPENDIX 6. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMOURS (RECIST V1.1) 
For this study, response and progression will be evaluated using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumours guideline version 1.1 
(RECIST v1.1; Eisenhauer,2009). 
Measurability of Tumor at Baseline 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or nonmeasurable as 
follows. 
a. 
Measurable Tumor Lesions 
Tumor Lesions. Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by computed tomography (CT) or magnetic resonance imagining (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm) 
• 10 mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as nonmeasurable) 
• 20 mm by chest X-ray 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
b. 
Nonmeasurable Tumor Lesions 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis), as well as truly nonmeasurable lesions. Lesions considered truly 
nonmeasurable include the following: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques. 
c. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone Lesions: 
• Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 

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or MRI can be considered measurable lesions if the soft tissue component meets the 
definition of measurability described above. 
• Blastic bone lesions are nonmeasurable. 
Cystic Lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor nonmeasurable) since they are, 
by definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same subject, these are preferred for selection as 
target lesions. 
Lesions with Prior Local Treatment: 
• Tumor lesions situated in a previously irradiated area or in an area subjected to other 
locoregional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
Specifications by Methods of Measurements 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
Methods of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
a. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm 
diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
b. 
Chest X-Ray 
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 

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c. 
CT and MRI 
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (eg, for body scans). 
d. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and because they are operator dependent, it cannot be guaranteed that the 
same technique and measurements will be taken from one assessment to the next. If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If 
there is concern about radiation exposure from CT, MRI may be used instead of CT in selected 
instances. 
e. 
Endoscopy and Laparoscopy 
The utilization of these techniques for objective tumor evaluation is not advised. However, they 
can be useful to confirm complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
f. 
Tumor Markers 
Tumor markers alone cannot be used to assess objective tumor response. If markers are initially 
above the upper normal limit, however, they must normalize for a subject to be considered in 
complete response. 
g. 
Cytology and Histology 
These techniques can be used to differentiate between partial response (PR) and CR in rare cases 
if required by protocol (eg, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). When effusions are known to be a potential adverse 
effect of treatment (eg, with certain taxane compounds or angiogenesis inhibitors), the 
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met criteria for response or stable 
disease in order to differentiate between response (or stable disease) and progressive disease 
(PD).  
Tumor Response Evaluation 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and to use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion, as detailed above. 
Baseline Documentation of “Target” and “Nontarget” Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 

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should be identified as target lesions and will be recorded and measured at baseline. This means 
that if a subject has only one or 2 organ sites involved, a maximum of 2 and 4 lesions, 
respectively, will be recorded. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement, in which circumstance, the next largest lesion which can be 
measured reproducibly should be selected. 
Lymph Nodes 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor. As noted above, pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of ≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI, the plane of 
acquisition may be axial, sagittal, or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis ≥10 
but <15 mm) should be considered nontarget lesions. Nodes that have a short axis <10 mm are 
considered nonpathological and should not be recorded or followed. 
Sum of Diameters 
A sum of the diameters (longest for non-nodal lesions and short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. As noted above, if 
lymph nodes are to be included in the sum, only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget lesions and should also be recorded at baseline. Measurements are not required, and 
these lesions should be followed as “present,” “absent,” or, in rare cases, “unequivocal 
progression.” In addition, it is possible to record multiple nontarget lesions involving the same 
organ as a single item on the case report form (CRF) (eg, “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases’). 
Response Criteria 
a. 
Evaluation of Target Lesions 
Response 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
nontarget) must have reduction in short axis to <10 mm). 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum of diameters. 

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Response 
Evaluation of Target Lesions 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. NOTE: the appearance of one or more new 
lesions is also considered progression. 
b. 
Special Notes on Assessment of Target Lesions 
Lymph Nodes: 
Lymph nodes identified as target lesions should always have the short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm. Thus, when lymph nodes are included as target lesions, the “sum” of 
lesions may not be zero even if CR criteria are met, since a normal lymph node is defined as 
having a short axis <10 mm. CRFs or other data collection methods may therefore be designed to 
have target nodal lesions recorded in a separate Section where, in order to qualify for CR, each 
node must achieve a short axis <10 mm. For PR, stable disease (SD), and PD, the actual short 
axis measurement of the nodes is to be included in the sum of target lesions. 
Target Lesions that Become “Too Small to Measure”: 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as “too small to 
measure.” 
When this occurs, it is important that a value be recorded on the case report form. If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly, but too small to measure, 
a default value of 5 mm should be assigned (derived from 5-mm slice thickness). 
Note: It is less likely that this rule will be used for lymph nodes since they usually have a 
definable size when normal and are frequently surrounded by fat such as in the retroperitoneum; 
however, if a lymph node is believed to be present and is faintly, but too small to measure, a 
default value of 5 mm should be assigned in this circumstance as well. To reiterate, however, if 
the radiologist is able to provide an actual measurement, it should be recorded even if it is below 
5 mm. 
Lesions that Split or Coalesce on Treatment: 
When non-nodal lesion “fragment,” the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
“coalesced lesion.” 

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c. 
Evaluation of Nontarget Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of nontarget lesions. Although some nontarget lesions may actually be measurable, they 
need not be measured and, instead, should be assessed only qualitatively at the timepoints 
specified in the protocol. 
Response 
Evaluation of Nontarget Lesions 
Complete Response (CR) 
Disappearance of all nontarget lesions and normalization of tumor marker level.  
All lymph nodes must be nonpathological in size (<10 mm short axis) 
Non-CR/ Non-PD 
Persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker 
level above the normal limits 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal existing nontarget 
l
i
d. 
Special Notes on Assessment of Progression of Nontarget Disease 
When the Subject Also Has Measurable Disease 
In this setting, to achieve “unequivocal progression” on the basis of the nontarget disease, there 
must be an overall level of substantial worsening in nontarget disease such that, even in presence 
of SD or PR 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 nontarget lesions is 
usually not sufficient to quality for unequivocal progression status. The face of SD or PR of 
target disease will therefore be extremely rare. 
When the Subject Has Only Nonmeasurable Disease 
This circumstance arises in some Phase III trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above, however, in this 
instance there is no measurable disease assessment to factor into the interpretation of an increase 
in nonmeasurable disease burden. Because worsening in nontarget disease cannot be easily 
quantified (by definition: if all lesions are truly nonmeasurable), a useful test that can be applied 
when assessing subjects for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in nonmeasurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease (ie, an increase in tumor 
burden representing an additional 73% increase in “volume,” which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include an increase in a pleural effusion 
from “trace” to “large,” an increase in lymphangitic disease from localized to widespread or may 
be described in protocols as “sufficient to require a change in therapy.” If “unequivocal 
progression” is seen, the subject should be considered to have had overall PD at that point. While 
it would be ideal to have objective criteria to apply to nonmeasurable disease, the very nature of 
that disease makes it impossible to do so; therefore, the increase must be substantial. 
e. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal (ie, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor [eg, some “new” bone 

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lesions that may be simply healing or flare of pre-existing lesions]). This is particularly 
important when the subject’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it 
is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The subject’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
f. 
FDG-PET 
While fluorodeoxyglucose PET (FDG-PET) response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in assessment of progression (particularly possible “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 
− A positive FDG-PET scan lesion is one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image 
• No FDG-PET at baseline and 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 scans 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 FDG-PET scan). 
− If the positive FDG-PET at follow-up corresponds to a preexisting site of disease 
on CT that is not progressing on the basis of the anatomic images, this is not PD. 
A “positive” FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected 
image.  

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Evaluation of 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). The subject’s best overall response assignment will depend on the 
findings of both target and nontarget disease and will also take into consideration the appearance 
of new lesions. 
a. 
Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs. Table A6-1 
provides a summary of the overall response status calculation at each timepoint for subjects who 
have measurable disease at baseline. 
When subjects have nonmeasurable (therefore nontarget) disease only, Table A6-2 is to be used. 
Table A6-1 
Timepoint Response: Subjects with Target Lesions (with or without 
Nontarget Lesions) 
Target Lesions 
Nontarget Lesions 
New Lesion? 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; NE, = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease. 
Table A6-2 
Time Point Response: Subjects with Nontarget Lesions Only 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD1  
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease. 
1 “Non CR/non PD” is preferred over “stable disease” for nontarget disease since stable disease is increasingly used as an 
endpoint for assessment of efficacy in some trials; thus, assigning “stable disease” when no lesions can be measured is not 
advised. 

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b. 
Missing Assessments and Unevaluable Designation 
When no imaging/measurement is done at a specific time point, the subject is not evaluable (NE) 
at that time point. If only a subset of lesion measurements is made at an assessment, usually the 
case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point 
response. This would be most likely to happen in the case of PD. For example, if a subject had a 
baseline sum of 50 mm with 3 measured lesions and, during the study, only 2 lesions were 
assessed, but those gave a sum of 80 mm, the subject will have achieved PD status, regardless of 
the contribution of the missing lesion. 
c. 
Best Overall Response: All Timepoints 
The best overall response is determined after all data for the subject is known. 
Best response determination in trials where confirmation of complete or partial response is 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point, as specified in the protocol (generally 4 weeks later). In this 
circumstance, the best overall response can be interpreted as in Table A6-3. 
Table A6-3 
Best Overall Response when Confirmation Is Required 
Overall Response 
at First 
Time Point 
Overall Response 
at Subsequent  
Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR1 
CR 
SD 
SD, provided minimum duration for SD was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration for SD was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration for SD was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration for SD was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration for SD was met; otherwise, NE 
NE 
NE 
NE 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease. 
1 If a CR is truly met at the first timepoint, any disease n at a subsequent timepoint, even disease meeting PR criteria relative to 
baseline, qualifies as PD at that point (since disease must have reappeared after CR). Best response would depend on whether the 
minimum duration for SD was met. However, sometimes CR may be claimed when subsequent scans suggest small lesions were 
likely still present and in fact the subject had PR, not CR, at the first timepoint. Under these circumstances, the original CR 
should be changed to PR and the best response is PR. 
d. 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (<10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 

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based on increase in size of the nodes. As noted earlier, this means that subjects with CR may not 
have a total sum of “zero” on the CRF. 
In trials where confirmation of response is required, repeated “NE” time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, 
in most trials it is reasonable to consider a subject with timepoint responses of PR-NE-PR as a 
confirmed response. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response; it is a reason for stopping study therapy. The objective response status of 
such subjects is to be determined by evaluation of target and nontarget disease as shown in 
Table A6-1.  
Conditions that define “early progression, early death and un-evaluability” are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine-needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar to 
a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 

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APPENDIX 7. EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE STATUS SCALE 
ECOG Performance Status 
0 
Fully Active, Able to Carry on All Pre-Disease Performance Without Restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature (eg, light housework or office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more 
than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Abbreviations: ECOG = Eastern Cooperative Oncology Group. 

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APPENDIX 8. LIST OF PROHIBITED MEDICATIONS WHILE 
RECEIVING TREATMENT 
A partial list of drug classes that potentially prolong corrected QT segment (QTc), are strong 
Cytochrome-P450 (CYP)3A inhibitors and/or inducers, are CYP3A sensitive substrates, or are 
P-Glycoprotein (P-gp) sensitive substrates is provided below.  
Medications known to prolong QTc 
Amiodarone 
Anagrelide 
Arsenic Trioxide  
Azithromycin 
Chloroquine 
Chlorpromazine 
Cilostazol 
Ciprofloxacin 
Citalopram 
Disopyramide 
Dofetilide 
Donepezil 
Dronedarone 
Droperidol 
Erythromycin 
Escitalopram 
Flecainide  
Fluconazole 
Haloperidol 
Ibutilide 
Levofloxacin 
Methadone 
Moxifloxacin 
Ondansetron 
Oxaliplatin 
Pentamidine  
Pimozide 
Procainamide 
Propofol 
Quinidine 
Sevoflurane 
Sotalol 
Thioridazine 
Vandetanib 
Proton Pump Inhibitors (PPIs) 
Omeprazole  
Lansoprazole  
Dexlansoprazole 
Rabeprazole 
Pantoprazole  
Esomeprazole 
H-2 Receptor Antagonists 
Ranitidine  
Famotidine  
Cimetidine  
Nizatidine  
Strong CYP3A Inhibitors 
Boceprevir 
Itraconazole 
Ritonavir 
Clarithromycin 
Ketoconazole 
Saquinavir and ritonavir 
Cobicistat 
Lopinavir and ritonavir 
Telaprevir 
Danoprevir and ritonavir 
Nefazodone 
Tipranavir and ritonavir 
Elvitegravir and ritonavir 
Nelfinavir 
Telithromycin 
Grapefruit juice 
Paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir) 
Troleandomycin 
Idelalisib  
Posaconazole 
Voriconazole 
Indinavir and ritonavir 

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Strong CYP3A Inducers 
Apalutamide 
Mitotane 
St. John’s wort 
Carbamazepine 
Phenytoin 
Enzalutamide 
Rifampin 
Sensitive CYP3A4 Substrates (require Principal Investigators’ review and approval) 
Alfentanil 
Avanafil 
Buspirone 
Conivaptan 
Darifenacin 
Darunavir 
Ebastine 
Everolimus 
Ibrutinib 
Lomitapide 
Lovastatin 
Midazolam 
Naloxegol 
Nisoldipine 
Saquinavir 
Simvastatin 
Sirolimus 
Tacrolimus 
Tipranavir 
Triazolam 
Vardenafil 
Budesonide 
Dasatinib 
Dronedarone 
Eletriptan 
Eplerenone 
Felodipine 
Indinavir 
Lurasidone 
Maraviroc 
Quetiapine 
Sildenafil 
Ticagrelor 
Tolvaptan 
Strong P-gp Inhibitors  
Amiodarone  
Carvedilol  
Clarithromycin  
Dronedarone  
Itraconazole  
Lapatinib 
Lopinavir and Ritonavir  
Propafenone  
Quinidine  
Ranolazine  
Ritonavir  
Saquinavir and Ritonavir  
Telaprevir  
Tipranavir and Ritonavir  
Verapamil 
Sensitive P-gp Substrates (require Principal Investigators’ review and approval) 
Dabigatran Etexilate 
Digoxin 
Fexofenadine 
Please note that this list is not comprehensive.  
The list and updates of medications that are known to prolong QTc may be obtained from www.crediblemeds.org.  
Additional information and updates concerning strong CYP3A inhibitors and inducers, and strong P-gp inhibitors 
can be found at www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractions 
Labeling/ ucm093664.htm. 
In addition, consult the prescribing information when determining whether a concomitant medication can be safety 
administered with study treatment. Contact the Medical Monitor if questions arise regarding medications not listed. 

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APPENDIX 9. POTENTIAL GENETIC MODIFIERS FOR 
ENROLLMENT INTO DOSE EXPANSION  
The listed genotypic mutations will be used to categorized subjects, based on their genomic 
report. The Sponsor may be contacted to assist in the identification of mutations that may not be 
listed in this appendix.  
Cohort 1 – only KRASG12C NSCLC (without any potential genetic modifiers) 
Cohort 2 – including the following:  
• STK11/LKB1  
• KEAP1 
• PIK3CA 
• BRAF Class 1/2/unclassified  
• ATRX 
• BRCA2 

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APPENDIX 10. CONTINGENCY MEASURES FOR A REGIONAL OR 
NATIONAL EMERGENCY THAT IS DECLARED BY A 
GOVERNMENTAL AGENCY 
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, pandemic, natural disaster, or terrorist attack) may prevent access to the clinical trial 
site.  
For an emergency that prevents access to the study site, possible contingency measures are 
suggested below in order to ensure the safety of subjects, consider continuity of clinical study 
conduct, protect trial integrity, and assist in maintaining compliance with International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
guidelines for Good Clinical Practice (GCP).  
Procedure modifications that may be considered in the event of a regional or national emergency 
declared by a governmental agency include the following:  
• If onsite visits are not possible, remote visits may be considered for the collection of 
possible data.  
• If onsite visits are not possible, noncritical assessments could be omitted.  
• Visit windows may be extended in cases where required assessments cannot be  
• obtained remotely.  
• Use of local laboratory locations may be allowed.  
• The direct-to-patient (DTP) supply of study medication from the PI/site/Sponsor may 
be allowed by local regulations and agreed upon by the subject. 
Contingencies implemented due to emergency will be documented.  
For the duration of the emergency, Sponsor agreement must be obtained prior to the 
implementation of these procedure modifications.  
It is the investigator’s responsibility to protect the rights, safety, and well-being of study 
subjects. Investigators must be able to manage and oversee study conduct and the safety of study 
subjects in order to continue enrolling and treating subjects in the study. During the emergency, 
if the site is unable to adequately follow protocol-mandated procedures, screening and 
administration of study treatment may be temporarily delayed.  
For a regional or national emergency declared by a governmental agency, contingency 
procedures may be implemented for the duration of the emergency. The subject or their legally 
authorized representative should be verbally informed prior to initiating any changes that are to 
be implemented for the duration of the emergency (eg, study visit delays/treatment extension or 
use of local laboratories).  
The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized in the clinical study report (eg, study discontinuation or 
discontinuation/delay/omission of the study treatment due to the emergency). Any additional 
analyses and methods required to evaluate the objectives and endpoints of the study (eg, missing 
data due to the emergency) will be detailed in the statistical analysis plan.  

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APPENDIX 11. MODIFIED TOXICITY PROBABILITY INTERVAL-2 
(MTPI-2) DESIGN DETAILS 
Dose escalation/de-escalation during the safety run-in phase will follow an mTPI-2 algorithm 
(Guo, 2017), with a target dose-limiting toxicity (DLT) probability of 0.30 and the acceptable 
toxicity probability interval of 0.25 to 0.35.  
DLT assessment will be performed on the DLT-evaluable population (see Section 9.3), as guided 
by the following mTPI-2 decision table.  
Dose Escalation Rule of the Modified Toxicity Probability Interval-2 Method 
 
Number of DLT–Evaluable Subjects Treated at Current Dose 
3 
4 
5 
6 
7 
8 
9 
Number of Dose-
Limiting 
Toxicities 
0 
E 
E 
E 
E 
E 
E 
E 
1 
S 
S 
E 
E 
E 
E 
E 
2 
D 
D 
D 
S 
S 
S 
E 
3 
DU 
DU 
D 
D 
D 
D 
S 
4 
 
DU 
DU 
DU 
D 
D 
D 
5 
 
 
DU 
DU 
DU 
DU 
DU 
6 
 
 
 
DU 
DU 
DU 
DU 
7 
 
 
 
 
DU 
DU 
DU 
8 
 
 
 
 
 
DU 
DU 
9 
 
 
 
 
 
 
DU 
Source: Guo W, Wang SJ, Yang S, et al. A Bayesian interval dose-finding design addressing Ockham’s razor: mTPI-2. Contemp 
Clin Trials. 2017;58:23-33. 
Abbreviations: D = de-escalate to the next-lower dose; DLT = dose-limiting toxicity; DU = de-escalate to the next-lower dose 
and the current dose will never be used again because of unacceptable high toxicity (ie, the probability that the DLT rate is higher 
than 30% at the current dose is greater than 95%); E = escalate to the next-higher dose; S = stay at the current dose. 

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APPENDIX 12. ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATE 
arterial thromboembolic events 
BCVA 
best corrected visual acuity 
BIW 
twice weekly 
BRAF Class 3 
class 3 type mutations in BRAF 
BRAT 
banana, rice, apples, toast 
BUN 
blood urea nitrogen 
C1, Cx, etc 
Cycle 1, Cycle x, etc 
C1D1, CxDx, etc 
Cycle 1 Day 1, Cycle x Day x, etc 
CAP 
College of American Pathologists 
CBC 
complete blood count 
CDX 
cell-line-derived xenograft 
CFR 
Code of Federal Regulation 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
central nervous system 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019  
CPK 
creatine phosphokinase 
CR 
complete response 
CRC 
colorectal cancer 
CrCl 
creatinine clearance 
CRISPR 
clustered regularly interspaced short palindromic repeats 
CRO 
contract research organization 

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Abbreviation 
Definition 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor deoxyribonucleic acid 
CYP 
cytochrome P-450 
D1, Dx, etc 
Day 1, Day x, etc 
DCR 
disease control rate 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DTP 
direct-to-patient 
EC50 
50% effective concentration 
EC75 
75% effective concentration 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End-of-Treatment 
ERK 
extracellular signal-regulated kinase 
FFPE 
formalin fixed; paraffin embedded 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GAP 
GTPase activating protein 
GCP 
Good Clinical practice 
GDP 
guanosine diphosphate 
GGT  
gamma-glutamyl transferase 
GI 
gastrointestinal 
GTP 
guanosine triphosphate 

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Abbreviation 
Definition 
H2-blockers 
H2-receptor antagonists 
HA 
Health Authorities 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HEENT 
head, eyes, ears, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
ILD 
interstitial lung disease 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISMC 
Internal Safety Monitoring Committee 
IUD 
Intrauterine device 
IUS 
intrauterine hormone-releasing system 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
KRASG12C 
KRAS with a mutation at codon 12, which encodes glycine (G) to cysteine (C) 
LLN 
lower limit of normal 
LMWH 
low molecular weight heparin 
LSLV 
last subject, last visit 
LTFU 
long-term follow-up 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTPI-2 
modified toxicity probability interval-2 
MUGA 
multigated acquisition 

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Abbreviation 
Definition 
NCI CTCAE v5 
National Cancer Institute Common Terminology Criteria for Adverse Events 
Version 5 
NF1 
neurofibromin 1 
NF1LOF 
mutations in NF1 predicted to result in loss of function 
NIH 
National Institute of Health 
NRAS 
neuroblastoma RAS viral oncogene homolog 
NSCLC 
non–small cell lung cancer 
OCT 
optical coherence tomography 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PDAC 
pancreatic ductal adenocarcinoma 
PDGF-R 
platelet-derived growth factor receptor 
PDX 
patient-derived xenograft 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-Glycoprotein 
PIC 
powder-in-capsule 
PK 
pharmacokinetic(s) 
PO 
oral(ly) 
PPI 
proton pump inhibitors 
PR 
partial response 
PS 
performance status 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QT interval corrected using Fridericia's formula 
RBC 
red blood cell 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumours, Version 1.1 
RNA 
ribonucleic acid 

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Abbreviation 
Definition 
ROS1 
reactive oxygen species proto-oncogene 1 
RP2D/RP2DS 
recommended Phase 2 dose/recommended Phase 2 dose and schedule 
RPED 
retinal pigment epithelial detachment 
RTK 
receptor tyrosine kinase 
RVO 
retinal vein occlusion 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SHP2 
Src homology 2 domain-containing protein tyrosine phosphatase 2 
SJS 
Stevens-Johnson syndrome 
SoA 
Schedule of Activities 
SOC 
standard-of-care 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse events 
TEN 
toxic epidermal necrolysis 
TKI 
tyrosine kinase inhibitor 
ULN 
upper limit of normal 
US 
United States 
VEGF-R 
vascular endothelial growth factor receptor 
VTE 
venous thromboembolic events 
WBC 
white blood cell 
WOCBP 
women of childbearing potential