A Randomized Phase 3 Study of MRTX849 Versus Docetaxel in Patients With Previously Treated Non-Small Cell Lung Cancer With KRAS G12C Mutation
Phase: PHASE3
Conditions: Metastatic Non Small Cell Lung Cancer, Advanced Non Small Cell Lung Cancer
Sponsor: Mirati Therapeutics Inc.

Official Title of Study: 
A Randomized Phase 3 Study of MRTX849 versus Docetaxel in Patients with Previously Treated Non-
Small Cell Lung Cancer with KRAS G12C Mutation 
 
NCT Number: NCT04685135 
Document Date (Date in which document was last revised): 24 March 2023 
 
 
 

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CLINICAL RESEARCH PROTOCOL 
DRUG(S): 
MRTX849 
Docetaxel 
STUDY NUMBER: 
849-012 
PROTOCOL TITLE: 
A Randomized Phase 3 Study of MRTX849 versus 
Docetaxel in Patients with Previously Treated 
Non-Small Cell Lung Cancer with KRAS G12C 
Mutation 
IND NUMBER: 
152385 
EudraCT NUMBER: 
2020-003645-11 
SPONSOR: 
Mirati Therapeutics, Inc. 
3545 Cray Court 
San Diego, California, 92121, USA 
ORIGINAL PROTOCOL DATE: 
24 August 2020 
VERSION NUMBER: 
7.0 
VERSION DATE: 
24 March 2023 
 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information and/or trade secrets of Mirati Therapeutics, Inc. As such, this 
document is protected from unauthorized disclosure or use by confidentiality agreement(s) and/or is exempt from 
public disclosure pursuant to applicable FDA and foreign counterpart regulations. 
 
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STUDY SUMMARY 
Title: 
A Randomized Phase 3 Study of MRTX849 versus Docetaxel in Patients 
with Previously Treated Non-Small Cell Lung Cancer with KRAS G12C 
Mutation 
Rationale: 
RAS proteins are part of the family of small GTPases and are activated 
in response to growth factor stimulation and various other extracellular 
stimuli to regulate intracellular signaling pathways responsible for 
growth, migration, survival and differentiation of cells. The activation of 
RAS proteins at the cell membrane by growth factors results in the 
binding of key effector molecules, formation of signaling complexes, 
and the initiation of a cascade of intracellular signaling pathways within 
the cell including the RAF and PI3 kinase pathways. RAS proteins 
normally alternate between GTP- and GDP-bound conformations, where 
the GTP-bound conformation represents the “On” and GDP-bound the 
“Off” state. Dependence of RAS and other GTPases on guanine 
nucleotide exchange factors (GEFs) and GTPase-activating proteins 
(GAPs) to switch them on and off allows both processes to be highly 
regulated and responsive to multiple signal inputs. In contrast, oncogenic 
mutants of RAS generally function by preventing hydrolysis of GTP, 
thereby generating constitutively active GTP-bound RAS molecules with 
severe consequences for the cell including uncontrolled cellular growth 
and malignant transformation. 
KRAS is the most frequently mutated gene of the RAS family, and KRAS 
mutations occur in approximately 30% of lung adenocarcinomas, 50% of 
colorectal cancers, and 90% of pancreatic ductal adenocarcinomas. 
Mutation of the glycine at residue 12 produces a steric block that 
prevents GAP proteins from accessing KRAS, thereby inhibiting GTP 
hydrolysis resulting in a highly activated GTP-bound form of RAS. 
Mutation of that amino acid residue to cysteine, noted as KRAS G12C 
(also known as KRAS p.G12C), comprises approximately 14% of lung 
adenocarcinoma and defines a unique segment of lung cancer without a 
current targeted therapy option. Large genomics studies characterizing 
lung cancers have indicated that KRAS mutations, including G12C, are 
mutually exclusive with other known oncogenic driver mutations in 
non-small cell lung cancer (NSCLC) including EGFR, ALK, ROS1, RET, 
and BRAF indicating that KRAS mutations define a unique segment of 
lung cancer without a current targeted therapy option. Functional 
genomics studies have demonstrated that NSCLC cancer cells exhibiting 
KRAS mutations are highly dependent on KRAS function for cell growth 
and survival. 
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MRTX849 (also known as adagrasib) is a potent and orally available 
small molecule inhibitor of KRAS G12C. MRTX849 demonstrated 
potent inhibition of KRAS-dependent signal transduction and cancer cell 
viability with selectivity for KRAS G12C of over 1000-fold compared to 
KRAS wild-type. MRTX849 demonstrated broad-spectrum antitumor 
activity across several KRAS G12C-positive patient- or cell-derived 
tumor models implanted in mice, including complete tumor responses in 
a subset of models. Collectively, these results support the evaluation of 
MRTX849 in patients with malignancies having KRAS G12C mutations. 
Initial clinical trial observations with MRTX849 include demonstration 
of confirmed objective responses in NSCLC and colorectal cancer. 
This Phase 3 study compares the efficacy of MRTX849 versus docetaxel 
in patients with unresectable, locally advanced or metastatic NSCLC 
with KRAS G12C mutation who have previously received treatment with 
a platinum-based chemotherapy regimen and an immune checkpoint 
inhibitor. 
Target 
Population: 
Patients with unresectable, locally advanced or metastatic NSCLC with 
KRAS G12C mutation and disease progression on or after treatment with 
a platinum-based regimen and an immune checkpoint inhibitor. 
Number in Trial:  
Approximately 450 patients 
Primary 
Objective: 
To compare the efficacy of MRTX849 versus docetaxel in patients with 
NSCLC with KRAS G12C mutation and who have received prior 
treatment with a platinum-based regimen and immune checkpoint 
inhibitor therapy. 
Secondary 
Objectives: 
• To evaluate secondary efficacy endpoints in the study population. 
• To evaluate the safety and tolerability in the study population. 
• To evaluate the pharmacokinetics (PK) of MRTX849 administered in 
the study population. 
• To evaluate health-related quality of life (HRQOL) and lung 
cancer-specific symptoms in the study population. 
Exploratory 
Objective 
• To explore correlations between gene alterations (baseline and upon 
treatment resistance) with efficacy. 
• To evaluate the Progression-Free Survival in the next-line of therapy 
(PFS2) in the study population.  
• To evaluate efficacy outcome in the central nervous system (CNS) 
• To explore intracranial activity in patients with brain metastases 
using exploratory efficacy endpoints  
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Primary 
Endpoint: 
• Progression-Free Survival (PFS)  
Secondary 
Endpoints: 
• Secondary efficacy endpoints: 
− Overall Survival (OS), 
− Objective Response Rate (ORR), 
− Duration of Response (DOR), and 
− 1-Year Survival Rate. 
• Safety characterized by type, incidence, severity, timing, seriousness 
and relationship to study treatment of adverse events (AEs), 
laboratory abnormalities, and number of patients discontinuing study 
treatment due to an adverse event. 
• Population PK parameters of MRTX849. 
• Patient Reported Outcome (PRO) scores using the following: 
− Lung Cancer Symptom Scale (LCSS), and 
− European Quality of Life Five Dimensions Questionnaire (EQ-
5D-5L). 
Exploratory 
Endpoints 
• Gene alterations in tumor tissue and circulating tumor 
deoxyribonucleic acid (ctDNA). 
• Progression-Free Survival-2 (PFS2). 
• Time to CNS Progression. 
• Intracranial activity using CNS RECIST 1.1 endpoints in patients 
with brain metastases, including intracranial objective response rate 
(icORR), intracranial duration of response (icDOR), intracranial 
progression-free survival (icPFS) and intracranial time to progression 
(icTTP). 
Study Design: 
Study 849-012 is an open-label, randomized Phase 3 clinical trial 
comparing the efficacy of MRTX849 (adagrasib) versus docetaxel in 
patients with NSCLC with KRAS G12C mutation and who have received 
prior therapy with a platinum-based regimen and an immune checkpoint 
inhibitor. Secondary objectives include evaluation of safety and 
tolerability, secondary efficacy endpoints, PROs, and MRTX849 PK in 
the study population. 
The presence of KRAS G12C mutation in tumor tissue for the purpose of 
patient eligibility must be established using Sponsor pre-approved 
methods and laboratories. Presence of tumor KRAS G12C mutation may 
be established using Sponsor-approved local tests or the 
Sponsor-provided central laboratory test. For all enrolled patients KRAS 
mutation status and correlative tumor gene alterations will be 
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retrospectively tested using the tumor samples submitted no later than 30 
days after the first dose of study treatment. 
Patient eligibility for study enrollment based on objective disease 
progression on or after a platinum-based regimen and an immune 
checkpoint inhibitor will be evaluated by the Investigator. 
Data entered into the case report form (CRF) are to include prior 
regimens, best overall response, if progression occurred on or after 
treatment and date of progression. 
Eligible patients will be randomized in a 2:1 ratio to receive MRTX849 
or docetaxel, respectively. Randomization will be stratified by: 
1. Region (non-Asia-Pacific versus Asia-Pacific) 
2. Sequential versus concurrent (administration of last prior 
platinum-based chemotherapy and anti-PD-1/PD-L1 antibody) 
The requirements for tumor KRAS G12C for determining eligibility are 
presented in Table 1 and Figure 1. The Schedule of Assessments is 
presented in Table 2. 
Study treatment will be administered in 3-week cycles. Patients 
randomized to the investigational arm will receive MRTX849 
administered orally (PO) at a starting dose of 600 mg twice daily (BID). 
Patients randomized to the comparator arm will receive treatment with 
docetaxel. Docetaxel will be administered by intravenous infusion at 
75 mg/m2 over 1 hour or according to institutional practices every 
3 weeks. Premedication with dexamethasone (or institutional equivalent) 
will be required in accordance with local standards. 
Disease response and progression will be evaluated in accordance with 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). 
Blinded independent central review (BICR) for disease response and 
progression will be performed for the purpose of statistical analyses of 
these study endpoints. Disease assessments must be performed as 
scheduled according to the calendar to prevent the introduction of bias in 
the assessment of efficacy based on toxicity. Timely and complete 
disease assessments and transfer of radiographic documentation to the 
Central Radiology Laboratory is critical to the integrity of this clinical 
trial. 
Patients will receive study treatment as assigned at randomization until 
disease progression, unacceptable AEs, Investigator decision, patient 
refusal or death. Patients experiencing clinical benefit in the judgment of 
the Investigator may continue study treatment beyond Investigator 
assessed disease progression as defined by RECIST 1.1. Patients 
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considering continuation of study treatment beyond RECIST 1.1-defined 
disease progression must be provided with and sign an informed consent 
form detailing any available therapies and potential clinical benefit that 
the patient may be foregoing by continuing study treatment and will 
continue to undergo disease assessments until study treatment is 
discontinued. Imaging should continue to be submitted for BICR review 
until BICR confirmed disease progression. In the event a patient 
discontinues study treatment for a reason other than objective disease 
progression, disease assessments post-treatment should continue until 
objective disease progression is documented by the Investigator and 
BICR or start of subsequent anticancer therapy, whichever is sooner.  
Patients randomized to the docetaxel arm will be offered the opportunity 
to crossover to the MRTX849 study treatment arm upon development of 
RECIST 1.1-defined disease progression per BICR provided that patient 
crossover eligibility criteria are met. Patients must sign a crossover 
informed consent form and meet all eligibility criteria for further 
treatment as described in Section 4.3 and Section 4.4 and will use the 
dosing regimen described in Section 5.3. The required assessments for 
patients who crossover are listed in Appendix 6. 
Statistical 
Considerations: 
Study 849-012 will utilize the fixed-sequence testing procedure on the 
endpoints with an overall 0.05 (2-sided) level of significance.  
For the PFS endpoint, the study has 90% power to detect a HR of 0.645 
(under an assumed median PFS for docetaxel arm of approximately 4 
months compared to 6.2 months for the MRTX849 arm) at a 2-sided 
level of significance of 0.05 based on 246 PFS events. 
For the secondary endpoint OS, the study has 80% power to detect a HR 
of 0.72 (under an assumed median OS for docetaxel arm of 
approximately 10 months compared to 13.9 months in the MRTX849 
arm) at a 2-sided level of significance of 0.05 based on 334 death events. 
Assuming an enrollment duration of approximately 37 months at an 
average rate of 12 patients per month (approximately 450 patients), and 
an additional 15 months of follow-up will be required to reach the 
number of required death events. 
There will be one analysis for the PFS endpoint and an interim analysis 
of OS (~50% of the expected death events), and one final analysis for the 
OS endpoint. The enrollment into the study is anticipated to be 
completed when the PFS analysis occurs. A group sequential design will 
be used with the O’Brien-Fleming boundary as implemented by the Lan-
DeMets alpha spending method. A nonbinding futility boundary using 
the Rho family spending function with parameter of 3.0 is also 
constructed for OS. If the OS endpoint is statistically significant at 
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interim, the formal OS final analysis will not be conducted per group 
sequential design, and a survival update following the PFS analysis may 
be conducted as warranted. 
 
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Table 1: 
Pre-Screening Assessments 
Patient eligibility for enrollment based on the presence of KRAS G12C mutation in the tumor may be established using Sponsor-
approved local tests or a Sponsor-provided central laboratory test.  
 
Guidance 
Evaluation of overall health 
status for potential clinical 
trial participation 
Study eligibility requires adequate performance status and organ function. Patients undertaking pre-screening with the goal of 
considering participation in this study should have health status consistent with meeting eligibility criteria. 
Informed Consent 
Prior to sending results of a local Sponsor-approved tumor genotyping test to the Sponsor for review or sending tumor tissue 
to the Sponsor-approved central laboratory for genotyping, informed consent must be obtained using the IRB/EC-approved 
pre-screening ICF. 
After local or central laboratory documentation of KRAS G12C mutation, the main study consent should be obtained, followed 
by the required study-specific screening procedures. 
Tumor Tissue Testing  
Testing for KRAS G12C mutation is required for all patients. 
• 
For patients with previous test results using a Sponsor-approved method demonstrating KRAS G12C mutation, the 
existing result may be used for pre-screening and enrollment.  
• 
For patients without prior testing, the Sponsor-provided central laboratory test should be used during the pre-screening 
period. 
• 
For all enrolled patients, retrospective KRAS G12C mutation status and evaluation of correlative tumor gene alterations 
will be performed using tumor sample submitted to the central laboratory during pre-screening or within 30 days after 
first dose of study treatment. 
For central laboratory genotyping, tumor samples from the most recent biopsy or excision are preferred; however, if no 
recently obtained materials are available, samples from any time during patient’s prior disease course are accepted. Tumor 
biopsies having significant risk should not be performed for the purpose of determining genetic eligibility. Note: Patients 
enrolled at sites in Germany will not undergo tumor lesion biopsy for the purpose of the study after the Screening period. 
 
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Figure 1: 
Timing of Pre-Screening Assessments 
 
– = negative test; + = positive test; ICF = informed consent form; R = randomization; T = treatment. 
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Table 2: 
Schedule of Assessments 
The Schedule of Assessments provides an overview of clinic visits and protocol procedures. Additional, unplanned assessments 
should be performed as clinically indicated, including for the purpose of fully evaluating AEs. 
 
Screening 
Within 
28 Days 
Cycles 1-4 
Cycles 5 + 
Day 1 
(± 2 days)19 
End of  
Treatment Visit1  
28-35 Days 
After Last Dose 
Long Term  
Follow-up 
Every 2 Months 
(± 14 days) 
Day 1 
C1 (- 2) 
C2-C4 (± 2) 
Day 15 
(± 2 days) 
Informed Consent2 
X 
 
 
 
 
 
Tumor Genotyping3 
X 
 
At disease progression (optional) 
 
Randomization 
X 
 
 
 
 
 
Medical History & Prior Therapy  
X 
 
 
 
 
 
ctDNA4 
X 
 
At disease progression (optional) 
 
Demographics & ECOG 
X 
 
 
 
 
 
Physical Exam5 - Full (F), Abbrev (A) 
F 
A 
A 
A 
F 
 
Vital Signs6 
X 
X 
X 
X 
X 
 
Hematology7 
X 
X 
X 
X 
X 
 
Chemistry7 
X 
X 
 
X 
X 
 
TSH7 
X 
C3 
 
C5 
X 
 
HIV, HBV, HCV Serology (in specified 
countries)8 
X 
 
 
 
 
 
Pregnancy or FSH Test9 
X 
As clinically indicated except where required routinely9 
X 
 
Single 12-Lead ECG10 
X 
As clinically indicated 
X 
 
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Screening 
Within 
28 Days 
Cycles 1-4 
Cycles 5 + 
Day 1 
(± 2 days)19 
End of  
Treatment Visit1  
28-35 Days 
After Last Dose 
Long Term  
Follow-up 
Every 2 Months 
(± 14 days) 
Day 1 
C1 (- 2) 
C2-C4 (± 2) 
Day 15 
(± 2 days) 
ECHO or MUGA (preferred except in 
Germany)11 
Within 45 
days 
 
 
C5 & C9 
(- 7 to + 2 day window) 
 
 
Disease Evaluation12 
X 
Every 6 weeks (± 10 days) until Week 49,  
then every 12 weeks 
 
 
PK Sampling13 & Triplicate ECGs14  
 
C1 & C2 – 
Predose & 
Peak; C3 – 
Predose 
 
C5 & C7 Predose 
 
 
MRTX849 Dispensing (D)  
& Reconciliation (R) 
 
D,  
R (C2-4) 
 
D, R 
R 
 
Docetaxel Admin. & Premeds15  
 
X 
 
X 
 
 
PRO Questionnaires16 
 
X 
X 
X 
X 
 
AEs17 & Concomitant Medications 
SAEs only 
Throughout 
 
Survival & Anticancer Therapies18 
 
 
 
 
 
X 
Abbreviations: A = abbreviated, symptom-directed evaluation, Ab = antibody; AE =adverse event; BICR = blinded independent central review; C = cycle; 
ctDNA = circulating tumor deoxyribonucleic acid; CTFG = Clinical Trials Facilitation Group; D = dispense; ECG = electrocardiogram; 
ECHO = echocardiogram; F = full physical examination; FSH = follicle stimulating hormone; HBcAb = hepatitis B core antibody; HBV = hepatitis B; 
HCV = hepatitis C virus antibody; HGRAC = Human Genetic Resource Administration of China; HIV = human immunodeficiency virus; ICF = informed 
consent form; LCSS = Lung Cancer Symptom Scale; LFT = liver function test; MUGA = multigated acquisition scan; PI = Principal Investigator; 
PK = pharmacokinetic; PRO = patient reported outcome; R = reconcile; RNA =ribonucleic acid; SAE = serious adverse event; TSH = thyroid-stimulating 
hormone. 
1 End of Treatment: Visit occurs 28-35 days after last dose of study treatment. Repeat of assessments completed in the previous 4 weeks is not required with the 
exception of assessment of AEs, hematology, chemistry and pregnancy test as applicable. 
2 Informed Consent: May be performed more than 28 days prior start of study treatment and must be completed prior to initiation of any study-specific 
assessments. 
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3 Tumor Genotyping for KRAS G12C and Other Mutations: Genotyping of tumor tissue for eligibility may occur at any time prior to the study screening period 
in patients considered for enrollment. If no prior genomic testing for KRAS mutation has been performed using a Sponsor-approved laboratory, testing to 
determine eligibility will be provided by the Sponsor. Informed consent using the pre-screening ICF is required prior to sending results of a local test to the 
Sponsor for review or submission of samples for study-specific testing. For all patients randomized into the study, adequate tumor tissue samples for 
retrospective testing of KRAS G12C mutation status and correlative gene alterations must be provided to the central laboratory during pre-screening or within 
30 days after first dose of study treatment. Tumor tissue samples for eligibility should be from the most recent biopsy or excision. Tumor biopsies having 
significant risk should not be performed for the purpose of determining patient eligibility. Optional tumor tissue may also be obtained at the time of progression 
for those patients with an objective tumor response or prolonged stable disease (> 4 months) on study. Note: Patients enrolled at sites in Germany will not 
undergo tumor lesion biopsy for the purpose of the study after the Screening period.  
4 Blood samples for ctDNA: Baseline sample collection may be performed during the screening period through the first dose day. Optional on-study blood 
samples for ctDNA may be obtained at the time of progression for those patients with an objective tumor response or prolonged stable disease (>4 months) on 
study. In China, the samples for ctDNA testing will be collected after the Human Genetic Resource Administration of China (HGRAC) approval. 
5 Physical Examinations: A full physical examination (F) required at Screening and End of Treatment only. All other evaluations will be abbreviated, 
symptom-directed evaluations (A). Allowed time windows permit evaluation within two calendar days (Friday assessments permitted for Monday dosing) in 
advance of busy days, eg, PK profile collection. 
6 Vital Signs: Weight, temperature, blood pressure, pulse rate, and respiratory rate to be assessed prior to dosing as indicated. Vital signs are to be performed in 
the semi-recumbent position. Height will be recorded at screening only. 
7 Safety Laboratory Assessments: Hematology, chemistry, and thyroid function will be performed using local laboratories. Parameters to be assessed are 
presented in Table 15. Repeat baseline assessment not required if assessment performed within 7 days before the first dose. Allowed time windows permit 
evaluation within two calendar days (Friday assessments permitted for Monday dosing) in advance of busy days, eg, PK profile collection. Additional 
assessments of any laboratory parameters may be performed according to standard of care or as clinically indicated. 
8 HIV, HBV, HCV Serology for sites in Germany, Czech Republic, and Portugal: Patients must be tested for HIV Ab, hepatitis B core antibody (HBcAb), and 
hepatitis C virus (HCV Ab) infection (by local laboratory) at screening. Patients with a positive HBcAb test should also be tested with HBsAg test, and those 
patients with a positive HBsAg test should also be tested for HBV DNA. Patients with a positive HCV Ab test should undergo a nucleic acid test for HCV 
RNA (also known as viral load). 
9 Pregnancy and Follicle Stimulating Hormone Test: If the patient is a woman of childbearing potential, negative urine or serum pregnancy test performed by the 
local laboratory at Screening and End of Treatment will be required (in the United Kingdom and Germany, screening test required ≤ 7 days and ≤ 72 hours, 
respectively, before first dose of study treatment). In addition, in regions where required by regulation (eg, European Union), monthly pregnancy testing will be 
performed until the end of systemic exposure to study treatments (testing may be performed at the beginning of each 3-week treatment cycle for convenience). 
At study sites in Austria, Belgium, France, Italy, Portugal, South Korea, and Spain and as required at other sites, pregnancy testing will be performed at the 
beginning of every treatment cycle and the same frequency (approximately monthly) for at least 1 month after the last dose of MRTX849 or docetaxel. 
Additional pregnancy testing is to be performed whenever pregnancy is suspected during the study. Verification of postmenopausal status at screening should 
be documented by follicle stimulating hormone (FSH) testing in countries operating in compliance with Clinical Trials Facilitation Group (CTFG) guidelines.  
10 Single 12-lead ECGs to be performed unless otherwise stated. In addition, ECGs are to be performed as clinically indicated. ECGs are to be performed in the 
semi-recumbent position. Assessments will include an evaluation of heart rate, PR, QRS, RR, QT, and QTc intervals. 
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11 MUGA or ECHO: MUGA is preferred (except in Germany where it is not an option); the same modality should be used throughout a patient’s participation 
when possible. May be performed within 45 days (different from 28-day window for other assessments). 
12 Disease Evaluations: To be performed at screening (28-day window allowed) and every 6 weeks from the date of randomization (± 10-day window for all other 
assessments except screening) until week 49 (~12 months) and then every 12 weeks. In Czech Republic, bone lesion assessment must be performed at 12-week 
intervals and no more than 4 times per year. Assessment locations to be included are listed in Table 13 and recommended imaging modalities are listed in 
Table 14. In the event of treatment discontinuation for reasons other than objective disease progression, disease assessments post-treatment should continue 
until objective disease progression is documented by the Investigator and BICR or start of subsequent anticancer therapy, whichever is sooner. More detailed 
guidance on assessments to be performed and exceptional circumstances is provided in Section 7.3. 
13 Pharmacokinetic Sampling: PK sampling will be collected from patients in the MRTX849 arm only. Predose samples should be collected up to 30 minutes 
prior to dosing in clinic. Peak samples should be collected 4 to 6 hours after dosing unless logistically infeasible. In addition to the scheduled samples, an 
unscheduled predose PK blood sample (along with a triplicate ECG, see below) should be collected as soon as possible after an SAE, immediately prior to 
treatment interruption or dose reduction for a treatment-related nonserious AE, and at a clinic visit at least one week following a dose reduction of MRTX849. 
If MRTX849 has been held or discontinued for ≥ 3 days, unscheduled PK collections are not required. 
14 Triplicate ECGs: Triplicate ECGs will be collected from patients in the MRTX849 arm only. To be performed after the patient has rested in the supine position 
for at least 5 minutes. All ECGs will be obtained prior to and as close as possible to PK sample collection. Three individual ECG tracings should be obtained as 
closely as possible in succession, between 1 and 2 minutes apart. The full set of triplicates should be completed in approximately 4 minutes or less. 
15 Docetaxel Administration and Premedication: Patients randomized into the docetaxel arm should receive premedication with dexamethasone (or institutional 
equivalent) and in accordance with labeling instructions and institutional guidelines. Initiation of glucocorticoid premedication should only occur after 
randomization but may be initiated a few days prior to docetaxel administration. Prior to each subsequent dose of docetaxel, blood counts and laboratory values 
(including LFTs) should be checked to ensure dosing consistent with package labeling. Patients randomized to the docetaxel arm will have the option to receive 
MRTX849 study treatment upon development of RECIST 1.1-defined disease progression per BICR, provided that all crossover eligibility criteria are met and 
the crossover informed consent form is signed. If patient has completed docetaxel treatment, in accordance with local standards, and is awaiting crossover 
eligibility, imaging should continue on schedule (including BICR submission) and end of docetaxel treatment information should be collected in the docetaxel 
End of Treatment Form. End of Treatment visit and Long-term Follow-up should only be completed once final study treatment is given (ie, after crossover 
treatment). Patients who complete docetaxel treatment in accordance with local standards are not required to complete on study visits every 3 weeks while 
awaiting crossover. 
16 PRO Questionnaires: Generally, to be performed prior to other assessments during clinic visits. Exceptions include assessments that are scheduled in other 
departments prior to the clinic visit, and vital signs if they are performed during patient check-in. EQ-5D-5L questionnaires should always be completed before 
LCSS. 
17 Adverse Events: SAEs should be reported from the time of the prescreening informed consent until resolution. During the pre-screening period (ie, after 
pre-screening informed consent and before the main study informed consent), reporting of SAEs is limited to events associated with study required assessments 
(eg, biopsies for tumor genotype testing). Beginning at the time of signing the main study informed consent to begin clinical eligibility screening, reporting of 
all SAEs is required. Other AEs occurring from the first day of study treatment until the End of Treatment visit should be recorded.  
18 Long-term Follow-up: Survival status and subsequent anticancer therapies will be collected as described in Section 6.4 every 2 months (± 14 days) from the 
End of Treatment visit until death or lost to follow-up. 
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19 Patients on MRTX849 for at least 12 months whom the PI believes are clinically stable on current dose regimen, may reduce frequency of clinic visits from 
every cycle to every other cycle (ie, Day 1 visits required every 6 weeks vs. 3 weeks). 
 
 
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TABLE OF CONTENTS 
CLINICAL RESEARCH PROTOCOL ...........................................................................................1 
STUDY SUMMARY.......................................................................................................................2 
LIST OF ABBREVIATIONS ........................................................................................................23 
1. 
INTRODUCTION AND RATIONALE .....................................................................28 
1.1. 
Therapeutic Strategy Targeting KRAS .......................................................................28 
1.2. 
Non-Small Cell Lung Cancer .....................................................................................29 
1.2.1. 
First-line Treatment of NSCLC ..................................................................................29 
1.2.2. 
Second-Line Treatment of NSCLC ............................................................................30 
1.3. 
MRTX849 ...................................................................................................................30 
1.3.1. 
MRTX849 Drug Substance ........................................................................................30 
1.3.2. 
Nonclinical Pharmacology of MRTX849 ...................................................................31 
1.3.2.1. 
In Vitro Activity of MRTX849 ...................................................................................31 
1.3.2.2. 
In Vivo Activity of MRTX849 ...................................................................................31 
1.3.2.3. 
Secondary Pharmacodynamics of MRTX849 ............................................................31 
1.3.2.4. 
Safety Pharmacology of MRTX849 ...........................................................................32 
1.3.3. 
Nonclinical Pharmacokinetics and Metabolism of MRTX849 ..................................32 
1.3.4. 
Nonclinical Toxicology of MRTX849 .......................................................................33 
1.3.5. 
MRTX849 Clinical Experience ..................................................................................34 
1.3.5.1. 
MRTX849 Clinical Safety ..........................................................................................35 
1.3.5.2. 
MRTX849 Clinical Pharmacokinetics ........................................................................37 
1.3.5.3. 
MRTX849 Clinical Activity .......................................................................................40 
1.4. 
Docetaxel ....................................................................................................................40 
1.4.1. 
Docetaxel Drug Substance ..........................................................................................40 
1.4.2. 
Docetaxel Nonclinical Data ........................................................................................41 
1.4.3. 
Docetaxel Clinical Data ..............................................................................................41 
1.4.3.1. 
Docetaxel Pharmacokinetics .......................................................................................41 
1.4.3.2. 
Docetaxel Adverse Reactions Common in Clinical Trials .........................................41 
1.5. 
Study Rationale ...........................................................................................................42 
1.5.1. 
Choice of Control Arm Treatment ..............................................................................43 
1.5.2. 
Choice of Dosing Regimen .........................................................................................43 
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1.5.3. 
Benefit/Risk Assessment ............................................................................................43 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................44 
2.1. 
Objectives ...................................................................................................................44 
2.1.1. 
Primary Objective .......................................................................................................44 
2.1.2. 
Secondary Objectives .................................................................................................44 
2.1.3. 
Exploratory Objectives ...............................................................................................44 
2.2. 
Endpoints ....................................................................................................................44 
2.2.1. 
Primary Endpoint ........................................................................................................44 
2.2.2. 
Secondary Endpoints ..................................................................................................44 
2.2.3. 
Exploratory Endpoints ................................................................................................45 
3. 
STUDY DESIGN .......................................................................................................45 
4. 
SUBJECT SELECTION AND ENROLLMENT .......................................................47 
4.1. 
Inclusion Criteria ........................................................................................................47 
4.2. 
Exclusion Criteria .......................................................................................................48 
4.3. 
Crossover Inclusion Criteria .......................................................................................50 
4.4. 
Crossover Exclusion Criteria ......................................................................................50 
4.5. 
Life Style Guidelines ..................................................................................................50 
4.5.1. 
Dietary Restrictions ....................................................................................................50 
4.5.2. 
Reproductive Health ...................................................................................................50 
4.5.2.1. 
Women ........................................................................................................................51 
4.5.2.2. 
Men .............................................................................................................................51 
4.6. 
Pre-screening, Screening and Randomization into Study ...........................................52 
4.6.1. 
Study Number Assignment .........................................................................................52 
4.6.2. 
Tumor Tissue KRAS Mutation Testing ......................................................................52 
4.6.3. 
Randomization ............................................................................................................53 
5. 
STUDY TREATMENTS ............................................................................................53 
5.1. 
Investigational and Non-Investigational Medicinal Products .....................................53 
5.2. 
MRTX849 Study Drug ...............................................................................................53 
5.2.1. 
MRTX849 Formulation ..............................................................................................53 
5.2.2. 
MRTX849 Preparation, Dispensing and Accountability ............................................54 
5.3. 
MRTX849 Patient Treatment .....................................................................................55 
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5.3.1. 
MRTX849 Oral Administration .................................................................................55 
5.3.2. 
MRTX849 Study Treatment .......................................................................................55 
5.3.2.1. 
Treatment Regimen ....................................................................................................55 
5.4. 
Guidelines for MRTX849 Dose Modification and Adverse Event 
Management ...............................................................................................................55 
5.4.1. 
Dose Reduction Steps for MRTX849 in Response to Treatment-Related 
Adverse Events ...........................................................................................................56 
5.4.2. 
Guidelines for the Management of Study Treatment-Related Adverse Events ..........56 
5.4.2.1. 
Hematological Toxicities ............................................................................................57 
5.4.2.2. 
Gastrointestinal Toxicities ..........................................................................................57 
5.4.2.3. 
Hepatic Toxicities .......................................................................................................58 
5.4.2.4. 
Other Laboratory Investigation-Based Toxicities ......................................................60 
5.4.2.5. 
Cardiac Toxicities .......................................................................................................60 
5.4.2.6. 
Pneumonitis ................................................................................................................61 
5.4.2.7. 
Other Toxicities ..........................................................................................................61 
5.4.2.8. 
Hormonal Contraceptives and Thrombotic Events .....................................................62 
5.5. 
Docetaxel Study Drug .................................................................................................62 
5.5.1. 
Docetaxel Formulation and Packaging .......................................................................62 
5.5.2. 
Docetaxel Preparation and Dispensing .......................................................................63 
5.5.3. 
Docetaxel Administration ...........................................................................................63 
5.5.4. 
Docetaxel Dose Modification .....................................................................................63 
5.6. 
Management of Docetaxel Adverse Events ................................................................64 
5.7. 
Medication Error .........................................................................................................64 
5.8. 
Crossover ....................................................................................................................64 
5.9. 
Concomitant Therapies ...............................................................................................65 
5.9.1. 
Concomitant Medications ...........................................................................................65 
5.9.2. 
Concomitant Surgery or Radiation Therapy ...............................................................68 
5.9.3. 
Other Anticancer or Experimental Therapy ...............................................................68 
6. 
STUDY ASSESSMENTS ..........................................................................................68 
6.1. 
Pre-screening, Clinical Screening, and Crossover Eligibility Screening ...................68 
6.2. 
Study Period ................................................................................................................69 
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6.3. 
End of Treatment Assessment ....................................................................................69 
6.4. 
Long-Term Follow-up and End of Study Assessment ...............................................69 
6.5. 
Patient Discontinuation/Withdrawal ...........................................................................69 
7. 
PROCEDURES ..........................................................................................................70 
7.1. 
Detection of KRAS G12C Tumor Mutation ................................................................70 
7.2. 
Documentation of Disease Progression On or After Prior Platinum-Based 
Chemotherapy and Checkpoint Inhibitor Therapy .....................................................72 
7.3. 
Efficacy .......................................................................................................................72 
7.4. 
Safety Assessments .....................................................................................................74 
7.4.1. 
Medical History ..........................................................................................................74 
7.4.2. 
Physical Examination and Vital Signs ........................................................................75 
7.4.3. 
Laboratory Safety Assessments ..................................................................................75 
7.4.4. 
Pregnancy and Follicle Stimulating Hormone Testing ...............................................76 
7.4.5. 
Hepatitis and Human Immunodeficiency Virus Testing ............................................77 
7.4.6. 
Electrocardiogram (ECG) ...........................................................................................77 
7.4.7. 
MUGA or ECHO ........................................................................................................77 
7.5. 
Laboratory Studies ......................................................................................................77 
7.5.1. 
Pharmacokinetic Evaluation .......................................................................................77 
7.5.1.1. 
PK for MRTX849 .......................................................................................................77 
7.5.2. 
Circulating Tumor DNA .............................................................................................78 
7.5.3. 
Correlative Molecular Analysis in Tumor Tissue ......................................................78 
7.5.4. 
Patient Reported Outcomes ........................................................................................78 
8. 
ADVERSE EVENT REPORTING ............................................................................79 
8.1. 
Sponsor Medical Monitor Personnel ..........................................................................79 
8.2. 
Adverse Events ...........................................................................................................79 
8.2.1. 
Laboratory Abnormalities ...........................................................................................80 
8.2.2. 
Severity Assessment ...................................................................................................80 
8.2.3. 
Causality .....................................................................................................................80 
8.3. 
Serious Adverse Events ..............................................................................................81 
8.3.1. 
Definition of a Serious Adverse Events ......................................................................81 
8.3.2. 
Exposure During Pregnancy .......................................................................................82 
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8.4. 
Reporting of SAEs and AEs .......................................................................................83 
8.4.1. 
Reporting Period .........................................................................................................83 
8.4.2. 
Reporting Requirements .............................................................................................83 
9. 
STATISTICS ..............................................................................................................84 
9.1. 
Phase 3 Hypothesis and Sample Size .........................................................................84 
9.2. 
Data Handling .............................................................................................................85 
9.3. 
Analysis Populations ..................................................................................................85 
9.3.1. 
Intent-to-Treat Population ..........................................................................................85 
9.3.2. 
Safety Population ........................................................................................................85 
9.3.3. 
Pharmacokinetic Evaluable Population ......................................................................85 
9.4. 
Efficacy Endpoint Definitions and Analyses ..............................................................85 
9.4.1. 
Progression-Free Survival ..........................................................................................85 
9.4.2. 
Overall Survival ..........................................................................................................86 
9.4.3. 
Objective Response Rate ............................................................................................86 
9.4.4. 
Duration of Response .................................................................................................86 
9.4.5. 
Progression-Free Survival-2 .......................................................................................87 
9.4.6. 
Time to CNS Progression ...........................................................................................87 
9.4.7. 
Intracranial activity using CNS RECIST 1.1 endpoints in patients with brain 
metastases ...................................................................................................................87 
9.4.8. 
Subgroup Analyses .....................................................................................................87 
9.5. 
Safety Data Presentations and Summaries .................................................................88 
9.5.1. 
Adverse Events ...........................................................................................................88 
9.5.2. 
Prior and Concomitant Medications ...........................................................................88 
9.5.3. 
Clinical and Laboratory Assessments .........................................................................88 
9.5.4. 
Patient Demographics, Baseline Characteristics and Disposition ..............................89 
9.5.5. 
Analysis of Study Treatment Dosing ..........................................................................89 
9.6. 
Other Study Endpoints ................................................................................................89 
9.6.1. 
Pharmacokinetic Analysis ..........................................................................................89 
9.6.2. 
Patient Reported Outcomes Analysis .........................................................................89 
9.6.3. 
Exploratory Analyses ..................................................................................................90 
9.7. 
Interim Analysis ..........................................................................................................90 
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9.8. 
Data Monitoring Committee .......................................................................................90 
10. 
ETHICS AND RESPONSIBILITIES .........................................................................91 
10.1. 
Ethical Conduct of the Study ......................................................................................91 
10.2. 
Obligations of Investigators ........................................................................................91 
10.3. 
Institutional Review Board/Ethics Committee/Research Ethics Board 
(IRB/EC/REB) ............................................................................................................91 
10.4. 
Informed Consent Form ..............................................................................................92 
10.5. 
Confidentiality and Privacy Protection .......................................................................92 
10.6. 
Reporting of Serious Breaches of the Protocol or ICH GCP ......................................93 
11. 
RECORDS MANAGEMENT ....................................................................................93 
11.1. 
Source Documentation and Data ................................................................................93 
11.2. 
Study Files and Records Retention .............................................................................94 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................94 
12.1. 
Monitoring Procedures ...............................................................................................94 
12.2. 
Auditing and Inspection Procedures ...........................................................................94 
13. 
CHANGES IN STUDY CONDUCT ..........................................................................95 
13.1. 
Protocol Amendments ................................................................................................95 
13.2. 
Plan for Communication of Study Decisions and Protocol Changes .........................95 
13.3. 
Protocol Deviations ....................................................................................................96 
14. 
END OF TRIAL .........................................................................................................96 
14.1. 
End of Trial in a European Union Member State .......................................................96 
14.2. 
End of Trial in all Other Participating Countries ........................................................96 
14.3. 
Premature Termination ...............................................................................................96 
15. 
STUDY REPORT AND PUBLICATION POLICY ..................................................96 
16. 
REFERENCES ...........................................................................................................97 
APPENDIX 1. ECOG PERFORMANCE STATUS ................................................................102 
APPENDIX 2. MEDICATIONS OR SUBSTANCES TO BE AVOIDED DURING 
TREATMENT WITH MRTX849 ............................................................................103 
APPENDIX 3. MEDICATIONS OR SUBSTANCES TO BE AVOIDED DURING 
TREATMENT WITH DOCETAXEL ......................................................................106 
APPENDIX 4. ABBREVIATED PRESENTATION OF RECIST VERSION 1.1 
GUIDELINES ...........................................................................................................108 
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APPENDIX 5. GUIDANCE TO STUDY SITES ON STUDY AND PATIENT 
MANAGEMENT DURING COVID-19 PUBLIC HEALTH EMERGENCY ........113 
APPENDIX 6. PATIENT CROSSOVER SCHEDULE OF ASSESSMENTS ........................115 
APPENDIX 7. DOCUMENT HISTORY .................................................................................118 
 
LIST OF TABLES 
Table 1: 
Pre-Screening Assessments ..........................................................................................8 
Table 2: 
Schedule of Assessments ............................................................................................10 
Table 3: 
Treatment-Related Treatment-Emergent Adverse Events Reported in ≥ 5% 
of Patients Administered MRTX849 Monotherapy (N = 202) ...................................35 
Table 4: 
Treatment-Emergent Adverse Events Reported in ≥ 5% of Patients 
Administered MRTX849 Monotherapy (N = 202) .....................................................36 
Table 5: 
MRTX849 Dose Reduction Steps in Response to Treatment-Related 
Adverse Events ...........................................................................................................56 
Table 6: 
Hematological Toxicities – MRTX849 Dose Modifications ......................................57 
Table 7: 
Gastrointestinal Toxicities – MRTX849 Dose Modifications ....................................58 
Table 8: 
Hepatic Toxicities – MRTX849 Dose Modifications .................................................59 
Table 9: 
Other Laboratory Investigation-Based Toxicities – MRTX849 Dose 
Modifications ..............................................................................................................60 
Table 10: Cardiac Toxicities – MRTX849 Dose Modifications .................................................61 
Table 11: Pneumonitis – MRTX849 Dose Modifications ..........................................................61 
Table 12: Other Toxicities – MRTX849 Dose Modifications ....................................................62 
Table 13: Tumor Assessment Locations .....................................................................................72 
Table 14: Recommended Imaging Modalities ............................................................................73 
Table 15: Laboratory Safety Parameters .....................................................................................76 
Table 16: Communication of Study Decisions and Protocol Amendments ...............................95 
Table 17: Examples of QT-Prolonging Medications to Avoid .................................................103 
Table 18: Examples of Medications and Substances to Avoid with MRTX849 
Treatment ..................................................................................................................104 
Table 19: Specific Concomitant Medications to Avoid with Docetaxel ..................................106 
 
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LIST OF FIGURES 
Figure 1: 
Timing of Pre-Screening Assessments .........................................................................9 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
Ab 
Antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALK 
Anaplastic Lymphoma Kinase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AT 
Accelerated Titration 
AUC 
Area Under the Curve 
BCRP 
Breast Cancer Resistance Protein 
BE 
Bioequivalence 
BICR 
Blinded Independent Central Review 
BID 
Twice daily 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CIT 
Checkpoint Inhibitor Therapy 
CK 
Creatine Kinase 
CLint 
Intrinsic Clearance 
CNS 
Central Nervous System 
CR 
Complete Response 
CRC 
Colorectal Cancer 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography Scan 
CTA 
Clinical Trial Application 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating Tumor Deoxyribonucleic Acid 
CTFG 
Clinical Trials Facilitation Group 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450 
DDI 
Drug-Drug Interaction 
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Abbreviation 
Definition 
DHEA 
Dehydroepiandrosterone 
DLT 
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
EQ-5D-5L 
European Quality of Life Five Dimensions Questionnaire  
ER 
Extraction Ratio 
ERK1/2 
Extracellular Signal-regulated Kinases 1/2  
EIU 
Exposure In-Utero 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
18F-NaF 
Fluorine 18–Sodium Fluoride  
FSH 
Follicle Stimulating Hormone 
GAP 
GTPase-Activating Proteins 
GCP 
Good Clinical Practice 
GEF 
Guanine Nucleotide Exchange Factor 
GSH 
Glutathione 
HBcAb 
Hepatitis B Core Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B  
HBC 
Hepatitis C 
HCV Ab 
Hepatitis C Virus Antibody 
HDPE 
High-Density Polyethylene 
hERG 
human Ether-a-go-go Related Gene 
HIV 
Human Immunodeficiency Virus 
HNSTD 
Highest Non Severely Toxic Dose 
hr 
Hour 
HR 
Hazard Ratio 
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Abbreviation 
Definition 
IB 
Investigator’s Brochure 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
icDOR 
Intracranial Duration of Response 
icORR 
Intracranial Objective Response Rate 
icPFS 
Intracranial Progression-Free Survival 
icTTP 
Intracranial Time to Progression 
IDMC 
Independent Data Monitoring Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IV 
Intravenous 
IWRS 
Interactive Web Response System  
kg 
Kilogram 
Ki 
Inhibition Constant 
LCSS 
Lung Cancer Symptom Scale  
LLN 
Lower Limit of Normal 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
MM 
Medical Monitor 
MMRM 
Mixed Effect Model Repeat Measurement 
MRI 
Magnetic Resonance Imaging 
msec 
Millisecond 
mTPI 
Modified Toxicity Probability Interval 
MUGA 
Multigated Acquisition Scan  
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NGS 
Next Generation Sequencing 
NOAEL 
No-Observed-Adverse-Event-Level 
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Abbreviation 
Definition 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBPK 
Physiologically-based Pharmacokinetics 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PD 
Objective Progression of Disease 
PD-1 
Programmed Cell Death 1 
PD-L1 
Programmed Cell Death Ligand 1 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
PO 
Oral 
PPI 
Proton Pump Inhibitor 
PR 
Partial Response 
PVC 
Polyvinyl Chloride 
PTR 
Peak-To-Trough Concentration Ratio 
QD 
Once Daily 
QTc 
Corrected QT Interval 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
shRNA 
Short Hairpin Ribonucleic Acid 
SMT 
Safety Management Team  
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Terminal Elimination Half-life 
TEAE 
Treatment-Emergent Adverse Event 
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Abbreviation 
Definition 
TI 
Therapeutic Index 
tmax 
Time to Maximum Plasma Concentration 
TMB 
Tumor Mutation Burden 
TPS 
Tumor Proportion Score 
TSH 
Thyroid-Stimulating Hormone 
UI 
Utility Index 
ULN 
Upper Limit of Normal 
US 
United States 
VAS 
Visual Analogue Scale 
VEGF 
Vascular Endothelial Growth Factor 
WHO 
World Health Organization 
WOCBP 
Women of Child Bearing Potential 
μg 
Microgram 
μM 
Micromolar 
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1. 
INTRODUCTION AND RATIONALE 
1.1. 
Therapeutic Strategy Targeting KRAS 
RAS proteins are part of the family of small GTPases that are activated in response to growth 
factor stimulation and various other extracellular stimuli to regulate intracellular signaling 
pathways responsible for growth, migration, survival and differentiation of cells. The activation 
of RAS proteins at the cell membrane by growth factors results in the binding of key effector 
molecules, formation of signaling complexes, and the initiation of a cascade of intracellular 
signaling pathways within the cell including the RAF and PI3 kinase pathways 
(Simanshu, 2017). Since defects in RAS may result in uncontrolled cellular signaling and 
malignant transformation, the activation of RAS proteins is tightly controlled in normal cells. To 
initiate intracellular signaling, RAS proteins must be activated or turned “on” by extracellular 
stimuli. RAS proteins normally alternate between GTP- and GDP-bound conformations, where 
the GTP-bound conformation represents the “On” and GDP-bound the “Off” state. Dependence 
of RAS and other GTPases on guanine nucleotide exchange factors (GEFs) and 
GTPase-activating proteins (GAPs) to switch them on and off allows both processes to be highly 
regulated and responsive to multiple signal inputs. In contrast, oncogenic mutants of RAS 
generally function by preventing hydrolysis of GTP, thereby generating constitutively active 
GTP-bound RAS molecules with severe consequences for the cell including uncontrolled cellular 
growth and malignant transformation. 
The RAS family of genes is comprised of 3 members; KRAS, NRAS, and HRAS and constitute the 
most frequently mutated family of oncogenes in human cancer. RAS mutant cancers account for 
nearly 25% of all human cancers and one million deaths per year worldwide. The majority of 
RAS family mutations are missense mutations that result in amino acid changes at residues 
(codons) 12, 13, and 61; the frequency of mutation at each of these residues, and the isoform 
mutated, varies across different cancer types (Ostrem, 2016). Among the RAS family members, 
missense mutations most frequently occur in KRAS (85%), and far less frequently in NRAS 
(12%) and HRAS (3%) (Simanshu, 2017). KRAS is the most frequently mutated gene of the RAS 
family, with mutations occurring in approximately 30% of lung adenocarcinomas, 50% of 
colorectal cancers, and 90% of pancreatic ductal adenocarcinomas. The vast majority of KRAS 
missense mutations affect residue 12. The mutation of the glycine at residue 12 to an amino acid 
residue other than proline produces a steric block that prevents GAP proteins from accessing 
KRAS, thereby inhibiting GTP hydrolysis and resulting in a highly activated GTP-bound form of 
RAS (Ostrem, 2016). 
In NSCLC, KRAS G12C is the most common mutation comprising nearly half of all KRAS 
mutations (Simanshu, 2017), followed by G12V and G12D (Campbell, 2016), (Matikas, 2017). 
Large genomics studies characterizing lung cancers have indicated that KRAS mutations, 
including G12C, are mutually exclusive with other known oncogenic driver mutations in NSCLC 
including EGFR, ALK, ROS1, RET, and BRAF, where the development of therapeutic strategies 
directly targeting oncogenic genomic alterations has resulted in substantial benefits for patients 
with a variety of cancers. These observations suggest that KRAS mutations similarly define a 
unique segment of lung cancer for which a targeted therapy option is currently unavailable 
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(Campbell, 2016). Importantly, large scale functional genomics studies utilizing short hairpin 
ribonucleic acid (shRNA) knockdown technology to block the function of thousands of gene 
products across hundreds of cancer cell lines have demonstrated that cancer cells exhibiting 
KRAS mutations are highly dependent on KRAS function for cell growth and survival 
(McDonald, 2017). Together, these findings illustrate a critical role for KRAS mutations as a 
causative factor in a significant number of human tumors and highlight a compelling opportunity 
for therapeutic agents targeting KRAS to make an impact in treating these cancers. 
Despite over 30 years of KRAS drug discovery research, development of therapies targeting 
KRAS has been elusive. Small molecules that bind tightly to KRAS proteins have been difficult 
to find, mostly because KRAS proteins lack a deep pocket to which small molecules could bind 
with high affinity. However, recent studies indicate that targeting the KRAS G12C mutant 
variant may be feasible through irreversible targeting of the mutated cysteine with covalent small 
molecule inhibitors that block the catalytic activity and signal transduction downstream of 
mutant KRAS (Ostrem, 2013), (Lito, 2016). This work led to the development of MRTX849, a 
potent and orally available small molecule inhibitor of KRAS G12C. MRTX849 binds 
covalently to the mutant cysteine residue, shows high selectivity, and has demonstrated 
broad-spectrum activity in xenograft models harboring the KRAS G12C mutation. Objective 
tumor responses in patients with NSCLC and CRC have also been observed in the Phase 1 
setting. 
1.2. 
Non-Small Cell Lung Cancer 
Lung cancer remains the leading cause of cancer-related death worldwide, with GLOBOCAN 
estimating approximately 2.1 million new cases diagnosed in 2018 and approximately 
1.76 million deaths attributed to lung cancer (Bray, 2018). Non-small cell lung cancer accounts 
for approximately 83% of lung cancer cases (Noone, 2018), of which approximately half are 
classified as adenocarcinoma of the lung; squamous cell carcinoma accounts for approximately 
one-quarter of NSCLC cases and large cell carcinoma is infrequently diagnosed. 
1.2.1. 
First-line Treatment of NSCLC 
Most patients with advanced NSCLC are treated with chemotherapy and immune checkpoint 
inhibitor therapy (CIT). Platinum-based chemotherapy doublets, with or without bevacizumab in 
selected patients, have until recently been the standard of care for most patients with advanced 
NSCLC in the first-line treatment setting (Schiller, 2002), (Sandler, 2006), (Scagliotti, 2008). 
The recent development of pembrolizumab for the treatment of NSCLC has led to its rapid 
incorporation of this agent as a key component of first-line treatment. Initially pembrolizumab 
was compared against standard chemotherapy in patients with untreated, advanced NSCLC 
characterized by ≥ 50% tumor PD-L1 tumor proportion score (TPS) expression, and an 
improvement in survival was observed along with a favorable safety profile (Reck, 2016), 
leading to US FDA approval of pembrolizumab in the first-line treatment setting for this patient 
population. Subsequently, efficacy of pembrolizumab was also demonstrated as monotherapy in 
untreated patients with nonsquamous NSCLC with a PD-L1 TPS of ≥ 1% (Mok, 2019), and in 
combination with a platinum agent and pemetrexed in patients with metastatic nonsquamous 
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NSCLC regardless of PD-L1 TPS (Gandhi, 2018). These trials led to broad use of 
pembrolizumab combined with platinum-based chemotherapy as a standard option for first-line 
treatment of nonsquamous NSCLC, and pembrolizumab monotherapy as an option for some 
patients with untreated, advanced NSCLC, particularly those with disease characterized by 
PD-L1 TPS of ≥ 50%. 
1.2.2. 
Second-Line Treatment of NSCLC 
For patients with advanced NSCLC previously treated with platinum-based chemotherapy, 
approved treatment options include docetaxel alone or in combination with ramucirumab, and 
pemetrexed. Median OS reported in randomized clinical trials using these regimens as 
experimental or comparator therapies has varied between approximately 5.7 and 10.5 months 
while median PFS has ranged between 2.3 to 4.5 months and ORR has ranged from 5.5 to 23% 
(Shepherd, 2000), (Hanna, 2004), (Krzakowski, 2010), (Scagliotti, 2009), (Tomasini, 2016), 
(Garon, 2014). More recently, immune CITs have been approved by the US FDA for second-line 
treatment of advanced NSCLC. Based on improved outcomes with nivolumab, pembrolizumab, 
and atezolizumab in the second-line setting compared to docetaxel (Borghaei, 2015), 
(Brahmer, 2015), (Garon, 2015), (Herbst, 2016), (Rittmeyer, 2017), these agents have been 
approved by the FDA for treatment of patients with advanced NSCLC with progression on or 
after platinum-based chemotherapy. However, the incorporation of pembrolizumab into first-line 
treatment of advanced NSCLC has limited the use of immune CITs in the second-line treatment 
setting for many patients, where options include a clinical trial or a docetaxel-based regimen. 
Thus, despite the significant advances of chemotherapy and immunotherapy for NSCLC, 
including those for patients with KRAS G12C tumor mutation, patients ultimately develop 
progressive disease, and the outcome of patients with advanced NSCLC after treatment with 
platinum-based chemotherapy and an immune CIT remains poor. 
1.3. 
MRTX849 
MRTX849 (also known as adagrasib) is a small molecule that elicits antitumor activity through 
selective, high affinity, covalent binding to and inhibition of the KRAS G12C mutant variant. 
Background information in addition to that presented below is available in the MRTX849 
Investigator’s Brochure. 
1.3.1. 
MRTX849 Drug Substance 
The chemical formulation of MRTX849 is as follows: 
MRTX849 Free Base 
Chemical Formula: 
C32H35ClFN7O2 
Molecular Weight: 
604.1 g/mol 
 
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1.3.2. 
Nonclinical Pharmacology of MRTX849 
Pharmacology studies have been conducted to characterize the pharmacologic targets, activity, 
mechanism of action, PD, and antitumor efficacy of MRTX849 both in vitro and in vivo 
(Hallin, 2020). 
1.3.2.1. 
In Vitro Activity of MRTX849 
Biochemical and cellular assays demonstrate that MRTX849 inactivates mutant KRAS by 
covalent binding to the cysteine 12 of KRAS G12C. MRTX849 proved to be highly selective for 
KRAS G12C over other surface-exposed cysteines in NCI-H358 cells. 
In studies of KRAS-dependent signal transduction pathways in cells with the KRAS G12C 
mutation, MRTX849 inhibited phosphorylated ERK1/2 with an IC50 value of 17 nM. In 
cell-based assays, MRTX849 inhibited viability in 17 KRAS G12C mutant cell lines in a 3D 
assay format (IC50 values from 0.2 to 1042 nM). In contrast, IC50 values were greater than 
3000 nM in 3 non-G12C-mutant KRAS models evaluated indicating that MRTX849 elicits 
antitumor activity mediated through selective binding to and inhibition of the KRAS G12C 
mutant variant. 
To evaluate the effect of two MRTX849 human metabolites, M11 and M68, on KRAS-
dependent downstream signal transduction, phosphorylation of ERK1/2 was evaluated over a 
range of concentrations. Metabolite M68 was not active and M11 was greater than 80-fold less 
active compared to MRTX849. These data suggests that both M11 and M68 do not contribute 
significantly to the pharmacological activity of MRTX849. 
1.3.2.2. 
In Vivo Activity of MRTX849 
MRTX849 effectively modified KRAS G12C protein and inhibited KRAS-dependent signal 
transduction in patient- and cell line-derived human tumor xenograft models harboring KRAS 
G12C mutations. A dose-dependent increase in MRTX849 plasma concentration, KRAS protein 
modification, and KRAS-dependent signal transduction through pERK and pS6 was observed 
following oral administration of 10, 30, and 100 mg/kg doses of MRTX849. Consistent with 
these observations, MRTX849 demonstrated dose-dependent antitumor efficacy in KRAS 
G12C-mutant xenograft models, with tumor growth inhibition observed at doses as low as 
3 mg/kg and maximal tumor regression observed at 100 mg/kg. MRTX849 administered at 
100 mg/kg demonstrated broad cytoreductive antitumor efficacy in 18 out of 23 patient- and cell 
line-derived KRAS G12C-mutant human tumor xenograft models but did not significantly inhibit 
tumor growth in 3 non-G12C-mutant KRAS models. 
1.3.2.3. 
Secondary Pharmacodynamics of MRTX849 
The selectivity of MRTX849 was profiled against a broad panel of 44 receptors, ion channels 
and enzymes. The initial screen at 10 µM resulted in 50% inhibition against 18 targets. The 
follow-up assay to determine Ki for these receptors identified 4 receptors with Ki values less than 
1 µM. The receptors included alpha 1A adrenergic antagonist, muscarinic M2 antagonist, 
serotonin 5HT1A agonist, and serotonin 5HT1B antagonist, with Ki of 0.15 µM, 0.30 µM, 
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0.17 µM, and 0.14 µM, respectively. These Ki values are approximately 2- to 4-fold higher than 
the observed geometric mean steady-state unbound Cmax of 0.08 μM associated with the 
MRTX849 600 mg twice daily (BID) in patients (Study 849-001, n = 17). 
1.3.2.4. 
Safety Pharmacology of MRTX849 
A series of in vitro and in vivo safety pharmacology studies demonstrate that MRTX849 poses 
minimal risk for adverse effects on major physiological systems. Based on in vitro human 
ether-a-go-go related gene (hERG) binding, an in vitro Guinea pig Langendorff study, and ECG 
parameters collected in the repeat-dose dog toxicology study, MRTX849 does not pose a risk for 
QT prolongation. In addition, there were no changes in heart rate or blood pressure in dogs 
treated at doses up to 25 mg/kg/day. CNS effects were monitored during the conduct of the rat 
and dog 28-day repeat-dose toxicology studies. There were no remarkable clinical signs 
suggestive of CNS effects, nor were there microscopic changes in neuronal tissues. 
1.3.3. 
Nonclinical Pharmacokinetics and Metabolism of MRTX849 
In vitro studies were conducted to assess MRTX849 absorption and protein binding. Assays 
using Caco-2 cells demonstrate that MRTX849 has high permeability. Studies indicated 
reversible protein binding for MRTX849 ranging from 97 to 99% across species. 
In vivo studies were conducted to assess MRTX849 pharmacokinetics and metabolism. 
MRTX849 exhibited good oral bioavailability and extensive tissue distribution. No major 
differences in pharmacokinetic properties related to sex were observed. In general, oral plasma 
exposure increased dose-proportionately within the projected efficacious dose range with 
less-than-proportional increases observed at relatively higher dose levels, possibly due to 
saturation of absorption. MRTX849 demonstrated moderate hepatic extraction ratios across 
species in vitro with oxidative metabolism identified as the predominant elimination route with 
additional contribution from GSH-mediated clearance. In vivo, MRTX849 parent was the 
predominant species identified in plasma circulation or excreted in urine and bile following oral 
administration. MRTX849 metabolites identified in vitro and in vivo include 2 major oxidative 
metabolites identified at the pyrrolidine ring as well as electrophile GSH and cysteine conjugates 
of both parent and oxidative metabolites. No individual metabolites comprised greater than 20% 
of all MRTX849-related material. The N-desmethyl metabolite exhibited comparable potency to 
MRTX849 and has the potential to contribute to antitumor activity. Reaction phenotyping studies 
indicated that CYPs 3A4 and 2C8 mediate the majority of oxidative metabolism. Overall, 
metabolite profiles were consistent in vitro and in vivo and across all species evaluated 
indicating that a similar overall metabolism pattern was present in nonclinical efficacy and 
toxicology species compared to humans. 
The contribution of CYP2C8 to MRTX849 metabolism at steady state when CYP3A4 is 
inhibited by MRTX849 (ie, auto-inhibition) was evaluated using human hepatocyte assays. 
Substrate depletion experiments were conducted in the presence of CYP3cide to inhibit all 
CYP3A4 mediated metabolism. With the addition of gemfibrozil glucuronide, MRTX849 
intrinsic clearance was inhibited by a further 46%. Therefore, CYP2C8 accounts for 46% of 
non-CYP3A4 mediated hepatic metabolism of MRTX849 at steady state. 
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Reversible or time-dependent inhibition of CYPs by MRTX849 was evaluated in human liver 
microsomes. MRTX849 did not inhibit CYP1A2, CYP2C8, and CYP2C19 (IC50 > 50 µM) and 
was found to be a weak to moderate reversible inhibitor of CYP2B6-, CYP2C9-, CYP2D6-, and 
CYP3A4-mediated substrate metabolism. The Ki values for inhibition exceeded 10 μM for all 
but CYP2B6, CYP2C9, and CYP3A4 which displayed Ki values of 4.0, 3.2, and 8.2 μM, 
respectively. MRTX849 was not a time-dependent inhibitor of CYP2C8, CYP2C9, or CYP2D6 
at concentrations up to 50 μM. MRTX849 was a time-dependent inhibitor of CYP3A4-mediated 
midazolam hydroxylation and the Kinact and Ki values were determined to be 0.035 min-1 and 
1.85 μM, respectively. These results indicate that MRTX849 is a moderately potent competitive 
inhibitor of CYP2B6, CYP2C9, and CYP3A4, as well as a time-dependent inhibitor of CYP3A4 
in vivo. MRTX849 inhibition of KRAS G12C was > 100-fold greater compared with Ki values 
for competitive or time-dependent inhibition of each evaluated CYP enzyme, indicating that the 
inhibition potential is predicted to be dependent on dose and plasma exposure of MRTX849 
achieved in human studies. 
Nonclinical studies were also conducted to investigate whether MRTX849 is a substrate as well 
as an inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in 
transfected-cell monolayer transport assays. MRTX849 was determined to be a substrate of both 
P-gp and BCRP. MRTX849 also inhibited P-gp and BCRP-mediated efflux of probe substrate 
molecules, indicating that it is also a likely inhibitor of P-gp and BCRP in vivo. The IC50 value 
for MRTX849 inhibition of P-gp-mediated quinidine efflux was 0.98 μM and the IC50 value for 
MRTX849 inhibition of BCRP-mediated prazosin efflux was 15.2 μM. Based on the estimate of 
the intestinal luminal concentration of MRTX849 (Igut) for a 600 mg dose relative to the IC50 for 
P-gp and BCRP inhibition, MRTX849 has a potential to inhibit P-gp and BCRP. MRTX849 is 
neither a substrate nor inhibitor of the OAT1, OAT3, OAT1B1, OATP1B3, or OCT2 uptake 
transporters. 
Collectively, these in vitro studies indicated that further investigations (ie, clinical drug-drug 
interaction study and/or modeling) are warranted to evaluate: 1) the clinical effect of MRTX849 
on CYPs 2B6, 2C9, 2D6, and 3A4 and drug transporters P-gp, BCRP, and MATE1; and 2) the 
clinical effect of strong inhibitor or inducer of CYP3A/P-gp and BCRP on the PK of MRTX849. 
Refer to Section 1.3.5.2 for PK results of these clinical investigations.  
1.3.4. 
Nonclinical Toxicology of MRTX849 
The nonclinical safety profile of MRTX849 was well characterized through the conduct of 
repeat-dose studies of up to 13-weeks in duration and genetic toxicology studies. The primary 
target organ effects in repeat-dose studies in both rats and dogs were primarily driven by possible 
phospholipidosis in multiple tissues. In the rat, the target tissues included lung, trachea, heart, 
skeletal muscle, bone marrow, spleen, pancreas and female sex organs. In the dog target tissues 
included bone marrow, lung, heart and spleen. The extent of vacuolization and the presence of 
foamy macrophages were more prominent in the rat as compared to dogs, and these effects 
occurred at doses above the projected human efficacious concentrations and were reversible. 
Phospholipidosis is a common finding in toxicology studies conducted with cationic amphiphilic 
drugs like MRTX849. 
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In both species, common target organs include the heart, spleen, lung and bone marrow. The 
changes in the lung appear to be associated with foamy alveolar macrophages, possibly due to 
phospholipidosis. Similarly, the splenic changes may also be related to scavenging of peripheral 
foamy inflammatory cells. This effect was not considered adverse in the dog, while in the 
moribund rats, it was associated with necrosis in the spleen and considered adverse. In the dog, 
the bone marrow changes of decreased erythropoiesis led to decreases in red blood cell 
parameters and decreased reticulocyte counts. However, in the rat 28-day study, a minor 
decrease in erythropoiesis was present within the bone marrow but was not reflective of a 
decrease in peripheral reticulocyte counts. In the heart, the microscopic findings differed 
between the rat and dog. In one high dose dog, the microscopic heart finding was characterized 
as myocardial necrosis in the papillary muscle. This type of cardiac lesion in dogs is commonly 
associated with exposure to positive inotropic/vasodilating drugs, and dogs appear to be overly 
sensitive to having this effect (Dogterom, 1992). Although MRTX849 did not appear to exhibit a 
blood pressure change in dogs as measured by indirect tail-cuff or changes in ECG parameters, 
MRTX849 was shown to inhibit the alpha-1-adrenergic receptor with a Ki value of 0.15 µM, 
which could lead to vasodilation. In the rat, the changes in the heart were limited to vacuolation 
in the 300 mg/kg/day group that was terminated in extremis on Day 23. There were no vacuole 
changes in the heart of rats treated at the designated no-observed-adverse-event-level (NOAEL) 
in the rat of 150 mg/kg/day, which results in average exposure that is 2-fold above the projected 
human efficacious exposures. Similarly, in the dog 28-day study, the NOAEL and HNSTD at 
25 mg/kg/day indicated a 2-fold safety margin above the human efficacious exposure. The 
nonclinical safety findings related to MRTX849 administration represent toxicities that are 
considered clinically manageable, reversible, and of acceptable risk in the advanced cancer 
setting. 
The genotoxicity of MRTX849 was assessed in vitro for mutagenicity and clastogenicity initially 
in screening assays followed by definitive studies. These in vitro assays were conducted with and 
without exogenous Aroclor-induced rat liver S9 and MRTX849 concentrations up to those 
limited by cytotoxicity or solubility. In vivo, the clastogenic effects of MRTX849 were evaluated 
in rats by measuring micronuclei present in peripheral blood reticulocytes after oral dosing at 
250, 500, and 1000 mg/kg/day for 2 days. MRTX849 was negative in all genotoxicity studies.  
1.3.5. 
MRTX849 Clinical Experience 
Study 849-001 is a multi-center, Phase 1/2, multiple expansion cohort trial evaluating the safety, 
PK, metabolites, PD and clinical activity/efficacy of MRTX849 in patients with advanced solid 
tumor malignancies with KRAS G12C mutation. The study includes evaluation of MRTX849 
monotherapy and in combination with selected cancer therapies. 
Study 849-001 began with the Accelerated Titration (AT) design in which single patient dose 
escalation cohorts receiving MRTX849 at 150 mg, 300 mg, 600 mg and 1200 mg administered 
once daily. Based on emerging results (post dosing emesis possibly affected by pill burden at the 
1200 mg dose), dose escalation using the once daily schedule was discontinued and a BID dosing 
schedule was initiated at 600 mg BID. In addition, the Phase 1 segment of the study transitioned 
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from the AT design to the mTPI design. MRTX849 administered at 600 mg BID has been 
selected for Phase 2 evaluation and is the starting dose in the Phase 1 combination sub-studies. 
1.3.5.1. 
MRTX849 Clinical Safety 
As of a data cutoff date of 27 November 2020, a total of 231 patients had been enrolled into 
Study 849-001, including 202 patients administered MRTX849 monotherapy and 29 patients 
administered MRTX849 in combination with pembrolizumab or cetuximab. Adverse events 
(AEs) are summarized for the 202 patients who were administered MRTX849 monotherapy. 
Among patients administered MRTX849 monotherapy, 197 initiated MRTX849 dosing at 
600 mg BID. The most frequently reported treatment-related AEs in patients administered 
MRTX849 monotherapy are shown in Table 3, and treatment-emergent adverse events (TEAEs) 
are shown in Table 4. Refer to the current version of Investigator’s Brochure (IB) for updated 
information. 
Table 3: 
Treatment-Related Treatment-Emergent Adverse Events Reported in ≥ 5% 
of Patients Administered MRTX849 Monotherapy (N = 202)  
Adverse Event 
Preferred Term, n (%) 
Any Grade  
n (%) 
Grade 1/2 
n (%) 
Grade 3/4 
n (%) 
Grade 5 
n (%) 
Any TEAE 
161 (79.7) 
108 (53.5) 
51 (25.2) 
2 (1.0) 
Nausea 
107 (53.0) 
100 (49.5) 
7 (3.5) 
0 
Diarrhoea 
94 (46.5) 
88 (43.6) 
6 (3.0) 
0 
Vomiting 
72 (35.6) 
68 (33.7) 
4 (2.0) 
0 
Fatigue 
55 (27.2) 
46 (22.8) 
9 (4.5) 
0 
Alanine aminotransferase increased 
33 (16.3) 
26 (12.9) 
7 (3.5) 
0 
Aspartate aminotransferase increased 
27 (13.4) 
22 (10.9) 
5 (2.5) 
0 
Blood creatinine increased 
27 (13.4) 
25 (12.4) 
2 (1.0) 
0 
Electrocardiogram QT prolonged 
24 (11.9) 
20 (9.9) 
4 (2.0) 
0 
Decreased appetite 
23 (11.4) 
20 (9.9) 
3 (1.5) 
0 
Anaemia 
20 (9.9) 
19 (9.4) 
1 (0.5) 
0 
Blood alkaline phosphatase increased  
16 (7.9) 
13 (6.4) 
3 (1.5) 
0 
Dysgeusia 
16 (7.9) 
16 (7.9) 
0 
0 
Lipase increased  
13 (6.4) 
6 (3.0) 
7 (3.5) 
0 
Oedema peripheral  
13 (6.4) 
13 (6.4) 
0 
0 
Abbreviation: TEAE = treatment-emergent adverse event. 
 
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Table 4: 
Treatment-Emergent Adverse Events Reported in ≥ 5% of Patients 
Administered MRTX849 Monotherapy (N = 202) 
Adverse Event 
Preferred Term, n (%) 
Any Grade n 
(%) 
Grade 1/2 
n (%) 
Grade 3/4 
n (%) 
Grade 5 
n (%) 
Any TEAE 
186 (92.1) 
78 (38.6) 
95 (47.0) 
13 (6.4) 
Nausea 
119 (58.9) 
110 (54.5) 
9 (4.5) 
0 
Diarrhoea  
105 (52.0) 
99 (49.0) 
6 (3.0) 
0 
Vomiting  
84 (41.6) 
79 (39.1) 
5 (2.5) 
0 
Fatigue  
76 (37.6) 
63 (31.2) 
13 (6.4) 
0 
Anaemia  
44 (21.8) 
32 (15.8) 
12 (5.9) 
0 
Blood creatinine increased  
39 (19.3) 
37 (18.3) 
2 (1.0) 
0 
Alanine aminotransferase increased  
38 (18.8) 
29 (14.4) 
9 (4.5) 
0 
Dyspnoea  
36 (17.8) 
25 (12.4) 
11 (5.4) 
0 
Aspartate aminotransferase increased  
33 (16.3) 
27 (13.4) 
6 (3.0) 
0 
Decreased appetite  
31 (15.3) 
27 (13.4) 
4 (2.0) 
0 
Oedema peripheral  
31 (15.3) 
28 (13.9) 
3 (1.5) 
0 
Hyponatraemia  
26 (12.9) 
17 (8.4) 
9 (4.5) 
0 
Electrocardiogram QT prolonged  
25 (12.4) 
21 (10.4) 
4 (2.0) 
0 
Abdominal pain  
23 (11.4) 
19 (9.4) 
4 (2.0) 
0 
Blood alkaline phosphatase increased  
23 (11.4) 
20 (9.9) 
3 (1.5) 
0 
Constipation  
21 (10.4) 
21 (10.4) 
0 
0 
Hypoalbuminaemia  
20 (9.9) 
18 (8.9) 
2 (1.0) 
0 
Hypokalaemia  
20 (9.9) 
17 (8.4) 
3 (1.5) 
0 
Dizziness  
18 (8.9) 
18 (8.9) 
0 
0 
Dysgeusia  
18 (8.9) 
18 (8.9) 
0 
0 
Rash  
18 (8.9) 
17 (8.4) 
1 (0.5) 
0 
Weight decreased  
18 (8.9) 
17 (8.4) 
1 (0.5) 
0 
Hypomagnesaemia  
17 (8.4) 
17 (8.4) 
0 
0 
Lipase increased  
17 (8.4) 
7 (3.5) 
10 (5.0) 
0 
Lymphocyte count decreased 
17 (8.4) 
6 (3.0) 
11 (5.4) 
0 
Arthralgia  
16 (7.9) 
16 (7.9) 
0 
0 
Back pain  
16 (7.9) 
15 (7.4) 
1 (0.5) 
0 
Dehydration  
16 (7.9) 
14 (6.9) 
2 (1.0) 
0 
Headache  
15 (7.4) 
15 (7.4) 
0 
0 
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Adverse Event 
Preferred Term, n (%) 
Any Grade n 
(%) 
Grade 1/2 
n (%) 
Grade 3/4 
n (%) 
Grade 5 
n (%) 
Pyrexia  
14 (6.9) 
14 (6.9) 
0 
0 
Hypotension  
13 (6.4) 
9 (4.5) 
4 (2.0) 
0 
Amylase increased  
11 (5.4) 
9 (4.5) 
2 (1.0) 
0 
Blood lactate dehydrogenase 
increased  
10 (5.0) 
10 (5.0) 
0 
0 
Dyspepsia  
10 (5.0) 
10 (5.0) 
0 
0 
Lung infection  
10 (5.0) 
3 (1.5) 
7 (3.5) 
0 
Muscular weakness  
10 (5.0) 
8 (4.0) 
2 (1.0) 
0 
Abbreviation: TEAE = treatment-emergent adverse event. 
 
Treatment-emergent serious adverse events have been reported for 68 of the 202 patients 
administered MRTX849 monotherapy; events reported in more than 4 (2.0%) of patients include 
pneumonia (n = 8, [4.0%]); n = 6 (3.0%) patients each for hyponatraemia and lung infection; 
n = 5 (2.5%) each for acute kidney injury, anaemia, and dyspnoea; and n = 4 (2.0%) each for 
blood creatinine increased, hypotension, hypoxia, malignant neoplasm progression, nausea, 
pyrexia, and vomiting. 
1.3.5.2. 
MRTX849 Clinical Pharmacokinetics 
The pharmacokinetics of MRTX849 in NSCLC patients was characterized in Study 849-001 
Phase 1/1b. MRTX849 exhibits the following single-dose PK characteristics following a single 
600 mg oral dose administration of MRTX849 capsules under fasting conditions: 
• Median tmax was 4.17 hours, indicating that MRTX849 is steadily absorbed following 
oral administration.  
• The between-patient variability for Cmax, and AUC∞ was relatively high as the 
geometric CV% ranged from 95% to 142%.  
• Geometric mean CL/F and Vz/F was 16.0 L/h and 527 L, respectively. 
• Arithmetic mean t1/2 was 23.0 h. 
MRTX849 exhibits the following multiple-dose PK characteristics following administration of 
MRTX849 600 mg BID (capsules) under fasting conditions: 
• Median tmax values on C1D1 and C1D8 were 6.03 and 2.96 hours, respectively. The 
shorter tmax on C1D8 could be due to the relatively flat concentration-time profile and 
low geometric mean peak-to-trough concentration ratio (PTR) of 1.07 on C1D8. 
• Between-patient variability (geometric mean CV%) for MRTX849 exposure 
measures (Cmax and AUCτ) reduced from C1D1 (approximately 76 to 95%) to C1D8 
(approximately 37 to 44%).  
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• Steady state appeared to have been reached by C1D8. The geometric mean Cmin on 
C1D8 was 2693 ng/mL. 
• Multiple dosing of 600 mg BID resulted in approximately 5- to 6-fold accumulation 
(Rac) and a low PTR of 1.07 at steady state. Additionally, steady-state concentrations 
exceeded the target efficacious average concentration derived from the least sensitive 
preclinical xenograft model.  
• Multiple dosing of 150 and 300 mg QD resulted in less drug accumulation 
(approximately 3- to 4-fold) and a higher PTR (approximately 3) in individual 
patients compared to the 600 mg BID regimen. Additionally, concentrations at C1D8 
were all substantially below the target efficacious average concentration derived from 
the least sensitive preclinical xenograft model. 
The relative bioavailability of the MRTX849 capsule and tablet formulations was evaluated in 
healthy subjects. Results showed comparable rate and extent of absorption of MRTX849 
following a single oral dose of 600 mg (3 × 200-mg) MRTX849 capsules or tablets under fasting 
conditions. Median tmax ranged from 6.07 to 7.50 hours for the capsules and 6.05 to 7.00 hours 
for the tablets. Between-subject variability (CV%) for exposure measures (Cmax, AUClast, and 
AUC∞) ranged up to approximately 59% for the capsules and up to approximately 63% for the 
tablets. Results from statistical analyses demonstrated that AUC∞ and AUClast met the regulatory 
bioequivalence (BE) criteria but Cmax did not meet the regulatory BE criteria. An equivalent 
AUC between the 2 formulations is expected to maintain the same efficacy profile for MRTX849 
as data from the nonclinical human xenograft models showed that AUC was the most closely 
correlated PK parameter with the extent of anti-tumor activity as opposed to Cmax for MRTX849. 
Therefore, the tablet and capsule formulations are considered functionally bioequivalent. A 
slightly lower Cmax (~15%) in the MRTX849 tablet formulation compared to Cmax in the capsule 
formulation is not considered to be clinically meaningful based on the following considerations: 
• A lower Cmax is not expected to impact the efficacy profile of MRTX849. On the 
other hand, a lower Cmax may improve the safety/tolerability profile of MRTX849.  
• Daily fluctuations in MRTX849plasma concentrations at steady state are low for the 
600-mg BID regimen in patients, with a mean peak-to-trough ratio at steady state of 
1.07. Therefore, a minor change in Cmax observed after a single dose of MRTX849 is 
anticipated to exhibit no meaningful effect on its flat PK profile at steady state.  
In conclusion, there is no clinically meaningful difference in MRTX849 exposure between the 
capsule and tablet formulation. 
The effect of a high-fat meal on the PK of MRTX849 tablets was also evaluated in healthy 
subjects. A high-fat, high-calorie meal increased Cmax and AUC∞ of the tablet formulation by 
approximately 20% and 38%, respectively. However, the increased exposure is not clinically 
relevant based on the following considerations: 
• The efficacy and safety profiles of MRTX849 in patients have been characterized for 
the 600 mg BID regimen in the Phase 1/2 Study 849-001 using only the capsule 
formulation under fasting conditions. 
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• Accounting for the relative bioavailability of the tablet formulation compared to the 
capsule formulation (under fasting conditions), the tablet formulation under fed 
conditions is expected to result in a similar Cmax and 22% higher AUC compared to 
the capsule formulation under fasted conditions for which MRTX849 safety and 
efficacy profiles were established. Furthermore, between-subject variability in 
MRTX849 tablet exposure was approximately 2-fold lower under fed conditions 
(~24% to 30%) compared to fasted conditions (~45% to 57%), indicating that food 
did not increase PK variability of the tablet formulation. 
Results from a clinical drug-drug interaction (DDI) study and physiologically-based PK (PBPK) 
modeling showed the following:  
• MRTX849 as a potential perpetrator of DDI: Coadministration of oral midazolam 
(a sensitive CYP3A4 substrate) with multiple doses of MRTX849 (400 mg BID) 
increased midazolam AUC by approximately 21-fold in healthy subjects. 
Administration of multiple doses of MRTX849 at 600 mg BID in patients is predicted 
to increase oral midazolam AUC by 31-fold. Coadministration of warfarin 
(a sensitive CYP2C9 substrate) with multiple doses of MRTX849 at 600 mg BID in 
patients is predicted to increase warfarin AUC by 2.93-fold, indicating that 
MRTX849 is a moderate inhibitor of CYP2C9. Administration of MRTX849 at 600 
mg BID in patients is predicted to increase dextromethorphan AUC by 2.37-fold, 
indicating that MRTX849 is a moderate inhibitor of CYP2D6. Administration of 
multiple doses of MRTX849 at 600 mg BID in patients is predicted to increase oral 
bupropion (a sensitive CYP2B6 substrate) AUC by 1.14-fold, indicating that 
MRTX849 is a weak inhibitor of CYP2B6. Administration of MRTX849 at 600 mg 
BID in patients is predicted to increase digoxin (a P-gp substrate) AUC by 1.48-fold, 
indicating that MRTX849 is a weak inhibitor of P-gp. Administration of MRTX849 
at 400 mg BID increased rosuvastatin AUC by 1.35-fold in healthy subjects, 
indicating that MRTX849 is a weak inhibitor of BCRP. Administration of MRTX849 
at 600 mg BID in patients is predicted to have no effect of the exposure of metformin, 
a MATE substrate. 
• MRTX849 as a potential victim of DDI: Coadministration of multiple doses of 
itraconazole 200 mg QD (a strong CYP3A4 and P-gp inhibitor) with a single 200 mg 
dose of MRTX849 increased MRTX849 Cmax and AUC by approximately 2.4-fold 
and 4-fold, respectively in healthy subjects (Study 849-006). However, 
coadministration of multiple doses of itraconazole 200 mg QD with multiple doses of 
MRTX849 (600 mg BID) in patients is predicted to have a negligible effect on 
MRTX849 steady-state exposure. The lack of itraconazole effect on MRTX849 
steady-state exposure is due to the extent of auto-inhibition by MRTX849 at 600 mg 
BID steady state, thus the majority of CYP3A4-mediated intrinsic clearance (CLint) is 
already inhibited by MRTX849. Based on these data, no dose adjustment of 
MRTX849 is needed when MRTX849 is coadministered with CYP3A/P-gp 
inhibitors. Coadministration of multiple doses of rifampin 600 mg QD (a strong 
CYP3A4 and P-gp inducer) with a single 600 mg dose of MRTX849 decreased 
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MRTX849 Cmax by 88% and AUC by 95% in healthy subjects. Coadministration of 
multiple doses of rifampin (600 mg QD) with multiple doses of MRTX849 (600 mg 
BID) in patients is predicted to decrease MRTX849 Cmax by 61% and AUC by 66%. 
MRTX849 is a substrate of BCRP. The effect of inhibitors of BCRP (eg, curcumin, 
cyclosporin, and eltrombopag) on MRTX849 has not been evaluated. 
• Coadministration of repeat doses of pantoprazole (a proton pump inhibitor, PPI) with 
a single dose of MRTX849 decreased MRTX849 Cmax and AUC by approximately 
38% and 32%, respectively, in healthy subjects. 
Based on these results, guidance on use of concomitant medications is provided in Section 5.9.1 
and Appendix 2. 
1.3.5.3. 
MRTX849 Clinical Activity 
Initial clinical trial observations of MRTX849 in patients with NSCLC who were previously 
treated with a platinum agent and a checkpoint inhibitor have shown clinical activity. The Phase 
2 segment of Study 849-001 is evaluating the clinical activity of MRTX849 in cohorts of patients 
having tumors with KRAS G12C mutation. As of 30 August 2020, clinical activity data has been 
reported for patients with NSCLC administered MRTX849 at the Phase 2 dose of 600 mg BID in 
Phase 1/1b or Phase 2 cohorts. 
Among patients with NSCLC with KRAS G12C mutation with measurable disease and at least 
1 on-study disease assessment, 23/51 patients (45%) experienced a Partial Response in 
accordance with RECIST 1.1 based on investigator assessment (Jänne, 2020). Unconfirmed 
responses were initially documented among 5/23 responders, all of which were confirmed during 
continued study treatment. The disease control rate (PR plus stable disease) was 96.1% (49/51 of 
patients). Refer to the current version of IB for updated information. 
1.4. 
Docetaxel 
Docetaxel is an antineoplastic agent belonging to the taxoid family. Docetaxel disrupts the 
microtubular network in cells that is essential for mitotic and interphase cellular functions. 
Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules 
while simultaneously inhibiting their disassembly, leading to the production of microtubule 
bundles without normal function and that inhibit mitosis. 
Background information in addition to that presented in this protocol is available in locally 
approved product label. 
1.4.1. 
Docetaxel Drug Substance 
Generic Name: 
Docetaxel 
Other Name:  
TAXOTERE® 
Molecular Weight:  
861.9 kDa 
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1.4.2. 
Docetaxel Nonclinical Data 
Docetaxel nonclinical experience is described in locally approved product label. 
1.4.3. 
Docetaxel Clinical Data 
The following reports information included in the TAXOTERE® US Prescribing Information 
(USPI TAXOTERE [docetaxel]) dated May 2020. Refer to the current locally approved 
product label for updates during the conduct of this clinical trial. 
1.4.3.1. 
Docetaxel Pharmacokinetics 
Absorption: The pharmacokinetics of docetaxel have been evaluated in cancer patients after 
administration of 20 mg/m2 to 115 mg/m2 in Phase 1 studies. The area under the curve (AUC) 
was dose proportional following doses of 70 mg/m2 to 115 mg/m2 with infusion times of 1 to 
2 hours. Docetaxel's pharmacokinetic profile is consistent with a three-compartment 
pharmacokinetic model, with half-lives for the α, β, and γ phases of 4 min, 36 min, and 11.1 hr, 
respectively. Mean total body clearance was 21 L/h/m2. 
Distribution: The initial rapid decline represents distribution to the peripheral compartments and 
the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the 
peripheral compartment. Mean steady-state volume of distribution was 113 L. In vitro studies 
showed that docetaxel is about 94% protein bound, mainly to α1-acid glycoprotein, albumin, and 
lipoproteins. In 3 cancer patients, the in vitro binding to plasma proteins was found to be 
approximately 97%. Dexamethasone does not affect the protein binding of docetaxel. 
Metabolism: In vitro drug interaction studies revealed that docetaxel is metabolized by the 
CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of 
compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4. 
Elimination: A study of 14C-docetaxel was conducted in 3 cancer patients. Docetaxel was 
eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester 
group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal 
excretion accounted for approximately 6% and 75% of the administered radioactivity, 
respectively. About 80% of the radioactivity recovered in feces is excreted during the first 
48 hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of 
unchanged drug. 
Population pharmacokinetic analyses have indicated that the pharmacokinetics of docetaxel were 
not influenced by age or gender and no significant differences were observed between Japanese 
and European/American populations. 
1.4.3.2. 
Docetaxel Adverse Reactions Common in Clinical Trials 
As of May 2020, the most common adverse reactions across all docetaxel indications are 
infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, 
neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, 
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pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence 
varies depending on the indication. 
In patients receiving docetaxel as monotherapy for unresectable, locally advanced or metastatic 
NSCLC previously treated with platinum-based chemotherapy, the most common 
treatment-emergent adverse reactions regardless of relationship (≥ 20%) were neutropenia, 
leukopenia, anemia, infection, fluid retention, neurosensory, skin reactions, nausea, vomiting, 
diarrhea, alopecia, asthenia, stomatitis, and pulmonary reactions. 
1.5. 
Study Rationale 
Elucidation of the underlying genetic aberrations occurring in lung adenocarcinoma by the 
Cancer Genome Atlas Research Network has demonstrated that recurrent aberrations leading to 
activation of the RTK/RAS/RAF pathway occur in 76% cases of lung adenocarcinoma, including 
activating KRAS mutations in 32.2% of cases (TCGA, 2014), thereby implicating this pathway in 
the underlying carcinogenesis. Additionally, KRAS mutations occur in up to approximately 2% 
of NSCLC patients with squamous histology (AACR Project GENIE Consortium, 2017), 
(TCGA, 2012) and are expected to play the same role in KRAS activation, notwithstanding the 
potential for histologic misclassification based on morphology (Rekhtman, 2012). The 
importance of RAS pathway is further supported by nonclinical data indicating the dependency 
of KRAS-mutant tumors on KRAS signaling (McDonald, 2017), and the clinical activity of 
several targeted agents approved for use in NSCLC, including those targeting EGFR, ALK1, 
BRAF, ROS1, and TRK family members. These observations suggest that KRAS mutations 
similarly define a unique segment of lung cancer for which a targeted therapy option is currently 
unavailable (Campbell, 2016). 
Notably, KRAS mutations have been associated with a worse prognosis (Slebos, 1990), 
(Mascaux, 2005), and despite the significant advances of chemotherapy and immunotherapy for 
NSCLC (see Section 1.2), including those for patients with KRAS G12C tumor mutation, patients 
ultimately develop progressive disease; thus, additional treatment options are warranted. The 
proposed population for this study, those treated in the second and higher lines of therapy, have 
an unmet medical need, and agents targeted against mutant KRAS hold the promise of 
significant clinical activity similar to that observed with other targeted agents in NSCLC. 
Subsequent to the initiation of this trial (Study 849-012), sotorasib, a direct inhibitor of KRAS 
G12C, received accelerated approval from the U.S. FDA (USPI LUMAKRAS [sotorasib]) for 
the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC 
who have received at least one prior systemic therapy. This approval provides clinical validation 
for direct KRAS G12C inhibition in patients with KRAS G12C mutant NSCLC in the second line 
and later treatment setting. Based on this shift in standard therapy and the clinical activity 
observed with the direct KRAS G12C inhibitor MRTX849 in this patient population 
(Section 1.3.5.3), the study design has been modified to allow patients randomized to the 
docetaxel arm who develop RECIST 1.1-defined progressive disease per blinded independent 
central review (BICR) while on study to crossover and receive MRTX849 study treatment, if the 
inclusion and exclusion requirements as outlined in Section 4.3 and Section 4.4 are met. 
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1.5.1. 
Choice of Control Arm Treatment 
After failure of front-line chemotherapy and checkpoint inhibition, docetaxel with or without 
ramucirumab remains the most common standard of care outside of a clinical trial. Although 
docetaxel has demonstrated efficacy, careful patient selection and monitoring are important due 
to the possibility of toxic deaths, hepatotoxicity, neutropenia, hypersensitivity reactions, and 
fluid retention. Additionally, ramucirumab, a recombinant monoclonal antibody that targets 
VEGF receptor, improves survival when used in combination with docetaxel, although AEs of 
special concern with the combination include risk for severe hemorrhage, Grade 3 to 4 
gastrointestinal bleeding, gastrointestinal perforation or fistula, impaired wound healing, and 
poorly controlled hypertension. Importantly, however, docetaxel monotherapy is recommended 
as a standard option for NSCLC patients after failure of chemotherapy and an inhibitor of 
PD-(L)1 (NCCN, 2020) and an appropriate comparator treatment for the intended study 
population, namely patients with unresectable, locally advanced or metastatic NSCLC with 
KRAS G12C mutation with disease progression on or after treatment with platinum-based 
chemotherapy and anti-PD-1/PD-L1 therapy. 
1.5.2. 
Choice of Dosing Regimen 
The starting dosing regimen of MRTX849 was selected based on the Phase 1 data demonstrating 
exposures predicted to sufficiently inhibit KRAS G12C with a manageable safety profile and 
preliminary evidence of clinical activity as described in Section 1.3.5.3. 
1.5.3. 
Benefit/Risk Assessment 
Patients with NSCLC harboring a KRAS G12C mutation and who have received prior treatment 
with a platinum regimen and CIT have a serious and life-threatening disease with an estimated 
median survival of 5.7 to 10.5 months. Treatment-related, Grade 3/4 adverse events reported 
with MRTX849 include fatigue, ALT increased, lipase increased, nausea, diarrhea, AST 
increased, QT prolongation, vomiting, blood alkaline phosphatase increased, decreased appetite, 
blood creatinine increased, and anemia, and the entry criteria and safety assessments have been 
included in the study to mitigate risks. Clinical activity has been reported for this patient 
population with a response rate of 45% among 51 patients treated with MRTX849 600 mg BID 
in the Phase 1/1b or Phase 2 setting, which exceeds the reported response rate of 23% reported 
with docetaxel plus ramucirumab. Taking risks into consideration with the preliminary clinical 
activity of MRTX849 in this population, as well as the adverse event risk mitigation procedures, 
the overall benefit/risk balance of this study is acceptable. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
To compare the efficacy of MRTX849 versus docetaxel in patients with NSCLC with KRAS 
G12C mutation and who have received prior treatment with a platinum-based regimen and 
immune CIT. 
2.1.2. 
Secondary Objectives 
• To evaluate secondary efficacy endpoints in the study population. 
• To evaluate the safety and tolerability in the study population. 
• To evaluate the pharmacokinetics (PK) of MRTX849 administered in the study 
population. 
• To evaluate health-related quality of life (HRQOL) and lung cancer-specific 
symptoms in the study population. 
2.1.3. 
Exploratory Objectives 
• To explore correlations between gene alterations (baseline and upon treatment 
resistance) with efficacy. 
• To evaluate the Progression-Free Survival in the next-line of therapy (PFS2) in the 
study population 
• To evaluate efficacy outcome in the CNS 
• To explore intracranial activity in patients with brain metastases using exploratory 
efficacy endpoints  
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
• Progression-Free Survival (PFS) 
2.2.2. 
Secondary Endpoints 
• Secondary efficacy endpoints: 
− Overall Survival (OS), 
− Objective Response Rate (ORR), 
− Duration of Response (DOR), and 
− 1-Year Survival Rate 
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• Safety characterized by type, incidence, severity, timing, seriousness and relationship 
to study treatment of AEs, laboratory abnormalities, and number of patients 
discontinuing study treatment due to an adverse event. 
• Population PK parameters of MRTX849. 
• Patient Reported Outcome (PRO) scores using the following: 
− Lung Cancer Symptom Scale (LCSS). 
− European Quality of Life Five Dimensions Questionnaire (EQ-5D-5L). 
2.2.3. 
Exploratory Endpoints 
• Gene alterations in tumor tissue and ctDNA. 
• Progression-Free Survival-2 (PFS2). 
• Time to CNS Progression. 
• Intracranial activity using CNS RECIST 1.1 endpoints in patients with brain 
metastases, including intracranial objective response rate (icORR), intracranial 
duration of response (icDOR), intracranial progression free survival (icPFS) and 
intracranial time to progression (icTTP). 
3. 
STUDY DESIGN 
Study 849-012 is an open-label, randomized Phase 3 clinical trial comparing the efficacy of 
MRTX849 versus docetaxel in patients with NSCLC with KRAS G12C mutation and who have 
received prior therapy with a platinum-based regimen and an immune checkpoint inhibitor. 
Secondary objectives include evaluation of safety and tolerability, secondary efficacy endpoints, 
PROs, and MRTX849 PK in the study population. 
The presence of KRAS G12C mutation in tumor tissue for the purpose of patient eligibility must 
be established using Sponsor pre-approved methods and laboratories. Presence of tumor KRAS 
G12C mutation may be established using Sponsor-approved local tests or the Sponsor-provided 
central laboratory test. For all enrolled patients KRAS G12C mutation status and correlative 
tumor gene alterations will be retrospectively tested using tumor samples submitted no later than 
30 days after the first dose of study treatment.  
Patient eligibility for study enrollment based on objective disease progression on or after a 
platinum-based regimen and an immune checkpoint inhibitor will be evaluated by the 
Investigator.  
Data entered into the case report form (CRF) are to include prior regimens, best overall response, 
if progression occurred on or after treatment and date of progression. 
Eligible patients will be randomized in a 2:1 ratio to receive MRTX849 (adagrasib) or docetaxel 
respectively. Randomization will be stratified by: 
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1. Region (non-Asia-Pacific versus Asia-Pacific) 
2. Sequential versus concurrent (administration of last prior platinum-based chemotherapy 
and anti-PD-1/PD-L1 antibody) 
The requirements for tumor KRAS G12C for determining eligibility are presented in Table 1 and 
Figure 1. The Schedule of Assessments is presented in Table 2. 
Study treatment will be administered in 3-week cycles. Patients randomized to the 
investigational arm will receive MRTX849 administered orally (PO) at a starting dose of 600 mg 
BID. Patients randomized to the comparator arm will receive treatment with docetaxel. 
Docetaxel will be administered by intravenous infusion at 75 mg/m2 over 1 hour or according to 
institutional practices every 3 weeks. Premedication with dexamethasone (or institutional 
equivalent) will be required in accordance with local standards. 
Disease response and progression will be evaluated in accordance with RECIST 1.1 
(Eisenhauer, 2009). Blinded independent central review for disease response and progression 
will be performed for the purpose of statistical analyses of these study endpoints. Disease 
assessments must be performed as scheduled according to the calendar to prevent the 
introduction of bias in the assessment of efficacy based on toxicity. Timely and complete disease 
assessments and transfer of radiographic documentation to the Central Radiology Laboratory is 
critical to the integrity of this clinical trial. 
Patients will receive study treatment as assigned at randomization until disease progression, 
unacceptable AEs, Investigator decision, patient refusal or death. Patients experiencing clinical 
benefit in the judgment of the Investigator may continue study treatment beyond disease 
progression as defined by RECIST 1.1, if the following criteria are met: absence of clinical 
symptoms or signs indicating clinically significant disease progression; no significant decline in 
performance status; absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (eg, CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention; and no significant, unacceptable 
or irreversible toxicities related to study treatment. Patients considering continuation of study 
treatment beyond RECIST 1.1-defined disease progression must be provided with and sign an 
informed consent detailing any available therapies and potential clinical benefit that the patient 
may be foregoing by continuing study treatment and will continue to undergo disease 
assessments until study treatment is discontinued. Imaging should continue to be submitted for 
BICR review until BICR confirmed disease progression. 
In the event a patient discontinues study treatment for a reason other than objective disease 
progression, disease assessments post-treatment should continue until objective disease 
progression is documented by the Investigator and BICR or start of subsequent anticancer 
therapy, whichever is sooner.  
Patients randomized to the docetaxel arm will be offered the opportunity to receive MRTX849 
treatment upon development of RECIST 1.1-defined disease progression per BICR. Patients 
must sign a crossover informed consent form and must meet all eligibility criteria for further 
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treatment as described in Section 4.3 and Section 4.4 and will use the dosing regimen described 
in Section 5.3. The required assessments for patients who crossover included in Appendix 6. 
4. 
SUBJECT SELECTION AND ENROLLMENT 
Patient eligibility must be reviewed and documented by an appropriately qualified member of the 
Investigator’s study team before patients are included in the study. No exceptions to the patient 
eligibility requirements will be granted by the Sponsor. 
4.1. 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study. 
1. Histologically or cytologically confirmed diagnosis of NSCLC with KRAS G12C 
mutation. 
2. Receipt of prior treatment with a platinum (cisplatin or carboplatin)-containing regimen 
and an immune checkpoint inhibitor (ie, anti-PD-1/PD-L1 inhibitor) concurrently or 
sequentially for advanced or metastatic disease with the outcome of objective disease 
progression on or after treatment. Source documents for historical disease evaluations to 
allow Investigator certification of disease progression on or after prior treatment must be 
available. 
3. Candidacy to receive treatment with docetaxel in accordance with the local product label. 
Patients with known hypersensitivity to docetaxel or polysorbate 80 are excluded from 
this study.  
4. Unresectable, locally advanced or metastatic disease. 
5. Presence of evaluable or measurable disease per RECIST version 1.1. 
6. Expected availability of representative tumor specimen (primary or metastatic, archival 
or newly obtained) for central laboratory testing of KRAS G12C mutation status and 
correlative gene alterations (minimum of 7 slides, preferably 15 slides). 
7. Age ≥ 18 years (Legal age of consent for participation in an adult clinical trial differs in 
each country. In countries where the legal age of consent is higher than 18 years, 
participants must meet the legal age requirements of that country). 
8. Life expectancy of at least 3 months. 
9. Recovery from the adverse effects of prior therapy to baseline or Grade 1 (excluding 
alopecia). 
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
11. Laboratory values within the screening period: 
a. Absolute neutrophil count ≥ 1,500/mm3 (≥ 1.5 × 109/L) 
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b. Platelet count ≥ 100,000/mm3 (≥ 100 × 109/L) 
c. Hemoglobin ≥ 9 g/dL, in the absence of transfusions for at least 2 weeks 
d. Total bilirubin ≤ 1.0 × upper limit of normal (ULN) 
e. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 × ULN; if 
associated with liver metastases, ≤ 5 × ULN. If alkaline phosphatase > 2.5 × ULN, 
then ALT and AST must be ≤ 1.5 × ULN with or without liver metastases. 
f. Creatinine clearance ≥ 50 mL/min, using the Cockcroft-Gault formula. 
12. Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees 
to use contraception while participating in this study, and for a period of 6 months 
following termination of study treatment. 
13. Completed informed consent process, including signing IRB/EC-approved informed 
consent form (ICF). 
14. Willing to comply with clinical trial instructions and requirements. 
4.2. 
Exclusion Criteria 
Patients presenting with any of the following will not be included in the study: 
1. Prior treatment with an agent targeting KRAS G12C (eg, AMG 510, sotorasib). 
2. Active brain metastases. Patients are eligible if brain metastases are treated and patients 
are neurologically stable for at least 2 weeks prior to randomization. If patients require 
the use of corticosteroids, patients must be on a stable or decreasing dose of ≤ 10 mg 
daily prednisone (or equivalent) prior to randomization. 
3. Carcinomatous meningitis. 
4. Major surgery within 4 weeks prior to randomization. 
5. History of intestinal disease or major gastric surgery likely to alter absorption of study 
treatment or inability to swallow oral medications. 
6. Any of the following cardiac abnormalities: 
a. Unstable angina pectoris or myocardial infarction within 6 months prior to 
randomization. 
b. Symptomatic or uncontrolled atrial fibrillation within 6 months prior to 
randomization. 
c. Congestive heart failure ≥ NYHA Class 3 within 6 months prior to randomization. 
d. Prolonged QTc interval > 480 milliseconds or family or medical history of congenital 
Long QT Syndrome. 
7. History of stroke or transient ischemic attack within 6 months prior to randomization. 
8. Ongoing need for a medication with any of the following characteristics that cannot be 
switched to alternative treatment prior to study entry (see Appendix 2): known risk of QT 
prolongation or Torsades de Pointes; sensitive CYP3A4 substrate listed in Appendix 2; 
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substrate of P-gp with narrow therapeutic index; strong inducer of CYP3A4; inhibitor of 
BCRP; and proton pump inhibitors. 
9. Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B 
(HBV) or C (HCV) infection. Note that the following are permitted: 
• Patients with prior HBV infections who are:  
− Considered to have past or resolved HBV infection (defined as the presence of 
hepatitis B core antibody [HBcAb] and absence of hepatitis B surface antigen 
[HBsAg]); or 
− Considered to be in an inactive HBV carrier state (defined as HBsAg-positive, 
with normal ALT, and HBV DNA <2,000 IU/mL or <10,000 copies/mL). 
Note: For patients in an inactive HBV carrier state or with a resolved HBV infection, the 
risk of HBV reactivation should be considered and the need for anti-HBV prophylaxis 
prior to randomization should be carefully assessed in accordance with local guidelines. 
• Patients treated for HCV with no detectable viral load. 
• Patients treated for HIV with no detectable viral load on current regimen for at least 
1 month prior to randomization. 
Note: Refer to Appendix 3 for medications to be avoided during treatment with 
docetaxel, in particular anti-HIV strong CYP3A4 inhibitors, and Exclusion Criterion 8 
regarding drug-drug interactions of concomitant anti-HIV agents and in particular 
sensitive CYP3A4 substrates. 
10. Known or suspected presence of another malignancy that could be mistaken for the 
malignancy under study during disease assessments. 
11. Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented 
prior to randomization. 
12. Breastfeeding or planning to breast-feed during the study or within 6 months after the last 
dose of study treatment. 
13. Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or 
uncontrolled infection, or other medical condition or history, including laboratory results, 
which, in the Investigator’s opinion, would be likely to interfere with the patient’s 
capacity to provide informed consent, with the patient’s participation in the study, or with 
the interpretation of the results. 
14. Hypersensitivity to any component of the MRTX849 drug product. 
15. Administration of a live/attenuated vaccine within 30 days before the first dose of study 
treatment.  
16. Patients who have received prior treatment with docetaxel. 
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4.3. 
Crossover Inclusion Criteria 
Patients randomized to docetaxel arm must meet all of the following criteria to be eligible for 
crossover into MRTX849 study treatment arm: 
1. Evidence of RECIST 1.1 defined disease progression on docetaxel per BICR.  
2. ECOG performance status 0 - 2. 
3. Laboratory values that meet criteria per Inclusion Criterion 11 at least 7 days after the last 
dose of docetaxel  
a. Exception: Allow hemoglobin ≥ 8 g/dL and transfusion of red blood cells  
4. Recovery from all docetaxel-related adverse effects to Grade 1 or baseline, with the 
exceptions of peripheral neuropathy and alopecia for which Grade 2 is acceptable. 
4.4. 
Crossover Exclusion Criteria 
Patients randomized to docetaxel arm presenting with any of the following will be excluded from 
crossover into MRTX849 study treatment arm: 
1. Receipt of any other systemic anti-cancer therapy after last administration of docetaxel on 
the study. 
2. Any severe acute or chronic medical or psychiatric condition, or laboratory abnormality 
that may increase the risk associated with continued study participation or study drug 
administration, or may interfere with the interpretation of study results, and in the 
judgment of the investigator would make the patient inappropriate for crossover to 
MRTX849 treatment. 
4.5. 
Life Style Guidelines 
4.5.1. 
Dietary Restrictions 
Patients should be instructed to avoid the following substances due to the possibility of 
interactions of these substances with the pharmacokinetics of MRTX849 and/or docetaxel: 
1. Grapefruit and grapefruit juice (avoid with docetaxel only) 
2. St. John’s wort and other herbal preparations (see Section 5.9.1) (avoid for both 
MRTX849 and docetaxel) 
4.5.2. 
Reproductive Health 
The informed consent process must include discussion of the risks associated with pregnancy 
and adequate contraception methods. Patients (including men whose partner is a WOCBP) who 
are biologically capable of having children and sexually active must agree to use at least one 
acceptable, highly effective method of contraception for the duration of the treatment period and 
for at least 6 months after the last dose of study treatment. In addition, in some regions 
participating in this study (eg, the European Union), patients are required to use 2 acceptable 
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methods of contraception, one of which must be highly effective, in accordance with local 
regulations. The Investigator will counsel the patient on selection of contraception method and 
instruct the patient in its consistent and correct use. Examples of methods of birth control 
considered to be highly effective include: 
4.5.2.1. 
Women  
1. Oral, inserted, injected or implanted hormonal methods of contraception, associated with 
inhibition of ovulation provided it has been used for an adequate period of time to ensure 
effectiveness. 
2. Correctly placed copper containing intrauterine device (IUD). 
3. Bilateral tubal ligation or bilateral salpingectomy. 
4. Sexual abstinence. Sexual abstinence is acceptable only as true abstinence, defined in the 
context of this protocol as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments, when this is in line with the preferred 
and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. The entire period of risk is defined as study treatment, including during 
temporary breaks from treatment, and at least 6 months after stopping study treatment. 
5. Vasectomy with confirmed absence of sperm for male partners of women patients who 
are of childbearing potential. 
4.5.2.2. 
Men 
1. Sexual abstinence. In the context of this protocol, sexual abstinence is considered a 
highly effective method of birth control only if refraining completely from heterosexual 
intercourse during the entire period of risk (ie, during study treatment, including during 
temporary breaks from treatment, and for at least 6 months after stopping study 
treatment). 
2. All men on study, including men who have had vasectomy, with partners of childbearing 
potential must use condoms for the duration of the treatment period and for at least 
6 months after the last dose of study drug. 
Highly effective or effective contraceptive methods may also be considered for female partners 
who are WOCBP. 
Acceptable birth control methods not considered highly effective include the following: 
1. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action. 
2. Male or female condom with spermicide is considered acceptable as one method of 
contraception in regions where patients are required to use 2 acceptable methods of 
contraception, however they are not considered highly effective. A combination of male 
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condom with either cap, diaphragm or sponge with spermicide (double barrier methods) 
is also considered one acceptable, but not highly effective, birth control methods. 
3. Cap, diaphragm or sponge with spermicide. 
The Investigator will instruct the patient to call immediately if the selected birth control method 
is discontinued or if pregnancy is known or suspected. 
Note: Women are considered post-menopausal and/or not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy) or tubal ligation at least 6 months ago. In case of any ambiguity and in 
countries operating in compliance with Clinical Trials Facilitation Group (CTFG) guidelines, the 
reproductive status of the woman should be confirmed by follicle stimulating hormone level 
assessment. 
In accordance with docetaxel product labeling in some regions in which this study will be 
conducted, men randomized to receive docetaxel should consider sperm preservation before 
starting study treatment.  
4.6. 
Pre-screening, Screening and Randomization into Study 
4.6.1. 
Study Number Assignment 
At the time of the pre-screening informed consent process, patients will be assigned an 
automatically generated patient number. The patient number must be used on all documentation 
and correspondence with the Sponsor, Contract Research Organization (CRO) and laboratory 
vendors throughout the patient’s experience in this study. 
4.6.2. 
Tumor Tissue KRAS Mutation Testing 
Patient eligibility for enrollment based on the presence of KRAS G12C mutation in the tumor 
may be established using Sponsor-approved local tests or a Sponsor-provided central test (see 
Table 1 and Section 7.1 for details). For all enrolled patients the KRAS mutation status and 
correlative tumor gene alterations will be retrospectively tested using tumor samples submitted 
no later than 30 days after the first dose of study treatment. 
If the Sponsor-provided central laboratory is used to perform tumor genotyping to establish 
eligibility for the study, an up to 10 to 14-day turn-around time should be expected from the time 
of receipt of adequate samples at the central lab to test results returned to the study site. 
Questions concerning adequacy of samples will cause delay beyond this timeframe. 
For central laboratory genotyping, tumor samples from the most recent biopsy or excision are 
preferred; however, if no recently obtained materials are available, samples from any time during 
patient’s prior disease course are accepted. When possible, the same tissue source used to 
establish study eligibility should be submitted to the central laboratory in order to minimize the 
potential for discordance between the local test and central laboratory test results. Tumor 
biopsies having significant risk should not be performed for the purpose of determining genetic 
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eligibility. Note: Patients enrolled at sites in Germany will not undergo tumor lesion biopsy for 
the purpose of the study after the Screening period. 
After local or central laboratory documentation of the KRAS G12C mutation, the main study 
consent should be obtained, followed by the required screening procedures. 
4.6.3. 
Randomization 
Following review of all screening procedures, patient eligibility will be confirmed by 
appropriately qualified staff at the investigational site. Patients will be randomized in a 2:1 ratio 
using a centralized Interactive Web Response System (IWRS) to receive treatment assignment to 
either MRTX849 or docetaxel. Study treatment should begin within 3 business days of 
randomization.  
5. 
STUDY TREATMENTS 
5.1. 
Investigational and Non-Investigational Medicinal Products 
Investigational medicinal products are pharmaceutical forms of an active substance or placebo 
being tested (ie, test substance) or used as a reference (ie, reference substance) in a clinical trial. 
In this clinical trial, the investigational medicinal products are:  
• MRTX849 – test substance, and 
• docetaxel – reference substance. 
Non-investigational medicinal products include medications used for preventative or therapeutic 
reasons. In this clinical trial, non-investigational medicinal products include pre-medications 
associated with docetaxel (eg, dexamethasone, or institutional equivalent) and medications used 
to treat docetaxel-related infusion reactions. 
5.2. 
MRTX849 Study Drug 
5.2.1. 
MRTX849 Formulation  
MRTX849 clinical trial material is provided by the study Sponsor.  
Two formulations of MRTX849 may be used in this study. See the Pharmacy Manual for further 
information including capsule and tablet unit strength and details on packaging description. 
MRTX849 Capsule Formulation and Packaging 
The MRTX849 capsule formulation contains active pharmaceutical ingredient (API). 
MRTX849 (capsule) clinical trial material is packaged in high-density polyethylene (HDPE), 
white opaque, round bottles. A tamper-proof heat induction seal and a child-resistant closure are 
used. 
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MRTX849 Tablet Formulation and Packaging 
The MRTX849 tablet formulation is available as immediate release, white to off-white, 
film-coated tablets. Excipients in the tablet formulation include microcrystalline cellulose, 
mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate. The film coat is 
Opadry II White (57U18539) which consists of hypromellose, titanium dioxide, polydextrose, 
talc, maltodextrin, and medium chain triglycerides (vegetable). 
MRTX849 tablets are packaged in HDPE white, opaque, square bottles with child resistant 
closures with heat induction seals. 
Labeling 
MRTX849 medication labels comply with the legal requirements of the US and/or other 
countries where clinical drug supply is used and will be printed in the languages required in the 
countries in which the study is conducted. 
Storage 
Clinical trial material should be stored in an area that is secure, with limited access and 
monitored for temperature using a calibrated thermostat or thermometer. MRTX849 clinical trial 
material should be stored under the conditions stated on the container labels and the Pharmacy 
Study Manual. 
Refer to the Pharmacy Study Manual for details on available dose strengths, packaging and 
suggested storage conditions. 
5.2.2. 
MRTX849 Preparation, Dispensing and Accountability 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents, including clinical trial material provided for this study. 
Study site personnel will dispense MRTX849 clinical trial material on Day 1 of each dose cycle, 
unless otherwise specified by the study site’s Standard Operating Procedures. Sufficient supply 
should be provided to patients for each cycle and extra may be provided to cover an additional 
2 days in case of delayed clinic visits or lost clinical trial material. The provided clinical trial 
material bottles may be labeled for specific patient use and given to the patient if the unit count is 
the needed number. 
Patients will be asked to record their daily dosing on Sponsor-provided diary cards and report 
any missed doses or lost doses. Written dosing instructions for MRTX849 are provided 
(eg., fasting instructions, take with water, etc.) on the back of each Sponsor-provided diary card. 
Patients should be told to bring study clinical trial material bottle(s) (empty or not) and 
completed dosing diaries (as applicable) with them to each clinic visit for a compliance check 
and capsule/tablet count. Study site personnel will retain the bottle(s) until a monitor has 
completed reconciliation and retain dosing diaries (as applicable) with site study files. 
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All MRTX849 study treatment supplies will be accounted for in the drug accountability 
inventory forms supplied by the Sponsor or using locally approved forms that include all 
required information. The drug accountability inventory forms must identify the study drug, 
including batch or lot numbers, and account for its disposition on a patient-by-patient basis, 
including specific dates and quantities. The forms must be signed by the individual who 
dispensed the drug. 
At the end of the study, all unused MRTX849 clinical trial material must be destroyed in 
accordance with local Standard Operating Procedure provided to the Sponsor for the Trial 
Master File, or returned to the Sponsor or its appointed agent, as directed by the Sponsor. 
5.3. 
MRTX849 Patient Treatment 
5.3.1. 
MRTX849 Oral Administration 
The following guidelines should be followed for oral administration of MRTX849: 
• On the days of PK sampling, the first doses of the day should be taken in the clinic 
and administration time recorded. 
• Twice daily dosing should be at 12-hour intervals to the extent possible. 
• MRTX849 tablets may be taken with or without food. 
• Study drug product should be taken with at least 240 mL (8 ounces) of water. 
• Study drug product should be swallowed whole and not chewed. 
• If vomiting occurs, doses should not be replaced. 
• If a dose is inadvertently missed, the dose should be skipped if > 4 hours has elapsed 
since the expected dosing time. Dosing may resume at the next appointed time. 
5.3.2. 
MRTX849 Study Treatment 
5.3.2.1. 
Treatment Regimen 
Study treatment will be expressed in 3-week cycles. 
The planned regimen for MRTX849 is 600 mg BID, administered orally on a continuous basis 
until disease progression. 
5.4. 
Guidelines for MRTX849 Dose Modification and Adverse Event 
Management 
Provided below are guidelines for the management of MRTX849 treatment-related AEs and 
recommended dose modifications. Severity of AEs as described in dose modification tables is as 
defined by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse 
Events [CTCAE, Version 5.0]. 
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5.4.1. 
Dose Reduction Steps for MRTX849 in Response to Treatment-Related Adverse 
Events 
In the event of treatment-related AEs requiring dose reduction (Section 5.4.2), available 
MRTX849 dose reduction steps are presented in Table 5. Further dose reductions may be 
undertaken after discussion with the Sponsor. 
Table 5: 
MRTX849 Dose Reduction Steps in Response to Treatment-Related Adverse 
Events 
Dose Level 
MRTX849 
Starting Dose Level 
600 mg BID 
-1 
400 mg BID 
-2 
600 mg QD 
 
The following are general guidelines for the interruption, resumption or re-challenge of treatment 
with MRTX849: 
• following MRTX849 dose reduction and control of the AE, re-challenge at a higher 
MRTX849 dose may be permitted after discussion with the Sponsor; 
• if resumption of dosing for MRTX849 is delayed for ≥ 14 days due to an AE that is at 
least suspected to be attributable to study treatment, then resumption at a reduced 
dose should be considered; 
• if treatment with MRTX849 is withheld for ≥ 22 consecutive days, then permanent 
discontinuation from treatment should be considered; and 
• if a treatment-related AE recurs despite dose reduction of MRTX849 to the lowest 
dose anticipated in Section 5.4.1, then permanent discontinuation from study 
treatment should be considered, unless after discussion with the Sponsor it is in the 
best interest of the patient to continue. 
Treatment interruptions and modification guidelines are provided in the tables below. 
Documentation of discussions with the Sponsor concerning study treatment decisions should be 
retained with patient records as source documents. 
5.4.2. 
Guidelines for the Management of Study Treatment-Related Adverse Events 
Provided below are guidelines for dose modification and management of potential study 
treatment-related AEs. In the event that dose reduction of MRTX849 is needed, available dose 
reduction steps are presented in Section 5.4.1. 
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5.4.2.1. 
Hematological Toxicities 
Hematological toxicities that are considered to be causally related to MRTX849 should initially 
be managed with interruption of MRTX849 as outlined in Table 6. Following resolution of 
toxicity to the specified degree, dose reduction of MRTX849 should be implemented. 
Table 6: 
Hematological Toxicities – MRTX849 Dose Modifications 
Hematological Toxicity 
Treatment Interruption 
Dose Modification 
Grade 1/2 AEs 
Implement at Investigator and Patient Discretion 
Specific Grade 3/4 AEs 
• 
Grade 4 Anemia 
• 
Grade 4 Neutropenia ≥ 8 days 
• 
Grade 3/4 Febrile Neutropenia 
• 
Grade 3 Thrombocytopenia with 
Clinically Significant Bleeding 
• 
Grade 4 Thrombocytopenia 
Hold until ≤ Grade 1 or return 
to baseline 
Decrease one dose level 
Other Grade 3/4 AEs 
Hold until ≤ Grade 1 or return 
to baseline 
May resume at the same dose 
level 
Abbreviation: AE = adverse event 
5.4.2.2. 
Gastrointestinal Toxicities 
Patients should be advised of the possibility of developing nausea, vomiting, and diarrhea. When 
possible, patients should have anti-emetics available to self-administer soon after onset. Patients 
assessed as having greater potential to develop nausea may be treated prophylactically. 
Alternatives to ondansetron should be used (due to the possibility of QT prolongation due to 
ondansetron; see Section 5.9.1 for additional guidance related to ondansetron). Due to the 
observation of creatinine increases with MRTX849, fluid status should be evaluated in patients 
who develop vomiting or diarrhea, and oral and/or intravenous hydration should be considered if 
clinically warranted. In addition, more frequent electrolyte monitoring that includes potassium 
and magnesium should be considered along with supplementation for levels below the lower 
limit of normal in order to mitigate the risk for QT prolongation. 
Gastrointestinal toxicities that are considered to be causally related to MRTX849 should initially 
be managed with treatment interruption as outlined in Table 7. Following resolution of toxicity 
to the specified degree, dose reduction of MRTX849 should be implemented. 
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Table 7: 
Gastrointestinal Toxicities – MRTX849 Dose Modifications 
Gastrointestinal Toxicity 
Treatment Interruption 
Dose Modification 
Grade 1/2 AEs 
Implement at Investigator and Patient Discretion 
Specific Grade 3/4 AEs 
• 
Grade 3 Nausea > 72 hours, despite 
therapy 
• 
Grade 3/4 Vomiting > 24 hours despite 
therapy (or > 72 hours while optimizing 
therapy) 
• 
Grade 3 Diarrhea > 48 hours, despite 
therapy 
Hold until ≤ Grade 1 or 
return to baseline 
Decrease one dose level 
• 
Grade 4 Diarrhea, despite therapy 
Discontinue study treatment 
• 
Asymptomatic Grade 3 Amylase or 
Lipase Elevation > 8 days 
Hold until ≤ Grade 1 or 
return to baseline 
May resume at the same dose 
level 
• 
Symptomatic Grade 3/4 Amylase or 
Lipase Elevation 
Hold until ≤ Grade 1 or 
return to baseline 
May resume one dose level lower 
• 
Grade 3/4 Pancreatitis 
Discontinue study treatment 
Other Grade 3 AEs 
Hold until ≤ Grade 1 or 
return to baseline 
May resume at the same dose 
level or one dose level lower 
Other Grade 4 AEs 
Discontinue study treatment 
Abbreviation: AE = adverse event 
 
5.4.2.3. 
Hepatic Toxicities 
Hepatic toxicities that are considered to be causally related to MRTX849 should initially be 
managed with treatment interruption as outlined in Table 8. Evaluation for confounding factors 
(eg, cholestasis, metastasis, or viral infection) should be performed as clinically indicated, and 
more frequent monitoring of a hepatic panel (including AST, ALT, alkaline phosphatase, and 
bilirubin) should be considered for those patients with transaminase increases. Following 
resolution of toxicity to the specified degree, dose reduction of MRTX849 should be 
implemented.  
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Table 8: 
Hepatic Toxicities – MRTX849 Dose Modifications 
Hepatic Toxicity 
Treatment Interruption 
Dose Modification 
Grade 1 AEs 
Implement at Investigator and Patient Discretion 
Specific Grade 2 AEs 
• 
Grade 2 Increased Hepatic Transaminase 
(ALT, AST) 
Not Required 
Decrease one dose level 
Other Grade 2 AEs 
Implement at Investigator and Patient Discretion 
Specific Grade 3/4 AEs 
• 
Grade 3 Increased Hepatic Transaminase 
(ALT, AST)  
Hold until ≤ Grade 1 or 
return to baseline 
Decrease one dose level 
• 
Grade 4 Increased Hepatic Transaminase 
(ALT, AST) 
• 
Hy’s Law Case1 
Discontinue study treatment 
• 
Grade 3 Increased Bilirubin ≤ 22 days 
(Without Increases in Transaminases or 
Alkaline Phosphatase) 
Hold until ≤ Grade 1 or 
return to baseline 
Decrease one dose level 
• 
Grade 3 Increased Bilirubin > 22 days 
(Without Increases in Transaminases or 
Alkaline Phosphatase) 
Discontinue study treatment 
Other Grade 3/4 AEs 
Hold until ≤ Grade 1 or 
return to baseline 
May resume at the same dose 
level or one dose level lower 
Abbreviation: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
ULN = Upper Limit of Normal. 
1 In the event a patient develops concurrent increase in AST and/or ALT ≥ 3 × ULN, bilirubin ≥ 2 × ULN but 
without concurrent increases in alkaline phosphatase (ie, alkaline phosphatase < 2 × ULN), that is not attributable 
to liver metastases or biliary obstruction (ie, meeting Hy’s Law), all study treatment should be permanently 
discontinued and steroids administered; these cases should be reported as SAEs in accordance with Section 8.2.1. 
 
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5.4.2.4. 
Other Laboratory Investigation-Based Toxicities 
Other laboratory investigation-based toxicities that are considered to be causally related to 
MRTX849 should initially be managed with treatment interruption of MRTX849 as outlined in 
Table 9. Following resolution of toxicity to the specified degree, dose reduction of MRTX849 
should be implemented.  
Table 9: 
Other Laboratory Investigation-Based Toxicities – MRTX849 Dose 
Modifications 
Other Laboratory 
Investigation-Based Toxicities 
Treatment Interruption 
Dose Modification 
Grade 1/2 AEs 
Implement at Investigator and Patient Discretion 
Specific Grade 3/4 AEs 
• 
Grade 3 or 4 Creatinine Increased ≤ 22 
days 
Hold until ≤ Grade 1 or return 
to baseline 
May resume at the same dose 
level or one dose level lower 
• 
Grade 3 or 4 Creatinine Increased > 22 
days 
Discontinue MRTX849 
Other Grade 3/4 AEs 
Hold until ≤ Grade 1 or return 
to baseline 
May resume at the same dose 
level or one dose level lower 
Abbreviation: AE = adverse event. 
 
5.4.2.5. 
Cardiac Toxicities 
Cardiac toxicities that are considered to be causally related to MRTX849 should initially be 
managed with treatment interruption of MRTX849 as outlined in Table 10. Cardiology 
consultation should be obtained for cases of QTcF prolongation or LVEF decreases falling into 
the categories indicated in Table 10. In addition, more frequent monitoring of electrolytes that 
include potassium and magnesium should be considered for patients with vomiting, diarrhea, or 
past instances of hypokalemia or hypomagnesemia that could recur, and oral and/or intravenous 
supplementation should be considered for levels below the lower limit of normal. Additionally, 
arrythmia should be included in the differential diagnosis of relevant AEs (eg, palpitations, 
syncope, pre-syncope, or unexplained dyspnea), and unscheduled ECGs should be performed for 
patients with such events or electrolyte abnormalities as clinically indicated. Patients who 
discontinue study treatment due to QTcF prolongation per the criteria listed in Table 10 should 
initiate close and clinically appropriate continuous ECG monitoring in a hospital setting until a 
cardiologist assessment is made. 
Following resolution of toxicity to the specified degree, dose reduction of MRTX849 should be 
implemented. 
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Table 10: 
Cardiac Toxicities – MRTX849 Dose Modifications 
Cardiac Toxicity 
Treatment Interruption 
Dose Modification 
QTcF Prolongation1 > 500 msec and 
increase > 60 msec on at least 2 ECGs ≤ 22 
days 
Hold until ≤ Grade 1 or return 
to baseline (< 15 msec above 
baseline) 
Decrease by one or 2 dose 
levels 
QTcF Prolongation1 > 500 msec and increase 
> 60 msec on at least 2 ECGs > 22 days 
Discontinue study treatment 
• 
Decrease in LVEF ≥ 20% from baseline 
and below LLN 
• 
Symptomatic left ventricular systolic 
dysfunction 
Discontinue study treatment 
Other Grade 3/4 AEs 
Hold until ≤ Grade 1 or return 
to baseline 
May resume at one dose level 
lower 
Abbreviation: AE = adverse event; ECG = electrocardiogram; LLN = lower limit of normal; LVEF = left ventricular 
ejection fraction; QTcF = QT interval corrected using Fridericia's formula. 
1 In addition to dose modifications for QTc prolongation, consideration should be given to supplement potassium 
and magnesium levels if they are below the lower limit of normal. Patients who discontinue study treatment due to 
QTcF prolongation per the criteria listed above should initiate close and clinically appropriate continuous ECG 
monitoring in a hospital setting until a cardiologist assessment is made. 
 
5.4.2.6. 
Pneumonitis 
Pneumonitis considered to be causally related to MRTX849 should be initially managed with 
treatment interruption of MRTX849 as outlined in Table 11. Following resolution of toxicity to 
the specified degree, dose reduction of MRTX849 should be implemented. 
Table 11: 
Pneumonitis – MRTX849 Dose Modifications 
Pneumonitis 
Treatment Interruption 
Dose Modification 
Grade 1 
Not Required 
Decrease by one dose level 
Grade 2 
Hold until ≤ Grade 1 or return 
to baseline 
For Grade 2 recurrent 
pneumonitis, discontinue study 
treatment 
If resumed, decrease by one 
dose level 
Grade 3 or 4 
Discontinue study treatment 
 
5.4.2.7. 
Other Toxicities 
Other toxicities that are considered to be causally related to MRTX849 should initially be 
managed with treatment interruption as outlined in Table 12. Following resolution of toxicity to 
the specified degree, dose reduction of MRTX849 should be implemented. 
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Table 12: 
Other Toxicities – MRTX849 Dose Modifications 
Other Toxicity 
Treatment 
Interruption 
Dose Modification 
Grade 3/4 Fatigue or Asthenia ≤ 8 
days 
Hold until ≤ Grade 1 or 
return to baseline 
May resume at same dose level or a lower dose 
level 
Grade 1/2 AEs 
Implement at Investigator and Patient Discretion 
Grade 3 AEs 
Hold until ≤ Grade 1 or 
return to baseline 
Resume one or more dose levels lower 
Grade 4 AEs 
Hold until ≤ Grade 1 or 
return to baseline 
For AEs that are not life-threatening and that 
can be managed, treatment may resume at a 
lower dose level. 
Otherwise, discontinue study treatment. 
Abbreviation: AE = adverse event 
 
5.4.2.8. 
Hormonal Contraceptives and Thrombotic Events 
In female patients using hormonal contraceptives, the potential exists for MRTX849 to inhibit 
hepatic cytochrome P450 CYP3A4 and increase exposure to hormonal contraceptive levels, with 
the associated risk of venous thromboembolism (eg, deep vein thrombosis or pulmonary 
embolism). Precautions should be taken in patients with recent, clinically significant thrombotic 
events, and all patients using hormonal contraceptives should be closely monitored for emerging 
signs of thrombotic events. Treatment with MRTX849 should be interrupted in patients with 
signs or symptoms of thrombosis and permanently discontinued in patients who develop 
clinically significant thromboembolic complications. If in the judgment of the Investigator 
resumption of treatment with MRTX849 is in the best interest of the patient, concomitant 
treatment with hormonal contraceptives should be discontinued. 
5.5. 
Docetaxel Study Drug 
Docetaxel will be obtained from commercial sources or provided by the Sponsor depending on 
local country requirements and managed in accordance with the locally approved product label. 
TAXOTERE® or generic equivalent (docetaxel) are acceptable for use in this study. 
The following reports information and guidance included in the TAXOTERE® USPI dated May 
2020. Refer to the current locally approved product label provided by the manufacturer for 
updates during the conduct of this clinical trial. 
5.5.1. 
Docetaxel Formulation and Packaging 
TAXOTERE® (docetaxel) Injection Concentrate, Intravenous Infusion (IV), is a sterile, 
non-pyrogenic, non-aqueous solution. TAXOTERE® is supplied in single use vials, 20 mg/mL, 
20 mg/0.5mL and 80 mg/4mL, 50/50 (volume/volume) ratio polysorbate 80/dehydrated alcohol. 
Refer to the current locally approved product label for further detail. 
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5.5.2. 
Docetaxel Preparation and Dispensing 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents. 
TAXOTERE® Injection requires no prior dilution with a diluent and is ready to add to the 
infusion solution. Use only a 21-gauge needle to withdraw TAXOTERE® from the vial because 
larger bore needles (eg, 18 and 19 gauge) may result in stopper coring and rubber particulates. 
Use of infusion equipment containing polyvinyl chloride (PVC) is not recommended. Add drug 
concentrate into a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% 
Dextrose solution to produce a final concentration of 0.3 mg/mL to 0.74 mg/mL. If a dose 
greater than 200 mg of TAXOTERE® is required, use a larger volume of the infusion vehicle so 
that a concentration of 0.74 mg/mL TAXOTERE® is not exceeded. Thoroughly mix the infusion 
by gentle manual rotation and inspect visually for particulate matter or discoloration prior to 
administration whenever the solution and container permit. 
5.5.3. 
Docetaxel Administration 
• TAXOTERE should be administered in a facility equipped to manage possible 
complication (eg, anaphylaxis). 
• Patients should be premedicated with oral corticosteroids such as dexamethasone 
16 mg per day (eg, 8 mg twice daily) for 3 days starting 1 day prior to TAXOTERE 
administration, unless contraindicated, in order to reduce the incidence and severity 
of fluid retention as well as the severity of hypersensitivity reactions. 
• For treatment of NSCLC after failure of prior platinum-based chemotherapy, the 
TAXOTERE recommended dose is 75 mg/m2 administered intravenously over 1 hour 
every 3 weeks. 
Before each cycle of docetaxel, 
• Liver function tests should be reviewed, and docetaxel should not be given if bilirubin 
> ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase 
> 2.5 × ULN. 
• Blood counts should be reviewed, and docetaxel should not be given if neutrophil 
counts are < 1500 cells/mm3 or platelet counts are < 100,000 cells/mm3. 
During this study, institutional or regional standard practice for administration of 
pre-medications and docetaxel may be followed with the exception of the initial (Cycle 1) dose 
which should remain 75 mg/m2.  
5.5.4. 
Docetaxel Dose Modification 
The following is guidance provided in the TAXOTERE® US Prescribing Information 
(USPI TAXOTERE [docetaxel]); a generic equivalent product may be used in the study. Patients 
who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils 
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< 500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other 
Grade 3/4 non-hematological toxicities during TAXOTERE® treatment should have treatment 
withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop 
≥ Grade 3 peripheral neuropathy should have TAXOTERE® treatment discontinued entirely. 
During this study, local standard practice for docetaxel administration, with the exception of the 
initial (Cycle 1) dose which should remain 75 mg/m2, may be used. Patients requiring more than 
2 dose reductions of docetaxel due to AEs should discontinue treatment with docetaxel. 
5.6. 
Management of Docetaxel Adverse Events 
Refer to locally approved product label for guidance concerning management of AEs during 
treatment with docetaxel. In addition to local product information and the administration 
guidelines described in Section 5.5, please specifically note: 
• Severe hypersensitivity reactions require immediate discontinuation of the docetaxel 
infusion and aggressive therapy. Patients with a history of severe hypersensitivity 
reactions should not be re-challenged with docetaxel. 
5.7. 
Medication Error 
Medication errors may involve patient exposure to a wrong study drug, at a wrong dosing 
frequency, or at a wrong dose level (eg, a dose that is not planned in the study). Medication 
errors occurring during the conduct of this study will be documented as AEs (regardless of 
whether clinical signs or symptoms are observed) and if serious consequences are observed, will 
be reported on serious adverse event (SAE) forms. In all cases of medication error, the Sponsor 
should be notified immediately. 
There is currently no specific treatment in the event of an overdose of MRTX849. The 
Investigator will use clinical judgment to treat any overdose. 
5.8. 
Crossover  
Patients randomized to docetaxel study treatment arm whose disease meets RECIST 1.1 criteria 
for disease progression according to BICR may crossover to receive treatment with MRTX849. 
Patients must sign a crossover informed consent form and must meet all eligibility criteria for 
further treatment as described in Section 4.3 and Section 4.4 and will use the dosing regimen 
described in Section 5.3. The required assessments for patients who crossover is included in 
Appendix 6.  
If a patient has been deemed to have disease progression according to Investigator assessment by 
RECIST 1.1, but is not confirmed by BICR, they are not eligible to crossover to MRTX849 
study treatment at that time. Should it be in the patient’s best interest, docetaxel treatment may 
be continued or patient may end treatment with docetaxel. If the patient continues to receive 
docetaxel or ends docetaxel treatment but has not yet started a subsequent anticancer therapy, 
sites are to continue to submit follow-up imaging for BICR review according to Table 2 for 
crossover eligibility.  
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5.9. 
Concomitant Therapies 
5.9.1. 
Concomitant Medications 
Prior medications, including chronically administered medication, used within the 28-day period 
preceding Day 1 of the trial, will be reviewed and recorded. Prior anticancer treatments will not 
be recorded as a prior medication but will be listed separately. 
Concomitant medications must be locally approved and used at doses and regimens that are 
considered standard of care for the treated indication. Treatment for comorbidities, disease signs 
and symptoms and TEAEs should be provided as necessary in the judgment of the Investigator. 
Patients may continue to use any ongoing medications not prohibited by the inclusion/exclusion 
criteria or treatment plan. 
Guidance on concomitant medications to be used with caution or avoided during treatment with 
MRTX849 or docetaxel is provided in Appendix 2 and Appendix 3, respectively. 
Prophylactic Medications: These medications may be used as indicated in the current approved 
product label. Prophylaxis for nausea or diarrhea may be used at Investigator discretion. 
Gastric Acid Reducing Medications: Because MRTX849 solubility is maximal at low pH, 
concomitant use with gastric acid reducing medications may decrease MRTX849 exposure 
which may reduce MRTX849 efficacy. PPIs should be avoided. As an alternative to PPIs, 
preference should be given first to antacids administered more than 2 hours before and more than 
2 hours after dosing with MRTX849, and second to H2 antagonists can be used with staggered 
administration (ie, administer MRTX849 at least 2 hours before or 2 hours after antacids, 
administer MRTX849 at least 2 hours before and 10 hours after the dose of H2 antagonists). 
Anti-emetics: Prophylactic anti-emetics may be used at the discretion of the Investigator. It is 
recommended that patients use drugs that do not cause QT prolongation. Note that some anti-
emetics have a known risk for Torsade de Pointes (see below Medications with QTc Prolonging 
Activity and Appendix 2). Ondansetron is included in the list of drugs with a known risk of 
Torsades de Pointes, and alternatives should be used. If effective alternative anti-emetics are not 
available, oral administration of ondansetron at doses up to 4 mg every 6 hours, with a maximum 
total daily dose of 16 mg, is permitted in patients without underlying bradycardia, congestive 
heart failure (CHF), or congenital Long QT Syndrome provided that an ECG is obtained at the 
beginning of each cycle, and that potassium and magnesium levels are obtained at the beginning 
of each cycle and supplemented if below the reference range. Oral dosing of ondansetron at 4 mg 
every 6 hours has been simulated to result in a mean difference in QTcF of 2.3 msec 
(Zuo, 2014). Use of intravenous administration of ondansetron is to be avoided. 
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Anti-diarrheals: Lomotil and octreotide can be used with MRTX849. Loperamide is included in 
the list of drugs with a known risk of Torsades de Pointes (cases of prolongation of the QT/QTc 
interval, Torsades de Pointes, other ventricular arrhythmias, cardiac arrest, some resulting in 
death, have been reported with use of higher than recommended doses per day of loperamide), 
and alternatives should be used. MRTX849 is expected to increase loperamide exposure by at 
least 4-fold. Considering the QTc effect of MRTX849 and loperamide and expected increase in 
loperamide concentration, loperamide should be avoided with MRTX849. If effective alternative 
anti-diarrheals are not available, oral administration of loperamide at low doses of 0.5 mg – 1 mg 
per dose, up to 3 mg total daily dose is permitted in patients without underlying bradycardia, 
CHF, or congenital Long QT Syndrome. An ECG, potassium and magnesium levels should be 
obtained at the beginning of each cycle and supplemented, if below the reference range. 
Strong Inducers of CYP3A4: MRTX849 is a substrate of CYP3A4. Coadministration of 
MRTX849 or docetaxel with strong CYP3A4 inducers may significantly decrease the exposure 
to the study treatment, which may decrease the efficacy of the study treatment. Discontinue use 
of strong inducers of CYP3A4 a minimum of 7 days or 5 times their half-life, whichever is 
longer, prior to study treatment. Therefore, use of strong inducers of CYP3A4 is to be avoided 
during the study (list of examples provided in Appendix 2). In accordance with labeling 
instructions for docetaxel, strong inducers of CYP3A4 should also be generally avoided. 
Consider using alternative medications that are not strong inducers of CYP3A4. 
Strong Inhibitors of CYP3A4: MRTX849 is a substrate of CYP3A4 and also inhibits its own 
CYP3A4 metabolism. Avoid concomitant use with strong CYP3A4 inhibitors until MRTX849 
has reached steady-state (eg, approximately 8 days after continuous MRTX849 dosing). Once 
MRTX849 is at steady-state there are no restrictions on concomitant use of strong inhibitors of 
CYP3A4. Docetaxel is metabolized by CYP3A4. Coadministration of docetaxel with strong 
CYP3A4 inhibitors may significantly increase the exposure docetaxel, which may increase the 
risk of adverse reactions. In accordance with labeling instructions for docetaxel, inhibitors of 
CYP3A4 are to be avoided for patients in the docetaxel arm during the study (list provided in 
Appendix 3).  
Strong Inhibitors of CYP2C8: CYP2C8 may play an important role in the metabolism of 
MRTX849 at steady-state. Concomitant use with strong CYP2C8 inhibitors may increase 
MRTX849 exposure. Strong inhibitors of CYP2C8 should be used with caution. 
Substrates of Cytochrome P450: MRTX849 is a strong inhibitor of CYP3A4. Concomitant use 
with MRTX849 increases exposure of CYP3A4 substrates, which may increase the risk of 
adverse reactions related to these substrates. Patients are advised to avoid co-administration of 
MRTX849 with sensitive CYP3A4 substrates unless otherwise recommended in the Prescribing 
Information for these substrates. Sensitive CYP3A4 substrates that must always be avoided are 
listed in Appendix 2. 
MRTX849 is a moderate inhibitor of CYP2C9 and CYP2D6. Concomitant use with MRTX849 
increases exposure of CYP2C9 and CYP2D6 substrates, which may increase the risk of adverse 
reactions related to these substrates. Patients are advised to avoid coadministration of MRTX849 
with sensitive substrates of CYP2C9 or CYP2D6 where minimal concentration changes may lead 
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to serious adverse reactions (ie, substrates with a narrow therapeutic index) unless otherwise 
recommended in the Prescribing Information for these substrates. 
For patients in the experimental arm (MRTX849), example substrates of the specified CYP 
isozymes that should be avoided are provided in Appendix 2. 
Inhibitors of BCRP: MRTX849 is a substrate of BCRP. The effect of inhibitors of BCRP (eg, 
curcumin, cyclosporin, and eltrombopaq) on MRTX849 has not been evaluated. For patients in 
the experimental arm (MRTX849), inhibitors of BCRP should be avoided (list of examples 
provided in Appendix 2).  
P-gp Substrates: MRTX849 inhibits P-gp. Avoid use with P-gp substrates where minimal 
concentration changes may lead to serious adverse reactions (ie, substrates with a narrow 
therapeutic index) unless otherwise recommended in the Prescribing Information for these 
substrates. 
Medications with QTc Prolonging Activity: A positive relationship between MRTX849 
concentrations and QTc change was observed in patients. Based on a linear mixed-effect 
concentration-QTc model, the predicted mean (90% CI) ΔQTcP and ΔQTcF were 18.8 (16.4, 
21.1) msec and 17.93 (15.13, 20.73) msec, respectively, at the population geometric mean Cmax,ss 
in patients after administration of MRTX849 600 mg BID. Use of medications known to prolong 
QTc and pose risk of Torsades de Pointes (as listed in Appendix 2) is to be avoided. 
Herbal Medications/Preparations: Herbal medications and preparations should be avoided 
throughout the study. Herbal medications include, but are not limited to: St. John’s wort, green 
tea, milk thistle, turmeric/curcumin, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe (yohimbine), saw palmetto, ginseng, quercetin and 
Schisandra extract. 
Transfusions: Packed red blood cell and platelet transfusions may be administered as clinically 
indicated. 
Antibiotics: Antibiotics should be used as needed. Patients with neutropenic fever or infection 
should be treated promptly. 
Supportive Care/Palliative Care: Supportive and palliative care for disease related symptoms 
may be administered at the Investigator’s discretion, including the use of analgesics. 
Bisphosphonates and RANKL Inhibitors: The use of bisphosphonates or RANKL inhibitors 
regardless of indication is allowed, provided patients have been on stable oral doses for at least 
2 weeks prior to study entry or stable with at least 2 parenteral injections prior to study entry; this 
stable dose should be maintained during the treatment period. Patients requiring initiation of 
bisphosphonates or a RANKL inhibitor during the course of the study should be evaluated to rule 
out disease progression. 
Growth Factors: Therapeutic colony-stimulating factors should be used in accordance with 
national or international guidelines. 
Vaccines: Vaccines made from inactivated micro-organisms, such as the injectable influenza 
vaccine, or from agents derived from or similar to pathogenic micro-organisms or toxins are 
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permitted. Vaccines developed using RNA technology, such as some COVID-19 vaccines, are 
permitted. Vaccines consisting of live, attenuated micro-organisms are not permitted and should 
not be used within 30 days prior to first dose of study treatment to 90 days after the last dose of 
study treatment. 
5.9.2. 
Concomitant Surgery or Radiation Therapy 
The use of elective surgery to manage cancer lesions during study treatment is discouraged. For 
patients with bone involvement, any foreseeable need for palliative radiotherapy should be 
addressed before study entry, if possible and clinically appropriate (eg, bone lesions at risk for 
spontaneous micro-fractures or painful lesions). However, these treatments may be used in cases 
where it is medically necessary. 
In the event that major surgery is needed during study treatment, the patient should, if possible, 
interrupt dosing with MRTX849 1 week in advance of the surgery and resume dosing 1 week 
after the surgery. Guidance for interruptions for radiation therapy will be made on a case-by-case 
basis taking into consideration the size and location of the radiation portal and the radiation dose. 
5.9.3. 
Other Anticancer or Experimental Therapy 
Use of approved or investigational anticancer treatment will not be permitted during the study 
treatment period, including chemotherapy, biological response modifiers, hormone therapy or 
immunotherapy. No other investigational drug may be used during treatment on this protocol. 
Concurrent participation in another therapeutic clinical trial is not allowed. 
Certain ongoing hormonal therapies taken to prevent recurrence of a malignancy not under study 
(eg, tamoxifen/aromatase inhibitor for breast cancer) may be permitted after discussion with and 
agreement of the Sponsor’s Medical Monitor. 
6. 
STUDY ASSESSMENTS  
6.1. 
Pre-screening, Clinical Screening, and Crossover Eligibility 
Screening 
Voluntary, written, dated, and signed informed consent must be obtained before any 
study-specific procedures are performed (see Section 4.6). Patients who complete the informed 
consent process but do not enroll on the study will be considered as screen failures. Limited 
information will be recorded in the CRF for these patients. 
For details on procedures during the pre-screening period (ie, testing for the presence of KRAS 
G12C mutation in tumor tissue), see the Pre-screening Assessments as shown on Table 1 and 
Figure 1, and procedure descriptions in Section 7.1. 
For details on procedures during the clinical screening period, see the Schedules of Assessments 
as shown in Table 2, and procedure descriptions in Section 7. 
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For details on procedures required during the crossover eligibility screening period, see 
Appendix 6.  
6.2. 
Study Period 
For details on procedures during the study period, see Schedules of Assessments as shown in 
Table 2, and procedure descriptions in Section 7. 
6.3. 
End of Treatment Assessment 
All patients will be followed for AEs for at least 28 days after the last dose of Study Treatment. 
See the Schedules of Assessments (Table 2) for evaluations to be performed at the End of 
Treatment visit. 
6.4. 
Long-Term Follow-up and End of Study Assessment 
Survival status and subsequent therapies will be collected during long term follow-up as outlined 
in the Schedules of Assessments (Table 2) until death or lost to follow-up. Beyond 28 days after 
last treatment, follow-up may be performed by visit, telephone, or e-mail. Treatments received 
following participation in the study will be collected in the CRF. 
6.5. 
Patient Discontinuation/Withdrawal 
Patients may discontinue from study treatment or from study follow-up at any time at their own 
request, or they may be discontinued at any time at the discretion of the Investigator or Sponsor 
for safety, behavioral reasons, or the inability of the patient to comply with the protocol required 
schedule of study visits or procedures at a given study site. 
For patients randomized to docetaxel study treatment arm whose disease meets RECIST 1.1 
criteria for disease progression according to BICR, crossover to MRTX849 may be an option. 
Refer to Section 5.8 for more information, including crossover inclusion (Section 4.3) and 
exclusion criteria (Section 4.4). 
Criteria that may be used to discontinue patients from receipt of study medication will include, 
but will not be limited to: 
• Objective disease progression according to RECIST 1.1 as determined by the 
Investigator (patients who may derive clinical benefit may continue on treatment at 
the discretion of the Investigator); 
• Global deterioration of health status requiring discontinuation; 
• Adverse event; 
• Significant protocol violation; 
• Lost to follow-up; 
• Refusal for further treatment; 
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• Study termination by Sponsor; 
• Pregnancy;  
• Death. 
Reasons for discontinuation from study follow-up may include: 
• Study terminated by Sponsor; 
• Lost to follow-up; 
• Refusal for further follow-up for survival; 
• Death. 
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient. At least 2 attempts should be made to contact the patient, and each attempt should be 
recorded in the source documents. In any circumstance, every effort should be made to document 
patient outcome, if possible. The Investigator should inquire about the reason for withdrawal, 
request that the patient returns for a final visit, and if applicable, follow-up with the patient 
regarding any unresolved AEs. 
If the patient withdraws from the study treatment and also withdraws consent for disclosure of 
future information, no further evaluations should be performed, and no additional data should be 
collected. The Sponsor may retain and continue to use any data collected before such refusal for 
further follow-up. 
7. 
PROCEDURES 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that there may be circumstances outside of the 
control of the Investigator that may make it infeasible to perform a protocol-specified 
assessment. In these cases, the Investigator will take all steps necessary to ensure the safety and 
well-being of the patient. When a protocol required test cannot be performed, the Investigator 
will record in the source document the reason and any corrective and preventive actions which 
he/she has taken to ensure that normal processes are adhered to as soon as possible. The study 
team will be informed of these incidents in a timely fashion. 
7.1. 
Detection of KRAS G12C Tumor Mutation  
The presence of KRAS G12C mutation in tumor tissue for the purpose of patient eligibility must 
be established using Sponsor pre-approved methods and laboratories. Presence of tumor KRAS 
G12C mutation may be established using Sponsor-approved local tests or the Sponsor-provided 
central laboratory test. For all enrolled patients, KRAS mutation status (to support a subsequent 
bridging study) and correlative tumor gene alterations will be tested retrospectively using tumor 
samples which must be submitted no later than 30 days after the first dose of study treatment.  
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Sponsor’s pre-approval process includes review of analytical performance and validation of tests 
to ensure locked-down assay cutoffs (ie, criteria to determine whether subjects are 
biomarker-positive or -negative) before use of the test(s) in the study for patient enrollment.  
The information required for Sponsor-approval of a specific local test to detect the presence of 
KRAS G12C mutation is as follows and should be emailed to 
:  
• Site number 
• Site name  
• Name of the test 
• Name of the laboratory running the test 
• Accreditation(s) of the laboratory running the test 
• Analytical validation/performance summary of the test 
• Copy of a sample report without any protected health information 
Confirmation of Sponsor approval or approval denial will be provided to sites via email by the 
Sponsor.  
In the United Kingdom (UK), the Sponsor will only approve local tests that are CE-marked for 
the detection of KRAS G12C or partially CE-marked for analytical performance to detect KRAS 
G12C.  
Informed consent using the study-specific pre-screening ICF is required prior to submission of 
results from local genotyping or submission of samples for central genotyping. Biopsies having 
significant risk should not be performed for the purpose of determining patient eligibility, 
including but not limited to biopsies of the lung/mediastinum or endoscopic procedures 
extending beyond the esophagus, stomach, or bowel. However, in the event that a patient desires 
to consider study participation and no tumor specimen is available, procedures having less risk 
may be considered. 
Platforms to be used for pre-screening tumor mutational analyses include Polymerase Chain 
Reaction (PCR) and Next-Generation Sequencing (NGS). The Sponsor-provided central 
laboratory test is: 
• Qiagen therascreen KRAS RGQ PCR Kit. 
Tumor tissue samples adequate for prospective or retrospective KRAS G12C mutation testing 
include a representative paraffin embedded tumor block or a minimum of 7 unstained slides 
(unless Sponsor approves fewer); however, 15 slides are preferable. Fresh biopsies are preferred, 
but archival biopsies are acceptable.  
Full details on sample collection, processing, storage and shipment will be provided in the Study 
Laboratory Manual. 
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7.2. 
Documentation of Disease Progression On or After Prior 
Platinum-Based Chemotherapy and Checkpoint Inhibitor Therapy 
Patient eligibility for study enrollment based on objective disease progression on or after a 
platinum-based regimen and an immune checkpoint inhibitor will be evaluated by the 
Investigator. 
Data entered into the case report form (CRF) are to include prior regimens, best overall response, 
if progression occurred on or after treatment and date of progression. 
7.3. 
Efficacy 
All patients enrolled in the study are to undergo disease evaluations as outlined in the Schedule 
of Assessments (see Table 2). 
Tumor assessment locations should include those outlined in Table 13 and using the 
recommended imaging modalities outlined in Table 14. 
Table 13: 
Tumor Assessment Locations 
Location 
Screening/ 
Baseline 
On-Study 
At Response 
Confirmation 
Brain 
Required 
Required 
If no brain metastases are present at 
baseline, may be obtained at every 
other imaging assessment  
(ie, at 12-week intervals) 
Required 
Chest 
Required 
Required 
Required 
Abdomen (including Pelvis) 
Required 
Required 
Required 
Bone 
Required 
Required 
May be obtained at every other imaging 
assessment (ie, at 12-week intervals)1 
Required 
1 In Czech Republic, bone lesion assessment must be performed at 12-week intervals and no more than 4 times per 
year. 
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Table 14: 
Recommended Imaging Modalities 
Location 
Preferred  
Option 1 
Preferred  
Option 2 
Contraindication for IV 
Contrast for CT 
Brain 
MRI with contrast1 
MRI with contrast1 
MRI with contrast 
Chest 
CT with IV contrast 
PET/CT (requires CT to 
be a diagnostic study 
with IV contrast and a 
reconstruction interval of 
2.5 to 5 mm) 
CT without IV contrast 
Abdomen 
(including Pelvis) 
CT with oral and  
IV contrast 
MRI with IV contrast2 
Bone 
Bone Scan or  
PET3 Scan 
Bone Scan or  
PET3 Scan 
CT = Computed Tomography Scan; PET = Positron Emission Tomography; MRI = Magnetic Resonance Imaging.  
1 If MRI of the brain cannot be obtained, CT with IV contrast is acceptable. 
2 If MRI with contrast is not expected to adequately depict the individual’s disease, CT without IV contrast may be 
used. 
3 A PET scan for bone imaging only may be performed using fluorodeoxyglucose (FDG) or fluorine 18 sodium 
fluoride (18F-NaF). 
 
For patients having effusions or ascites, cytological proof of malignancy should be obtained prior 
to selection of the effusion as a non-target lesion. Effusions that have not been evaluated using 
cytology or were found to be non-malignant should not be considered to be cancer lesions. 
The allowable window for screening/baseline assessments is 28 days prior to randomization. 
Assessments will be performed at 6-week intervals, based on a calendar beginning from 
randomization, until approximately 1-year and then every 12 weeks. The allowable windows for 
on-study assessments is ± 10 days.  
CT scans should be performed with contrast agents unless contraindicated for medical reasons. If 
intravenous contrast is medically contraindicated, the imaging modality to be used (either CT 
without contrast or MRI with contrast) should be the modality which best evaluates the disease, 
and the choice should be determined by the Investigator in conjunction with the local radiologist. 
Depending on the adequacy for evaluation of disease, a combination of CT without contrast and 
MRI with contrast should most often be used. CT without contrast is preferred for evaluation of 
lesions in lung parenchyma. MRI is not adequate for evaluation of lung parenchyma but should 
also be performed to evaluate all other aspects of the chest. MRI with contrast of the abdomen 
and pelvis should substitute for CT with contrast unless the method does not adequately depict 
the individual’s disease, in which case CT without IV contrast is preferred. New fluid collections 
identified on-study and existing non-malignant fluid collections that change in character require 
cytological proof of malignancy in order to be reported as a new lesion. 
Disease response will be assessed in accordance with RECIST 1.1 (Eisenhauer, 2009). 
Appendix 4 provides guidance in using the response criteria and includes modifications to 
RECIST 1.1 to address potential temporary treatment effects including tumor necrosis, 
cavitation, flare response or pseudoprogression. For patients with brain metastases for whom 
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central radiology review is performed, disease response will be assessed by CNS RECIST 1.1 for 
intracranial response. 
Patients experiencing tumor response (Partial Response [PR] or Complete Response [CR]) 
should undergo confirmatory assessment at least 4 weeks after initial documentation; it is 
acceptable to perform confirmatory assessments at the next appointed evaluation per protocol 
(ie, 6 weeks after the observation of tumor response). 
Potential exists for individual patients to experience tumor flare or pseudoprogression or, for 
individual tumor lesions to cavitate or become otherwise difficult to evaluate for a period of time 
as the result of beneficial study treatment impact. For this reason, in patients who are otherwise 
clinically stable, Investigators may delay reaching the conclusion of disease progression until 
subsequent on-study disease assessments are performed. Confirmatory assessments may be 
performed at least 4 weeks after the initial documentation; it is acceptable to perform 
confirmatory assessments at the next appointed evaluation per protocol (ie, 6 weeks after the 
observation of tumor increase). 
BICR for disease response and progression will be performed for the purpose of statistical 
analyses of these study endpoints. 
In the event a patient discontinues study treatment for a reason other than objective disease 
progression, disease assessments post-treatment should continue until objective disease 
progression is documented by the Investigator and BICR or start of subsequent anticancer 
therapy, whichever is sooner. Patients randomized to the docetaxel arm will be offered the 
opportunity to crossover to the MRTX849 study treatment arm upon development of RECIST 
1.1-defined disease progression per BICR provided that patient crossover eligibility criteria are 
met.  
Disease assessments must be performed as scheduled according to the calendar to prevent the 
introduction of bias in the assessment of efficacy based on toxicity. Timely and complete disease 
assessments and transfer of radiographic documentation to the Central Radiology Laboratory is 
critical to the integrity of this clinical trial. 
Tumor markers are not required for assessment of efficacy. 
7.4. 
Safety Assessments 
7.4.1. 
Medical History 
Medical history, including clinically significant past and present medical conditions, will be 
recorded at the time of screening. Cancer history will be recorded separately. Signs and 
symptoms of the patient’s cancer diagnosis and/or comorbidities present on Cycle 1 Day 1 and 
throughout treatment will be recorded in the CRF as AEs. The actual date of onset should be 
recorded in all cases. Thus, for signs and symptoms that are clinically relevant and present on 
Cycle 1 Day 1, the date of onset may pre-date start of study treatment. 
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7.4.2. 
Physical Examination and Vital Signs 
A physical examination including all major body systems is mandated at Screening and End of 
Treatment Visits only. During study treatment, symptom directed physical examinations will be 
performed. 
Vital signs to be assessed include weight, body temperature, blood pressure, pulse rate and 
respiratory rate. Height will be recorded at screening only. On days where both vital signs and 
PK sampling are scheduled, the vital signs should be assessed prior to blood sampling. 
Clinically significant findings noted during screening will be reflected on the medical history 
CRF, while those noted as present and clinically relevant on Cycle 1 Day 1 of study treatment 
and throughout study treatment will be collected on the AE CRFs. 
7.4.3. 
Laboratory Safety Assessments 
Laboratory safety assessments for which data will be collected in this study will include 
hematology, thyroid tests and chemistry parameters presented in Table 15. 
Laboratory tests will be drawn at the time points described in the Schedule of Assessments 
(Table 2) and analyzed at local laboratories. Additional laboratory tests may be performed per 
standard of care, at the Investigator’s discretion for the purpose of planning treatment 
administration, dose modification, following AEs, or as clinically indicated.  
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Table 15: 
Laboratory Safety Parameters 
Hematology Panel 
Blood Chemistry Panel 
Hemoglobin 
Aspartate aminotransferase (AST) 
Platelet count 
Alanine aminotransferase (ALT) 
White blood cell count (WBC) 
Alkaline phosphatase (ALP) 
Neutrophil count 
Total bilirubin (if Total bilirubin is ≥ 2 × ULN and no 
evidence of Gilbert’s syndrome, then fractionate into 
direct and indirect bilirubin) 
Lymphocyte count 
Creatinine 
Monocyte Count 
Blood urea nitrogen (BUN)1 
 
Uric acid 
 
Total protein 
 
Albumin 
 
Glucose (non-fasted preferred) 
Thyroid Function 
Sodium 
Thyroid-stimulating hormone (TSH) 
Potassium 
 
Chloride 
 
Bicarbonate or CO2 
 
Total calcium 
 
Phosphate 
 
Magnesium 
 
Lipase 
 
Amylase 
 
Creatine kinase (if elevated, abnormal creatine kinase 
value should be handled by the Investigator in 
accordance with their site standard of care practices)  
1 Urea is acceptable if blood urea nitrogen (BUN) is not an option. 
 
7.4.4. 
Pregnancy and Follicle Stimulating Hormone Testing 
For patients who are women of childbearing potential, a urine or serum pregnancy test will be 
performed by the local laboratory at Screening and at End of Treatment. In addition, in regions 
where required by regulation (eg, European Union), monthly pregnancy testing will be 
performed until the end of systemic exposure to study treatments (testing may be performed at 
the beginning of each 3-week treatment cycle for convenience). Pregnancy tests will also be 
done whenever pregnancy is suspected during the study. 
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In countries operating in compliance with CTFG guidelines, a follicle stimulating hormone test 
should be performed at screening to confirm a postmenopausal state in women considering 
enrollment into this study.  
7.4.5. 
Hepatitis and Human Immunodeficiency Virus Testing  
In Germany, Czech Republic, and Portugal only, patients must be tested for HIV, HBV and HCV 
infection (all tests performed by local laboratory) at screening. Testing for HIV infection should 
typically be performed using an HIV Ab test, and if warranted, further testing by local standards 
(eg, nucleic acid test). Hepatitis B serology to include the following: hepatitis B core antibody 
(HBcAb/anti-HBc), and if positive hepatitis B surface antigen (HBsAg); HBV DNA should be 
performed if HBsAg is positive. Hepatitis C serology: HCV antibody (anti-HCV); HCV RNA 
performed only if anti-HCV is positive. 
7.4.6. 
Electrocardiogram (ECG)  
Single and triplicate ECGs are to be performed as outlined in the Schedule of Assessments (see 
Table 2). It is preferable that the machine used has a capacity to calculate the standard intervals 
automatically. 
7.4.7. 
MUGA or ECHO 
A Multigated Acquisition Scan (MUGA) (preferred except in Germany where it is not an option) 
or echocardiogram (ECHO) will be performed as outlined in the Schedule of Assessments (see 
Table 2). Additional assessments of LVEF may be performed as clinically indicated at the 
Investigator’s discretion if there are signs or symptoms of cardiotoxicity. The same assessment 
method (MUGA or echocardiogram) should be used for all cardiac imaging examinations 
throughout the study for each patient. 
7.5. 
Laboratory Studies 
Full details on sample collection, processing, storage and shipment are presented in the Study 
Laboratory Manual. 
7.5.1. 
Pharmacokinetic Evaluation 
7.5.1.1. 
PK for MRTX849 
The PK blood samples will be collected at specified time points as outlined in Table 2. Every 
effort will be made to collect PK samples at the exact nominal times relative to dosing. A 
variation window is allowed for each time point as outlined in Table 2. If MRTX849 treatment is 
interrupted on a scheduled PK collection day, a pre-dose PK sample should still be collected. 
However, if MRTX849 is being held or has been discontinued prior to the scheduled PK 
collection day, then no PK samples are required to be collected. If MRTX849 has been held or 
discontinued for ≥ 3 days, Unscheduled PK collections are not required. The actual time of each 
sample collection will be recorded on the source document and CRF. 
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All plasma samples will be stored frozen and shipped on dry ice according to instructions 
provided. Full details on sample collection, processing, storage and shipment will be provided in 
the Study Laboratory Manual. 
All plasma PK samples will be measured for concentrations of MRTX849 using a validated 
bioanalytical method(s). 
7.5.2. 
Circulating Tumor DNA 
Blood samples for ctDNA analysis will be collected as outlined in Table 2. Whole blood samples 
will be collected into two 10 mL Streck brand Cell-Free DNA Blood Collection tubes allowing 
shipping and stability at ambient temperatures. Tumor gene mutation profiling utilizing ctDNA 
samples will be determined using NGS performed by a central laboratory. Full details on sample 
collection, processing, storage and shipment will be provided in the Study Laboratory Manual. 
7.5.3. 
Correlative Molecular Analysis in Tumor Tissue 
Evidence is emerging that in advanced NSCLC patients, certain recurrent mutations may 
independently impact prognosis or response to therapy. Therefore, tumor tissue sent to determine 
or confirm KRAS G12C status will be analyzed for tumor mutations of other genes, such as 
STK11, KEAP1, NF1, CDKN2A, and TP53 for an exploratory analysis of correlation of 
mutations with prognosis and efficacy endpoints. In addition (except in Germany), collection of 
tumor samples at the time of disease progression in patients with an objective tumor response or 
prolonged stable disease (> 4 months) on study is requested. Individual genetic alterations in 
target genes, including mutations, gene amplifications, deletions, and rearrangements, as well as 
tumor mutation burden (TMB), will be evaluated utilizing the Sponsor-provided NGS assay 
performed by the central laboratory. 
Tumor tissue for profiling selected genetic alterations that are present in patients harboring KRAS 
G12C mutations will be collected as outlined in Table 2. Full details on sample collection, 
processing, storage and shipment will be provided in the Study Laboratory Manual. 
7.5.4. 
Patient Reported Outcomes 
Patient reported outcomes (PROs) will evaluate lung cancer-specific symptoms and 
health-related quality of life using 2 validated measures: the LCSS (Hollen, 1993), 
(Hollen, 1994), (Hollen, 1995), (Hollen, 2004) and the European Quality of Life Five 
Dimensions Questionnaire (EQ-5D-5L) (EuroQoL, 2020), (Herdman, 2011). 
The LCSS is a disease specific measure of quality of life. The patient version of the LCSS 
includes 9 questions and utilizes visual analogue scales (VAS) to score the degree of impairment 
as reported by patients (range 0-100) across 6 symptoms (appetite loss, fatigue, cough, dyspnea, 
hemoptysis, pain) and 3 summary global items (symptom distress, activity level, overall quality 
of life). This patient version will be used in the assessment of health-related quality of life. 
The EQ-5D-5L questionnaire includes 2 components – the EQ-5D-5L descriptive assessment of 
5 dimensions (inclusive of mobility, self-care, usual function status, pain and/or discomfort, and 
anxiety and/or depression) with 5 possible response levels (no problems, slight problems, 
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moderate problems, severe problems or unable to/extreme problems), and the EQ VAS for the 
patient’s self-rated overall health based on a vertical visual analogue scale, which ranges from 
0 (worst imaginable) to 100 (best imaginable).  
PRO assessments will be collected as outlined in Table 2. EQ-5D-5L questionnaires should 
always be completed before LCSS. 
8. 
ADVERSE EVENT REPORTING 
8.1. 
Sponsor Medical Monitor Personnel 
The contact information for the Sponsor’s Medical Monitor personnel for this trial is available in 
the study contact list located in the Study Manual. 
8.2. 
Adverse Events 
An AE is any reaction, side effect or other undesirable medical event that occurs during 
participation in a clinical trial, regardless of treatment group or suspected causal relationship to 
study treatment. Assessment of AE events will include type, incidence, severity (graded by the 
National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE, 
Version 5.0]), timing, seriousness, and relatedness to study treatment. A treatment-emergent AE 
(TEAE) is an AE that occurs after the first dose of any study treatment or any pre-existing 
condition that increases in severity after the first dose of study treatment. 
All observed or volunteered AEs will be recorded in source documents and reported in the CRF. 
The best available medical terminology should be used to describe AEs in source documents and 
CRFs. Terms describing the diagnosis are preferred over individual signs and symptoms of the 
diagnosis. If determination of the diagnosis is delayed, record signs and symptoms and add the 
diagnosis as an additional AE when available; follow all recorded AEs to resolution. The actual 
date of onset should be recorded in all cases. Ongoing AEs that change in attribution or severity 
should have the date of change entered as the “end date” and a new AE record should be opened 
with the changed details. Examples of AEs include but are not limited to: 
• Signs or symptoms of co-morbidity, illness, or toxicity of study treatment; 
• Signs or symptoms of worsening malignancy under study (disease progression 
assessed by measurement of malignant lesions should not be reported as an AE). 
• Laboratory abnormalities (see Section 8.2.1 for guidance for reporting in CRF); 
• Hypersensitivity; 
• Drug abuse, dependency, overdose, withdrawal or misuse; 
• Signs or symptoms of drug interactions; 
• Extravasation; 
• Exposure during pregnancy or via breastfeeding; 
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• Medication error; or 
• Occupational exposure. 
8.2.1. 
Laboratory Abnormalities 
An abnormal laboratory test result should be reported as an AE in the CRF only if it is associated 
with one or more of the following:  
• Clinical symptoms; 
• Requires additional tests (beyond repeats), treatment or intervention; 
• Results in change in study treatment dosing; 
• Requires discontinuation from study treatment; and/or 
• Considered by the Investigator or Sponsor to be an AE. 
Hy’s Law 
Hepatic function abnormality defined by an increase in AST and/or ALT to ≥ 3 × ULN 
concurrent with an increase in total bilirubin to ≥ 2 × ULN but without increase in alkaline 
phosphatase (ie, alkaline phosphatase < 2 × ULN) meets the criteria for Hy’s Law and raises the 
concern for drug-induced liver injury when no other cause of the abnormal laboratory results is 
identified. Follow-up investigations and inquiries will be initiated promptly by the 
investigational site to determine whether the findings are reproducible and/or whether there is 
objective evidence that clearly supports causation by a disease (eg, cholelithiasis and bile duct 
obstruction with distended gallbladder) or an agent other than the investigational product. 
Cases meeting Hy’s Law should be reported as SAEs. Study drug should be permanently 
discontinued for a Hy’s Law case (see Section 5.4.2.3). 
8.2.2. 
Severity Assessment 
AEs occurring during this study will be graded in accordance with the NCI CTCAE v5.0. 
Documentation of AE grading in the source documents and CRF should be consistent with 
provided definitions. 
8.2.3. 
Causality 
For each AE, the Investigator should determine and document whether there exists a reasonable 
possibility that the study treatment caused or contributed to the AE. The Investigator’s 
assessment should be recorded in the source document. The CRF will provide the options for 
attribution to each study treatment as “related” or “not related.” If the Investigator’s causality 
assessment is “unknown but not related to investigational product,” this should be recorded in 
the CRF as “not related.” If the Investigator does not know whether or not the study treatment is 
causally related to the event, reporting for study purposes will be as “related” to study treatment. 
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Collection of causal relationship for AEs associated with study procedures (eg, tumor biopsy) is 
provided for separately in the CRF. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definition of a Serious Adverse Events 
An SAE is any event that meets any of the following criteria: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/permanent damage (substantial 
disruption of the ability to conduct normal life functions); 
• Results in congenital anomaly/birth defect. 
• Other: Important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such events are: 
− Intensive treatment in an emergency room or at home for allergic bronchospasm; 
− Blood dyscrasias or convulsions that do not result in inpatient hospitalization; 
− Development of drug dependency or drug abuse. 
Progression of the malignancy under study, including any signs or symptoms of progression that 
may require hospitalization, should not be reported as an SAE unless the outcome is fatal within 
the safety reporting period. 
Definition of Terms 
Life-threatening: An AE is life-threatening if the patient was at immediate risk of death from the 
event as it occurred; ie, it does not include a reaction that if it had occurred in a more serious 
form might have caused death. For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life-threatening even though drug-induced 
hepatitis can be fatal. 
Hospitalization: In general, hospitalization signifies that the patient 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. 
When in doubt as to whether ‘hospitalization’ occurred or was necessary, the AE should be 
considered serious. Hospitalization for elective surgery or routine clinical procedures that are not 
the result of AE (eg, elective surgery for a pre-existing condition that has not worsened) need not 
be considered AEs or SAEs. If anything untoward is reported during the procedure, that 
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occurrence must be reported as an AE, either ‘serious’ or ‘non-serious’ according to the usual 
criteria. 
Disability/permanent damage: An AE is disabling or caused permanent damage if it resulted in a 
substantial disruption of a person’s ability to conduct normal life functions, eg, a significant, 
persistent or permanent change, impairment, damage or disruption in body function/structure, 
physical activities and/or quality of life. 
8.3.2. 
Exposure During Pregnancy 
Exposure during pregnancy (ie, exposure in-utero [EIU]) may occur in a female study 
participant, the female partner of a male study participant or study site personnel working with 
the investigational product (eg, occupational exposure) if: 
• A female becomes or is found to be pregnant during treatment or within 6 months 
after discontinuing treatment or having been directly exposed to the investigational 
product; 
• A male is exposed to the investigational product within 1 month prior to or around the 
time of conception or during the pregnancy of his partner. 
If EIU occurs, the Investigator must submit an SAE Form and an EIU Supplemental Form within 
24 hours of awareness of the exposure, regardless of whether an AE or SAE has occurred. 
In the event of pregnancy in a female study participant, if the pregnancy is continued, study 
treatment will be immediately discontinued. 
In the event of exposure of the pregnant partner of a male study participant, the study participant 
should be asked to deliver an EIU Pregnant Partner Release of Information Form to his partner. 
The Investigator must document on the EIU Form that the patient was given this letter to provide 
to his partner. 
Follow-up to obtain pregnancy outcome information is to be conducted for all EIU reports. In the 
case of a live birth, the health of the neonate should be assessed at the time of birth and for up to 
3 months after birth. Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays). In the event the pregnancy is 
terminated, the reason(s) for termination should be reported and, if clinically possible, the 
structural integrity of the terminated fetus should be assessed by gross visual inspection. 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly), an SAE 
report should be submitted to the Sponsor. 
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8.4. 
Reporting of SAEs and AEs 
Special guidance is provided in Appendix 5 for reporting AEs and SAEs impacted by 
documented or suspected COVID-19 infection during the public health emergency. 
8.4.1. 
Reporting Period 
The active reporting period for SAEs begins from the time that the patient provides informed 
consent (ie, prior to undergoing any study-specific procedure or assessment). During the pre-
screening period (ie, after pre-screening informed consent and before the main study informed 
consent), reporting of SAEs is limited to events associated with study required assessments 
(eg, biopsies for tumor genotype testing). Beginning at the time of signing the main study 
informed consent to begin clinical eligibility screening, reporting of all SAEs is required. SAE 
reporting continues for at least 28 days after last administration of study treatment. All SAEs 
ongoing on Day 28 after the last dose should be followed until they have resolved or stabilized to 
a chronic condition, whichever is later. If a patient begins a subsequent anticancer therapy, the 
reporting period for new SAEs ends at the time the new treatment is started. Death must be 
reported if it occurs within at least 28 days after the last administration of study treatment, 
regardless of whether a subsequent anticancer therapy is administered. Serious adverse events 
occurring in a patient after the active reporting period has ended should be reported to the 
Sponsor if the Investigator becomes aware of them and if the Investigator assesses at least a 
reasonable possibility of being related to study drug. These SAEs should be followed until 
resolved or stabilized to a chronic condition. 
The reporting period for non-serious AEs begins from the day of first dose of study treatment 
and continues until at least 28 days after last administration of study treatment. If a patient begins 
a subsequent anticancer therapy, the AE reporting period ends at the time the new treatment is 
started. 
8.4.2. 
Reporting Requirements 
All SAEs must be reported within 24 hours of Investigator/site knowledge of the event, 
irrespective of the extent of available AE information, by faxing the SAE report to the Sponsor’s 
pharmacovigilance representative designated in the Study Manual. The 24 hour timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports and to 
the initial and follow-up reporting of exposure during pregnancy and exposure via breastfeeding. 
For sites in Germany, all SAEs must be reported immediately, without undue delay, upon 
Investigator/site knowledge of the event, irrespective of the extent of available AE information. 
In Germany, this timeframe requirement also applies to additional new information (follow-up) 
on previously forwarded SAE reports and to the initial and follow-up reporting of exposure 
during pregnancy and exposure via breastfeeding. The need for an expedited report to regulatory 
authorities will be determined by the Sponsor and necessary reporting will be performed by the 
Sponsor. The Sponsor will notify study Investigators of all Suspected, Unexpected (as judged 
against the Investigator Brochure) Serious Adverse Reaction (SUSAR) reports. The Investigator 
is responsible for reporting all SUSARs to the IRB/EC.  
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The Sponsor’s Safety Management Team (SMT) is responsible for monitoring and evaluation of 
safety data for the study treatment to assess the benefit-risk to decide appropriate actions for 
patient safety and to mitigate risk. All AEs (including SAEs) must be documented in source 
documents. Beginning on the first day of study treatment, all AEs (including SAEs) are to be 
reported in the CRF. Please note that the CRF and SAE report forms may collect information in 
somewhat different formats. Where the requested data overlap in different formats, the 
information should be consistent between the two forms. 
9. 
STATISTICS 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be maintained by the Sponsor. 
The SAP may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol amendment. 
9.1. 
Phase 3 Hypothesis and Sample Size 
Study 849-012 is adequately powered for the PFS endpoint with an overall 0.05 (2-sided) level 
of significance. The study plans to randomize approximately 450 patients in a 2:1 ratio to receive 
MRTX849 or docetaxel, respectively. The sample size of 450 for the study is primarily estimated 
from the secondary endpoint of OS, which is also adequately powered under the assumption of 
proportional hazards. 
For the PFS endpoint, the study has 90% power to detect a HR of 0.645 (under an assumed 
median PFS for docetaxel arm of approximately 4 months compared to 6.2 months for the 
MRTX849 arm) at a 2-sided level of significance of 0.05 based on 246 PFS events.  
For the secondary endpoint OS, the study has 80% power to detect a HR of 0.72 (under an 
assumed median OS for docetaxel arm of approximately 10 months compared to 13.9 months in 
the MRTX849 arm) at a 2-sided level of significance of 0.05 based on 334 death events. 
Assuming an enrollment duration of approximately 37 months at an average rate of 12 patients 
per month (approximately 450 patients), and an additional 15 months of follow-up will be 
required to reach the number of required death events. 
There will be one analysis for the PFS endpoint and an interim analysis of OS (~50% of the 
expected death events), and one final analysis for the OS endpoint. The enrollment into the study 
is anticipated to be completed when the PFS analysis occurs. A group sequential design will be 
used with the O’Brien-Fleming boundary as implemented by the Lan-DeMets alpha spending 
method. A nonbinding futility boundary using the Rho family spending function with parameter 
of 3.0 is also constructed for OS (see Section 9.7 for further detail). If the OS endpoint is 
statistically significant at interim, the formal OS final analysis will not be conducted per group 
sequential design, but a subsequent survival update may be conducted as warranted.  
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9.2. 
Data Handling 
Listings of all patient data will be prepared. Data summaries will be presented in tabular and/or 
graphical format and summarized descriptively, where appropriate. Further details of planned 
analyses will be described in the SAP. 
For all variables, only the observed data from patients will be used in the statistical analyses; 
there is no plan to estimate missing data. Patients without a valid clinical response assessment 
will be assigned a best overall response of not evaluable (NE). Data from patients who are lost to 
follow-up or have missing observations before reaching an endpoint in any of the time-to-event 
analyses will be treated as censored with specific rules defined in the SAP. 
9.3. 
Analysis Populations 
9.3.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population is defined as all patients who are randomized into this 
study. The ITT population will be used to describe demographics and in the analyses for the 
PRO and efficacy endpoints. 
9.3.2. 
Safety Population 
The safety population is defined as all patients who received any part of a dose of study 
medication (ie, MRTX849 or docetaxel). The safety population will be used for all safety 
analyses. 
9.3.3. 
Pharmacokinetic Evaluable Population 
The PK evaluable population will consist of all patients who received treatment with MRTX849 
and have adequate and reliable data for the evaluation of MRTX849 PK. For patients who were 
noncompliant with respect to of MRTX849 administration, or for patients with incomplete data, 
a decision as to their inclusion in the analysis will be made on a case-by-case basis. 
9.4. 
Efficacy Endpoint Definitions and Analyses 
9.4.1. 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the time from randomization to the date of PD or 
death due to any cause, whichever occurs first. The distribution of PFS will be estimated using 
the Kaplan-Meier method. The stratified log-rank test will be used to compare the PFS between 
the 2 treatment arms. Due to the shift of region stratification factor in protocol version 4 
(USA/Canada versus other to non-Asia-Pacific versus Asia-Pacific), the stratification factors for 
analysis will be based on the actual region (non-Asia-Pacific versus Asia-Pacific) and the prior 
treatment administration of last prior platinum-based chemotherapy and anti-PD-1/PD-L1 
antibody (sequential versus concurrent). 
Censoring for the PFS endpoint will be assigned on the date of the last tumor assessment if no 
assessment of tumor progression is recorded and the patient does not die while on study. If PD or 
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death occurs following ≥ 2 consecutive missed tumor assessments, PFS will be censored at the 
last tumor assessment date prior to the PD or death. For patients who start a subsequent 
anticancer therapy prior to PD or death, PFS will be censored at the date of the last tumor 
assessment prior to the start of the new therapy. For patients without a tumor assessment after 
randomization, PFS will be censored on the date of randomization with duration of 1 day. If a 
patient discontinues from the study before PD, PFS will be censored on the date of last tumor 
assessment prior to discontinuation. Additional details are provided in the SAP.  
9.4.2. 
Overall Survival 
Overall survival is defined as the time from date of randomization to date of death due to any 
cause. The distribution of OS will be estimated using the Kaplan-Meier method. The stratified 
log-rank test will be used to compare the OS between the 2 treatment arms. Due to the shift of 
region stratification factor in protocol version 4 (USA/Canada versus other to non-Asia-Pacific 
versus Asia-Pacific), the stratification factors for analysis will be based on the actual region 
(non-Asia-Pacific versus Asia-Pacific) and the prior treatment administration of last prior 
platinum-based chemotherapy and anti-PD-1/PD-L1 antibody (sequential versus concurrent). 
The Kaplan-Meier method will be used to estimate the median OS and 1-year survival rate; the 
95% CI of the median OS and 1-year survival rate will also be reported. Censoring for the 
survival endpoint will be assigned on the date of the last known survival date. 
With the allowance of patients in the docetaxel arm to crossover and receive MRTX849, 
sensitivity analysis adjusting for the crossover will also be carried out for the OS endpoint. If a 
substantial proportion of patients in the docetaxel arm were to crossover to receive MRTX849 
treatment, a weighted log-rank test may be carried out to account for non-proportional hazards 
due to treatment crossover (Lin, 2020), (Therneau, 2000); Restricted Mean Survival Time 
(RMST) method may also be considered (Uno, 2014). Additional analyses may be conducted to 
account for treatment crossover and to elucidate the non-proportional hazards assumption. 
Details will be provided in the SAP. 
9.4.3. 
Objective Response Rate 
Objective disease response will be categorized in accordance with RECIST v1.1 (Appendix 4). 
Objective Response Rate is defined as the percent of patients documented to have a confirmed 
CR or PR. Descriptive statistics (frequency and percentage) for ORR will be presented. The 
Cochran-Mantel-Haenszel (CMH) test will be used to compare the response rates between the 
2 treatment arms. In the event some cells have low frequency count (eg, < 5), a Chi-square test 
may be used instead of CMH.  
9.4.4. 
Duration of Response 
Duration of Response (DOR) is defined as the time from date of the first documentation of 
objective tumor response (CR or PR) to the first documentation of either Progression of Disease 
(PD) or death due to any cause, whichever occurs first. The DOR analysis only applies to those 
patients who have confirmed objective response per RECIST v1.1. The distribution of DOR will 
be estimated using the Kaplan-Meier method. 
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Censoring for the DOR endpoint will be assigned on the date of the last evaluable tumor 
assessment if no assessment of tumor progression is recorded and the patient does not die while 
on study. If PD or death occurs after a documentation of response followed by ≥ 2 consecutive 
missed tumor assessments, DOR will be censored at the last evaluable tumor assessment date 
prior to the PD or death. For patients who start a subsequent anticancer therapy prior to PD or 
death, DOR will be censored at the date of the last evaluable tumor assessment prior to the start 
of the new therapy. If a patient discontinues from the study before PD, DOR will be censored on 
the date of last evaluable tumor assessment prior to discontinuation. Additional details are 
provided in the SAP. 
9.4.5. 
Progression-Free Survival-2 
Exploratory analysis of Progression-Free Survival-2 (PFS2) is defined as the time from 
randomization to disease progression on the next-line of therapy, or death from any cause, 
whichever first. The distribution of PFS will be estimated using the Kaplan-Meier method. The 
non-stratified log-rank test will be used to compare the PFS2 between the 2 treatment arms. 
Additional details are provided in the SAP as needed. 
9.4.6. 
Time to CNS Progression 
Time to CNS progression is defined as the time from randomization to newly developed CNS 
metastases or progression of pre-existing brain lesions, whichever presents first. The distribution 
of time to CNS progression will be estimated using the Kaplan-Meier method. The non-stratified 
log-rank test will be used to compare the time to CNS progression between the 2 treatment arms. 
Additional details are provided in the SAP. 
9.4.7. 
Intracranial activity using CNS RECIST 1.1 endpoints in patients with brain 
metastases  
Intracranial activity using CNS RECIST 1.1 endpoints in patients with brain metastases at 
baseline, including icORR, icDOR, icPFS and icTTP, will be analyzed in patients with brain 
metastases only. Additional details are provided in the SAP. 
9.4.8. 
Subgroup Analyses 
Baseline characteristics to be evaluated in subgroup analyses include: 
• Gender 
• Age 
• Race 
• ECOG status (0 vs 1) 
• Smoking history (lifetime non-smoker, past smoker, vs current smoker) 
• Region (non-Asia-Pacific vs Asia-Pacific) 
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• Prior treatment administration of last prior platinum-based chemotherapy and anti-
PD-1/PD-L1 antibody (sequential vs concurrent) 
• Number of prior lines of therapy in advanced disease (1 vs 2 vs > 2) 
• Brain metastasis at baseline (yes vs no) 
• Liver metastasis at baseline (yes vs no) 
• Bone metastasis at baseline (yes vs no) 
• Tumor proportion score (PD-L1 protein expression) (< 1% vs 1-49% vs ≥ 50%) 
• Best overall response of the last prior therapy in advanced/metastatic setting  
Efficacy endpoints of OS and PFS will be presented descriptively per each subgroup. Forest 
plots will be used to present the results of the subgroup analysis for OS and PFS. Additional 
subgroup analyses will be provided in the SAP. 
9.5. 
Safety Data Presentations and Summaries 
9.5.1. 
Adverse Events 
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system. Listings will include the verbatim term, preferred term, and 
system organ class (SOC). The number of patients with treatment-emergent AEs and the 
incidence of TEAEs by SOC and preferred term will be summarized. TEAEs will be summarized 
by maximum intensity and relationship to study therapy. Separate summaries will be provided 
for TEAEs, TESAEs, treatment-related AEs, treatment -related SAEs, and other significant AEs 
(eg, AEs leading to study discontinuation). 
9.5.2. 
Prior and Concomitant Medications 
Collected prior and concomitant medications will be coded using the World Health Organization 
(WHO) medical dictionary; patients who received these medications will be listed and 
summarized.  
9.5.3. 
Clinical and Laboratory Assessments 
Clinical and laboratory assessments include clinical laboratory tests (hematology, thyroid 
function tests and chemistry), vital signs, MUGA or ECHO and 12-lead ECGs. 
Clinical laboratory results will be listed by patient and, as appropriate, summarized descriptively, 
which will include a display of change from baseline. Selected parameters will be presented in 
shift tables of baseline against worst grade test result. Laboratory values outside of the normal 
ranges will be identified. Laboratory values that meet Grade 3 or 4 criteria according to NCI 
CTCAE v5.0 will be listed and summarized. 
Electrocardiogram assessments will be evaluated for change of QTc from baseline. The 
Investigator’s interpretation of QTc will be used in the clinical management of patients. The 
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study analysis will use Fridericia’s formula applied programmatically to the ECG data collected 
in CRFs using the QT interval and either the RR interval or the heart rate if the RR interval is not 
reported. 
Vital signs, MUGA or ECHO and, ECG measurements will be listed for each patient at each 
visit. Descriptive statistics of observed values and changes from baseline will be summarized by 
treatment group. 
9.5.4. 
Patient Demographics, Baseline Characteristics and Disposition 
Presentations of patient characteristics will include a summary of the following for all patients 
enrolling in the study: 
• Demographics 
• Baseline disease characteristics 
• Pre-existing conditions/concurrent illness 
• Prior therapies/surgeries 
A summary of patient enrollment and disposition will include reasons for study discontinuation. 
9.5.5. 
Analysis of Study Treatment Dosing 
Study treatment administration will be described in terms of the total number of cycles 
administered, the median (range) of cycles administered, dose intensity, and reasons for the 
deviations from planned therapy. 
9.6. 
Other Study Endpoints 
9.6.1. 
Pharmacokinetic Analysis 
Descriptive summary statistics of MRTX849 concentrations will be reported. 
Sparse PK data from this study will be included with other MRTX849 studies for population PK 
analysis to identify potential covariates. Results of population PK analysis will be issued in a 
separate report. Exposure-response analysis for safety and efficacy endpoints will be explored 
and results will be issued in a separate report. 
9.6.2. 
Patient Reported Outcomes Analysis 
For the LCSS, change from baseline scores in the overall, symptom and three-item global 
components will be compared between treatment arms using mixed effect model repeated 
measurement (MMRM) analysis. The least-squares mean differences between treatments will be 
presented. Descriptive statistics will be reported by visit, as well as the change from baseline for 
the overall, diseases-associated symptom and three-item global components of the LCSS. 
For the EQ-5D-5L descriptive system, patient health states will be converted into a single 
dimension descriptive health utility index (UI). The EQ-5D UI and VAS will be analyzed using a 
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MMRM analysis as described above. Descriptive statistics will also be reported for both the 
EQ-5D UI and VAS scores as well as change from baseline scores. 
Further detail of analyses to be performed using the PRO endpoints will be provided in the SAP. 
9.6.3. 
Exploratory Analyses 
No formal statistical analysis of exploratory endpoints will be performed. Possible relationships 
between correlative endpoints, PK parameters, safety, and efficacy may be examined if 
appropriate. 
9.7. 
Interim Analysis 
For the secondary endpoint OS, a group sequential design will be utilized with one interim 
analysis and one final analysis. The interim analysis for OS is conducted at the time when the 
required PFS events (ie, ~246 PFS events) is observed. The exact alpha spend for OS will be 
adjusted according to the observed number of events (ie, death) at the time of analysis. The 
enrollment into the study is anticipated to be completed by the time of the interim analysis. If the 
number of death events for the interim analysis for OS is maturing slower than expected at the 
time of the PFS analysis, a decision will be made if PFS analysis will proceed as planned or the 
analysis will be delayed until an appropriate number of death events has occurred. A nonbinding 
futility boundary for OS is also constructed using a Rho family spending function with parameter 
3.0. 
The fixed-sequence testing procedure to control the familywise error rate (FWER) will be used 
for testing of the primary endpoint PFS and the secondary efficacy endpoints in this study. 
Initially, PFS hypothesis will be tested at α = 0.05 (2-sided). If PFS test is statistically 
significant, the ORR hypothesis will be tested at α = 0.05 (2-sided). If the ORR test is 
statistically significant, the OS hypothesis will be tested at α = 0.05 (2-sided) with the Lan-
DeMets O'Brien-Fleming spending function at the interim analysis. Further details will be 
provided in the SAP. 
9.8. 
Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will oversee the conduct of the study as 
outlined in the IDMC Charter. The IDMC will have access to open-label trial data and will 
perform the following functions: 
• Review the conduct of the study and accruing safety data at approximate 6-month 
intervals and on an ad hoc basis as safety questions arise. 
• Review the interim analysis and recommend the appropriate course of action as 
outlined in Section 9.7. 
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10. 
ETHICS AND RESPONSIBILITIES 
10.1. 
Ethical Conduct of the Study 
This study will be conducted in accordance with International Ethical Guidelines for Biomedical 
Research Involving Human Patients (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practice (GCP) (International Council for 
Harmonisation [ICH] 1996), ICH E6 (R2) and concepts that have their origin in the Declaration 
of Helsinki (World Medical Association 1996, 2008 & 2013). 
Specifically, this study is based on adequately performed laboratory and animal experimentation; 
the study will be conducted under a protocol reviewed and approved by an IRB/EC; the study 
will be conducted by scientifically and medically qualified persons; the benefits of the study are 
in proportion to the risks; the rights and welfare of the patients will be respected; the physicians 
conducting the study do not find the hazards to outweigh the potential benefits; and each patient 
will give his or her written informed consent before any protocol-driven tests or evaluations are 
performed. 
10.2. 
Obligations of Investigators 
The Investigator is responsible for complying with the protocol and all applicable regulations 
and guidelines governing clinical research. Additionally, he/she is responsible for ensuring that 
all participating staff members are adequately trained and competent to perform his/her assigned 
tasks. 
All Investigators must provide the Sponsor with a current curriculum vitae. Only Investigators 
and designated Sub-Investigators are permitted to sign CRFs and examination findings 
(eg, laboratory results or ECGs). 
The Investigator or designee is responsible for informing the patient of all available information 
relevant to his/her safety and obtaining signed, written consent from all participating patients. 
Additionally, the Investigator is responsible for monitoring patient safety and providing periodic 
and requested reports to the IRB/EC/Research Ethics Board (REB). 
The Investigator is responsible for the accuracy and completeness of all study records including 
CRFs, source documents, and the Site Trial Master File. The Investigator will allow the Site 
Monitor, Sponsor, auditor, regulatory agencies, and IRB/EC/REB full access to the study and 
source documents. 
10.3. 
Institutional Review Board/Ethics Committee/Research Ethics Board 
(IRB/EC/REB) 
Prior to the shipment of clinical supplies or initiation of the study, the clinical trial protocol along 
with the ICF, Investigator’s Brochure, and any other written information or instructions for the 
patient must be submitted to the IRB/EC/REB for written approval. The Investigator will provide 
the Sponsor with a copy of the IRB/EC/REB’s written approval, as well as the membership list 
or a compliance statement from the IRB/EC/REB. The Investigator is responsible for notifying 
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the IRB/EC/REB of any Sponsor-approved amendments to the protocol or ICF, SAEs occurring 
in patients treated at the study site in accordance with local IRB/EC/REB practice, and all 
expedited safety reports from SAEs occurring at other study sites participating in the drug 
development program. 
10.4. 
Informed Consent Form 
The ICF must contain all elements required by the FDA under 21 Code of Federal Regulations 
(CFR) Part 50 and the ICH GCP guidelines (ICH E6 (R2)) in addition to any other elements 
required by applicable national, state, provincial, and local regulations, or institutional policies. 
All patients who choose to participate in the study must provide written consent after having had 
adequate time to consider whether they will participate in the study. The written consent must be 
obtained prior to any protocol-related procedures that are not part of the patient’s normal medical 
care. The patient must be advised of his/her right to withdraw from the study at any time. 
Written documentation of consent must be recorded in the patient’s source documents, study 
records and CRF indicating the date the consent was signed. The patient should receive a signed 
copy of the consent form according to GCP guidelines. 
10.5. 
Confidentiality and Privacy Protection 
All information generated in this study is considered confidential, is subject to applicable privacy 
rules and regulations, and must not be disclosed to any person or entity not directly involved 
with the study without the Sponsor’s prior written consent or in accordance with applicable law 
or regulations. Persons or entities involved with the study who may have access to the 
information will be subject to contractual confidentiality requirements. However, authorized 
regulatory officials, such as IRB/EC/REB, the Sponsor and its authorized representatives (as and 
to the extent authorized in the patient’s ICF) are allowed access to the records. 
Identification of patients in CRFs shall be by study assigned patient numbers only. If required, 
the patient's full name may be made known to authorized third parties, to the extent permitted by 
applicable laws and regulations and mentioned in the ICF. 
The identifying patient information collected for and during the clinical trial will be kept 
confidential. However, study information may be published in formal reports and medical papers 
and may include de-identified medical information of the patient, to the extent permitted in the 
ICF. In either way, the patient name will not be used in publicly available documents. 
Records and documents which identify the individual patient will be stored securely for the 
length of time required by applicable clinical research, health information and data privacy laws, 
as described in Section 11.2 and in the ICF. 
Regarding Privacy and Data Protection, the Sponsor ensures that personal data is collected and 
processed in accordance with all the applicable laws and regulations. 
Ethnic factors could influence the effects (safety and efficacy) of medicines and the risk/benefit 
assessment in different populations. Race and ethnicity data are collected (not applicable in 
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France) in CDISC SDTM (SDTM Implementation Guide v.3.2) format, in accordance with ICH 
guidance (ICH E5) adopted by the EMA and FDA, to support population pharmacokinetic (PK) 
analysis, which is a well-established, quantitative method that can quantify and explain the 
variability in drug concentrations among patients. Variability can be attributed to intrinsic factors 
(eg, body weight, age, gender, race/ethnicity), or to extrinsic factors (eg, concomitant 
medications). In some cases, intrinsic or extrinsic factors lead to clinically relevant changes in 
drug concentrations that require a change in the dose or dosing regimen. Results from population 
PK analyses will be incorporated into drug product labeling to provide guidance on the dose or 
dosing regimen including any potential dose adjustment in some subpopulations (eg, race or 
ethnic group). Therefore, collecting race/ethnicity data in the study is essential to understand 
whether race/ethnicity could influence the PK, safety and/or efficacy. 
Detailed description of the conditions for the collection and processing of personal data is made 
available to the patient in the ICF and, if applicable, the relating Data Protection Privacy Policy. 
The Sponsor, as data controller, collects and processes personal data related to (i) patient identity 
and health in order to conduct the study, and (ii) financial data and identification data for 
administrative tasks, under the conditions set forth in the ICF. 
In accordance with all applicable data protection rules, the patient will have the right to access, 
rectify, delete, limit or oppose the processing of his/her personal data, the right to define 
guidelines for the storage, deletion and communication of the data after his/her death and the 
right to the portability of his/her personal data. The Investigator is in charge of the exercising of 
the rights. The Sponsor may also have appointed a Data Protection Officer to whom it will be 
permitted access to directly identifying personal data when necessary to answer a patient’s 
request. 
The Sponsor has implemented appropriate protocols and mechanisms in case of a breach of 
confidentiality. 
10.6. 
Reporting of Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction (ie, clinical hold) imposed by an applicable 
Regulatory Authority, or if the Investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the Sponsor must 
be informed immediately. In addition, the Investigator will inform the Sponsor immediately of 
any serious breaches of this protocol or of ICH GCP of which the Investigator becomes aware. 
11. 
RECORDS MANAGEMENT 
11.1. 
Source Documentation and Data 
Source documents to be used for verification of data in the CRF (electronic data capture system) 
include hospital or clinical patient charts, pertinent historical medical records, local laboratory 
test reports, ECG tracings, pathology reports, radiographs, etc. All source documents must be 
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legible. Data reported in CRFs and evidence of patient’s informed consent must be documented 
in source documents. 
In addition, source data for this study will be obtained from the IWRS, web-based portals for 
clinician reported outcomes, mobile electronic applications for patient reported outcomes, central 
laboratories, specialty laboratories, the central radiology review laboratory, and/or other vendors 
specified by the Sponsor. 
11.2. 
Study Files and Records Retention 
A CRF must be completed for each patient for whom informed consent for the study is obtained. 
The CRFs must be maintained by properly trained and delegated site representatives. The 
Principal Investigator has responsibility for ensuring the authenticity, accuracy, completeness 
and timeliness of all data collected in the CRF. CRFs must be signed by the Principal 
Investigator or by an authorized Sub-Investigator to attest that the information included is true. 
Each study site will maintain a Site Trial Master File in accordance with GCPs. 
The Investigator shall retain all records for the longest of the following periods: (i) 15 years; 
(ii) the period of time that conforms to ICH GCP guidelines; (iii) the period of time required by 
applicable law or regulations, or (iv) the period of time specified in the Clinical Research 
Agreement. 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. 
Monitoring Procedures 
Sponsor appointed Site Monitor(s) must be allowed access to all study records, original source 
documents, and investigational products throughout the duration of the study. These personnel 
are responsible to assess compliance with the protocol, appropriate health authority regulations, 
ICH GCP guidelines, and Sponsor requirements. 
The Site Monitor is responsible for complying with the monitoring guidelines established by the 
Sponsor for the study, assessing the site’s needs, and liaising with the assigned Sponsor staff. 
If the Investigator withdraws from the study and relinquishes his/her responsibility for the 
maintenance and retention of records, he/she must notify the Sponsor in writing so arrangements 
can be made to properly store the study materials. 
12.2. 
Auditing and Inspection Procedures 
The Sponsor’s Quality Assurance representatives, IRB/EC/REB reviewers, or inspectors from 
regulatory agencies may perform an audit or inspection at any time during or after completion of 
the clinical study. All study-related documentation must be made available to the designated 
auditor. In addition, representatives of applicable regulatory health authorities may choose to 
inspect a study. A Sponsor representative will be available to assist in the preparation for such an 
inspection. 
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13. 
CHANGES IN STUDY CONDUCT 
13.1. 
Protocol Amendments 
Changes to the study protocol, except those intended to reduce immediate risk to study patients, 
may be made only by the Sponsor. A protocol change intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, provided the IRB/EC/REB is 
notified within 5 days. Any urgent safety measures taken by the Investigator to protect the study 
patients against any immediately life-threatening hazard must be reported immediately to the 
Sponsor. 
Any permanent change to the protocol must be handled as a protocol amendment. The change 
and the justification will be documented in writing by the Sponsor, as an Administrative Letter or 
amended protocol. Protocol amendments will include a list of all changes. The written 
Administrative Letter or amendment must be submitted to the IRB/EC/REB and the Investigator 
must await approval before implementing the changes. The Sponsor will be responsible for 
submitting protocol amendments to the appropriate regulatory authorities for approval. 
If in the judgment of the IRB/EC/REB, the Investigator, and/or the Sponsor, the amendment to 
the protocol substantially changes the study design and/or increases the potential risk to the 
patient and/or has an impact on the patient’s involvement as a study participant, the currently 
approved written ICF will require similar modification. In such cases, informed consents (revised 
as appropriate to address protocol amendments) will be obtained for patients enrolled in the 
study before continued participation. 
13.2. 
Plan for Communication of Study Decisions and Protocol Changes 
This Phase 3 trial includes multiple points at which decisions will be made concerning direction 
of the study. Table 16 lists decision makers, initial communication methods and ultimate 
documentation of decisions and protocol amendments. 
Table 16: 
Communication of Study Decisions and Protocol Amendments 
Study Decision or 
Protocol Change 
Decision Maker 
Documentation for 
Implementation 
Ultimate Documentation 
Protocol change to 
address serious safety 
concern 
Sponsor 
Administrative Letter to 
Investigators 
Reiteration in next 
protocol amendment 
Change in formulation of 
MRTX849 
Sponsor 
Administrative Letter to 
Investigators 
Reiteration in next 
protocol amendment 
Update of fed/fasted 
dosing instructions 
Sponsor 
Administrative Letter to 
Investigators 
Reiteration in next 
protocol amendment 
Update AE management 
guidelines 
Sponsor 
Administrative Letter to 
Investigators 
Reiteration in next 
protocol amendment 
Update list of medications 
to use with caution  
Sponsor 
Administrative Letter to 
Investigators 
Reiteration in next 
protocol amendment 
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13.3. 
Protocol Deviations 
Prospective permission to deviate from the eligibility criteria for this protocol will not be 
provided by the Sponsor. Study specified assessments should not be omitted and the study 
treatment regimen should not deviate from protocol specifications. Minor, occasional 
adjustments in the clinic visit schedule may be necessary for logistical reasons (eg, due to 
weather conditions) but must not become routine or systematically alter the study schedule. The 
IRB/EC/REB should be informed of any deviations that may affect a patient’s treatment or 
informed consent, especially those increasing potential risks, which must receive prior written 
approval by the IRB/EC/REB. 
14. 
END OF TRIAL 
14.1. 
End of Trial in a European Union Member State 
In accordance with Regulation EU No 536/2014, the End of Trial in a Member State of the 
European Union is defined as the last visit of the last patient included in a member state, or at a 
later point in time defined in the protocol. 
14.2. 
End of Trial in all Other Participating Countries 
End of Trial in all other participating countries is defined as the time at which all patients 
enrolled in the study have completed the last study visit and data from those visits have been 
reviewed by the Investigator or designee. 
14.3. 
Premature Termination 
Premature termination of this study may occur at any time because of a regulatory authority 
decision, change in opinion of the IRB/EC/REB, drug safety concerns, or at the discretion of the 
Sponsor. In addition, the Sponsor retains the right to discontinue development of MRTX849 at 
any time. If termination becomes necessary, the Sponsor will inform the appropriate regulatory 
authorities of the termination and the reason. The Principal Investigator will inform the 
IRB/EC/REB of the same. In terminating the study, the Sponsor and the Principal Investigator 
will assure that adequate consideration is given to the protection of the patients’ interests. 
15. 
STUDY REPORT AND PUBLICATION POLICY 
The Sponsor is responsible for preparing and providing the appropriate regulatory authorities 
with clinical study reports according to the applicable regulatory requirements. 
The publication of study results will be governed by the applicable Clinical Research Agreement 
between the Sponsor and the Study Site and Investigator (as applicable). 
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16. 
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
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EuroQol Research Foundation. EQ-5D-5L User Guide, 2019. Available from: 
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FDA Guidance for Industry, Investigators and Institutional Review Boards: Conduct of clinical 
trials of medical products during COVID-19 public health emergency, August 2021 
Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in 
metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. 
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Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus 
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APPENDIX 1. ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS 
Grade 
ECOG 
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 house work, office work 
2 
Ambulatory and capable of all self care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair 
5 
Dead 
 
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APPENDIX 2. MEDICATIONS OR SUBSTANCES TO BE AVOIDED 
DURING TREATMENT WITH MRTX849 
Examples are provided for QT-prolonging medications to avoid (Table 17), and medications and 
substances to avoid with MRTX849 treatment (Table 18). Refer to Section 5.9 for additional 
information on concomitant use of medications and substances during the study.  
Table 17: 
Examples of QT-Prolonging Medications to Avoid 
Examples of Medications to Avoid 
Potential Effect 
Amiodarone, anagrelide, azithromycin, chloroquine, 
chlorpromazine, ciprofloxacin, citalopram, 
clarithromycin, cocaine, disopyramide, domperidone, 
donepezil, erythromycin, escitalopram, fluconazole, 
gatifloxacin, haloperidol, hydroxychloroquine, 
levofloxacin, loperamide1, methadone, moxifloxacin, 
ondansetron1, oxaliplatin, pentamidine, propofol, 
quinidine, sotalol, terfenadine, thioridazine, vandetanib 
Known risk of QT-prolongation and Torsades de 
Pointes 
Source: Compiled from https://www.crediblemeds.org/druglist (accessed July 2021). This list of examples is not 
exhaustive; refer to the source for additional examples. 
1 Refer to Section 5.9 for additional guidance related to concomitant use of loperamide and ondansetron. 
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Table 18: 
Examples of Medications and Substances to Avoid with MRTX849 
Treatment 
Characteristic 
Examples of Medications/Substances to Avoid 
Potential Effect 
Effect of MRTX849 on other medications or substances 
Sensitive CYP3A4 
substrates1 
Alfuzosin, alprazolam, aprepitant, avanafil, 
budesonide (oral), carbamazepine, conivaptan, 
daridorexant, dihydroergotamine, dronedarone, 
eletriptan, eplerenone, ergotamine, everolimus, 
finerenone, isavuconazole, ivabradine, 
lomitapide, lonafarnib, lopinavir, lovastatin, 
lurasidone, midazolam, mitapivat, naloxegol, 
nisoldipine, rivaroxaban, sildenafil (for 
pulmonary arterial hypertension), simeprevir, 
simvastatin, sirolimus, ticagrelor, tipranavir, 
tolvaptan, triazolam, ubrogepant, vardenafil, 
voclosporin 
Increased exposure of CYP3A4 
substrates, potentially increasing risk 
of SAEs associated with con med 
Sensitive CYP2D6 
substrates with 
narrow therapeutic 
index1 
Eliglustat, pimozide, propafenone, thioridazine 
Increased exposure of CYP2D6 
substrate, potentially increasing risk 
of toxicities associated with con med 
Sensitive CYP2C9 
substrates with 
narrow therapeutic 
index1 
Warfarin2 
Increased exposure of CYP2C9 
substrate, potentially increasing risk 
of toxicities associated with con med 
P-gp substrates with 
narrow therapeutic 
index3 
Colchicine, dabigatran, digoxin 
Increased exposure of P-gp 
substrates, potentially increasing risk 
of SAEs associated with con 
medication 
Effect of other medications or substances on MRTX849 
Strong Inhibitor of 
CYP3A44 
Boceprevir, clarithromycin, cobicistat, 
danoprevir, itraconazole, ketoconazole, 
lopinavir, nefazodone, nelfinavir, posaconazole, 
ritonavir, telaprevir, telithromycin, 
troleandomycin, voriconazole 
Increased exposure of MRTX849, 
potentially increasing risk of SAEs 
associated with MRTX849 (only 
avoid until MRTX849 reaches 
steady state after approximately 
8 days of continuous dosing) 
Strong Inducer of 
CYP3A4  
Carbamazepine, mitotane, phenobarbital, 
phenytoin, rifampin, St. John’s wort 
Decreased exposure of MRTX849, 
potentially reducing efficacy 
Inhibitor of BCRP 
Eltrombopag, curcumin, cyclosporine 
Increased exposure of MRTX849, 
potentially increasing risk of SAEs 
associated with MRTX849 
Proton pump 
inhibitors 
Dexlansoprazole, esomeprazole, ilaprazole, 
lansoprazole, omeprazole, pantoprazole, 
rabeprazole 
Decreased exposure of MRTX849, 
potentially reducing efficacy 
Abbreviations: BCRP = breast cancer resistance protein; con med = concomitant medication, CYP = cytochrome 
P450 enzyme; P-gp = P-glycoprotein; SAE = serious adverse event. 
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Sources: Compiled from the University of Washington Drug Interaction Database 
(https://didb.druginteractionsolutions.org/), https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers (accessed February 2023). This list of 
examples is not exhaustive and excludes anti-neoplastic agents; refer to the sources for additional examples. 
For other sensitive substrates not listed in the examples, refer to their Prescribing Information for recommended use. 
1 For other sensitive substrates not listed in the examples, refer to their Prescribing Information for recommended 
use. 
2 In certain cases, warfarin may be used after approval from the Sponsor and with additional international 
normalized ratio (INR) monitoring. 
3 Some concomitant medications, upon approval by the Sponsor, may be used in accordance with the Prescribing 
Information for these medications. 
4 Concomitant use of strong inhibitors of CYP3A4 do not need to be avoided once MRTX849 has reached steady-
state (eg, approximately 8 days after continuous MRTX849 dosing). 
 
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APPENDIX 3. MEDICATIONS OR SUBSTANCES TO BE AVOIDED 
DURING TREATMENT WITH DOCETAXEL 
Based on information presented in approved product label, concomitant use of docetaxel and 
drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. The 
potential for drug-drug interactions during use of docetaxel is further discussed in approved 
product label. Specific concomitant medications to be avoided during docetaxel use are listed in 
Table 19. Note that strong inducers of CYP3A4 may decrease exposure to docetaxel and should 
also be generally avoided. 
Table 19: 
Specific Concomitant Medications to Avoid with Docetaxel 
Drug Name 
Characteristic 
Potential DDI Effect 
Usage 
Atazanavir 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Boceprevir 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Clarithromycin 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Cobicistat 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Danoprevir and 
Ritonavir 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Darunavir and 
Ritonavir 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Elvitegravir and 
Ritonavir 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Grapefruit Juice 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Idelalisib 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Indinavir and 
Ritonavir 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Itraconazole 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Ketoconazole 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Lopinavir and 
Ritonavir 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Nefazodone 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Nelfinavir 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
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Drug Name 
Characteristic 
Potential DDI Effect 
Usage 
Paritaprevir and 
Ritonavir and 
(Ombitasvir and/or 
Dasabuvir) 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Posaconazole 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Ritonavir 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Saquinavir and 
Ritonavir 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Telaprevir 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Telithromycin 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Tipranavir and 
Ritonavir 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Troleandomycin 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
Voriconazole 
Strong CYP3A4 Inhibitor 
Increased Exposure of 
Docetaxel 
Avoid 
 
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APPENDIX 4. ABBREVIATED PRESENTATION OF RECIST VERSION 
1.1 GUIDELINES 
A modification to RECIST 1.1 has been made to account for the possibility of temporary 
changes resulting from tumor necrosis, cavitation, flare response or pseudoprogression. 
Categorizing Lesions at Baseline 
Measurable Lesions 
• Not previously irradiated, unless disease progression in the lesion was documented 
after completion of radiotherapy. 
• Accurately measured in at least one dimension. 
• When assessed by CT or MRI, longest diameter at least 10 mm or greater (slice 
thickness 5-8 mm), measured in the axial plane. If the slice thickness is greater than 
5 mm (including any inter-slice gap), the longest diameter must be at least twice the 
slice thickness. 
• Malignant lymph nodes with a short axis (defined as the largest measurement 
perpendicular to the longest diameter of the lesion) 15 mm or greater when assessed 
by CT or MRI. 
The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all other 
lesions. 
Non-Measurable Disease 
• Lesions too small to be considered measurable (including nodes with short axis 
between 10 and 14.9 mm) or truly non-measurable disease such as pleural or 
pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, and abdominal masses identified by 
physical exam that are not measurable by reproducible imaging techniques. 
• Bone disease is non-measurable with the exception of soft tissue components that can 
be evaluated by CT or MRI and meet the definition of measurability at baseline. 
• Previously irradiated lesions (or those subjected to other local treatment) are 
non-measurable unless they have progressed since completion of treatment. 
Normal Lesions 
• Non-malignant simple cysts should not be recorded either as target or non-target 
disease. Cystic lesions thought to represent cystic metastases can be measurable 
lesions, if they meet the specific definition above. 
• Lymph nodes with short axis < 10 mm are considered normal and should not be 
followed as disease. 
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Tumor Assessments 
All sites of disease must be assessed at baseline. Baseline assessments should be done as close as 
possible prior to study start. All required scans must be done within the window of time specified 
in the Schedule of Assessments prior to treatment. If the baseline assessment is inadequate, 
subsequent statuses generally should be indeterminate. 
The determination of whether lesions are measurable is performed only at baseline. 
“Measurable” at baseline means eligible for selection as target lesions, and thus for quantitative 
assessment throughout the trial. Once selected as a target lesion, a lesion remains target 
throughout the trial. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative 
of all involved organs, should be identified as target lesions at baseline. Target lesions should be 
selected on the basis of size (longest lesions) and suitability for accurate repeated measurements. 
Record the longest diameter for each lesion, except in the case of pathological lymph nodes for 
which the short axis should be recorded. The sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions at baseline will be the basis for 
comparison to look for PR at later assessments. 
• If 2 target lesions coalesce the longest diameter measurement of the coalesced mass is 
used. If a large target lesion splits, the sum of the parts is used. 
• Measurements for target lesions that become small should continue to be recorded. If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded. 
• When nodal lesions decrease to < 10 mm (normal), the actual measurement should 
still be recorded. 
• Patients who receive palliative locoregional treatment such as complete resection or 
radiotherapy to target lesions after initiating study treatment will be censored from 
response evaluation in the efficacy analyses at the time the patient receives the 
palliative locoregional treatment. 
Non-Target Lesions 
All non-measurable disease is non-target. All measurable lesions not identified as target lesions 
are also included as non-target disease. Measurements are not required but rather qualitative 
evaluations of status will be recorded. Multiple non-target lesions in one organ may be recorded 
as a single item on the CRF (eg, ‘multiple liver metastases’). 
Objective Response Status at Each Evaluation 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast. If not, subsequent objective statuses may be indeterminate. 
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Target Disease 
• Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease. All target nodes must decrease to normal size (short axis 
< 10 mm). All target lesions must be assessed. 
• Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions. The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions. All target lesions must be assessed. 
• Stable Disease (SD): Does not qualify for CR, PR or Progression. All target lesions 
must be assessed. Stable can follow PR only in the rare case that the sum increases by 
less than 20% from the nadir, but enough that a previously documented 30% decrease 
no longer holds. 
• Progressive Disease (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy) with a minimum absolute increase of 5 mm. 
• Indeterminate: Progression has not been documented, and 
− one or more target lesions have not been assessed,  
− or assessment methods used were inconsistent with those used at baseline and 
impaired assessment, 
− or one or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure), 
− or one or more target lesions were excised or irradiated and have not reappeared 
or increased. 
Non-Target Disease 
• CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels. All lymph nodes must be ‘normal’ in size (< 10 mm short axis). 
• Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 
• PD: Unequivocal progression of pre-existing lesions. Generally, the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy. In the presence 
SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 
• Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline. 
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New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology. If 
repeat assessments confirm the lesion, then progression should be recorded on the date of the 
initial assessment. A lesion identified in an area not previously scanned will be considered a new 
lesion. 
Lesion Changes That May Be Transient 
Potential exists for individual tumor lesions to develop necrosis, cavitate, have a flare response to 
treatment, demonstrate pseudoprogression or become otherwise difficult to evaluate for a period 
of time as the result of study treatment impact. For example, tumor necrosis, cavitation, flare or 
pseudoprogression may result in increase in overall size of individual lesions, unclear tumor 
margins, or observation of apparently new lesions prior to recovery to smaller lesions, 
development of scar tissue, or complete resolution. The true tumor measurements of lesions 
should be recorded but the conclusion of progressive disease may be suspended until continued 
assessment clarifies the nature of the tumor change. If repeat assessments indicate progression of 
disease, then PD should be recorded on the date of the first assessment giving the impression of 
progression. If repeat assessments indicate that the change was a process of transition, then NE 
should be recorded during the period of transition, and PR or CR may be recorded for subsequent 
evaluations. The CRF will collect information on the observations during the period of transition 
to support the assessment conclusions. 
Supplemental Investigations 
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate. If no disease is identified, objective status is CR. 
Best Objective Response 
Target Lesions 
Non-Target 
Lesions 
New Lesion 
Point in Time 
Response 
Best Response 
CR 
CR 
No 
CR 
CR and PR require confirmation 
at least 4 weeks after first 
observation 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
SD requires an on-study 
assessment after at least 6 weeks 
on treatment. 
Unconfirmed PR or CR are 
reported as SD. 
PD 
Any 
Yes or No 
PD 
 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
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Subjective Progression 
Patients requiring discontinuation of treatment due to worsening health status attributable to 
advancement of the malignancy under study but without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs. This should be indicated 
on the end of treatment CRF as off treatment due to Global Deterioration of Health Status. 
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APPENDIX 5. GUIDANCE TO STUDY SITES ON STUDY AND 
PATIENT MANAGEMENT DURING COVID-19 PUBLIC 
HEALTH EMERGENCY 
The content of this appendix is consistent guidance issued by the US FDA in March 2020 and 
updated 30 August 2021 (FDA, 2021). Addressed are issues in study conduct impacted by the 
COVID-19 public health emergency such as patient visits, documentation of deviations to the 
protocol and recording of data. The changes made to the protocol and clinical trial conduct are 
temporary and will remain in effect until a future Administrative Letter to Investigators notifies 
study sites to resume study conduct in accordance with the full protocol and normal practices. 
Adjustments to Visit Windows and Study Assessments 
Study assessments associated with ± 2-day visit windows are assigned a ± 5-day window. Visits 
conducted within the expanded window are not considered protocol deviations. Visits outside of 
the expanded window may be considered protocol deviations. Data should be recorded on the 
CRF associated with the nominal visit day. 
Imaging assessments may be performed using an alternative modality and will not be reported as 
protocol deviations if the Sponsor is made aware in advance. 
Study procedures that cannot be conducted due to institutional restrictions will not be reported as 
protocol deviations if the Sponsor is made aware in advance on a case-by-case basis. Such 
procedures may include PK blood sample collection and corresponding ECGs at timepoints of 
4 hours and later, and collection of tumor tissue sample at the time of disease progression. 
Remote Patient Visits 
• If permitted by institutional guidelines, remote patient visits may be conducted with 
site staff by telephone or using video technology and/or with a visit by a home health 
care professional. Depending on local IRB/EC/REB policy, a revised ICF may be 
needed to allow remote patient visits. 
• If new local laboratories are used during remote visits for safety laboratory 
assessments (eg, hematology and chemistry), ensure all test results, laboratory 
certifications, and reference normal laboratory values are collected and documented 
in the site records consistent with institutional guidelines. The laboratory normal 
ranges should be provided to the Sponsor for entry into the clinical database. 
• Ensure all details of remote patient visits are documented in patient site records. 
Shipment of MRTX849 Clinical Trial Material to Patients 
MRTX849 tablets may be shipped to the homes of study participants being visited by home 
health professionals under 3 conditions: 1) such clinical trial material shipment is permitted by 
local institution policy, 2) shipment is by a secure, trackable method and documentation of 
shipment and receipt is retained with the patient or pharmacy records, and 3) the material is 
shipped in packaging that monitors and records internal package temperature. Clinical trial 
material exposed to temperature excursions should be replaced. In the patient’s home, clinical 
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trial material must be stored under the conditions stated on the container labels and the Pharmacy 
Study Manual. Unused material and empty containers should be returned to the study site to 
enable the pharmacy to maintain accountability records. 
Study Drug Administration Delay or Interruption 
If study drug administration is delayed or interrupted due to inability to obtain study drug during 
the COVID-19 public health emergency, this reason should be recorded in the patient site record 
and reported in the CRF as the reason for delay or interruption. Such delays and interruptions 
will be documented as a protocol deviation. 
Action and Reporting in the Event of Documented or Suspected COVID-19 Infection: 
Study Treatment 
• Patients in Screening for Study Entry – Patients who exhibit symptoms consistent 
with COVID-19 infection or have recent COVID-19 test results consistent with active 
viral replication should delay study entry and start of study treatment until resolution 
of symptoms and evaluation by the Investigator. Questions should be directed to the 
Sponsor’s Medical Monitor. 
• Patients in Study Treatment – For patients on study treatment exhibiting symptoms 
consistent with COVID-19 infection, contact the Sponsor’s Medical Monitor as soon 
as feasible. 
Reporting in CRF 
• Adverse Events Involving COVID-19 
− "COVID-19" should be recorded as an AE in the AE CRF form for patients 
diagnosed with COVID-19. 
− "COVID-19 PCR test positive" should be recorded in the AE CRF for 
asymptomatic patients with positive PCR testing. 
− "COVID-19 serology test positive" should be recorded in the AE CRF for 
asymptomatic patients with positive serology testing. 
− "COVID-19 pneumonia" should be recorded in the AE CRF for patients 
experiencing pneumonia due to SARS-CoV-2 infection (the virus that causes 
COVID-19). 
− Any other COVID-19 related complications that meet the definition of an 
AE/SAE should also include "COVID-19" in the CRF entry/SAE report, 
eg, multiple-organ failure due to COVID-19. 
− Any AEs meeting any of the seriousness criteria should also be reported as SAEs. 
• COVID-19 Testing – Record “COVID-19 testing” PCR test or antibody test in the 
concomitant procedure CRF. 
 
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APPENDIX 6. PATIENT CROSSOVER SCHEDULE OF ASSESSMENTS 
 
Crossover 
Baseline 
Assessments1 
Crossover Cycles 1-4  
Crossover 
Cycles 5 + 
Day 1 
(± 2 days)18 
End of 
Treatment 
Visit2 
28-35 Days 
After Last Dose 
Long Term 
Follow-up 
Every 2 Months 
(± 14 days) 
Day 1 
C1 (- 2) 
C2-C4 (± 2) 
Day 15 
(± 2 days) 
Crossover Informed Consent3 
X 
 
 
 
 
 
ctDNA4 
 
C1 
At disease progression (optional) 
 
ECOG 
X 
 
 
 
 
 
Physical Exam5 - Full (F), Abbrev 
(A) 
F 
A 
A 
A 
F 
 
Vital Signs6 
X 
X 
X 
X 
X 
 
Hematology7 
X 
X 
X 
X 
X 
 
Chemistry7 
X 
X 
 
X 
X 
 
TSH7 
 
C3 
 
C5 
X 
 
Pregnancy Test8 
X 
As clinically indicated except where required routinely8 
X 
 
Single 12 Lead ECG9 
 
As clinically indicated 
X 
 
ECHO or MUGA (preferred except 
in Germany)10 
X 
 
 
C5 & C9 
(- 7 to + 2 day 
window) 
 
 
Disease Evaluation11 
X 
Every 6 weeks (± 10 days) until Week 26,  
then every 12 weeks 
 
 
PK Sampling12 &  
Triplicate ECGs13 
 
C1 & C2 – 
Predose & Peak; 
C3 – Predose 
 
C5 & C7 
Predose 
 
 
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Crossover 
Baseline 
Assessments1 
Crossover Cycles 1-4  
Crossover 
Cycles 5 + 
Day 1 
(± 2 days)18 
End of 
Treatment 
Visit2 
28-35 Days 
After Last Dose 
Long Term 
Follow-up 
Every 2 Months 
(± 14 days) 
Day 1 
C1 (- 2) 
C2-C4 (± 2) 
Day 15 
(± 2 days) 
MRTX849 Dispensing (D) & 
Reconciliation (R)14 
 
D,  
R (C2-4) 
 
D, R 
R 
 
PRO Questionnaires15 
 
X 
 X 
X 
X 
 
AEs16 & Concomitant Medications 
Throughout 
 
Survival & Anticancer Therapies17 
 
 
 
 
 
X 
Abbreviations: A =abbreviated, symptom directed evaluation; C = cycle; D = dispense; F =full physical examination; R = reconcile. 
1 The window for all Crossover baseline assessments is within 28 days of MRTX849 treatment initiation except for laboratory requirements (Section 4.1 and 
Section 4.3), which must be performed at least 7 days after the last administration of docetaxel, and MUGA or ECHO, which may be performed within 45 days 
of MRTX849 treatment initiation. 
2 End of Treatment: Visit occurs 28-35 days after last dose of study treatment. Repeat of assessments completed in the previous 4 weeks is not required with the 
exception of assessment of AEs, hematology, chemistry and pregnancy test as applicable. 
3 Informed consent to crossover using the crossover ICF is required after BICR confirmed progression of disease and prior to first MRTX849 administration. 
4 Blood samples for ctDNA: Blood samples for ctDNA are to be obtained at crossover Cycle 1 Day 1.  
5 Physical Examinations: A full physical examination (F) required at Crossover Screening and End of Treatment only. All other evaluations will be abbreviated, 
symptom directed evaluations (A). Allowed time windows permit evaluation within two calendar days (Friday assessments allowed for Monday dosing) in 
advance of busy days, eg, PK profile collection. 
6 Vital Signs: Weight, temperature, blood pressure, pulse rate, and respiratory rate to be assessed prior to dosing as indicated. Vital signs are to be performed in 
the semi-recumbent position. Height is not required if recorded at main study screening. 
7 Safety Laboratory Assessments: Laboratory assessments for Crossover Screening and Eligibility (Section 4.1 and Section 4.3) must have been performed at 
least 7 days after the last administration of docetaxel on study. Hematology, chemistry, and thyroid function will be performed using local laboratories. 
Parameters to be assessed are presented in Table 15. Repeat baseline assessment not required if assessment performed within 7 days before the first dose. 
Allowed time windows permit evaluation within two calendar days (Friday assessments allowed for Monday dosing) in advance of busy days, eg, PK profile 
collection. Additional assessments of any laboratory parameters may be performed according to standard of care or as clinically indicated. 
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8 Pregnancy Test: If the patient is a woman of childbearing potential, negative urine or serum pregnancy test performed by the local laboratory at time of 
crossover baseline assessments and End of Treatment will be required (in the United Kingdom and Germany, screening test required ≤ 7 days and ≤ 72 hours, 
respectively, before first dose of MRTX849). In addition, in regions where required by regulation (eg, European Union), monthly pregnancy testing will be 
performed until the end of systemic exposure to MRTX849 (testing may be performed at the beginning of each 3-week treatment cycle for convenience). At 
study sites in Austria, Belgium, France, Italy, and Spain and as required at other sites, pregnancy testing will be performed at the beginning of every treatment 
cycle and the same frequency (approximately monthly) for at least 1 month after the last dose of MRTX849. Additional pregnancy testing is to be performed 
whenever pregnancy is suspected during the study. 
9 Single 12-lead ECGs to be performed unless otherwise stated. In addition, ECGs are to be performed as clinically indicated. ECGs are to be performed in the 
semi-recumbent position. Assessments will include an evaluation of heart rate, PR, QRS, RR, QT, and QTc intervals. 
10 MUGA or ECHO: MUGA is preferred (except in Germany where it is not an option); the same modality should be used throughout a patient’s participation 
when possible. For patients in crossover, if a MUGA or ECHO has been performed within 45 days of MRTX849 treatment initiation, then the crossover 
screening MUGA/ECHO is not required. 
11 Disease Evaluations: To be performed as part of the crossover eligibility criteria and every 6 weeks from the date of first MRTX849 administration (± 10-day 
window for all other assessments except crossover eligibility) until week 26 (~6 months) and then every 12 weeks. If an on-study disease evaluation was 
performed within 35 days of MRTX849 treatment initiation, then an additional crossover eligibility disease evaluation is not required. Assessment locations to 
be included are listed in Table 13 and recommended imaging modalities are listed in Table 14. BICR scans submission is not required after patient has crossed 
over. More detailed guidance on assessments to be performed and exceptional circumstances is provided in Section 7.3. 
12 Pharmacokinetic Sampling: Predose samples should be collected up to 30 minutes prior to dosing in clinic. Peak samples should be collected 4 to 6 hours after 
dosing unless logistically infeasible. In addition to the scheduled samples, an unscheduled pre-dose PK blood sample (along with a triplicate ECG, see below) 
should be collected as soon as possible after an SAE, immediately prior to treatment interruption or dose reduction for a treatment-related nonserious AE, and 
at a clinic visit at least one week following a dose reduction of MRTX849. If MRTX849 has been held or discontinued for ≥ 3 days, Unscheduled PK 
collections are not required. 
13 Triplicate ECGs: To be performed after the patient has rested in the supine position for at least 5 minutes. All ECGs will be obtained prior to and as close as 
possible to PK sample collection. Three individual ECG tracings should be obtained as closely as possible in succession, between 1 and 2 minutes apart. The 
full set of triplicates should be completed in approximately 4 minutes or less. 
14 Patients should have a minimum of 7 days from last docetaxel administration prior to MRTX849 treatment initiation. Patients who crossover will initiate 
MRTX849 at a dose of 600 mg BID. 
15 PRO Questionnaires: Generally, to be performed prior to other assessments during clinic visits. Exceptions include assessments that are scheduled in other 
departments prior to the clinic visit, and vital signs if they are performed during patient check-in. EQ-5D-5L questionnaires should always be completed before 
LCSS. After six months, perform every other cycle on Day 1 and conclude after one year.  
16 Adverse Events: Must continue to be reported for crossover patients until the End of Treatment visit. 
17 Long-term Follow-up: Survival status and subsequent anticancer therapies will be collected as described in Section 6.4 every 2 months (± 14 days) from the 
End of Treatment visit until death or lost to follow-up. 
18Patients on MRTX849 for at least 12 months whom the PI believes are clinically stable on current dose regimen, may reduce frequency of clinic visits from 
every cycle to every other cycle (ie, Day 1 visits required every 6 weeks vs. 3 weeks). 
 
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APPENDIX 7. DOCUMENT HISTORY 
Document 
Version Date 
Summary of Changes 
Original Protocol, 
Version 1.0 
24 August 2020 
NA 
Amendment 1, 
Version 2.0 
16 November 2020 
  
• 
Added that patients with known hypersensitivity to 
docetaxel or polysorbate 80 are excluded from this study. 
• 
Changed the designation of the MRTX849 600 mg BID 
dose level from ‘highest planned dose level’ to ‘starting 
dose level.’ 
• 
Changed AE management guideline in the event of 
MRTX849-related pneumonitis to require dose reduction 
rather than consider dose reduction. 
• 
Cautioned against use of infusion equipment containing 
PVC for docetaxel administration. 
To ensure greater clarity and consistency across the MRTX849 
program –  
• 
Explicitly stated that central radiology reviewers will be 
blinded to treatment assignment. 
• 
Clarified that the timeframe for several exclusion criteria is 
relative to randomization. 
• 
Reiterated within the Concomitant Medications section that 
strong CYP3A4 inhibitors be avoided in both treatment 
arms and strong CYP3A4 inducers should be avoided in 
the MRTX849 treatment arm. 
• 
Reiterated within the Concomitant Medications section that 
substrates of CYP2C9, CYP3A4 and CYP2B6 with low 
therapeutic index should be used with caution for patients 
in the MRTX849 treatment arm. 
• 
Clarified guidance for study treatment discontinuation in 
the event of increased bilirubin in the MRTX849 treatment 
arm. 
• 
Deleted use of the stratified log-rank test to compare the 
two treatment arms for the secondary efficacy endpoint 
DOR. 
• 
Clarified when irradiated lesions can be chosen as target 
lesions, and the impact of on-study locoregional treatment 
of target lesions on response evaluation. 
Country specific details added to meet regulatory requirements 
in participating regions –  
• 
Specified that pregnancy testing in women of child-bearing 
potential be performed monthly where required by 
regulation. 
• 
Specified that in the United Kingdom, screening pregnancy 
test required ≤ 7 days before first dose of study treatment. 
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Document 
Version Date 
Summary of Changes 
• 
Added HIV, HBV and HCV serology testing during study 
screening in Germany and Czech Republic. 
• 
Added detail to entry criteria concerning HIV, HBV and 
HCV to address regulations in Germany.  
• 
Specified that in Germany, ECHO examination is to be 
used rather than MUGA. 
• 
Added locally approved docetaxel product labels to the 
reference list.  
• 
Clarified definition of End of Trial in European Union 
Member State. 
Amendment 2, 
Version 3.0 
09 March 2021 
• 
Updated the study population to include patients with 
unresectable, locally advanced disease in addition to 
patients with metastatic disease. Treatment setting retained; 
patients are to have previously received treatment with a 
platinum-based chemotherapy regimen and an immune 
checkpoint inhibitor. 
• 
Updated nonclinical MRTX849 pharmacokinetics and 
metabolism background. 
• 
Updated nonclinical toxicology background to include 13-
week studies and additional genotoxicity studies. 
• 
Updated MRTX849 clinical safety and pharmacokinetics 
background sections. 
• 
Updated guidance on use of concomitant medications 
based on preliminary clinical pharmacokinetic data. 
• 
Clarified circumstances under which presence of KRAS 
G12C mutation should undergo confirmatory testing. 
• 
Updated minor errors in the text of the document. 
Amendment 3, 
Version 4.0 
17 November 2021 
• 
Updated the study endpoints to specify PFS as the sole 
primary endpoint and OS as a secondary endpoint. 
• 
Added the option of crossover for patients in the 
comparator arm (docetaxel) who experience disease 
progression as defined by RECIST 1.1 by blinded 
independent central review to receive MRTX849. 
• 
Updated the statistical considerations and region 
stratifications. Revised the Phase 3 hypothesis and sample 
size estimates, decreased the estimated sample size to 340, 
added statistical considerations if a substantial proportion 
of patients in the comparator (docetaxel) arm were to 
crossover to receive MRTX849 treatment. 
• 
Added Appendix 6, Patient crossover schedule of 
assessments. 
• 
Changed MRTX849 administration instructions to allow 
dosing with or without food.  
• 
Removed HIV, HBV and HCV serology testing during 
study screening in Czech Republic. 
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Document 
Version Date 
Summary of Changes 
• 
Added exclusion criteria of hypersensitivity to any 
component of the MRTX849 drug product and 
administration of a life/attenuated vaccine within 30 days 
before the first dose of study treatment.  
• 
Updated Reproductive Health sections for men and 
women. 
• 
Added benefit/risk of MRTX849 treatment. 
• 
Updated the address for Mirati Therapeutics, Inc. 
• 
Updated nonclinical PK and metabolism section. 
• 
Updated clinical PK section. 
• 
Updated concomitant medication sections. 
• 
Added ethnic factors to the Confidentiality and Privacy 
Protection section. 
• 
Updated country specific requirements. 
• 
Updated guidelines for MRTX849 dose modification and 
adverse event management. 
Amendment 4, 
Version 5.0 
31 May 2022 
• 
Update of In Vitro Activity data for MRTX849. 
• 
Updated MRTX849 clinical pharmacokinetics sections 
including DDI’s. 
• 
Updated guidance on the use of concomitant medication in 
Section 5.9.1 and Appendix 2 and dietary restrictions in 
Section 4.5.1. 
• 
Added exploratory endpoints of Time to CNS Progression 
and intracranial activity using CNS RECIST endpoints in 
patients with brain metastases. 
• 
Added exclusionary text regarding prior docetaxel use. 
• 
Updated creatinine clearance inclusion criteria. 
• 
Updated HIV, Hepatitis B and C eligibility criteria. 
• 
Updated the minimum number of slides to 7. 
• 
Clarified age of consent for participation in countries 
where the legal age of consent is higher than 18 years of 
age.  
• 
Clarified stratifications used for statistical analyses. 
• 
Decreased interruption time for MRTX849 with major 
surgery to align with program. 
• 
Updated dose modification tables to align with MRTX849 
program and IB. 
• 
Added ORR into the testing sequence. 
• 
Updated Section 7.1 to clarify percentage of indeterminate 
or discordant KRAS G12C results necessary before 
requiring central mutation detection prior to enrollment. 
• 
Updated Section 7.5.1.1 for PK sampling if dose 
modification. 
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Document 
Version Date 
Summary of Changes 
• 
Updated Section 8.4.2 Reporting Requirements. 
• 
Updated minor errors in the text of the document. 
Amendment 5, 
Version 6.0 
19 December 2022 
• 
Removed requirement of live (on-study) central 
confirmation of local KRAS mutation and discordance ICF 
• 
Clarified that stratification of sequential versus concurrent 
prior treatment is based on the administration of the last 
prior platinum-based chemotherapy and anti-PD-1/PD-L1 
antibody. 
• 
Specified that in UK and Germany, screening pregnancy 
test required ≤ 7 days and <72 hours before first dose of 
study treatment. 
• 
Clarified that patients enrolled at sites in Germany will not 
undergo tumor lesion biopsy after the Screening period. 
• 
Clarified that if MRTX849 has been held or discontinued 
for ≥ 3 days, unscheduled PK collections are not required. 
• 
Clarified exclusion criterion #2 for active brain metastases 
• 
Added an exception for hemoglobin and transfusion of red 
blood cells in the inclusion criteria for crossover treatment. 
• 
Updated guidance on diarrhea management and the use of 
loperamide as concomitant medication in Section 5.9.1 and 
Appendix 2. 
• 
Clarified Table 15 glucose chemistry as non-fasted 
preferred  
• 
Removed requirement to perform fractionation in patients 
who have abnormal creatine kinase laboratory results.  
• 
Allow urea to be tested when blood urea nitrogen is not 
available to be tested. 
• 
Updated minor errors in the text of the document. 
• 
Clarified Exclusion Criteria #9 to refer to Appendix 3 for 
medications to be avoided with docetaxel (strong CYP3A4 
inhibitors). 
• 
Added footnote to Table 2 and Appendix 6 to allow 
patients on MRTX849 for at least 12 months, whom the PI 
believes are clinically stable on current dose regimen, to 
reduce frequency of clinic visits from every cycle to every 
other cycle (ie, Day 1 visits required every 6 weeks vs. 3 
weeks). 
• 
Updated the primary and secondary endpoints to dual 
primary endpoints (PFS and OS). Updated statistical 
considerations and sample size estimates, increased the 
sample size to 589.  
• 
Updated crossover design to allow only upon positive PFS 
readout for patients enrolled in version 6.0 or later 
• 
Revised secondary PK endpoint for accuracy. 
Characterization of metabolites was removed because 
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Document 
Version Date 
Summary of Changes 
human Absorption, Metabolism and Excretion study 
showed no major pharmacologically active metabolites 
associated with MRTX849 PK. 
• 
Updated Exclusion #8, Nonclinical PK and metabolism 
data (Section 1.3.3) Concomitant medications 
(Section 5.9.1) and Appendix 2 impacted by updated PK 
data 
• 
Updated KRAS G12C tumor mutation and the 
documentation of disease progression (Section 7.1 and 
Section 7.2, respectively) to clarify the testing of tumor 
samples and CRF requirements for radiographic evaluation 
for disease progression determination following platinum-
based chemotherapy and checkpoint inhibitor therapy. 
• 
Clarified Table 2 footnote 15 Docetaxel Administration 
that patients who are pending crossover should continue to 
send in imaging to BICR and collect EOT information but 
not complete EOT visit nor enter into long-term follow-up. 
Amendment 6, 
Version 7.0 
24 March 2023 
• 
Updated the primary and secondary endpoints making PFS 
a single primary endpoint and Overall Survival a secondary 
endpoint. Updated statistical considerations and sample 
size estimates, decreased the sample size to 450.  
• 
Clarified that disease assessments should continue to be 
sent to BICR until BICR confirms disease progression in 
patients treated beyond Investigator assessed (local) 
progression. 
• 
Reverted crossover design to Version 5.0 which allows 
crossover for patients in the comparator arm (docetaxel) 
who experience disease progression as defined by RECIST 
1.1 by blinded independent central review to receive 
MRTX849 and meet all other crossover criteria. 
• 
Updated Exclusion Criteria #8 to align with new 
concomitant medication guidance. 
• 
In Section 5.8 Clarified options if locally assessed PD but 
not confirmed by BICR for patients on docetaxel. 
• 
Updated guidance on the use of concomitant medication in 
Section 5.9.1 and Appendix 2. 
• 
Exempted patients enrolled at sites in Germany from the 
optional tumor lesion biopsy at the time of disease 
progression or prolonged stable disease. 
• 
Changed guidance for sites in Germany to require 
immediate (without undue delay) SAE reporting to the 
Sponsor. 
• 
Added baseline characteristics for subgroup analyses in 
Section 9.4.8. 
 
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