A Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib in Combination With Other Anti-Cancer Therapies in Participants With Previously Untreated Advanced or Metastatic Non-Small Cell Lung Cancer With a KRAS G12C Mutation

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, pharmacokinetics (PK), and activity of divarasib combined with other anti-cancer therapies in participants with previously untreated, advanced or metastatic non-small cell lung cancer (NSCLC).

Official Title
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A Phase Ib/II, Open-Label, Multicenter Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib in Combination With Other Anti-Cancer Therapies in Patients With Previously Untreated Advanced Or Metastatic Non-Small Cell Lung Cancer With a KRAS G12C Mutation

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Divarasib
* Drug: Pembrolizumab
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmation of Biomarker eligibility Pre-treatment tumor tissue along with an associated pathology report is required for all participants enrolled on study. Representative tumor specimens must be in formalin-fixed, paraffin embedded (FFPE) blocks (preferred) or 15 unstained, freshly cut, serial slides. Although 15 slides are required, if only 10 slides are available, the participant may be eligible for the study following consultation with the Sponsor. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 Histologically or cytologically documented locally advanced unresectable or metastatic NSCLC that is not eligible for curative surgery and/or definitive chemoradiotherapy No prior systemic treatment for advanced unresectable or metastatic NSCLC Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Exclusion Criteria: Known concomitant second oncogenic driver with available targeted treatment Squamous cell histology NSCLC Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases Prior treatment with a KRAS G12C inhibitor Known hypersensitivity to any of the components of divarasib or pembrolizumab; or known hypersensitivity to pemetrexed, carboplatin, or cisplatin (Cohort B only) History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis, active tuberculosis, significant cardiovascular disease within 3 months prior to initiation of study treatment History of malignancy other than NSCLC within 5 years prior to initiation of study treatment, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate more >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal breast carcinoma in situ, or Stage I uterine cancer Uncontrolled tumor related pain, pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures, uncontrolled or symptomatic hypercalcemia

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A - Combination Dose Finding + Dose Expansion<br>Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) once a day (QD) combined with pembrolizumab 200 mg intravenous (IV) infusion every 3 weeks (Q3W). During the expansion stage, some participants are planned to be randomized to one divarasib combination dose level; other participants are planned to be randomized to another divarasib combination dose level. Divarasib will be given in combination with pembrolizumab. | Drug: Divarasib<br>* Participants will receive one of two doses of divarasib orally (PO), QD on days 1-21 of each 21-day cycle.<br>Drug: Pembrolizumab<br>* Participants will receive a 200 mg IV infusion of pembrolizumab Q3W on Day 1 of each 21-day cycle.<br>|
| Experimental: Cohort B - Combination Dose Finding + Dose Expansion<br>Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed. | Drug: Divarasib<br>* Participants will receive one of two doses of divarasib orally (PO), QD on days 1-21 of each 21-day cycle.<br>Drug: Pembrolizumab<br>* Participants will receive a 200 mg IV infusion of pembrolizumab Q3W on Day 1 of each 21-day cycle.<br>Drug: Carboplatin<br>* Participants will receive IV carboplatin Q3W for four 21-day cycles.<br>Drug: Cisplatin<br>* Participants will receive IV cisplatin Q3W for four 21-day cycles.<br>Drug: Pemetrexed<br>* Participants will receive IV pemetrexed Q3W.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Adverse Events (AEs) |  | Baseline until 60 days after the final dose of study treatment or until initiation of another anti-cancer therapy, whichever occurs first (up to approximately 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | The percentage of participants who experience a complete response or partial response, as determined by the investigator, according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Up to approximately 3 years | 
| Duration of Response (DOR) | The time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1 | Up to approximately 3 years | 
| Progression Free Survival (PFS) | The time from randomization, or date of first treatment for participants enrolled prior to the expansion stage, to the first occurrence of disease progression or death from any cause during the study (whichever occurs first), as determined by the investigator according to RECIST v1.1 | Up to approximately 3 years | 
| Number of Participants Reporting Presence, Frequency, Severity, and/or Degree of Interference with Daily Function of Symptomatic Side Effects as Assessed Through the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) |  | Up to approximately 3 years | 
| Change from Baseline in Symptomatic Side Effects, as Assessed Through use of the PRO-CTCAE |  | Baseline up to approximately 3 years | 
| Percentage of Participants Reporting Frequent or Almost Constant Diarrhea During the First Three Cycles of Treatment According to the PRO-CTCAE Criteria |  | Up to approximately 3 years | 
| Percentage of Participants Reporting Severe or Very Severe Nausea or Vomiting During the First Three Cycles of Treatment According to the PRO-CTCAE |  | Up to approximately 3 years | 
| Frequency of Participant's Response of the Degree they are Troubled with Treatment Symptoms, as Assessed Through use of the Single-item European Organisation for Research and Treatment of Cancer (EORTC) Item List 46 (IL46) |  | Up to approximately 3 years | 
| Plasma Concentration of Divarasib at Specified Timepoints |  | At Days 1, 8 and 15 of Cycles 1 and 2; Days 1 and 15 of Cycles 3 and 4; Day 1 of every other Cycle after Cycle 5, until treatment discontinuation (up to approximately 3 years). Each cycle is 21 days. | 
| Identification of Divarasib Recommended Dose | The recommended dose will be based upon the totality of safety, activity, and PK data. | Up to approximately 3 years |