A Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Participants With Previously Untreated, KRAS G12C-Mutated, Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer

Phase 3

Not yet recruiting

• Conditions: Non-Small Cell Lung Cancer; KRAS G12C Lung Cancer
• Interventions: Drug: Divarasib; Drug: Pembrolizumab; Drug: Pemetrexed; Drug: Carboplatin; Drug: Cisplatin

• Registration Number: NCT06793215
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of divarasib and pembrolizumab compared with pembrolizumab and pemetrexed and carboplatin or cisplatin, for the first-line treatment of adult participants with KRAS G12C-mutated, advanced or metastatic non squamous non-small cell lung cancer (NSCLC).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-01-20
• Study First Submitted QC: 2025-01-20
• Study First Posted: 2025-01-27
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-14
• Last Update Posted: 2025-05-15
• Study Start: 2025-12-01
• Primary Completion: 2028-11-30
• Study Completion: 2030-10-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 600

Inclusion Criteria

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Histologically or cytologically confirmed diagnosis of advanced or metastatic non squamous NSCLC that is not eligible for curative surgery and/or definitive chemoradiotherapy
• Measurable disease, as defined by RECIST v1.1
• No prior systemic treatment for advanced or metastatic NSCLC
• Documentation of the presence of a KRAS G12C mutation
• Documentation of known PD-L1 expression status in tumor tissue
• Availability of a representative tumor specimen
• Adequate end-organ function
• Eligible to receive a platinum-based chemotherapy regimen

Exclusion Criteria Related to NSCLC:

• Known concomitant second oncogenic driver with available targeted treatment
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
• Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for >=2 weeks prior to randomization
• History of leptomeningeal disease
• Uncontrolled tumor-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once a month or more frequently)

Exclusion Criteria Related to Current or Prior Treatments:

• Any anti-cancer systemic therapy, including hormonal therapy, within 21 days prior to randomization, or is expected to require any other form of antineoplastic therapy while in the study
• Radiation therapy including palliative RT to bone metastases within 2 weeks prior to randomization and RT to the lung >30Gy within 6 months prior to randomization
• Prior treatment with KRAS G12C inhibitors or pan-KRAS/RAS inhibitors
• Treatment with systemic immunosuppressive or immunostimulatory medications, including CD137 agonists and immune checkpoint inhibitors
• Current treatment with medications that are well known to prolong the QT interval
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to randomization
• Prior allogeneic stem cell or solid organ transplantation

Exclusion Criteria Related to General Health:

• History of malignancy other than NSCLC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival [OS] rate >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
• Individuals with chronic diarrhea, short bowel syndrome or significant upper gastrointestinal surgery including gastric resection, a history of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) or any active bowel inflammation (including diverticulitis), malabsorption syndrome, conditions that would interfere with enteral absorption
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on the screening chest computed tomography scan
• Significant cardiovascular disease within 3 months prior to screening

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Divarasib + Pembrolizumab	Divarasib	Participants will receive divarasib orally, once daily (QD) and pembrolizumab via intravenous (IV) infusion every 3 weeks (Q3W)
Divarasib + Pembrolizumab	Pembrolizumab	Participants will receive divarasib orally, once daily (QD) and pembrolizumab via intravenous (IV) infusion every 3 weeks (Q3W)
Pembrolizumab + Pemetrexed + Carboplatin or Cisplatin	Pembrolizumab	Participants will receive pembrolizumab, pemetrexed and carboplatin or cisplatin via IV infusion Q3W
Pembrolizumab + Pemetrexed + Carboplatin or Cisplatin	Pemetrexed	Participants will receive pembrolizumab, pemetrexed and carboplatin or cisplatin via IV infusion Q3W
Pembrolizumab + Pemetrexed + Carboplatin or Cisplatin	Carboplatin	Participants will receive pembrolizumab, pemetrexed and carboplatin or cisplatin via IV infusion Q3W
Pembrolizumab + Pemetrexed + Carboplatin or Cisplatin	Cisplatin	Participants will receive pembrolizumab, pemetrexed and carboplatin or cisplatin via IV infusion Q3W

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS)	Up to approximately 5 years	PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by blinded independent central review (BICR) according to RECIST v1.1, or death from any cause (whichever occurs first)
Overall Survival (OS)	Up to approximately 5 years	OS is defined as the time from randomization to death from any cause

Secondary Outcome Measures

Name	Time	Method
Frequency of Participants' Response of the Degree they are Troubled with Treatment Symptoms, as Assessed Through use of the single-item EORTC Item List (IL46)	Up to approximately 5 years
Change from Baseline on the EORTC QLQ-C30 and QLQ-LC13 Functional and Global Health Status Score/Quality of Life Score (GHS/QoL)	Up to approximately 5 years
Number of Participants Reporting Presence, Frequency, Severity, and/or Degree of Interference with Daily Function of Symptomatic Treatment Toxicities Assessed by NCI Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE)	Up to approximately 5 years
Change from Baseline in the Severity of Selected Symptomatic Treatment Toxicities as Assessed Through use of the NCI PRO-CTCAE	Up to approximately 5 years
Objective Response	Up to approximately 5 years	Objective response is defined as complete response (CR) or partial response (PR) on two consecutive occasions \>=4 weeks apart, as determined by BICR according to RECIST v1.1
Change from Baseline on the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Supplemental Lung Cancer Module (EORTC QLQ-LC13) Cough Scale	Baseline up to Cycle 5 Day 1 (each cycle is 21 days)
Change from Baseline on the EORTC Quality of Life Questionnaire (QLQ-C30) Dyspnea Item and Physical Functioning Scale	Baseline up to Cycle 5 Day 1 (each cycle is 21 days)
Duration of Response (DOR)	Up to approximately 5 years	DOR is defined as the time from the first occurrence of a documented objective response to disease progression, as determined by BICR according to RECIST v1.1, or death from any cause (whichever occurs first)
Percentage of Participants with Adverse Events (AEs)	Up to approximately 5 years