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RecruitingInterventionalPhase 3

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

NCT ID: NCT06793215Sponsor: Hoffmann-La RocheLast updated: 2026-06-09

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).

Arms & interventions

  • DrugDivarasib

    Divarasib will be administered orally QD

  • DrugPembrolizumab

    Pembrolizumab will be administered via IV infusion Q3W

  • DrugPemetrexed

    Pemetrexed will be administered via IV infusion Q3W

  • DrugCarboplatin

    Carboplatin will be administered via IV infusion Q3W

  • DrugCisplatin

    Cisplatin will be administered via IV infusion Q3W

Outcome measures

Primary

  • Progression-Free Survival (PFS)

    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)

    Time frame: Up to approximately 5 years

  • Overall Survival (OS)

    OS is defined as the time from randomization to death from any cause

    Time frame: Up to approximately 5 years

Secondary

  • Objective Response

    Time frame: Up to approximately 5 years

  • 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

    Time frame: 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

    Time frame: Baseline up to Cycle 5 Day 1 (each cycle is 21 days)

  • Duration of Response (DOR)

    Time frame: Up to approximately 5 years

  • Percentage of Participants with Adverse Events (AEs)

    Time frame: 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)

    Time frame: 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

    Time frame: Up to approximately 5 years

  • 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)

    Time frame: 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)

    Time frame: Up to approximately 5 years

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No
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

Study locations (50)

Alaska Oncology and Hematology

Anchorage, Alaska, 99508

Recruiting

City of Hope - Phoenix

Goodyear, Arizona, 85338

Recruiting

Marin Cancer Care Inc

Greenbrae, California, 94904

Recruiting

Hoag Memorial Hospital

Newport Beach, California, 92658

Recruiting

Palo Alto Medical Foundation Research Center

Palo Alto, California, 94301

Recruiting

Sutter Institute for Medical Research

Roseville, California, 95661

Recruiting

California Pacific Medical Center

San Francisco, California, 94115

Recruiting

UC Health Oncology Research

Colorado Springs, Colorado, 80909

Recruiting

Poudre Valley Health Care, Inc. d/b/a Poudre Valley Health System

Fort Collins, Colorado, 80528

Recruiting

Hartford Hospital

Hartford, Connecticut, 06102-5037

Recruiting

Florida Cancer Specialists - SOUTH - SCRI - PPDS

Fort Myers, Florida, 33901-8108

Recruiting

University of Florida Health at Shands

Gainesville, Florida, 32610

Recruiting

BioResearch Partner

Hialeah, Florida, 33013

Recruiting

Memorial Healthcare System - Memorial Regional Hospital

Hollywood, Florida, 33021

Recruiting

Sylvester Comprehensive Cancer Center

Miami, Florida, 33136

Recruiting

Ascension Sacred Heart

Pensacola, Florida, 32504

Recruiting

Florida Cancer Specialists - NORTH - SCRI - PPDS

St. Petersburg, Florida, 33701

Recruiting

Florida Cancer Specialists - EAST - SCRI - PPDS

West Palm Beach, Florida, 33401-3406

Recruiting

Piedmont Cancer Institute, PC

Atlanta, Georgia, 30318

Recruiting

City of Hope® Atlanta

Newnan, Georgia, 30265

Recruiting

Summit Cancer Care PC

Savannah, Georgia, 31405

Recruiting

St. Luke's Cancer Institute

Boise, Idaho, 83712

Recruiting

Affiliated Oncologists, LLC

Chicago Ridge, Illinois, 60415

Recruiting

Hope and Healing Cancer Services

Hinsdale, Illinois, 60521

Withdrawn

City of Hope® Cancer Center Chicago

Zion, Illinois, 60099

Recruiting

Mission Cancer + Blood - IMMC

Des Moines, Iowa, 50309

Recruiting

University of Iowa

Iowa City, Iowa, 52242

Recruiting

Saint Agnes Hospital - Baltimore - Hunt - PPDS

Baltimore, Maryland, 21229-5201

Recruiting

Massachusetts General Hospital

Boston, Massachusetts, 02114

Recruiting

Profound Research, LLC

Farmington Hills, Michigan, 48334

Recruiting

Missouri Baptist Medical Center

St Louis, Missouri, 63131

Recruiting

NHO Revive Research Institute

Lincoln, Nebraska, 68506

Recruiting

San Juan Oncology Associates

Farmington, New Mexico, 87401

Recruiting

Montefiore Einstein Cancer Center

The Bronx, New York, 10461

Recruiting

Clinical Research Alliance

Westbury, New York, 11590

Recruiting

Firsthealth of The Carolinas

Pinehurst, North Carolina, 28374

Recruiting

Ohio State University

Columbus, Ohio, 43210

Recruiting

Oregon Health and Science University

Portland, Oregon, 97239

Recruiting

St. Luke's University Health Network

Bethlehem, Pennsylvania, 18015

Recruiting

Allegheny Cancer Center

Pittsburgh, Pennsylvania, 15212

Recruiting

Reading Hospital - McGlinn Cancer Institute

West Reading, Pennsylvania, 19611

Recruiting

Baptist Cancer Center

Memphis, Tennessee, 38120

Recruiting

Renovatio Clinical - El Paso

El Paso, Texas, 79915

Recruiting

JPS Health Network

Fort Worth, Texas, 76104

Recruiting

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030-4000

Recruiting

Community Clinical Trials

Kingwood, Texas, 77339

Recruiting

Texas Tech Health Science Center

Lubbock, Texas, 79415

Recruiting

Renovatio Clinical

The Woodlands, Texas, 77380

Recruiting

University of Texas Health Center at Tyler

Tyler, Texas, 75708

Recruiting

Virginia Oncology Associates

Norfolk, Virginia, 23502

Recruiting