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Divarasib plus pembrolizumab versus pembrolizumab with pemetrexed and platinum chemotherapy for first-line KRAS G12C advanced non-squamous non-small cell lung cancer

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

Phase 3 Interventional Hoffmann-La Roche · NCT06793215

This trial tests whether adding divarasib to pembrolizumab works better than standard pembrolizumab with pemetrexed plus carboplatin or cisplatin for adults with untreated, KRAS G12C-mutant advanced non-squamous non-small cell lung cancer.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment600 (estimated)
Ages18 Years and up
SexAll
SponsorHoffmann-La Roche Industry-sponsored
Drugs / interventionschemotherapy, radiation, pembrolizumab
Locations240 sites (Anchorage, Alaska and 239 other locations)
Trial IDNCT06793215 on ClinicalTrials.gov

What this trial studies

This randomized Phase 3 trial enrolls adults with previously untreated, measurable, advanced or metastatic non-squamous NSCLC carrying a KRAS G12C mutation and an ECOG performance status of 0–1. Participants are randomized to receive divarasib with the PD-1 inhibitor pembrolizumab or the standard first-line regimen of pembrolizumab combined with pemetrexed and a platinum agent (carboplatin or cisplatin). Key requirements include documented KRAS G12C mutation, known PD-L1 status, available tumor tissue, and adequate organ function. Tumor response is monitored by imaging per RECIST v1.1 and safety and efficacy endpoints are compared between arms.

Who should consider this trial

Good fit: Ideal candidates are adults with previously untreated, advanced or metastatic non-squamous NSCLC harboring a KRAS G12C mutation, ECOG 0–1, measurable disease, known PD-L1 status, and who are eligible to receive platinum-based chemotherapy.

Not a fit: Patients unlikely to benefit include those with other actionable oncogenic drivers, symptomatic untreated CNS metastases, prior systemic therapy for advanced disease, poor performance status, or contraindications to immunotherapy or the study drugs.

Why it matters

Potential benefit: If successful, the combination could improve response rates and survival compared with current first-line therapy and might provide a more targeted option for patients with KRAS G12C mutations.

How similar studies have performed: KRAS G12C inhibitors have shown benefit in later-line settings and pembrolizumab with pemetrexed plus platinum is an established first-line standard, but combining KRAS G12C targeted therapy with immunotherapy in first-line is experimental with limited early-phase data.

Eligibility criteria

Show full inclusion / exclusion criteria 
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

Where this trial is running

Anchorage, Alaska and 239 other locations

+190 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Non-Small Cell Lung CancerKRAS G12C Lung CancerAdvanced Non-Small Cell Lung CancerKRAS G12 Lung CancerAdvanced Lung CancerMetastatic lung cancerDivarasibKRAS G12C Inhibitor
Last reviewed 2026-06-14 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.