Efficacy and Safety of Divarasib and Pembrolizumab vs. Pembrolizumab with Pemetrexed and Carboplatin or Cisplatin in KRAS G12C-Mutated NSCLC

The primary objective of this study is to evaluate the efficacy of divarasib and pembrolizumab compared to pembrolizumab combined with pemetrexed and either carboplatin or cisplatin in patients with previously untreated, KRAS G12C-mutated, advanced or metastatic non-small cell lung cancer. Efficacy is assessed based on progression-free survival and overall survival. 5

Secondary objectives include the assessment of:

• Confirmed objective response.
• Duration of response.
• Safety and tolerability.
• Health-related quality of life, symptoms, and functioning from the participant's perspective.

The study population consists of 318 participants diagnosed with non-squamous non-small cell lung cancer that is advanced or metastatic and ineligible for curative surgery or definitive chemoradiotherapy. The cohort includes both male and female patients within the age ranges of 18-44 and 45-64 years. Inclusion requires documentation of a KRAS G12C mutation through central laboratory testing or preexisting results. Participants must exhibit an Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy of at least 12 weeks, and measurable disease according to RECIST v1.1. Individuals must have received no prior systemic treatment for their condition.

This Phase III, randomized, open-label study is designed to evaluate the efficacy and safety of divarasib and pembrolizumab compared to pemetrexed and carboplatin or cisplatin plus pembrolizumab. The research focuses on patients with previously untreated, KRAS G12C-mutated, advanced or metastatic non-small cell lung cancer. The primary endpoints are progression-free survival and overall survival. The trial is expected to continue through December 2030. The methodology includes a screening visit to confirm measurable disease, ECOG performance status, and the presence of the specific genetic mutation via central laboratory testing or preexisting results. Following randomization, participants will undergo treatment and subsequent follow-up visits to monitor objective response, duration of response, and potential adverse events. Assessment of quality of life and symptomatic toxicities will be conducted throughout the study duration. Early termination from the study may occur based on predefined clinical criteria or participant withdrawal.

Divarasib is an experimental medication administered as a film-coated tablet via the oral route.

Pembrolizumab is an experimental medication administered as a solution for infusion via intravenous infusion.

Carboplatin is a comparator treatment administered as a solution for infusion via intravenous infusion.

Pemetrexed is a comparator treatment administered as a solution for infusion via intravenous infusion.

Cisplatin is a comparator treatment administered as a solution for infusion via intravenous infusion or intravenous injection.

Budesonide is an auxiliary medication administered as a gastro-resistant hard capsule via the oral route.

The efficacy of the investigational combination will be evaluated using several primary and secondary endpoints. The primary endpoints consist of progression-free survival, defined as the interval from randomization to disease progression as determined by blinded independent central review (BICR) according to RECIST v1.1 or death from any cause, and overall survival, defined as the time from randomization to death from any cause.

Secondary efficacy assessments include:

• Confirmed objective response, defined as complete response or partial response on two consecutive occasions at least 4 weeks apart, assessed by BICR per RECIST v1.1.
• Duration of response, defined as the time from the first documented objective response to disease progression or death.
• Changes from baseline in quality of life and functional status, measured using the EORTC QLQ-C30 and EORTC QLQ-LC13 scales. Specific assessments include the cough item, dyspnea item, and physical functioning scale.
• Evaluation of treatment-related symptomatic toxicities and their interference with daily function using the NCI PRO-CTCAE and the EORTC Item List 46.
• Changes from baseline in selected vital signs, ECG parameters, and clinical laboratory test results.