Krascendo-170 Lung: A phase Ib/II study of divarasib + pembrolizumab ± platinum-based chemotherapy and pemetrexed in untreated KRAS G12C+advanced non-small cell lung cancer (NSCLC)

Abstract

Background: The KRAS G12C mutation, present in ~12% of NSCLC patients, drives oncogenic signaling and cancer formation and is associated with poor prognosis. The current first-line treatment for advanced KRAS G12C+ NSCLC is checkpoint inhibitor (CPI) 6 chemotherapy (CT). Novel combinations using a more targeted, biomarker-directed approach are supported by pre-clinical evidence and may further improve outcomes. Divarasib is an oral KRAS G12C inhibitor with potent pre-clinical and clinical anti-tumor activity. We hypothesize that divarasib + CPI 6 CT may improve outcomes for patients with KRAS G12C+ NSCLC. Methods: Krascendo-170 Lung (NCT05789082) is a phase Ib/II, open-label study evaluating the safety and activity of divarasib + pembrolizumab in patients with PD-L1 tumor cell expression $1% (Cohort A) and of divarasib + pembrolizumab with platinum-based CT and pemetrexed in patients with any PD-L1 tumor cell expression level (Cohort B). Patients must be $18 years old with untreated unresectable/ metastatic non-squamous NSCLC (measurable per RECIST v1.1), a confirmed KRASG12C mutation , and an Eastern Cooperative Oncology Group performance status 0/1. Each cohort will have two stages: divarasib combination dose finding and dose expansion, with two planned dose levels of divarasib (Table). Tumor assessments will be performed at baseline and every 6 weeks for 48 weeks, then every 9 weeks thereafter. Plasma samples will be taken at various timepoints before and after divarasib and pembrolizumab dosing to characterize pharmaco-kinetics. Patients will be treated until disease progression per RECIST v1.1 or unacceptable toxicity. The co-primary endpoints are adverse events and change from baseline in targeted safety parameters. Key secondary endpoints include objective response rate, progression-free survival and duration of response (all investigator assessed per RECIST v1.1). Enrollment into the combination dose finding stage of Cohort A has been completed without dose-limiting toxicities and enrollment into the dose expansion stage is continuing. Clinical trial information: NCT05789082. Research Sponsor: F. Hoffmann-La Roche Ltd.