P3.12D.07 Divarasib Versus Adagrasib or Sotorasib in Pretreated KRAS G12C+ Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

Document Type

Conference Proceeding

Publication Date

10-1-2024

Publication Title

J Thorac Oncol

Abstract

Introduction: KRAS G12C mutations occur in approximately 12% of patients with NSCLC. Patients with advanced/metastatic KRAS G12C+ NSCLC who have previously received standard-of-care therapies (platinum-based chemotherapy, immunotherapy, or a combination of both) have a poor prognosis. Adagrasib and sotorasib are oral, selective KRAS G12C inhibitors with accelerated FDA and conditional EMA approvals for the treatment of patients with previously treated advanced/metastatic KRAS G12C+ NSCLC. However, an unmet need remains for more effective treatments with acceptable safety and tolerability profiles to improve patient outcomes. Divarasib is an oral, selective, KRAS G12C inhibitor previously shown to be 5-20 times as potent and ≤50 times as selective for KRAS G12C in vitro as adagrasib and sotorasib. Divarasib monotherapy (≤400mg once daily [QD]) previously demonstrated encouraging antitumor activity and an acceptable safety profile in patients with advanced/metastatic KRAS G12C+ solid tumors, including NSCLC (confirmed objective response rate [ORR]: 56.4%, 95% CI 39.6-72.2; progression-free survival [PFS]: 13.7 months, 95% CI 8.1-not estimable, in patients with NSCLC; 400mg dose). The observed adverse events were mostly low grade, manageable, and reversible. The phase 3 trial presented here will evaluate the efficacy and safety of divarasib versus adagrasib or sotorasib in patients with previously treated KRAS G12C+ advanced/metastatic NSCLC. Methods: This phase 3, randomized, active control, open-label multicenter study (EudraCT: 2024-510908-37-00) will enroll patients aged ≥18 years with histologically/cytologically confirmed, unresectable, advanced/metastatic (stage IIIC or IV) NSCLC harboring a KRAS G12C mutation (Figure). Patients must have experienced disease progression on ≥1 prior systemic therapy in the metastatic setting, have measurable disease per RECIST v1.1, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1. Prior KRAS inhibitor therapy is not permitted. Patients will be randomized 1:1 to receive divarasib or either adagrasib or sotorasib (based on local approval status and investigator’s choice) until disease progression, intolerable adverse events, consent withdrawal, death, or study termination. Tumor assessments will occur at screening, every six weeks for the initial 48 weeks, and every nine weeks thereafter. The primary endpoint is PFS per RECIST v1.1. Secondary endpoints include: overall survival; patient-reported outcomes (time to confirmed deterioration of cough [EORTC QLQ-LC13], dyspnea, or physical functioning [both EORTC QLQ-C30]); ORR and duration of response per RECIST v1.1; and safety. [Formula presented] Keywords: Advanced NSCLC, Divarasib, KRAS G12C+ NSCLC

Volume

19

Issue

10

First Page

S349

Find It @ Sladen

Share

COinS