Outcomes of Combination Platinum-Doublet Chemotherapy and Anti-PD(L)-1 Blockade in KRAS(G12C)-Mutant Non-Small Cell Lung Cancer

BACKGROUND: Direct KRAS(G12C) inhibitors are approved for patients with non-small cell lung cancers (NSCLC) in the second-line setting. The standard-of-care for initial treatment remains immune checkpoint inhibitors, commonly in combination with platinum-doublet chemotherapy (chemo-immunotherapy). Outcomes to chemo-immunotherapy in this subgroup have not been well described. Our goal was to define the clinical outcomes to chemo-immunotherapy in patients with NSCLC with KRAS(G12C) mutations. PATIENTS AND METHODS: Through next-generation sequencing, we identified patients with advanced NSCLC with KRAS mutations treated with chemo-immunotherapy at 2 institutions. The primary objective was to determine outcomes and determinants of response to first-line chemo-immunotherapy among patients with KRAS(G12C) by evaluating objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). We assessed the impact of coalterations in STK11/KEAP1 on outcomes. As an exploratory objective, we compared the outcomes to chemo-immunotherapy in KRAS(G12C) versus non-G12C groups. RESULTS: One hundred and thirty eight patients with KRAS(G12C) treated with first-line chemo-immunotherapy were included. ORR was 41% (95% confidence interval (CI), 32-41), median PFS was 6.8 months (95%CI, 5.5-10), and median OS was 15 months (95%CI, 11-28). In a multivariable model for PFS, older age (P = .042), squamous cell histology (P = .008), poor ECOG performance status (PS) (P < .001), and comutations in KEAP1 and STK11 (KEAP1(MUT)/STK11(MUT)) (P = .015) were associated with worse PFS. In a multivariable model for OS, poor ECOG PS (P = .004) and KEAP1(MUT)/STK11(MUT) (P = .009) were associated with worse OS. Patients with KRAS(G12C) (N = 138) experienced similar outcomes to chemo-immunotherapy compared to patients with non-KRAS(G12C) (N = 185) for both PFS (P = .2) and OS (P = .053). CONCLUSIONS: We define the outcomes to first-line chemo-immunotherapy in patients with KRAS(G12C), which provides a real-world benchmark for clinical trial design involving patients with KRAS(G12C) mutations. Outcomes are poor in patients with specific molecular coalterations, highlighting the need to develop more effective frontline therapies.