Outcomes of Combination Platinum-Doublet Chemotherapy and Anti-PD-1 Blockade in [KRAS.sup.G12C]-Mutant Non-Small Cell Lung Cancer

Background: Direct [KRAS.sup.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.sup.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.sup.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.sup.G12C] versus non-G12C groups. Results: One hundred and thirty eight patients with [KRAS.sup.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 ([KEAP.sup.1MUT]/[STK11.sup.MUT]) (P = .015) were associated with worse PFS. In a multivariable model for OS, poor ECOG PS (P = .004) and [KEAP.sup.1MUT]/[STK11.sup.MUT] (P = .009) were associated with worse OS. Patients with [KRAS.sup.G12C] (N = 138) experienced similar outcomes to chemoimmunotherapy compared to patients with non-[KRAS.sup.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.sup.G12C], which provides a real-world benchmark for clinical trial design involving patients with [KRAS.sup.G12C] mutations. Outcomes are poor in patients with specific molecular coalterations, highlighting the need to develop more effective frontline therapies. Key words: non-small cell lung cancer; [KRAS.sup.G12C]; combination therapy; chemotherapy; immunotherapy.