Outcomes of Combination Platinum-Doublet Chemotherapy and Anti-PD(L)-1 Blockade in KRASG12C-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. This study aimed to define the clinical outcomes of first-line chemo-immunotherapy in patients with non-small cell lung cancer with KRASG12C mutations and to examine the significance of PD-L1 tumor proportion score and comutation status (KEAP1 and STK11) on outcomes. [ABSTRACT FROM AUTHOR]