Outcomes Following First-Line Immune Checkpoint Inhibitors With or Without Chemotherapy Stratified by KRAS Mutational Status-A Real-World Analysis in Patients With Advanced NSCLC

Abstract

Introduction: Prior studies evaluating the efficacy of first line (1 L) immune checkpoint inhibitor (ICI) monotherapy or combined chemoimmunotherapy in advanced NSCLC found improved outcomes with chemoimmunotherapy independent of PD-L1 and KRAS mutation status. As such, combined chemoimmunotherapy was proposed as the preferred comparator arm for 1 L trials in KRAS mutated (KRAS mt) NSCLC. Herein, we report a multimodal, real world data (RWD) analysis for outcomes with 1 L therapy in patients with advanced NSCLC stratified by KRAS mutation status and PD-L1 levels.

Patients and methods: Deidentified, multimodal RWD from the Tempus database was utilized to retrospectively analyze 1980 patients with advanced NSCLC receiving 1 L ICI containing therapy. Patients were stratified by tumor KRAS mutational status. Subgroup analyses were performed using Cox model stratified by KRAS mutational status, PD-L1 levels, and the presence of pathogenic alterations in STK11, KEAP1 and TP53.

Results: KRAS mutations were identified in 33.4% (662/1980) of patients. There was a higher proportion of PD-L1 high tumors in the KRASmt to KRAS wild-type cohort. Among KRASmt NSCLC, median overall survival (mOS) was longest in the PD-L1 high cohort. Patients with KRAS G12C and PD-L1 high tumors had the longest mOS at 30.28 months. Finally, pathogenic mutations in KEAP1 and STK11 correlated with worse outcomes in KRASmt tumors.

Conclusions: Outcomes following 1 L therapy in KRASmt advanced NSCLC varied based on PD-L1 levels and the presence of STK11 and KEAP1 co-mutations, indicating that KRASm NSCLC represents a heterogeneous disease.

Keywords: Immunotherapy; KEAP1; PD-L1; STK11; TP53.