Brief Report: Not Created Equal: Survival Differences by KRAS Mutation Subtype in NSCLC Treated With Immunotherapy

Area of Science:

• Oncology
• Genetics
• Immunotherapy

Background:

• The prognostic and predictive value of KRAS mutation (KRASm) subtypes in metastatic non-small cell lung cancer (NSCLC) remains unclear.
• Immune checkpoint inhibitor (ICI)-based therapies are standard treatments for advanced NSCLC, but response varies significantly among patients.

Purpose of the Study:

• To investigate whether KRASm subtypes differentially impact survival in metastatic NSCLC patients receiving ICI-based therapy.
• To analyze these differences across varying levels of programmed death-ligand 1 (PD-L1) expression.

Main Methods:

• A nationwide observational study included advanced nonsquamous NSCLC patients receiving first-line ICI-based therapy (2016-2021).
• Patients had known PD-L1 expression and comprehensive genomic profiling, including KRAS, STK11, KEAP1, and TP53.
• Cox multivariable regression and Kaplan-Meier methods assessed the association between KRASm subtypes (G12C, G12V, G12D, other) and overall survival within PD-L1 subgroups (<1%, 1%-49%, ≥50%).

Main Results:

• Among 1539 patients, 720 had KRASm (296 G12C, 143 G12V, 97 G12D, 184 other).
• In the PD-L1 ≥50% subgroup, KRAS G12V patients showed significantly worse overall survival (median OS = 8.2 months) compared to KRAS wild type (mOS = 13.3 months) and other KRASm subtypes (mOS = 13.4–19.9 months).
• Adjusted analysis confirmed KRAS G12V was associated with a 1.53–1.78 fold increased hazard of death compared to KRAS wild type and other KRASm subtypes (p < 0.05).

Conclusions:

• KRASm subtypes are not uniform predictors of ICI response, even in high PD-L1 expressing NSCLC.
• KRAS G12V tumors are associated with worse outcomes in ICI-based therapy and may benefit from treatment intensification.
• These findings highlight the importance of specific KRAS mutation subtyping for personalized NSCLC treatment strategies.