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

Year: 2024

Type: article

Abstract: Introduction The predictive and prognostic implications of different KRAS mutation ( KRAS m) subtypes in metastatic NSCLC have not been clearly defined. We used a nationwide observational database to investigate whether KRAS m subtypes differ in their association with survival in metastatic NSCLC treated with immune checkpoint inhibitor (ICI)-based therapy, across programmed death-ligand 1 (PD-L1) levels. Methods Patients with advanced nonsquamous NSCLC who initiated first-line ICI-based therapy from 2016 to 2021 and had known PD-L1 expression and comprehensive genomic profiling including KRAS , STK11 , KEAP1 , and TP53 were included. Within PD-L1 expression subgroups (<1%, 1%–49%, ≥50%), Cox multivariable regression was used to evaluate the association between KRAS m subtypes (G12C, G12V, G12D, other KRAS m) and overall survival, estimated using Kaplan-Meier methodology. Results Among the 1539 patients, 819 patients were KRAS wild type ( KRAS wt) and 720 were KRAS m (296 KRAS G12C, 143 KRAS G12V, 97 KRAS G12D, 184 other KRAS m). In the 50% or higher PD-L1 subgroup, patients with KRAS G12V had worse survival (median overall survival [mOS] = 8.2 mo) compared with KRAS wt (mOS = 13.3 mo) and other KRAS subgroups (mOS ranging from 13.4 to 19.9 mo). On adjusted Cox multivariable regression in the 50% or higher PD-L1 subgroup, the hazard ratio for death for KRAS G12V ranged from 1.53 to 1.78 compared with KRAS wt and other KRAS m subtypes (all p < 0.05). Conclusions Although patients with 50% or higher PD-L1 with KRAS G12C, G12D, and other subtypes exhibited similar survival to KRAS wt, KRAS G12V was associated with significantly worse survival than KRAS wt and other KRAS m subtypes. All KRAS m should not be regarded as uniform predictors of ICI responsiveness, even with high PD-L1 expression; KRAS G12V tumors may have worse outcomes with ICI-based therapy and benefit from treatment intensification.

Source: JTO Clinical and Research Reports

DOI: 10.1016/j.jtocrr.2024.100755

Authors: Lova Sun, Yunyun Zhou, Elizabeth A. Handorf, Hossein Borghaei, Jessica Bauman, Charu Aggarwal

Institutions: University of Pennsylvania, Fox Chase Cancer Center

Language: English

Topic: Lung Cancer Treatments and Mutations

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,000