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

Introduction: The predictive and prognostic implications of different mutation (m) subtypes in metastatic NSCLC have not been clearly defined. We used a nationwide observational database to investigate whether 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 , , , and were included. Within PD-L1 expression subgroups (<1%, 1%-49%, ≥50%), Cox multivariable regression was used to evaluate the association between m subtypes (G12C, G12V, G12D, other m) and overall survival, estimated using Kaplan-Meier methodology.

Results: Among the 1539 patients, 819 patients were wild type (wt) and 720 were m (296 G12C, 143 G12V, 97 G12D, 184 other m). In the 50% or higher PD-L1 subgroup, patients with G12V had worse survival (median overall survival [mOS] = 8.2 mo) compared with wt (mOS = 13.3 mo) and other 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 G12V ranged from 1.53 to 1.78 compared with wt and other m subtypes (all < 0.05).

Conclusions: Although patients with 50% or higher PD-L1 with G12C, G12D, and other subtypes exhibited similar survival to wt, G12V was associated with significantly worse survival than wt and other m subtypes. All m should not be regarded as uniform predictors of ICI responsiveness, even with high PD-L1 expression; G12V tumors may have worse outcomes with ICI-based therapy and benefit from treatment intensification.