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.