Time-Varying Hazard Patterns and Co-Mutation Profiles of KRAS G12C and G12D in Real-World NSCLC

TL;DR

This study compares KRAS G12C and G12D mutations in NSCLC, revealing that G12D has early treatment benefit and better overall survival, emphasizing the need for allele-specific therapies.

Contribution

It introduces a time-varying hazard model to analyze real-world data, uncovering differential survival patterns between G12C and G12D mutations in NSCLC.

Findings

G12D shows early TTNT advantage in NSCLC patients

G12D associated with improved overall survival

G12C tumors have higher TMB and more co-mutations

Abstract

Background: KRAS mutations are the largest oncogenic subset in NSCLC. While KRAS G12C is now targetable, no approved therapies exist for G12D. We examined time-to-next-treatment (TTNT) and overall survival (OS) differences between G12C and G12D, allowing for time-varying hazard effects. Methods: De-identified data from AACR Project GENIE BPC NSCLC v2.0-public were analyzed. TTNT served as a real-world surrogate for progression-free survival. Co-mutations (TP53, STK11, KEAP1, SMARCA4, MET), TMB, and PD-L1 were harmonized. Kaplan-Meier, multivariable Cox, and a pre-specified piecewise Cox model (split at median TTNT = 23 months) were applied. Schoenfeld residuals assessed proportional hazards; bootstrap resampling (B=1000) evaluated stability. Results: Among 162 TTNT-evaluable patients (G12C n=130; G12D n=32), median TTNT was 28.6 versus 32.0 months (log-rank p=0.79). Adjusted Cox regression showed no overall hazard difference (HR=0.85; 95% CI 0.53-1.37; p=0.50), but Schoenfeld testing indicated borderline non-proportionality (p=0.053). Piecewise Cox modeling revealed time-varying effects: early TTNT hazard favored G12D (HR=0.41; 95% CI 0.17-0.97; p=0.043) with significant KRAS x period interaction (HR=3.33; p=0.021) and late-period attenuation (HR=1.38; 95% CI 0.77-2.47; p=0.285). Bootstrap resampling confirmed this pattern (median HRearly=0.39; HRlate=1.41). Among 278 OS-evaluable patients (133 deaths), G12D showed improved OS (adjusted HR=0.63; 95% CI 0.39-0.99; p=0.048). G12C tumors exhibited higher TMB (9.79 vs 7.83 mut/Mb; p=0.002) and greater STK11/KEAP1 enrichment. Conclusions: KRAS G12D demonstrated early TTNT advantage and improved OS. Late-period TTNT differences were non-significant (post-hoc power: 12.3%). These exploratory findings require validation in larger cohorts but support allele-specific therapeutic development for G12D.