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

Robert Amevor, Dennis Baidoo, Emmanuel Kubuafor

TL;DR

These exploratory findings require validation in larger cohorts but support allele-specific therapeutic development for G12D, which demonstrated early TTNT advantage and improved OS.

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.

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

TL;DR

These exploratory findings require validation in larger cohorts but support allele-specific therapeutic development for G12D, which demonstrated early TTNT advantage and improved OS.

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.
Paper Structure (34 sections, 7 figures, 4 tables)

This paper contains 34 sections, 7 figures, 4 tables.

Table of Contents

  1. Introduction
  2. Methods
  3. Data Source
  4. Cohort Construction
  5. Endpoint Definitions
  6. Time-to-Next-Treatment (TTNT).
  7. Overall Survival (OS).
  8. Genomic Variable Harmonization
  9. Statistical Analysis
  10. Descriptive and Comparative Analyses
  11. Kaplan--Meier and Standard Cox Models
  12. Time-Varying Hazard Models
  13. Time-dependent Cox model.
  14. Pre-specified piecewise Cox model.
  15. Bootstrap Internal Validation
  16. ...and 19 more sections

Figures (7)

  • Figure 1: Graphical result
  • Figure 2: CONSORT-style flow diagram of patient selection for TTNT and OS analyses.
  • Figure 3:
  • Figure 4: Kaplan--Meier curves for time-to-next-treatment (TTNT) by KRAS allele (G12C $n=130$; G12D $n=32$). Median TTNT: 28.6 vs. 32.0 months; log-rank $p = 0.787$.
  • Figure 5: Period-specific hazard ratios for KRAS G12D vs G12C from the piecewise Cox model (cut-point: 23 months). HR$_{\text{early}} = 0.41$ (95% CI 0.17--0.97); HR$_{\text{late}} = 1.38$ (95% CI 0.77--2.47). Dashed line at HR = 1.0. Late-period HR did not reach statistical significance ($p = 0.285$).
  • ...and 2 more figures