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.

翻译：背景：KRAS突变是非小细胞肺癌（NSCLC）中最大的致癌突变亚群。尽管KRAS G12C现已有靶向疗法，但针对G12D突变尚无获批治疗方案。本研究通过允许时变风险效应，比较了G12C与G12D突变患者的至下次治疗时间（TTNT）和总生存期（OS）差异。方法：分析来自AACR Project GENIE BPC NSCLC v2.0-public数据库的去标识化数据。TTNT作为真实世界中无进展生存期的替代指标。对共突变基因（TP53、STK11、KEAP1、SMARCA4、MET）、肿瘤突变负荷（TMB）和PD-L1表达进行标准化整合。采用Kaplan-Meier法、多变量Cox回归及预设的分段Cox模型（以中位TTNT=23个月为界点）进行分析。使用Schoenfeld残差检验比例风险假设；通过Bootstrap重抽样（B=1000）评估模型稳定性。结果：在162例可评估TTNT的患者中（G12C n=130；G12D n=32），中位TTNT分别为28.6个月与32.0个月（时序检验p=0.79）。校正后的Cox回归显示总体风险无差异（HR=0.85；95% CI 0.53-1.37；p=0.50），但Schoenfeld检验提示边界性非比例风险（p=0.053）。分段Cox模型揭示时变效应：早期TTNT风险倾向于G12D更优（HR=0.41；95% CI 0.17-0.97；p=0.043），且存在显著的KRAS突变型×时期交互作用（HR=3.33；p=0.021），晚期风险差异减弱（HR=1.38；95% CI 0.77-2.47；p=0.285）。Bootstrap重抽样证实该模式（早期HR中位数=0.39；晚期HR中位数=1.41）。在278例可评估OS的患者中（133例死亡事件），G12D患者OS更优（校正后HR=0.63；95% CI 0.39-0.99；p=0.048）。G12C肿瘤具有更高的TMB（9.79 vs 7.83 mut/Mb；p=0.002）及更显著的STK11/KEAP1富集。结论：KRAS G12D突变在早期TTNT中显现优势并具有更佳的OS。晚期TTNT差异无统计学意义（事后检验效能：12.3%）。这些探索性发现需在更大规模队列中验证，但为G12D等位基因特异性疗法的开发提供了依据。