Contemporary Chemotherapy Benchmarks for Molecularly Defined Advanced NSCLC: Reconstructed Individual Patient-Level Data of 22 Randomized Trials

Abstract Purpose The increasing adoption of targeted therapies over chemotherapy has made randomized controlled trials (RCT) with chemotherapy increasingly challenging in advanced NSCLC with actionable genomic alterations (AGA), particularly for rare subgroups. Contemporary chemotherapy outcomes specific to AGAs are lacking despite growing reliance on single-arm studies and external-control analyses. We sought to establish first-line platinum-doublet chemotherapy outcomes in advanced NSCLC with AGAs using data from RCTs. Methods We extracted objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) data from Phase 2/3 RCTs. Individual patient-level data were reconstructed from Kaplan–Meier curves to pool and compare PFS and OS across AGAs. Results Twenty-two RCTs ( n = 2132) were included. Across most AGAs, platinum-doublet chemotherapy produced similar outcomes-pooled ORRs ranging from 28.7 to 39.0% and median PFS from 6.0 to 7.3 months. Pairwise comparisons showed better ORR/PFS for RET fusion (one trial with control arm-chemotherapy/pembrolizumab) and shorter OS for KRAS mutation versus other AGAs (logrank P <.001). Detailed pooled ORR and median PFS and OS were: ALK rearrangement ( n = 461)—ORR 39.0% (95% CI 25.8–52.2), PFS 7.0 months (6.8–7.2), OS 43.0 months (32.2-inestimable); common EGFR mutation ( n = 1038)—ORR 28.7% (22.3–35.1), PFS 6.0 months (5.7–6.3), OS 27.4 months (26.1–29.3); uncommon EGFR mutation ( n = 61)—ORR 35.1% (12.6–57.7), PFS 6.7 months (5.2–8.4), OS 29.5 months (13.3—inestimable); EGFR exon 20 insertion ( n = 330)—ORR 38.3% (21.7–55.0), PFS 7.3 months (6.9–8.6), OS 30.1 months (29.1—inestimable); KRAS mutation ( n = 140)—ORR 21.7% (12.4–30.9), PFS 6.2 months (4.7–6.9), OS 10.8 months (8.8–12.7); RET fusion ( n = 102)—ORR 65.0% (54.5–75.5), PFS 11.4 months (8.9–16.9), OS not available. Conclusion Platinum-doublet chemotherapy yields remarkably consistent ORR and PFS across most advanced NSCLC with AGAs. These data provide contemporary molecularly defined benchmarks that may support interpretation of single-arm studies, development of external-control analyses, and future trial design in this rare population.