Afatinib versus chemotherapy in advanced NSCLC with uncommon <i>EGFR</i> mutations: A pooled individual patient–level survival analysis of ACHILLES/TORG1834 and LUX-Lung 2/3/6.

e20736 Background: Uncommon EGFR mutations represent a biologically and clinically heterogeneous subset of non–small cell lung cancer (NSCLC), for which optimal first-line treatment remains uncertain due to limited randomized evidence. While afatinib has shown activity in post hoc analyses of the LUX-Lung program, prospective comparative data have been scarce until the recent ACHILLES/TORG1834 randomized trial. We conducted a pooled individual patient–level analysis to comprehensively quantify the progression-free survival (PFS) benefit of afatinib versus chemotherapy in advanced NSCLC harboring uncommon EGFR mutations. Methods: Individual patient data were pooled from ACHILLES/TORG1834 and the prospective LUX Lung 2, 3, and 6 studies. Eligible patients had advanced NSCLC with uncommon EGFR mutations treated with afatinib or platinum-based chemotherapy. Exon 20 insertions and de novo T790M mutations were excluded. The primary endpoint was PFS. Treatment effects were estimated using Cox proportional hazards models with likelihood ratio testing. Kaplan–Meier methods were used to estimate median PFS and landmark PFS rates. Results: Among 170 patients included, 101 PFS events occurred. Afatinib significantly reduced the risk of disease progression or death compared with chemotherapy (HR 0.54; 95% CI, 0.36–0.84; p = 0.005), supported by a significant likelihood ratio test (p = 0.007). Median PFS was 10.8 months (95% CI, 8.4–13.0) with afatinib versus 6.0 months (95% CI, 5.2–8.3) with chemotherapy. Landmark PFS rates consistently favored afatinib at 6 months (75.3% vs 48.9%), 12 months (41.1% vs 17.9%), 18 months (27.9% vs 13.5%), and 24 months (19.8% vs 4.5%), demonstrating durable disease control. Conclusions: This pooled individual patient–level analysis demonstrates that afatinib confers a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy in patients with advanced NSCLC harboring sensitizing uncommon EGFR mutations. The consistency of benefit across randomized and prospective trials, together with sustained landmark PFS advantages, supports afatinib as a preferred treatment option for this heterogeneous molecular subgroup and provides robust evidence to inform clinical decision-making and guideline development. Progression-Free survival by treatment in patients with uncommon EGFR-Mutant NSCLC. Treatment Median PFS (months) 95% CI HR (95% CI) vs Chemo p-value 6-mo PFS 12-mo PFS 18-mo PFS 24-mo PFS Chemotherapy 5.97 5.18–8.28 Reference – 48.90% 17.90% 13.50% 4.50% Afatinib 10.79 8.38–13.03 0.54 (0.36–0.84) 0.005 75.30% 41.10% 27.90% 19.80%