Afatinib versus osimertinib for non–small cell lung cancer with uncommon epidermal growth factor receptor mutations: Real-world outcomes (HOT-Next001/HOT2501).

8605 Background: Non–small cell lung cancers (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations exhibit considerable biological and clinical heterogeneity. Consequently, the optimal first-line EGFR tyrosine kinase inhibitor (EGFR-TKI) and the role of subsequent immune checkpoint inhibitor (ICI)–based regimens remain uncertain. Methods: This multicenter retrospective cohort study was conducted at 29 institutions in Japan and included patients with advanced or recurrent non-squamous NSCLC harboring uncommon EGFR mutations who received first-line afatinib or osimertinib between January 2015 and January 2024. Exon 20 insertions and de novo T790M mutations were excluded. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and the effectiveness of subsequent systemic therapies, including ICI plus platinum doublet chemotherapy (ICI-Chemo) and platinum doublet chemotherapy alone. To adjust for baseline imbalances, analyses used inverse probability of treatment weighting (IPTW) based on covariate-balancing propensity scores. Results: Among 162 patients, 95 received afatinib and 67 received osimertinib. After IPTW adjustment, no significant differences were observed in PFS (median, 11.3 vs 5.9 months; hazard ratio HR, 1.04; 95% confidence interval CI, 0.60–1.80) or OS (28.0 vs 25.5 months; HR, 1.34; 95% CI, 0.73–2.44). Afatinib yielded a higher ORR (70.2% vs 47.2%) and DCR (93.7% vs 82.5%) than osimertinib, while adverse events requiring dose reduction were more frequent (76.8% vs 31.3%) but generally manageable. Subgroup analyses suggested greater benefit with osimertinib in L861X mutations and with afatinib in compound mutations. In patients with PD-L1 ≥50%, afatinib was associated with significantly longer PFS (15.5 vs 2.6 months; HR, 0.14; 95% CI, 0.04–0.46), whereas OS was numerically longer (30.5 vs 12.9 months; HR, 0.38; 95% CI, 0.07–1.93). Among 56 patients who received subsequent systemic therapy and were chemotherapy- and ICI-naïve, IPTW-adjusted analyses showed that ICI-Chemo did not improve outcomes compared with platinum doublet chemotherapy: median PFS, 6.7 vs 7.3 months (HR, 1.08; 95% CI, 0.53–2.19) and post–EGFR-TKI OS, 14.6 vs 19.7 months (HR, 1.30; 95% CI, 0.63–2.68). Conclusions: In one of the largest multicenter real-world cohorts, afatinib and osimertinib demonstrated comparable survival outcomes as first-line EGFR-TKIs in NSCLC with uncommon EGFR mutations, with treatment effects modulated by mutation subtype and PD-L1 expression. ICI-based regimens did not improve outcomes compared with platinum doublet chemotherapy and conferred no meaningful clinical benefit as post–EGFR-TKI therapy in this population.