First-Line Afatinib 30 mg Versus 40 mg in Non-small Cell Lung Cancer Patients With Uncommon EGFR Mutations: Real-world Efficacy and Tolerability in Taiwan

Background/Aim: Afatinib is an irreversible EGFR-TKI effective against uncommon EGFR mutations in non–small cell lung cancer (NSCLC), but the influence of mutation subtype and starting dose on treatment outcomes remains unclear. This study aimed to evaluate the clinical outcomes of patients with uncommon EGFR-mutated NSCLC treated with afatinib, focusing on whether a reduced starting dose (30 mg) provides comparable efficacy and tolerability to the standard 40 mg dose. Additionally, we sought to explore the potential impact of specific uncommon EGFR mutation subtypes on treatment response.

Patients and Methods: We retrospectively analyzed patients with stage IV NSCLC harboring uncommon EGFR mutations who received afatinib 30 mg or 40 mg daily at two university affiliated hospitals. Mutations were categorized as single uncommon, compound (rare + common), or double rare (rare + rare). Clinical characteristics, treatment response, and survival outcomes were compared between mutation subgroups and dosing cohorts. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier analysis and compared with the log-rank test.

Results: A total of 46 patients were included (30 mg: n=28; 40 mg: n=18). The objective response rate was 71.7%, and disease control rate 93.5%. Patients with double-rare mutations had significantly longer survival than those with single uncommon mutations (median PFS 37.1 vs. 12.3 months, p=0.01; median OS 63.7 vs. 19.6 months, p=0.042). In the 30 mg group, this benefit was more pronounced (PFS p=0.0039; OS p=0.0287), whereas survival differences by mutation subtype were not significant in the 40 mg cohort. Treatment was well tolerated, with fewer grade ≥3 adverse events in the 30 mg group.

Conclusion: Afatinib 30 mg daily achieved comparable efficacy and better tolerability than 40 mg, with significantly longer PFS and OS in patients harboring compound or double-rare EGFR mutations. These findings suggest that lower-dose afatinib may optimize efficacy and safety in patients with uncommon EGFR-mutant NSCLC.