First-line Osimertinib for Lung Cancer With Uncommon EGFR Exon 19 Mutations and EGFR Compound Mutations

Introduction: Up to 20% of EGFR-mutated NSCLC cases harbor uncommon EGFR mutations, including atypical exon 19 and compound mutations. Relatively little is known about the efficacy of osimertinib in these cases. Methods: Patients treated with first-line osimertinib for NSCLC with rare EGFR exon 19 (non E746_A750del) or compound mutations were included. Response assessment and time to progression were determined using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Kaplan-Meier analyses were used to estimate progression-free survival (PFS), time to treatment discontinuation (TTD), and overall survival (OS). Results: Thirty-seven patients with NSCLC harboring an atypical EGFR exon 19 mutation or compound mutation were treated with first-line osimertinib at Johns Hopkins from 2016 to 2021. Overall response rate (ORR) was 76% and median PFS, TTD, and OS were 13 months (95% confidence interval [CI]: 10–15), 22 months (95% CI: 17–32) and 36 months (95% CI, 29–48), respectively. Among atypical exon 19 mutations (n = 25), ORR was 80%, median PFS was 12 months (95% CI: 10–15), median TTD was 19 months (95% CI: 17–38), and median OS was 48 months (95% CI: 25–not reached). Compound mutations (n = 12) had an ORR of 67%, median PFS of 14 months (95% CI: 5–22), median TTD of 26 months (95% CI: 5–36), and median OS of 36 months (95% CI: 20–46). Twelve patients (32%) continued first-line osimertinib after local therapy for oligoprogression. Conclusions: Osimertinib exhibited favorable outcomes for rare EGFR exon 19 and compound mutations. The heterogeneity in outcomes among these groups of tumors with similar mutations underscores the need for continued reporting and further study of outcomes among rare variants to optimize management for each patient.