Osimertinib vs. Afatinib in 1L therapy of atypical EGFR-mutated metastatic non-small cell lung cancer (mNSCLC): A multi-institution, real-world survival analysis.

Background: Data are limited on the efficacy of different TKIs for patients with atypical EGFR-mutated (AM) mNSCLC, a heterogeneous group excluding classical mutations (CM) L858R and exon19del. In our previous single-institution analysis, AM patients had longer survival with osimertinib than afatinib, but outcomes for patients with specific mutations could not be compared due to sample size.

Methods: We performed a multi-institution, retrospective survival analysis of atypical EGFR mutated (AM) mNSCLC patients treated with 1L osimertinib or afatinib between 2015-2021 at 12 US institutions. Time to discontinuation (TTD) and overall survival (OS) were estimated using Kaplan-Meier curves and compared using log rank tests between treatment or mutation groups.

Results: Among 52 patients identified, 32 (62 %) were treated with osimertinib and 20 (38 %) with afatinib. 20 had mutations in G719X (38 %), 12 in L861Q (23 %), and 5 in S768I (10 %). 34(65 %) had compound mutations: 20(62 %) had AM + CM, and 14(38 %) had ≥ 2 AMs. Among G719X (n = 20), afatinib was associated with longer time to discontinuation (TTD) (log-rank: p = 0.047) and longer OS (p = 0.043) vs. osimertinib. Median TTD (mTTD) was 20.3 m[95 %CI 7.3-24.2] and 9.4[1.7-14.0], respectively. For L861Q (n = 12), osimertinib was associated with longer TTD vs. afatinib (p = 0.004), with no statistical difference in OS (p = 0.215). mTTD was 7.2 m[2.2-12.3] and 1.3[0-3.1], respectively. In AM + CM (n = 20), osimertinib was associated with longer TTD and OS compared to those receiving afatinib (p = 0.037, p = 0.042, respectively).

Conclusions: Patients with G719X alterations experienced longer TTD and OS with afatinib than osimertinib. In contrast, patients with L861Q alterations had longer TTD with osimertinib. In AM + CM pts, TTD and OS with osimertinib were longer than afatinib, suggesting that classical mutations may be driving the outcomes. Atypical EGFR mutations may warrant distinct treatment recommendations based on the specific mutation(s) identified, but more studies are needed.