Real-world outcomes of osimertinib (Osi) vs. afatinib or erlotinib in patients with classical vs. atypical EGFR-mutated metastatic non-small cell lung cancer (mNSCLC).

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8566 Background: Limited data are available on the efficacy of osi for mNSCLC with atypical EGFR mutations (AM) such as L861Q, G719X, S768I, and exon20 insertions. Afatinib is FDA approved for mNSCLC harboring L861Q, G719X, and S768I. Real-world analyses comparing osi to afatinib and erlotinib for AM have yielded mixed results. Methods: We performed a single-institution retrospective analysis of patients with EGFR-mutated mNSCLC treated from 2007-2023 with EGFRTKIs. Clinical trial patients were excluded. Patients with classical EGFRmutations (CM) were compared to those with AM. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the EMR. Median PFS and OS were estimated and compared via Kaplan-Meier log-rank analysis. Independent sample t-tests and chi-square analyses were used for univariate comparisons. P-values<0.05 were considered statistically significant. Results: Among 355 patients with 1L EGFR-mutated mNSCLC, 315 (90%) had CM (exon19 del [N=182; 51%] and L858R [N=119; 34%]), while 36 (10%) harbored AM in G719X (N=21; 6%), Exon 20 (N=11; 3%), L861Q (N=7; 2%), and S768I (N=4; 1%). Patients with CM vs AM had similar median age at diagnosis (63, p=0.406), gender (65% F; p=0.213), racial composition (p=0.653), and history of smoking (44%, p=0.167). At diagnosis, 45% vs 48% of patients had CNS involvement (p=0.434). 52% vs 41% received osi, 36% vs 20% patients received erlotinib, and 11% vs 37% received afatinib (p<0.001). Patients with CM had superior mPFS (29 vs 15m; p=0.021) and mOS (49 vs 13m; p<0.001) vs AM (Table). In AM patients (N=36), osi had superior mPFS (15m [7-23]) vs afatinib (11m [8-15]; p=0.005) or erlotinib (8m [6-10]; p=0.001). mOS was likewise superior for osi (29m [6-50]) vs afatinib (13m [9-17]; p<0.001) or erlotinib (14m [6-21]; p<0.001). 121 CM and 7 AM patients were rechallenged with a TKI; mPFS2 for AM was 13m for osi (N=4) vs 4m for afatinib (N=3; p=0.114). Dose-reduction due to AE was lower for osi (19%) vs afatinib (24%; p=0.003) or erlotinib (23%; p=0.002). Discontinuation due to AE was lower for osi vs afatinib (1% vs 2%; p<0.001) or erlotinib (2%; p=0.004). Conclusions: Retrospectively, AM were associated withinferior PFS and OS compared to CM. Osi demonstrated superior survival and tolerability compared to afatinib or erlotinib for AM. [Table: see text]