Abstract 3526: Pre-treatment EGFR mutation analysis predicts clinical outcome in a retrospective analysis of 24 non-squamous non-small-cell lung cancer (NSCLC) patients treated with second line afatinib.
Authors: van der Wekken Anthonie J. , Kuiper Justine L. , Heideman Daniëlle A.m. , Schuuring Ed , Timens Wim , Thunnissen Erik , Groen Harry J.M. , Smit Egbert F. 
Published: August 2014

Abstract
Purpose
Stage IV EGFR mutation positive NSCLC patients treated with reversible tyrosine kinase inhibitors(TKI) (i.e., erlotinib (E) or gefitinib (G)) develop resistance after 6-12 months, in half of the patients mediated by the T790M gatekeeper mutation. Afatinib (BIBW2992, Boehringer Ingelheim) has shown in a phase III study to prolong progression free survival (PFS) in patients progressing on EGFR TKI. The EGFR mutational pattern underlying these responses to afatinib is unknown. The current study was set out to evaluate response rate to afatinib in relation to tumor EGFR genotype.
Material/Methods
Patients with activating EGFR mutations, or without known EGFR mutations meeting Jackman criteria, progressing on E/G, and who had a re-biopsy before afatinib treatment were included. Mutations in exons 18-21 of the EGFR-gene were tested using high-resolution melting with reflex Sanger sequencing in both centers. We retrospectively studied EGFR mutations, PFS, and overall survival after treatment with afatinib. Statistical analysis was performed using Kaplan-Meier and Chi-square test.
Results
Initially 21/24 (88%) patients had stage IV NSCLC with a mean performance score of 1 (range 0-2). Before afatinib treatment 17/24 (71%) of patients received a platinum doublet. All patients received E or G. Three patients received both TKI sequentially. Four patients without mutation were treated for more than 6 months with E/G resulting in stable disease. PFS on previous E/G was 16 months (range, 2.0 - 37.9). At rebiopsy, 12/24 (50%) patients had a T790M mutation, no other secondary mutations were detected. There was no difference in duration of E/G administration neither in occurrence of T790M mutation (median 12.4 months (range, 6.8-34.4) with T790M vs. 19.2 months (range, 2.0-37.9) without T790M at rebiopsy; p=0.22). After PD on E/G, patients received afatinib mostly as 2nd or 3rd line therapy.Tumor response rate on afatinib was 12.5% (n=3). Of these, 1 had a T790M mutation. Disease control rate was 71%, median PFS was 3,0 months (range, 1.2-18.7 months). Median OS was 6.8 months (range, 1.3-19.0 months). The presence of T790M mutation did not influence PFS (with T790M, 2.9 vs without T790M, 3.2 months; p=0.684). However, it did influence OS (7.2 months vs. 3.5 months; p=0,039).
Conclusion
In our cohort of patients, PFS on afatinib was similar to the Lux-lung 1 study and similar for patients with or without T790M mutations. Duration of first generation TKI administration did not influence occurrence of T790M mutation. T790M mutation was in favor of a longer OS on afatinib.
Citation Format: Anthonie J. van der Wekken, Justine L. Kuiper, Daniëlle A.m. Heideman, Ed Schuuring, Wim Timens, Erik Thunnissen, Harry J.M. Groen, Egbert F. Smit. Pre-treatment EGFR mutation analysis predicts clinical outcome in a retrospective analysis of 24 non-squamous non-small-cell lung cancer (NSCLC) patients treated with second line afatinib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3526. doi:10.1158/1538-7445.AM2013-3526