Afatinib for the Treatment of Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: An Updated Database of 1023 Cases Brief Report

Abstract

IntroductionPreviously, we developed a database of 693 patients with NSCLC and uncommon EGFR mutations treated with afatinib. Here, we provide an update of >1000 patients, with more data on specific mutations.MethodsPatients were identified from a prospective database developed by Boehringer Ingelheim and via literature review. Mutations were categorized as T790M-positive, exon 20 insertions, major uncommon (G719X, L861Q, S768I) and ‘others’. Patients with compound mutations (≥2 EGFR mutations) were analyzed separately. Key endpoints were time to treatment failure (TTF) and objective response rate (ORR).ResultsOf 1023 patients included, 587 patients were EGFR TKI-naïve and 425 were EGFR TKI-pretreated. The distribution of mutation categories was: major uncommon (41.4%); exon 20 insertions (22.3%); T790M (20.3%); and ‘others’ (15.9%); 38.6% had compound mutations. Overall, median TTF (TKI naïve/pretreated) was 10.7 and 4.5 months. ORR was 49.8% and 26.8%, respectively. In TKI-naïve patients, afatinib demonstrated activity against major uncommon mutations (median TTF: 12.6 months; ORR: 59.0%), ‘other’ mutations (median TTF: 10.7 months; ORR: 63.9%) including strong activity against E709X (11.4 months; 84.6%) and L747X (14.7 months; 80.0%), and compound mutations (11.5 months; 63.9%). Although sample sizes were small, notable activity was observed against specific exon 20 insertions at residues A763, M766, N771, and V769, and against osimertinib resistance mutations (G724S, L718X, C797S).ConclusionAfatinib should be considered as a first-line treatment option for NSCLC patients with major uncommon, compound, ‘other’ (including E709X and L747X) and some specific exon 20 insertion mutations. Moderate activity was seen against osimertinib resistance EGFR mutations.

Afatinib in Untreated Stage IIIB/IV Lung Adenocarcinoma with Major Uncommon Epidermal Growth Factor Receptor (EGFR) Mutations (G719X/L861Q/S768I): A Multicenter Observational Study in Taiwan

“…The four previous studies also did not provide clinical information related to resistance to first-line afatinib therapy, such as the presence of secondary T790M mutations and treatments following first-line afatinib. In our study, patients with the G719X mutation had the longest PFS with first-line afatinib therapy, whereas those with the S768I mutation had the longest TTF in the two previous studies by Yang et al, while the L861Q mutation resulted in the longest TTF in the study by Li et al [22][23][24]. These differences may need to be verified in future studies.…”

Association of smoking status with non-small cell lung cancer patients harboring uncommon epidermal growth factor receptor mutation

“…Chiu et al (13) reported that first-generation EGFR-TKIs were less effective in patients with the G719X, L861Q, and S768I mutations than in those with common mutations. Recently, Yang et al conducted a post-hoc analysis of 1023 cases and showed that a second-generation EGFR-TKI, afatinib, was highly effective in patients with certain types of uncommon mutations (14).…”

“…Recently, Yang et al. conducted a post-hoc analysis of 1023 cases and showed that a second-generation EGFR -TKI, afatinib, was highly effective in patients with certain types of uncommon mutations ( 14 ).…”

Durable response to afatinib rechallenge in a long‐term survivor of non‐small cell lung cancer harboring EGFR L858R and L747V mutations

“…L747X (L747P, L747S, and L747V) mutations are rare in NSCLC; only 2.2% of all uncommon mutations are L747X mutations 3 . Afatinib has shown better activity against NSCLCs carrying EGFR L747P/S mutations than gefitinib and erlotinib, 3–5 which is supported by preclinical studies showing higher sensitivities of afatinib to L747P‐ or L747S‐mutant cells 6,7 .…”

“…L747X (L747P, L747S, and L747V) mutations are rare in NSCLC; only 2.2% of all uncommon mutations are L747X mutations 3 . Afatinib has shown better activity against NSCLCs carrying EGFR L747P/S mutations than gefitinib and erlotinib, 3–5 which is supported by preclinical studies showing higher sensitivities of afatinib to L747P‐ or L747S‐mutant cells 6,7 . Regarding L747V mutations, a lung adenocarcinoma patient with EGFR L858R and L747V mutations achieved a 6‐month PFS with erlotinib, 8 while another patient with lung adenocarcinoma harboring EGFR G719A and L747V mutations responded to afatinib with a 25‐month PFS 9 .…”