Afatinib in patients with metastatic HER2-mutant lung cancers: An international multicenter study.

Abstract

9071 Background: Human epidermal growth factor 2 ( HER2, ERBB2) mutations have been identified as oncogenic drivers in 3% of lung cancers. Afatinib is an irreversible tyrosine kinase inhibitor of HER1 (EGFR), HER2 and HER4 and has been described in case reports to have activity in HER2-mutant lung cancers. However, there is little data to inform the clinical use of afatinib. Methods: We reviewed patients with metastatic HER2-mutant lung cancers treated with afatinib among 7 institutions between 2009 and 2016. The primary endpoint was investigator assessed overall response rate using RECIST v1.1. Other data collected included types of HER2mutations, duration of afatinib treatment and overall survival. Results: We identified 27 patients with metastatic HER2-mutant lung cancers treated with afatinib. Median age at diagnosis was 63 (range 40 to 84); majority were men (n = 16; 59%) and never-smokers (n = 18; 67%). All tumors were adenocarcinomas, and the majority were Stage IV at initial diagnosis (n = 16; 59%). A 12-base pair (bp) in-frame insertion YVMA in exon 20 (p.A775_G776insYVMA) was present in 16 patients (59%). In addition, there were three 9-bp insertions, two 3-bp insertions and two single bp substitutions (L755F and D769H) in exon 20; two single bp substitutions (S310F) in exon 8; one exon 17 V659E mutation; and one single-nucleotide polymorphism (Ile655Val). Median duration on afatinib was 2 months (range 1 to 27); median line of prior treatment was 3 (range 1 to 6). Eight patients had previously received trastuzumab prior to afatinib and one concurrently with afatinib. Overall response rate was 15% (n = 4; 95% CI 4 to 34%); the four partial responses lasted 5, 5, 6 and 10 months. The 3 longest partial responders had a 12-bp insertion in exon 20 (YVMA); the remaining partial responder had a 9-bp insertion in exon 20. Median overall survival from diagnosis date of metastatic disease was 23 months (95% CI 18 to 62). Conclusions: Afatinib produced partial responses in 15% of patients with metastatic HER2-mutant lung cancers, including insertion YVMA. Our findings confirm the activity of afatinib and provide data supporting a framework for its use in the care of patients with HER2-mutant lung cancers.

Report from the ESMO 2017 Congress, Madrid, 8th–12th September, 2017

“…This was similar to early clinical trial data with PD-(L)-1 inhibitors [11,12,14] and compared favourably to current chemotherapy options. With 13 additional patients achieving SD, DCR was 52 %.…”

“…Predictors of improved survival with pembrolizumab included good performance status, early line of treatment, and sarcomatoid histology. Survival results obtained in these selected groups resembled those from the KEYNOTE-028 trial and the Chicago cohort [11,12]. On the other hand, the outcomes in the allcomer population included in this registry were clearly inferior to those observed in the trials.…”

“…While the majority of nivolumab data are based on treatment until disease progression or unacceptable toxicity, findings from the phase I CheckMate 003 study suggest that approximately two years of nivolumab monotherapy are sufficient for longterm clinical benefit in patients with previously treated NSCLC [11]. CheckMate 153 was the first randomised study to evaluate duration of treatment with a PD-(L)1 inhibitor [12]. It compared continuous administration of nivolumab versus nivolumab treatment limited to one year.…”

“…No OS difference was observed between the two arms [11]. Sequist et al conducted a retrospective analysis of subsequent therapy outcomes in patients with common EGFR mutations in LUX-Lung 3, 6 and 7, with the aim of contributing to establishing the optimal treatment sequence for patients with EGFR-mutant NSCLC [12]. Among 579 patients with common mutations randomised to afatinib, 553 had discontinued afatinib treatment at the time of analysis.…”

“…In the KEY-NOTE-028 study, DCR was 72 %, and median OS amounted to 18 months [11]. The Chicago cohort showed a DCR of 80 % and a median OS of 11.9 months [12]. Based on these trials, pembrolizumab started to be used for the off-label treatment of relapsed MPM in Switzerland.…”