Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers: Results from a phase II basket trial.

Abstract

8510 Background: Human epidermal growth factor receptor 2 ( HER2, ERBB2) mutations occur in 2% of lung cancers, resulting in receptor dimerization and kinase activation with in vitro sensitivity to trastuzumab. Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate linking trastuzumab with the anti-microtubule agent emtansine. Methods: Patients (pts) with HER2 mutant lung cancers were enrolled into a cohort of the basket trial of ado-trastuzumab emtansine in HER2amplified or mutant cancers, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1. A Simon two stage optimal design was used with type I error rate under 2.7% (and a family wise error rate across baskets under 10%), power of 89%, H0 10%, H1 40%; the H0 will be rejected if 5 or more responses are observed in 18 pts. Other endpoints include duration of response (DOR), progression-free survival (PFS) and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing (NGS), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Results: The cohort completed accrual with 18 pts treated. The median age was 63 (range 47-74 years), 72% were female, 39% were never smokers and all had adenocarcinomas. The median lines of prior systemic therapy was 2 (range 0-4). ORR was 33% (5/15 confirmed, 95% CI 12-62%) not including a partial response awaiting confirmation and 3 pts pending response evaluation. Median DOR was not reached (range 3 to 7+ mo), median PFS was 4mo (95% CI 3mo-not reached). Toxicities were mainly grade 1 or 2 including infusion reaction, thrombocytopenia and transaminitis, there were no dose reductions or treatment related deaths. There were 10 (56%) exon 20 insertions and 8 (44%) point mutations; responders were seen across mutation subtypes (A775_G776insYVMA, G776delinsVC, V659E, S310F). HER2amplification was negative for all pts by NGS and positive for 1 of 12 pts by FISH. There was no IHC3+ in 10 pts tested. Conclusions: Ado-trastuzumab emtansine is active and well tolerated in pts with HER2 mutant lung cancers. This study has met its primary endpoint. Further development in a multicenter study is warranted. Clinical trial information: NCT02675829.