A phase II study of neratinib (Nera) in combination with chemotherapy/trastuzumab/pembrolizumab (C/T/P) in HER2 overexpressing gastroesophageal cancers (GECs).

Abstract

TPS514 Background: Human epidermal growth factor receptor 2 (HER2) is overexpressed in about 15-20% of GECs and is tested using immunohistochemistry and/or in-situ hybridization. Per 3 rd interim analysis of KN-811 study, addition of P to C/T improved overall response rate (ORR) and overall survival (OS) in patients with HER2 positive tumors. HER2 heterogeneity and activation of other signaling pathways ultimately leading to T resistance limits its potential to have a durable response. Nera is an anilinoqiunoline derivative intracellular oral kinase inhibitor that irreversibly binds to epidermal growth factor receptor (EGFR), HER2 and HER4. In this study, we hypothesize that targeting other oncogenic pathways with Nera may help derive additional therapeutic benefit in HER2 positive GECs when combined with C/T/P. Methods: This is an open-label, single arm, multi-institutional Phase II study of Nera in combination with C/T/P in HER2 overexpressing GECs as 1 st line treatment. The first 6 pts as a lead-in phase will be evaluated for toxicity. If no dose limiting toxicity (DLT), a total of 30 patients (include the first 6pts in the lead-in phase) will be used to evaluate efficacy in the phase II portion. All pts will receive standard dose mFOLFOX/trastuzumab q2w along with pembrolizumab 400 mg q6w. Nera will be dosed at 240 mg daily. In case of DLTs observed with this dose, a dose of 160 mg/day for Nera will be considered. Estimated sample size is 30-36 pts using Simon 2 stage design. Primary endpoint in ORR. The null hypothesis will be rejected if 26 or more responses are observed in 30 patients. Key inclusion criteria include: HER2 positive GECs (as determined by local testing), treatment naïve for stage IV disease, measurable disease, ECOG 0-1, preserved cardiac function. Uncontrolled brain metastases or impaired organ function that poses risk with treatment are key exclusion criteria. Primary endpoint is ORR and secondary endpoints include safety, duration of response, clinical benefit rate and OS. The trial is registered on clinicaltrials.gov under NCT06109467. Clinical trial information: NCT06109467 .