Background: Somatic HER2 (ERBB2) and HER3 (ERBB3) mutations can lead to constitutive HER2 activation in the absence of gene amplification. They occur in a variety of solid tumors with a prevalence that does not exceed 5-10% in any tumor type. Activating HER2 mutations occur in the HER2 receptor extracellular and transmembrane domains, and at multiple hotspots in the kinase domain, with no single mutation predominating. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, inhibits growth of HER2- and HER3-mutant tumors in preclinical models. We explored the clinical activity of neratinib in pts with HER2/HER3 mutant cancers in SUMMIT, a global (9 countries), multicenter, multi-histology, phase II ‘basket’ trial.

Methods: Pts with advanced solid tumors and locally documented HER2/HER3 mutations received neratinib 240 mg daily with high-dose loperamide prophylaxis during cycle 1. Primary endpoint: objective response rate at week 8 (ORR8) per RECIST 1.1; pts without RECIST-measurable disease were assessed separately using FDG-PET. Retrospective confirmation of HER2/HER3 mutations, as well as a broader cancer gene profiling, was performed using both tumor and plasma-derived cfDNA. For each tumor type, using Simon’s optimal 2-stage design, a true ORR8 ≤10% was considered unacceptable (null hypothesis) whereas a true ORR8 ≥30% (alternative hypothesis) merited further study. Interim data cut: 16-Dec-2016. NCT01953926.

Results: 141 (125 HER2, 16 HER3) pts have received neratinib including 125 efficacy-evaluable pts (110 HER2, 15 HER3). 21 unique cancer types were enrolled (most common: breast, lung, bladder, colorectal cancer). 30 HER2 and 12 HER3 mutations were observed, the most frequent HER2 variants involving S310, L755, A755_G776insYVMA and V777. In the HER2-mutant cohort, clinical responses were observed in tumors with S310, L755, V777, P780_Y781insGSP, and A775_G776insYVMA. When stratified by tumor type, responses were observed in pts with breast, cervical, biliary, salivary and non-small-cell lung cancers, which led to indication-specific cohort expansions. No activity was observed in the HER3-mutant cohort. Tumor and/or cfDNA from 116 pts has been sequenced centrally. Of these, the locally reported HER2/3 mutation was confirmed in 108 (93%), a discordant HER2/3 mutation detected in 5 (4%), and not detected in 3 (3%). Co-mutation patterns in different tumor types and their association with neratinib sensitivity/resistance are under review.

Conclusions: SUMMIT provides the largest body of clinical data to date on the use of a pan-HER inhibitor in pts with solid tumors with somatic HER2/HER3 mutations. Responses in HER2 mutants varied by type of tumor and the specific HER2 mutation, suggesting: 1) mutant HER2 is a driver oncogene in some cancers; and 2) not all mutations generate the same level of HER2 hyperactivity and/or oncogene dependence.

Citation Format: David M. Hyman, Sarina A. Piha-Paul, Jordi Rodon, Cristina Saura, Geoffrey I. Shapiro, David I. Quinn, Victor Moreno, Ingrid A. Mayer, Carlos Arteaga, Valentina Boni, Emiliano Calvo, Sherene Loi, Albert C. Lockhart, Lillian M. Smyth, Joseph Erinjeri, Maurizio Scaltriti, Gary Ulaner, Jean Torrisi, Juber Patel, Jiabin Tang, Fanli Meng, Duygu Selcuklu, Helen Won, Nancy Bouvier, Michael F. Berger, Richard E. Cutler, Feng Xu, Anna Butturini, Lisa D. Eli, Grace Mann, Alshad S. Lalani, Richard P. Bryce, Funda Meric-Bernstam, José Baselga, David B. Solit. Neratinib in HER2 or HER3 mutant solid tumors: SUMMIT, a global, multi-histology, open-label, phase 2 "basket" study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT001. doi:10.1158/1538-7445.AM2017-CT001