Treating HER2-mutant advanced biliary tract cancer with neratinib: benefits of HER2-directed targeted therapy in the phase 2 SUMMIT ‘basket’ trial

Introduction: Genomic profiling studies have reported somatic mutations in HER2 (ERBB2) biliary tract cancers at rates of 2–9%, depending on cancer subtype [cBioportal 06 March 2019]. Preclinical studies indicate that HER2 mutations are oncogenic in multiple tumor types and are targetable by pan-HER kinase inhibitors. Preliminary clinical data from the SUMMIT study demonstrate that neratinib, a pan-HER irreversible tyrosine kinase inhibitor, has clinical activity against several HER2-mutant solid tumors [Hyman et al. Nature 2018;554:189–94]. Updated results from the biliary tract cohort treated with neratinib monotherapy will be provided. Methods: SUMMIT is a multi-histology, open-label, phase 2 ‘basket’ study for patients whose tumors harbor somatic HER2 mutations to receive treatment with neratinib (ClinicalTrial.gov NCT01953926; EudraCT 2013-002872-42). Patients with HER2-mutant cancers of the biliary tract (i.e. tumors of the bile duct, gallbladder, and ampulla of Vater) were treated with neratinib monotherapy at 240 mg oral daily; anti-diarrheal prophylaxis with loperamide was required during the first cycle. Efficacy endpoints included objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS). CBR was defined as those patients achieving a complete or partial response or stable disease lasting ≥16 weeks. Toxicity and response were assessed by CTCAE v4.0 and RECIST version 1.1, respectively. Genomic profiling from fresh/archival tumor tissues and/or plasma cfDNA was performed retrospectively by next-generation sequencing (MSK-IMPACT). Results: As of January 10, 2019, 19 patients with HER2-mutant biliary tract cancers have been enrolled in the study. The study population included patients with cholangiocarcinomas (47%), cancers of the gallbladder (42%) and ampulla (11%) who were refractory to prior gemcitabine and platinum-containing regimens (74%). The median number of systemic regimens in the metastatic setting was 1 (range 0–7). The S310F/Y variant accounted for nearly half of HER2 mutations observed (n = 9). Additional HER2 mutations included V777L (n = 3), L755S (n = 2), V842I (n = 2) and other known activating mutations. The confirmed ORR was 10.5% (95% CI 1.3–33.1) and CBR was 31.6% (95% CI, 12.6–56.6), including 2 confirmed PRs and 4 patients achieving stable disease. Median PFS was 1.8 months (95% CI, 1.0–3.7). Post-progression biopsy from one gallbladder cancer patient with a partial response revealed loss of HER2 mutation. The most frequently reported adverse events of any grade were diarrhea and vomiting; each was reported in 10 patients. Diarrhea was the most common Grade 3 event (21%); no Grade 4 diarrhea events were recorded. No patients in this cohort discontinued the study drug due to diarrhea. Conclusion: HER2-directed targeted therapy represents a novel and tolerable treatment approach for advanced biliary tract cancers harboring somatic HER2 mutations. Given the observed antitumor activity in a patient subset, enrollment will continue to further define the benefit of monotherapy, and ongoing tissue correlates will inform combination strategies to further enhance responses and outcomes.