Targeting HER2 (ERBB2) mutation-positive advanced biliary tract cancers with neratinib: Results from the phase II SUMMIT ‘basket’ trial.

Authors

null

James J. Harding

Memorial Sloan Kettering Cancer Center, New York, NY

James J. Harding , James M. Cleary , David I. Quinn , Irene Braña , Victor Moreno , Mitesh J. Borad , Sherene Loi , Iben Spanggaard , Haeseong Park , James M. Ford , Monica Arnedos , Salomon M. Stemmer , Christelle De La Fouchardiere , Santiago Viteri Ramirez , Christos Fountzilas , Jie Zhang , Feng Xu , Alshad S. Lalani , Sarina Anne Piha-Paul , Ghassan K. Abou-Alfa

Organizations

Memorial Sloan Kettering Cancer Center, New York, NY, Dana-Faber Cancer Institute, Boston, MA, USC Norris Cancer Hospital, Los Angeles, CA, Vall d’Hebron University Hospital, Vall d’Hebrón Institute of Oncology, Barcelona, Spain, START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid, Spain, Mayo Clinic, Scottsdale, AZ, Peter MacCallum Cancer Centre, Melbourne, Australia, Rigshospitalet University Hospital of Copenhagen, Copenhagen, Denmark, Alvin J Siteman Cancer Center, Washington University, St. Louis, MO, Stanford Cancer Institute, Stanford, CA, Gustave Roussy Cancer Campus, Villejuif, France, Research Institute of Oncology Davidoff Center, Rabin Medical Center, Tel Aviv, Israel, Centre Léon Bérard, Lyon, France, Quirón Dexeus, Barcelona, Spain, Roswell Park Comprehensive Cancer Center, Buffalo, NY, Puma Biotechnology Inc., Los Angeles, CA, The University of Texas, MD Anderson Cancer Center, Houston, TX

Research Funding

Pharmaceutical/Biotech Company
Puma Biotechnology Inc.

Background: Genomic profiling studies have reported somatic HER2 mutations in ~2–5% of biliary tract cancers (BTC). Clinical data from the SUMMIT study demonstrate that neratinib, a pan-HER irreversible tyrosine kinase inhibitor, has encouraging clinical activity in multiple types of HER2-mutant solid tumor malignancies. Methods: SUMMIT is a multi-histology, open-label, phase II ‘basket’ study of neratinib in patients with somatic HER2 mutations (ClinicalTrials.gov NCT01953926). Patients with activating somatic HER2 mutations with different histologies, including BTC, received neratinib monotherapy (240 mg oral daily). Loperamide prophylaxis was mandatory during cycle 1. Efficacy endpoints: objective response rate (ORR, RECIST v1.1); clinical benefit rate (CBR); duration of response; progression-free survival (PFS). Adverse events (AEs) were assessed by CTCAE v4.0. Genomic profiling from fresh/archival tumor tissues and/or plasma cfDNA was performed retrospectively by next-generation sequencing (MSK-IMPACT). Results: As of 3-Sep-2020, 25 patients with HER2-mutant BTC were enrolled: gallbladder (40%); intrahepatic (24%); extrahepatic (20%); ampulla of Vater (16%). 68% of patients received ≥2 systemic regimens (96% received prior gemcitabine-based regimens). The S310F/Y variant accounted for nearly half of HER2 mutations (n=11). Other HER2 mutations: V777L (n=5); L755S (n=2); V842I (n=2); R678Q (n=2). Confirmed ORR in 25 evaluable patients was 12% (95% CI 3–31%) and CBR was 20% (95% CI 7–41%), including 3 confirmed PRs and 2 patients with SD for ≥16 weeks. Tumor shrinkage was observed in multiple HER2-activating mutations and enriched in gallbladder and extrahepatic subtypes of BTC. Median PFS was 2.8 (95% CI 1.1–3.7) months; median overall survival (OS) was 5.4 (95% CI 3.7–11.7) months. Nine (36%) patients (3 of whom with ECOG PS 2) came off study within 28 (range 6–47) days of treatment due to clinical deterioration (unrelated to study drug) followed by death. The most common treatment-related AEs (any grade) were diarrhea (56%) and vomiting (48%). Diarrhea was the most common Grade 3 event (24%); 4 patients (16%) required a neratinib dose reduction; no patients discontinued treatment due to diarrhea. Conclusions: Neratinib is safe and tolerable in patients with advanced BTC patients and somatic HER2 mutations. The antitumor activity of neratinib appears comparable to current standards of care, with similar PFS and OS in heavily pretreated patients. Analysis of co-occurring oncogenic mutations and response is ongoing, and consideration is being given to neratinib-based combination regimens to further improve outcomes in this setting. Clinical trial information: NCT01953926

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Abstract Details

Meeting

2021 Gastrointestinal Cancers Symposium

Session Type

Poster Session

Session Title

Poster Session: Hepatobiliary Cancer

Track

Hepatobiliary Cancer

Sub Track

Therapeutics

Clinical Trial Registration Number

NCT01953926

Citation

J Clin Oncol 39, 2021 (suppl 3; abstr 320)

DOI

10.1200/JCO.2021.39.3_suppl.320

Abstract #

320

Poster Bd #

Online Only

Abstract Disclosures