Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers

James J. Harding (), Sarina A. Piha-Paul, Ronak H. Shah, Jessica J. Murphy, James M. Cleary, Geoffrey I. Shapiro, David I. Quinn, Irene Braña, Victor Moreno, Mitesh Borad, Sherene Loi, Iben Spanggaard, Haeseong Park, James M. Ford, Mónica Arnedos, Salomon M. Stemmer, Christelle Fouchardiere, Christos Fountzilas, Jie Zhang, Daniel DiPrimeo, Casey Savin, S. Duygu Selcuklu, Michael F. Berger, Lisa D. Eli, Funda Meric-Bernstam, Komal Jhaveri, David B. Solit and Ghassan K. Abou-Alfa
Additional contact information
James J. Harding: Memorial Sloan Kettering Cancer Center
Sarina A. Piha-Paul: The University of Texas, MD Anderson Cancer Center
Ronak H. Shah: Memorial Sloan Kettering Cancer Center
Jessica J. Murphy: Memorial Sloan Kettering Cancer Center
James M. Cleary: Dana-Farber Cancer Institute
Geoffrey I. Shapiro: Dana-Farber Cancer Institute
David I. Quinn: USC Norris Cancer Comprehensive Cancer Center
Irene Braña: Vall d’Hebron University Hospital
Victor Moreno: START MADRID-FJD, Hospital Fundación Jiménez Díaz
Mitesh Borad: Mayo Clinic
Sherene Loi: Peter MacCallum Cancer Centre
Iben Spanggaard: Copenhagen University Hospital
Haeseong Park: Washington University School of Medicine in St. Louis
James M. Ford: Stanford Cancer Institute
Mónica Arnedos: Villejuif, France (currently at: Institut Bergonie
Salomon M. Stemmer: Davidoff Center, Rabin Medical Center
Christelle Fouchardiere: Centre Léon Bérard
Christos Fountzilas: Roswell Park Comprehensive Cancer Center
Jie Zhang: Puma Biotechnology Inc
Daniel DiPrimeo: Puma Biotechnology Inc
Casey Savin: Memorial Sloan Kettering Cancer Center
S. Duygu Selcuklu: Memorial Sloan Kettering Cancer Center
Michael F. Berger: Memorial Sloan Kettering Cancer Center
Lisa D. Eli: Puma Biotechnology Inc
Funda Meric-Bernstam: The University of Texas, MD Anderson Cancer Center
Komal Jhaveri: Memorial Sloan Kettering Cancer Center
David B. Solit: Memorial Sloan Kettering Cancer Center
Ghassan K. Abou-Alfa: Memorial Sloan Kettering Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in HER2-mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumours harbouring oncogenic HER2 somatic mutations (ClinicalTrials.gov: NCT01953926). The primary objective of the BTC cohort, which is now complete, is first objective response rate (ORR) to neratinib 240 mg orally daily. Secondary objectives include confirmed ORR, clinical benefit rate, progression-free survival, duration of response, overall survival, safety and tolerability. Genomic analyses were exploratory. Among 25 treatment-refractory patients (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers), the ORR is 16% (95% CI 4.5–36.1%). The most common HER2 mutations are S310F (n = 11; 48%) and V777L (n = 4; 17%). Outcomes appear worse for ampullary tumours or those with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations are identified at progression in one responder. Diarrhoea is the most common adverse event, with any-grade diarrhoea in 14 patients (56%). Although neratinib demonstrates antitumour activity in patients with refractory BTC harbouring HER2 mutations, the primary endpoint was not met and combinations may be explored.

Date: 2023
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DOI: 10.1038/s41467-023-36399-y

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