TY - JOUR
T1 - Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers
AU - Harding, James J.
AU - Piha-Paul, Sarina A.
AU - Shah, Ronak H.
AU - Murphy, Jessica J.
AU - Cleary, James M.
AU - Shapiro, Geoffrey I.
AU - Quinn, David I.
AU - Braña, Irene
AU - Moreno, Victor
AU - Borad, Mitesh
AU - Loi, Sherene
AU - Spanggaard, Iben
AU - Park, Haeseong
AU - Ford, James M.
AU - Arnedos, Mónica
AU - Stemmer, Salomon M.
AU - de la Fouchardiere, Christelle
AU - Fountzilas, Christos
AU - Zhang, Jie
AU - DiPrimeo, Daniel
AU - Savin, Casey
AU - Duygu Selcuklu, S.
AU - Berger, Michael F.
AU - Eli, Lisa D.
AU - Meric-Bernstam, Funda
AU - Jhaveri, Komal
AU - Solit, David B.
AU - Abou-Alfa, Ghassan K.
N1 - Funding Information:
The SUMMIT trial was sponsored/funded by Puma Biotechnology, Inc. Investigators from MSKCC who participated in the trial were also supported in part by a Cancer Center Support Grant (P30 CA008748) and Cycle for Survival. Puma Biotechnology, Inc was involved in the following: study design; data collection, analysis and interpretation of the data; writing of the report; the decision to submit the article for publication. The authors would like to thank all patients and their families for participating in the SUMMIT trial. The authors acknowledge David Hyman (Memorial Sloan Kettering), Richard Bryce (Puma Biotechnology), and Alshad Lalani (Puma Biotechnology) for their important contributions to the original SUMMIT study design, oversight, and interpretation, and Feng Xu (Puma Biotechnology) and Jane Liang (Puma Biotechnology) for statistical and programming support. The authors also thank Lee Miller and Deirdre Carman (Miller Medical Communications Ltd) for medical writing/editing assistance, which was funded by Puma Biotechnology, Inc.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-023-36399-y
DO - 10.1038/s41467-023-36399-y
M3 - Article
C2 - 36746967
AN - SCOPUS:85147461227
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 630
ER -