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. 2023 Feb 6;14(1):630.
doi: 10.1038/s41467-023-36399-y.

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

James J Harding  1   2 , Sarina A Piha-Paul  3 , Ronak H Shah  4   5 , Jessica J Murphy  4   5 , James M Cleary  6 , Geoffrey I Shapiro  6 , David I Quinn  7 , Irene Braña  8   9 , Victor Moreno  10 , Mitesh Borad  11 , Sherene Loi  12 , Iben Spanggaard  13 , Haeseong Park  14 , James M Ford  15 , Mónica Arnedos  16 , Salomon M Stemmer  17   18 , Christelle de la Fouchardiere  19 , Christos Fountzilas  20   21 , Jie Zhang  22 , Daniel DiPrimeo  22 , Casey Savin  4   5 , S Duygu Selcuklu  4   5 , Michael F Berger  4   5 , Lisa D Eli  22 , Funda Meric-Bernstam  3 , Komal Jhaveri  4   23 , David B Solit  4   23   5 , Ghassan K Abou-Alfa  4   23
Affiliations

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

James J Harding et al. Nat Commun. .

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.

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Conflict of interest statement

J.J.H. has received institutional research support from Bristol Myers Squibb, Boehringer Ingelheim, CytomX, Calithera, Eli Lilly, Genoscience, Incyte, Loxo, Novartis, Pfizer, Yiviva, and Zymeworks and has consulted for Adaptimmune, Bristol Myers Squibb, CytomX, Eisai, Eli Lilly, Exelixis, Merck, QED, and Zymeworks. S.A.P.-P.: has received clinical trial support (to institution) from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceuticals, Inc., Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Inc., Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Limited, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., HiberCell, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Lytix Biopharma AS, Medimmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Silverback Therapeutics, Synlogic Therapeutics, Taiho Oncology, Tesaro, Inc., and TransThera Bio, and research grant NCI/NIH P30CA016672 – Core Grant (CCSG Shared Resources). R.H.S.: no conflicts declared. J.J.M.: no conflicts declared. JMC: has received research support from Merck, AstraZeneca, Esperas, Tesaro, and Bayer, and payments or honoraria from Syros and Blueprint. G.I.S.: has received research funding from Eli Lilly, Merck KGaA/EMD Serono, Merck, and Sierra Oncology. He has served on advisory boards for Pfizer, Eli Lilly, G1 Therapeutics, Merck KGaA/EMD Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics, Blueprint Medicines, Kymera Therapeutics, Janssen and Xinthera. In addition, he holds a patent entitled, “Dosage regimen for sapacitabine and seliciclib,” also issued to Cyclacel Pharmaceuticals, and a pending patent, entitled, “Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition,” together with Liam Cornell. DIQ: has received institutional research support from Merck Sharp and Dohme, Pfizer, Genentech, and Millennium and has consulted for Astellas, Aveo, BMS, Bayer, Genentech/Roche, EMD Serono, Merck Sharp and Dohme, Pfizer and Seagen, received payments or honoraria from Astellas, Aveo, BMS, Bayer, Genentech/Roche, EMD Serono, Merck Sharp and Dohme, Pfizer and Seagen, undertaken data safety monitoring for Eisai and US Biotest, and has employment with AbbVie. I.B.: has received research funding from Puma Biotechnology Inc for the manuscript (to institution), a personal grant from the Spanish National Health Institute, research funding from Institut Salud Carlos III (personal grant Rio Hortega Contract - CM15/00255) and La Caixa Foundation Institutional grant LCF/PR/CEO7/50610001, research funding from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Gliknik, Incyte, ISA Pharmaceuticals, Janssen Oncology, Kura, Merck Serono, Merck Sharp & Dohme, Novartis, Northern Biologics, Orion Pharma, Regeneron, Seattle Genetics, Shattuck Labs, and VCN Biosciences (all institutional research funding to the principal investigator), personal consulting fees from Achilles Therapeutics, Cancer expert Now, eTheRNA Immunotherapies, Merck Sharp & Dohme, and Rakuten Pharma, payments or honoraria from Bristol Myers Squibb, Merck Serono, and Merck Sharp & Dohme (personal fees), support for attending meetings from Merck Serono, and Merck Sharp & Dohme (personal fees), and is an advisory board member of the ESMO Head and Neck Tract, EORTC Head and Neck Group, and Cancer Core Europe Clinical Taskforce. VM: research funding to institution from AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, BMS, Boehringer, Boston, Celgene, Daiichi Sankyo, DEBIOPHARM, Eisai, e-Terapeutics, Exelixis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Sponsor, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, and Upsher-Smith Laboratories, and personal consulting fees from Roche, Bayer, Janssen, and Basliea. M.B.: reports grants from Adaptimmune, grants from Senhwa Pharmaceuticals, grants from Agios Pharmaceuticals, personal fees from Merck, grants from EMD Serono, grants from Halozyme, grants from Celgene, grants from Toray, grants from Dicerna, grants from Taiho, grants from Sun Biopharma, grants from Isis Pharmaceuticals, grants from Redhill Pharmaceuticals, grants from Boston Biomed, grants from Basilea, grants from Incyte Pharmaceuticals, grants from Mirna Pharmaceuticals, grants from Medimmune, grants from Bioline, grants from Sillajen, grants from ARIAD, grants from Puma Pharmaceuticals, grants from QED, grants from Novartis Pharmaceuticals, personal fees from ADC Therapeutics, personal fees from Exelixis, personal fees from Inspyr, personal fees from G1 Therapeutics, personal fees from Immunovative, personal fees from OncBioMune, personal fees from Western Oncolytics, personal fees from Lynx Group, personal fees from Genentech, personal fees from HUYA, grants from AstraZeneca, outside the submitted work. S.L.: receives research funding to her institution from Novartis, Bristol Myers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech and Seattle Genetics. She has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer and Roche-Genentech. She has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, Puma Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Amunix, Tallac Therapeutics, Eli Lilly and Bristol Myers Squibb. I.S.: has received research support (to institution) from Puma Biotechnology, Roche/Genentech, AstraZeneca, Incyte, Pfizer, Orion Pharma, MSD, Bristol Myers Squibb, Novartis, Loxo Oncology, Amgen, and Genmab, and support for travel and attending meetings from Roche and Novartis. H.P.: writing support for the manuscript from Puma Biotechnology Inc, research grant UM1 CA186689, research support to institution from Adlai Nortye USA, Alpine Immune Sciences, Ambrx, Amgen, Aprea Therapeutics AB, Array BioPharma, Bayer, BeiGene, BJ Bioscience, Bristol Myers Squibb, Daiichi Pharmaceutical, Eli Lilly, Elicio Therapeutics, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Hoffmann-LaRoche, Hutchison MediPharma, ImmuneOncia Therapeutics, Incyte, Jounce Therapeutics, Mabspace Biosciences, MacroGenics, Medimmune, Medivation, MERCK, Millennium, Mirati Therapeutics, Novartis Pharmaceuticals, Oncologie, Pfizer, PsiOxus Therapeutics, Puma Biotechnology, Regeneron, Pharmaceuticals, RePare Therapeutics, Seattle Genetics, Synermore Biologics, Taiho Pharmaceutical, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, Xencor Inc, honorarium from Medscape, and support for attending meetings from Daiichi Sankyo and Vedanta. JMF: has received research funding from Puma Biotechnology Inc for the manuscript (to institution), and research support from Pfizer, Genentech, Merus, Incyte, and AstraZeneca (all to institution). M.A.: has received research funding from Puma Biotechnology Inc for the manuscript (to institution), research funding from Eli Lilly (to institution), consulting fees from AbbVie (to self), payments or honoraria from Pfizer (to self), Roche (to institution), and AstraZeneca (to institution), and support for attending meetings from Pfizer and AstraZeneca (to self). S.M.S.: has received research funding from Puma Biotechnology, Inc. CdelaF: has received grants or contracts from Pierre Fabre Oncologie; payments or honoraria from Amgen, Bayer, Eisai, Servier, Ipsen, and Lilly; payments for expert testimony from Incyte, MSD, Pierre Fabre Oncologie, Ipsen, Roche, and Daiichi Sankyo; support for attending meetings and/or travel from Amgen, Roche, MSD, and Merck. C.F.: has received research funding from Puma Biotechnology Inc for the manuscript (to institution), research funding from the National Comprehensive Cancer Network Oncology Research Program, Taiho Oncology, and Pfizer Inc (all to institution), and equipment, materials, drugs, medical writing, gifts or other services from Pfizer Inc and Taiho Oncology (both to institution). J.Z.: was an employee of and shareholder in Puma Biotechnology, Inc. D.DiP.: is an employee of and shareholder in Puma Biotechnology, Inc. C.S.: no conflicts declared. S.D.S.: no conflicts declared. M.F.B.: has received research funding from Grail and consulting fees from Eli Lilly and PetDx. L.D.E.: is an employee of and shareholder in Puma Biotechnology, Inc. F.M.-B.: has received research funding from Puma Biotechnology Inc for the manuscript (to institution), research funding from Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, and Taiho Pharmaceutical Co. (all to institution), consulting fees from AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffmann-La Roche Ltd., Genentech Inc., IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, and Zymeworks, an honorarium for speaking engagement from Chugai Biopharmaceuticals, and advisory board membership for Black Diamond, Biovica, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, and Zentalis. K.J.: has received research funding from Puma Biotechnology Inc for the manuscript (to institution). D.B.S. has received consulting fees from BridgeBio, Pfizer, Loxo/Lilly Oncology, FORE Therapeutics, Scorpion Therapeutics, and Vividion Therapeutics and owns stock or stock options in Loxo Oncology, Scorpion Therapeutics, and Vividion Therapeutics. GKA-A has received research funding from Puma Biotechnology Inc for the manuscript, institutional research support from Arcus, Agios, AstraZeneca, BioNTech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Silenseed, and Yiviva, consulting support form Adicet, Alnylam, AstraZeneca, Autem, Bayer, Beigene, Berry Genomics, Celgene, Cend, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Merck, Nerviano, QED, Redhill, Rafael, Servier, Silenseed, Sobi, Surface Oncology, Therabionics, Vector, and Yiviva, and a patent (International Patent Application No. PCT/US2014/031545 filed on March 24, 2014, and priority application Serial No.: 61/804,907; Filed: March 25, 2013).

Figures

Fig. 1
Fig. 1. Study flow.
*Death was due to progressive disease. EOS end of study.
Fig. 2
Fig. 2. Activity of treatment (n = 25).
a Waterfall plot for 19 patients with Response Evaluation Criteria in Solid Tumours (version 1.1)-evaluable disease; six patients who were not evaluable are not depicted. Dotted line indicates −30% tumor shrinkage; b Time on treatment and response assessment for all 25 study patients. Data cut-off: January 22, 2021. CI confidence interval. Source data are provided as a Source Data file.
Fig. 3
Fig. 3. Esimated Survial For HER2-mutant Biliary Tract Cancer Patients Treated with Neratenib.
Kaplan–Meier curves for a progression-free survival and b overall survival. Source data are provided as a Source Data file.
Fig. 4
Fig. 4. Genomic determinates of response to neratinib (n = 23).
a Lollipop diagram of the HER2 gene annotated with centrally confirmed mutations and tumour responses. Letters within circles indicate matching samples, i.e., patients with more than one mutation; b OncoPrint of co-occurring genomic alterations annotated with objective response, central next-generation sequencing confirmation assay best tumour shrinkage, PFS, and OS. NE not estimable, OS overall survival, PD progressive disease, PFS progression-free survival, PR partial response, SD stable disease. Source data are provided as a Source Data file.
Fig. 5
Fig. 5. Polyclonal resistance to neratinib.
A patient with adenosquamous carcinoma of the gallbladder harbouring a HER2 amplified/S310F mutation who had progression of disease on gemcitabine plus cisplatin, FOLFOX, and FOLFIRI achieved a confirmed PR on treatment with neratinib. a Cross-sectional and treatment course imaging showing tumour response and progression (purple arrow); b serial cfDNA and c paired paired-tissue next-generation sequencing. cfDNA cell-free DNA, EOT end of treatment, FOLFIRI 5-fluorouracil/folinic acid + irinotecan, FOLFOX 5-fluorouracil/folinic acid + oxaliplatin, MSK-ACCESS Memorial Sloan Kettering-Analysis of Circulating cfDNA to Evaluate Somatic Status, MSK-IMPACT Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, PR partial response, tx treatment. Source data are provided as a Source Data file.
See this image and copyright information in PMC

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