Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study
- PMID: 34339623
- DOI: 10.1016/S1470-2045(21)00336-3
Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study
Abstract
Background: Systemic therapies for metastatic biliary tract cancers are few, and patients have a median overall survival of less than 1 year. MyPathway evaluates the activity of US Food and Drug Administration-approved therapies in non-indicated tumours with potentially actionable molecular alterations. In this study, we present an analysis of patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both treated with a dual anti-HER2 regimen, pertuzumab plus trastuzumab, from MyPathway.
Methods: MyPathway is a non-randomised, multicentre, open-label, phase 2a, multiple basket study. Patients aged 18 years and older with previously treated metastatic biliary tract cancers with HER2 amplification, HER2 overexpression, or both and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled from 23 study sites in the USA and received intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) plus trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary outcome and adverse events were analysed in all patients who received at least one dose of pertuzumab and trastuzumab. This trial is registered with ClinicalTrials.gov, NCT02091141, and is ongoing.
Findings: 39 patients enrolled in the MyPathway HER2 biliary tract cancer cohort between Oct 28, 2014, and May 29, 2019, were evaluable for anti-tumour activity by the March 10, 2020, data cutoff date. Median follow-up was 8·1 months (IQR 2·7-15·7). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11-39]). Grade 3-4 treatment-emergent adverse events were reported in 18 (46%) of 39 patients, most commonly increased alanine aminotransferase and increased aspartate aminotransferase (each five [13%] of 39). Treatment-related grade 3 adverse events were reported in three (8%) of 39 patients, including increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, and blood bilirubin. Serious treatment-emergent adverse events were observed in ten (26%) of 39 patients, of which only abdominal pain occurred in more than one patient (two [5%] of 39). There were no treatment-related serious adverse events, treatment-related grade 4 events, or deaths.
Interpretation: Treatment was well tolerated in patients with previously treated HER2-positive metastatic biliary tract cancer. The response rate is promising for the initiation of randomised, controlled trials of pertuzumab plus trastuzumab in this patient population.
Funding: F Hoffmann-La Roche-Genentech.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Conflict of interest statement
Declaration of interests MJ has received research funding from QED, Novartis, and Meclun; has received honoraria from Taiho, Seattle Genetics, and Merck; has served as a consultant for Origimed, More Health, EDO, Incyte, Taiho, EMD Serono, and Oncosil; and his institution has received research funding from Arqule and Lilly. MJB has served as a consultant for ADC Therapeutics, Exelixis Pharmaceuticals, Inspyr Therapeutics, G1 Therapeutics, Immunovative Therapies, OncBioMune Pharmaceuticals, Western Oncolytics, Lynx Group, Genentech, Merck, and Huya; has received travel reimbursement from AstraZeneca; and his institution has received research funding from Senhwa Pharmaceuticals, Adaptimmune, Agios Pharmaceuticals, Halozyme Pharmaceuticals, Celgene Pharmaceuticals, EMD Merck Serono, Toray, Dicerna, Taiho Pharmaceuticals, Sun Biopharma, Isis Pharmaceuticals, Redhill Pharmaceuticals, Boston Biomed, Basilea, Incyte Pharmaceuticals, Mirna Pharmaceuticals, Medimmune, Bioline, Sillajen, ARIAD Pharmaceuticals, PUMA Pharmaceuticals, Novartis Pharmaceuticals, QED Pharmaceuticals, and Pieris Pharmaceuticals. NSA has served on advisory boards for GSK and QED, and has received research funding from Astex, Intensity, Celgene, BMS, Merck, Array, Bayer, Syndax, Incyte, Debio, Taiho, Daiichi, EMD Serono, and Eli Lilly. RK has received research funding from Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Konica Minolta, DeBiopharm, Boehringer Ingelheim, and OmniSeq; has served as a consultant or advisor for LOXO, X-Biotech, Actuate Therapeutics, Roche, NeoMed, Gaido, and Solventis; has served on a speaker's bureau for Roche; has received honoraria from Roche, NeoGenomics, Sysmex, NeoMed Therapeutics, Advanced Therapy Program, LEK Consulting, Chugai, CME Education, Avera, Wiley, and LOXO AACR; has an ownership interest or stock in IDbyDNA CureMatch and Soluventis; and has a leadership role in CureMatch. GKA-A has received research funding from Arcus, Agios, AstraZeneca, Bayer, BioNtech, BMS, Celgene, Flatiron, Genentech–Roche, Genoscience, Incyte, Polaris, Puma, QED, Sillajen, and Yiviva, and served as a consultant for Agios, AstraZeneca, Alnylam, Autem, Bayer, Beigene, Berry Genomics, Celgene, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech–Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, LOXO, Merck, MINA, QED, Redhill, Rafael, Silenseed, Sillajen, Sobi, Surface Oncology, Therabionics, Twoxar, Vector, and Yiviva. BG has served as a consultant for Celgene, Ipsen, Foundation Medicine, Bristol Myers Squibb, Exelixis, Taiho Oncology, and Roche–Genentech; has received research funding from B Braun CeGaT, Celgene, Foundation Medicine, Roche–Genentech, Taiho Oncology, Boehringer Ingelheim, Tolero, Toray, and NGM Biopharmaceuticals. JH has received research funding paid to his institution from Astellas, AstraZeneca, Genentech, and Novartis; and has served as a consultant or advisor for Roche. FM-B has received honoraria from Chugai Biopharmaceuticals, Mayo Clinic, and Rutgers Cancer Institute of New Jersey; has received research funding for her institution from Aileron Therapeutics, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis, CytomX Therapeutics, Daiichi Sankyo, Debiopharm International, eFFECTOR Therapeutics, Genentech, Guardant Health, Millennium Pharmaceuticals, Novartis, Puma Biotechnology, and Taiho Pharmaceutical; has served as a consultant for Aduro BioTech, Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F Hoffman-La Roche, Genentech, IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer, Samsung Bioepis, Seattle Genetics, Tyra Biosciences, Xencor, and Zymeworks; has served on advisory committees for Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology, Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, and Zentalis; and has received travel reimbursement from Beth Israel Deaconess Medical Center. CS has received grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx, and Ono Pharmaceutical; has served as an advisory board member and chief investigator for the MeRmaiD-1 clinical trial for AstraZeneca; has served as a consultant for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Celgene, AstraZeneca, Illumina, Amgen, Genentech, Roche-Ventana, GRAIL, Medicxi, Bicycle Therapeutics, and the Sarah Cannon Research Institute; owns stock in Apogen Biotechnologies, Epic Bioscience, GRAIL, and Achilles Therapeutics (co-founder); and holds patents relating to assay technology to detect tumour recurrence (PCT/GB2017/053289), targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), establishing whether HLA LOH is lost in a tumour (PCT/GB2018/052004), predicting survival rates of cancer patients (PCT/GB2020/050221), treating cancer by targeting insertion–deletion mutations (PCT/GB2018/051893), identifying insertion–deletion mutation targets (PCT/GB2018/051892), detecting tumour mutations (PCT/US2017/028013), and identifying responders to cancer treatment (PCT/GB2018/051912). CJS has served as a consultant for Amgen, Astellas Pharma, AstraZeneca, Bayer, Tolmar, Genentech–Roche, Janssen Biotech, and Sanofi; owns stock in Leuchemix; and has patents with Leuchemix and Exelixis; his institution has received research funding from Astellas Pharma, Exelixis, and Janssen Biotech. CFF has served on scientific advisory boards (unpaid) for Merck and Genentech, and her institution has received research funding from Bristol Myers Squibb, Merck, AstraZeneca, Daiichi, and Genentech. RB has served as a consultant for Roche–Genentech; has received honoraria from Roche–Genentech, Foundation Medicine, and Novartis; and has received research funding from Puma Biotechnology. DRS has a leadership role with Centennial Medical Center (HCA; BOT-chair); has served as a consultant for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Evelo Therapeutics, Foundation Medicine, Genentech–Roche, GlaxoSmithKline, Illumina, Lilly, Merck, Moderna Therapeutics, Nektar, Novartis, Pfizer, PharmaMar, Precision Oncology, Takeda, and TRM Oncology; has received travel reimbursement from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, EMD Serono, Genentech, Genzyme, Intuitive Surgical, Lilly, Merck, Perdue Pharma, Pfizer, Spectrum Pharmaceuticals, and Sysmex; and his institution has received research funding from AbbVie, Acerta Pharma, Aeglea Biotherapeutics, Amgen, ARMO BioSciences, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Foundation Medicine, GlaxoSmithKline, G1 Therapeutics, Genentech–Roche, GRAIL, Ipsen, Lilly, Merck, Millennium, Nektar, Novartis, Neon Therapeutics, Pfizer, Takeda, Tesaro, Transgene, and The University of Texas Southwestern Medical Center—Simmons Cancer Center. YW, JL, KS, VC, and AP are employed by and own stock in Roche–Genentech. HB reports employment, leadership and an ownership interest or stock in HCA Healthcare–Sarah Cannon; has been paid for expert testimony by Novartis; has served as consultant or advisor with fees paid to his institution for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eisai, FORMA Therapeutics, Incyte, Janssen, MedImmune, Mersana, Novartis, Roche–Genentech, Tolero Pharmaceuticals; and has received research funding paid to his institution from Agios, Arch, Arvinas, AstraZeneca, BioAtla, BioMed Valley Discoveries, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CicloMed, CytomX Therapeutics, eFFECTOR Therapeutics, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Immunocore, Incyte, Janssen, Jiangsu Hengrui Medicine, Jounce Therapeutics, Kyocera, Lilly, LOXO, Macrogenics, MedImmune, Merck, Millennium, Moderna Therapeutics, Novartis, Revolution Medicines, Roche/Genentech, Seattle Genetics, Takeda, Tesaro, TG Therapeutics, Verastem, and Vertex. All authors received non-financial support from F Hoffmann-La Roche in the form of medical writing support for this manuscript.
Comment in
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Paving a pathway for drug development in HER2-positive biliary tract cancer.Lancet Oncol. 2021 Sep;22(9):1204-1206. doi: 10.1016/S1470-2045(21)00465-4. Lancet Oncol. 2021. PMID: 34478661 No abstract available.
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