Persistence and resistance of HER2 amplification after T-DM1 in a basket trial for patients with solid tumors

BackgroundTrastuzumab emtansine (T-DM1) is a HER2-targeted antibody conjugate approved for HER2-positive breast cancers, with preliminary efficacy seen in other HER2-amplified solid tumors. Uncertainty exists regarding HER2 loss in solid tumors post-T-DM1 exposure, impacting treatment strategies.MethodsPatients with HER2-amplified advanced lung cancer, salivary gland cancer, or endometrial cancer participated in a T-DM1 basket trial. HER2 amplifications were identified by next-generation sequencing (NGS). Our investigation focused on reviewing HER2 immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and NGS data derived from tissue or plasma samples before and after treatment. Specifically, we analyzed samples from patients who initially responded partially (PR) or completely (CR) to T-DM1 treatment but later progressed. Descriptive statistics were employed.ResultsA total of 27 patients diagnosed with lung (n=9), salivary gland (n=13), or endometrial cancer (n=5) achieved either PR or CR. Among the 5 patients who had paired NGS on pre- and post-treatment tissue biopsies, HER2 amplification was detected in 4 of the post-treatment samples. All 6 patients who had paired HER2 IHC tests displayed IHC 3+ results both before and after treatment. Additionally, 2 patients who had paired HER2 FISH tests showed positive results in both pre- and post-treatment biopsies. Among the 27 patients who achieved PR/CR with T-DM1 treatment, 10 patients received alternative anti-HER2 therapies after disease progression, with 8 of them experienced subsequent PR/CR. In 3 out of 4 patients with estimated circulating tumor DNA (ctDNA) fractions of >3% both at pre-and post-treatment, we detected HER2 amplification at both timepoints. Moreover, the magnitude of estimated fold change of HER2 was concordant with the ctDNA fraction estimated from point mutations, suggesting persistence of HER2 amplification without negative clonal selection in these patients.ConclusionsMost patients retained HER2 amplification post-T-DM1, irrespective of cancer type, suggesting resistance mechanisms independent of the target. Sequential HER2 targeted therapies may be a viable treatment strategy in this patient population.Clinical trial identificationNCT02675829.Legal entity responsible for the studyMemorial Sloan Kettering Cancer Center.FundingConquer Cancer Foundation of the American Society of Clinical Oncology; U.S. National Institutes of Health.DisclosureV. Makker: Financial Interests, Institutional, Funding, Study funding: Merck, Eisai, Clovis, Karyopharm, AstraZeneca; Financial Interests, Institutional, Funding, Study support: Zymeworks; Financial Interests, Institutional, Funding, Study Support: BMS, Duality, Faeth, Takeda; Financial Interests, Institutional, Local PI: Cullinan; Non-Financial Interests, Principal Investigator: Merck; Non-Financial Interests, Advisory Role: Eisai, Clovis, Novartis, Lilly, GSK, Karyopharm, Iteos, Faeth, Duality, ZYmeworks, Morphosys, Moreo; Other, Travel to Scientific Congress-SGO2024: AstraZeneca. D. Buonocore: Financial Interests, Personal, Stocks or ownership: Merck, Novartis. R. Yaeger: Financial Interests, Personal, Other, Honoraria: Zai Lab; Financial Interests, Institutional, Research Funding: Array BioPharma, Boehringer Ingelheim, Mirati Therapeutics, Pfizer. M.D. Offin: Financial Interests, Personal, Other, Honoraria: OncLive; Financial Interests, Personal, Advisory Role: American Society for Radiation Oncology, Jazz Pharmaceuticals, Novartis, Targeted Oncology; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck Sharp & Dohme. D. Solit: Financial Interests, Personal, Stocks or ownership: Fore Biotherapeutics, Pyramid Biosciences, Scorpion Therapeutics, Vividion Therapeutics; Financial Interests, Personal, Advisory Role: BridgeBio Pharma, Fog Therapeutics, Fore Biotherapeutics, Pfizer, Scorpion Therapeutics, Vividion Therapeutics. A.E. Drilon: Financial Interests, Personal, Advisory Board: 14ner/Elevation Oncology, AbbVie, Amgen, ArcherDX, AstraZeneca, BeiGene, BerGenBio, Blueprint Medicines, EcoR1, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Liberum, Loxo/Bayer/Lilly, Melendi, Monopteros, Monte Rosa, Novartis, Pfizer, Remedica Ltd., TP Therapeutics, Takeda/Ariad/Millennium, Tyra Biosciences, Verastem Oncology; Financial Interests, Personal, Other, CME: AiCME, Clinical Care Options, MJH Life Sciences, Med Learning, Medscape, Medscape, Onclive, Paradigm Medical Communications, PeerView Institute, PeerVoice, Physicians Education Resources, Targeted Oncology, WebMD; Financial Interests, Personal, Other, Consulting: Applied Pharmaceutical Science, Inc, EPG Health, Entos, Harborside Nexus, Merus, Nuvalent, Ology, Prelude, TouchIME, Treeline Bio, mBrace; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, RV More, Remedica Ltd; Financial Interests, Personal, Stocks/Shares: Treeline Biosciences; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, stocks: mBrace; Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, PharmaMar, GSK, Teva, Taiho; Financial Interests, Personal, Funding, Research: Foundation Medicine; Non-Financial Interests, Member: ASCO, AACR, IASLC; Other, Food/Beverage: Merck, PUMA, Merus; Other: Boehringer Ingelheim. C.M. Rudin: Financial Interests, Personal, Advisory Role: AbbVie, Amgen, AstraZeneca, Bridge Medicines, Daiichi Sankyo/UCB Japan, Earli, Epizyme, Genentech/Roche, Harpoon Therapeutics, Ipsen, Jazz Pharmaceuticals, Kowa, Merck, Syros Pharmaceuticals; Financial Interests, Institutional, Research Funding: Merck (Inst), Roche/Genentech (Inst). M.G. Kris: Financial Interests, Personal, Advisory Role: AstraZeneca, BerGenBio, Janssen, Merus, Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, Genentech. P. Razavi: Financial Interests, Personal, Stocks or ownership: Odyssey Biosciences; Financial Interests, Personal, Advisory Board: AstraZeneca, Epic Sciences, Guardant Health, Inivata, Natera, Novartis, PAIGE.AI, Prelude Therapeutics, SAGA Diagnostics, Tempus; Financial Interests, Institutional, Research Funding: Invitae/Archer, AstraZeneca, bioTheranostics, Epic Sciences, Grail, Guardant Health, Illumina, Novartis, Tempus, Inivata, Biovica, Personalis, Myriad; Financial Interests, Personal, Advisory Role: Pfizer, Lilly/Loxo, Foundation Medicine; Financial Interests, Personal, Research Funding: Myriad. J. Drago: Financial Interests, Personal, Advisory Role: AmMax Bio, AstraZeneca, GenagonTherapeutics, NuProbe, Launchpad Therapeutics, MEDACorp; Financial Interests, Personal, Speaker, Consultant, Advisor: Intellisphere, Llc; Financial Interests, Institutional, Research Funding: AstraZeneca. S. Chandarlapaty: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Effector, Nuvalent, Genesis Therapeutics, Prelude Therapeutics, SAGA Diagnostics, Neogenomics, Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares, Company with PI3K inhibitor asset - will not be discussed at all in the conference: Totus Medicines; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Paige.ai, AstraZeneca; Financial Interests, Institutional, Steering Committee Member: Lilly; Non-Financial Interests, Advisory Role: Breast Cancer Research Foundation. M. Berger: Financial Interests, Personal, Advisory Role: AstraZeneca, Lilly, PetDx. A.L. Ho: Financial Interests, Personal, Invited Speaker, discussed head and neck cancer therapies: Chinese American Hematologist and Oncologist Network; Financial Interests, Personal, Invited Speaker, Discussed salivary cancer therapies: Lurie Cancer Center (Northwestern); Financial Interests, Personal, Invited Speaker, discussed thyroid cancer therapies: Physician Education Resource; Financial Interests, Personal, Invited Speaker, Discussed thyroid cancer therapies: Endocrine Society; Financial Interests, Personal, Invited Speaker, Discussed head and neck cancer therapies: University of Pittsburgh Medical Center; Financial Interests, Personal, Invited Speaker, Discussed thyroid cancer therapeutics: New York University; Financial Interests, Personal, Advisory Board, Serve on DSMC: Affyimmune; Financial Interests, Personal, Other, Serve on the NCI Head and Neck Steering Committee: National Cancer Institute; Financial Interests, Personal, Advisory Board, Member of advisory board: Exelixis, Remix Therapeutics, Elevar Therapeutics, Prelude Therapeutics, Eisai, Ayala, Kura Oncology; Financial Interests, Personal, Other, Member of Safety Monitoring Committee: Kura Oncology; Financial Interests, Personal, Advisory Board, Member of advisory board: Merck; Financial Interests, Personal, Other, Consultant: ExpertConnect; Financial Interests, Personal, Advisory Board, Member of advisory board and consulting.: Rgenta; Financial Interests, Personal, Full or part-time Employment: Memorial Sloan Kettering Cancer Center; Financial Interests, Personal, Stocks/Shares, options: Rgenta Therapeutics; Financial Interests, Institutional, Other, Listed as inventor for: Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Coordinating PI, Serve as PI, also served on paid advisory board: Ayala; Financial Interests, Institutional, Coordinating PI, Serve as trial PI, also serve on paid SMC/advisory board: Kura Oncology; Financial Interests, Institutional, Local PI, Trial PI and served on an advisory board: Elevar Therapuetics; Financial Interests, Institutional, Coordinating PI, PI of IIT: Novartis, Merck, Bristol Meyer Squibb; Financial Interests, Institutional, Coordinating PI, PI of several IIT trials: Bayer; Financial Interests, Institutional, Coordinating PI, PI of trial: Bioatla, TILT Biotherapeutics, Genentech Roche, Astellas, Celldex; Financial Interests, Institutional, Local PI, PI of trial: OncC4; Financial Interests, Institutional, Coordinating PI, PI of several IITs: AstraZeneca; Financial Interests, Institutional, Coordinating PI, PI of trial and was part of paid advisory board: Eisai; Financial Interests, Institutional, Local PI, co-PI of trial: Poseida Therapuetics; Financial Interests, Institutional, Local PI: Hookipa; Non-Financial Interests, Advisory Role: Cellestia, Inxmed; Non-Financial Interests, Member of Board of Directors: International Thyroid Oncology Group; Non-Financial Interests, Leadership Role: International Rare Cancer Initiative; Non-Financial Interests, Leadership Role, for the head and neck working group: Alliance for Clinical Trials in Oncology. B.T. Li: Financial Interests, Personal, Royalties, Intellectual property rights as a book author: Karger Publishers, Shanghai Jiao Tong University Press; Financial Interests, Institutional, Other, Inventor on institutional patents at MSK (US62/685,057, US62/514,661): Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Coordinating PI, Institutional clinical trials funding to Memorial Sloan Kettering Cancer Center: Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui, Lilly; Financial Interests, Institutional, Funding, Institutional clinical trial funding to Memorial Sloan Kettering Cancer Center: Revolution Medicines; Non-Financial Interests, Advisory Role, Uncompensated advisor and consultant: Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Lilly; Non-Financial Interests, Other, Academic travel support, but without compensation: More Health, Jiangsu Hengrui Pharmaceuticals; Non-Financial Interests, Member: American Society of Clinical Oncology, International Association for the Study of Lung Cancer. All other authors have declared no conflicts of interest.