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In the past decade, ERBB2 (formerly HER2)–directed antibody-drug conjugates (ADCs) have substantially changed treatment of both advanced and early-stage ERBB2-positive breast cancer. Novel conjugates are now showing activity in trials of other ERBB2-associated tumors, leading to the recent US Food and Drug Administration approval of trastuzumab deruxtecan for ERBB2-positive gastric cancer, as well as beneficial results in colorectal, lung, and bladder cancer. It is thus possible that anti-ERBB2 ADCs may become a treatment option for multiple types of tumors because many have at least some expression of ERBB2. Despite an improved overall therapeutic index, clinical observations have recently raised a concern regarding potential lung toxicity of anti-ERBB2 ADCs. Deaths related to interstitial lung disease (ILD) have been reported with variable incidence in trials testing anti-ERBB2 conjugates, warranting appropriate training of clinicians for the identification and management of this toxic effect.
Although no specific guidelines are available for the diagnosis and management of ADC-related ILD, some recommendations can be derived based on general principles adopted for drug-induced and immunotherapy-related ILD. Overall, in symptomatic ILD, the ADC should be discontinued. Reintroduction of the conjugate can be considered only in asymptomatic cases after complete resolution. Corticosteroids represent the cornerstone of ILD treatment, and dosing should be adapted according to the severity of the event. Additional treatments can be considered based on the clinical scenario.
Conclusions and Relevance
This review summarizes the current knowledge on the pathogenesis and epidemiologic characteristics of anti-ERBB2 ADC-related lung toxicity, proposing strategies for its diagnosis and treatment. Earlier diagnosis and more adequate treatment of ADC-induced ILD may improve the therapeutic index of this important class of anticancer agents, allowing for a safe expansion of anti-ERBB2 ADCs across tumor types.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: March 17, 2021.
Published Online: October 14, 2021. doi:10.1001/jamaoncol.2021.3595
Corresponding Author: Giuseppe Curigliano, MD, PhD, Division of Early Drug Development–European Institute of Oncology IRCCS, Via Ripamonti 435, Milan, Italy, 20141 (firstname.lastname@example.org).
Author Contributions: Dr Tarantino had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Andrè and Curigliano contributed equally to the work.
Concept and design: Tarantino, Hamilton, Curigliano.
Acquisition, analysis, or interpretation of data: Modi, Tolaney, Cortés, Kim, Toi, Andrè, Curigliano.
Drafting of the manuscript: Tarantino, Hamilton, Curigliano.
Critical revision of the manuscript for important intellectual content: Tarantino, Modi, Tolaney, Cortés, Kim, Toi, Andrè, Curigliano.
Administrative, technical, or material support: Modi, Hamilton, Curigliano.
Supervision: Tarantino, Tolaney, Cortés, Curigliano.
Conflict of Interest Disclosures: Dr Modi reported receiving research funding and speaking/consulting fees from Genentech, Daiichi Sankyo, AstraZeneca, and Seattle Genetics, and consulting fees from MacroGenics during the conduct of the study. Dr Tolaney reported receiving grants from AstraZeneca, Bristol Myers Squibb, Cyclacel Pharmaceuticals, Eisai, Eli Lilly, Exelixis, Genentech/Roche, Immunomedics/Gilead studies, Merck, NanoString, Nektar, Novartis, Odonate, Pfizer, Sanofi, and Seattle Genetics to the institution outside the submitted work; she also reported receiving honoraria for consultant or advisory board service from AstraZeneca, Athenex, Bristol Myers Squibb, Certara, CytomX, Daiichi Sankyo, Eisai, Eli Lilly, Genentech/Roche, Immunomedics/Gilead, Kyowa Kirin Pharmaceuticals, Merck, Mersana Therapeutics, NanoString, Nektar, Novartis, Odonate, OncoPep, Pfizer, Puma Biotechnology, Samsung Bioepis, Sanofi, and Seattle Genetics. Dr Cortés reported receiving honoraria for consulting from Daiichi Sankyo and AstraZeneca during the conduct of the study; honoraria for consulting from Roche, Celgene, Cellestia, Bio-Thera, Merus, Seattle Genetics, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Novartis, Eisai, Pfizer, Samsung Bioepis, and Kyowa Kyrin outside the submitted work; and holding stock in MedSIR. Dr Hamilton reported research funding to the institution from OncoMed Research, Genentech/Roche, Zymeworks, Rgenix, ArQule, Clovis, Silverback Therapeutics, Millennium Pharmaceuticals, Medivation, Acerta Pharma, Sermonix, Aravive, Torque, Black Diamond, Karyopharm, Infinity Pharmaceuticals, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, Fujifilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova, Dana-Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Puma Biotechnology, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Takeda, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, NuCana, Leap Therapeutics, Zenith, Harpoon, Orinove, AstraZeneca, Tesaro, MacroGenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Polyphor, Immunogen, Plexxicon, and Amgen; advisory fees paid to the institution from Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, and AstraZeneca outside the submitted work. Dr Kim reported receiving research funding to the institution from Novartis and Sanofi Genzyme. Dr Toi reported receiving grants from Chugai; lecture honoraria and grants from Daiichi Sankyo; and lecture and advisory honoraria for drug development during the conduct of the study; grants and lecture honoraria from Takeda, Pfizer, Kyowa Kirin, and Taiho; grants from the JBCRG Association, Eisai, AstraZeneca, and Eli Lilly; honoraria for lecture and as an advisor for drug development from Exact Sciences; honoraria for lecture from Novartis; grants from Astellas; honoraria as an advisor for drug development from Bristol Myers Squibb; grants and lecture honoraria from Shimadzu Yakult and Nippon Kayaku; grants from AFI Technologies; honoraria as an advisor from Athenex Oncology; honoraria as an advisor for drug development from Bertis; honoraria as an advisor for device development from Terumo; grants for device development from Luxonus; grants from Shionogi Research and GL Sciences; honoraria for an advisory role from Kansai Medical Net outside the submitted work; and honoraria for serving on the board of directors for JBCRG Association, Kyoto Breast Cancer Research Network, and Organisation for Oncology and Translational Research. Dr Andre reported receiving grants to the institution from Novartis, Roche, Pfizer, AstraZeneca, Daiichi Sankyo, and Lilly outside the submitted work. Dr Curigliano reported receiving honoraria for lectures and serving on the Daiichi Sankyo advisory board, grants from Merck for investigator-initiated research, and serving on the advisory boards of AstraZeneca, Bristol Myers Squibb, Roche, Lilly, Pfizer, Novartis, Exact Sciences, and Seagen outside the submitted work. No other disclosures were reported.
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