Antibody–drug conjugates: smart chemotherapy delivery across tumor histologies

Antibody-drug conjugates; Enfortumab vedotin; Smart chemotherapy Conjugats anticossos-medicament; Enfortumab vedotin; Quimioteràpia intel·ligent Conjugados anticuerpos-fármaco; Enfortumab vedotin; Quimioterapia inteligente As distinct cancer biomarkers have been discovered in recent years, a need to reclassify tumors by more than their histology has been proposed, and therapies are now tailored to treat cancers based on specific molecular aberrations and immunologic markers. In fact, multiple histology-agnostic therapies are currently adopted in clinical practice for treating patients regardless of their tumor site of origin. In parallel with this new model for drug development, in the past few years, several novel antibody–drug conjugates (ADCs) have been approved to treat solid tumors, benefiting from engineering improvements in the conjugation process and the introduction of novel linkers and payloads. With the recognition that numerous surface targets are expressed across various cancer histologies, alongside the remarkable activity of modern ADCs, this drug class has been increasingly evaluated as suitable for a histology-agnostic expansion of indication. For illustration, the anti-HER2 ADC trastuzumab deruxtecan has demonstrated compelling activity in HER2-overexpressing breast, gastric, colorectal, and lung cancer. Examples of additional novel and potentially histology-agnostic ADC targets include trophoblast cell-surface antigen 2 (Trop-2) and nectin-4, among others. In the current review article, the authors summarize the current approvals of ADCs by the US Food and Drug Administration focusing on solid tumors and discuss the challenges and opportunities posed by the multihistological expansion of ADCs. Paulo Tarantino reports personal fees from AstraZeneca outside the submitted work. Roberto Carmagnani Pestana reports consulting fees from Bayer and honoraria from Pfizer, Merck, Bayer, and Servier outside the submitted work. Shanu Modi reports grants and nonfinancial support from Daiichi-Sankyo, Genentech, Novartis, Synta Pharmaceuticals, Seattle Genetics, Macrogenics, Carrick Pharmaceuticals, and Eli Lilly outside the submitted work. Aditya Bardia reports institutional grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics Inc, Mersana, Innocrin, and Biotheranostics Inc; consulting fees from Biotheranostics Inc, Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics Inc, Spectrum Pharma, Taiho, Sanofi, Daiichi Pharma, AstraZeneca, Puma, Phillips, and Eli Lilly; and meeting support from Biotheranostics Inc, Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics Inc, Spectrum Pharma, Taiho, Sanofi, and Phillips outside the submitted work. Sara M. Tolaney reports consulting fees from Novartis, Eli Lilly, Pfizer, Merck, AstraZeneca, Eisai, Puma, Genentech, Immunomedics Inc, Nektar, Tesaro, Daiichi-Sankyo, Athenex, Bristol Myers Squibb, and Nanostring outside the submitted work. Javier Cortes reports grants from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH-Servier Affaires, Bayer Healthcare, Eisai, F Hoffman-LaRoche, Guardant Health, MSD, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London; intellectual property for MedSIR; consulting fees from Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceuticals, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Bioasis, and Clovis Oncology; and honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, and Daiichi-Sankyo outside the submitted work. Jean-Charles Soria was formerly employed at AstraZeneca and is now employed by Amgen; owns stock in AstraZeneca, Gritstone Bio, and Relay Therapeutics; and serves on the Board of Directors for Hookipa Pharmaceuticals outside the submitted work. Giuseppe Curigliano reports a grant from Merck; consulting fees from Roche, Pfizer, Novartis, Seattle Genetics, Lilly, Ellipses Pharma, Foundation Medicine, Samsung, Daichii-Sankyo, and Exactsciences; honoraria from Pfizer, Novartis, Seattle Genetics, and Daichii-Sankyo; and meeting support from Foche and Pfizer outside the submitted work. Chiara Corti made no disclosures.