Efficacy and safety of antibody-drug conjugates in pretreated HER2-low metastatic breast cancer: A systematic review and network meta-analysis
- PMID: 39709655
- DOI: 10.1016/j.ctrv.2024.102865
Efficacy and safety of antibody-drug conjugates in pretreated HER2-low metastatic breast cancer: A systematic review and network meta-analysis
Abstract
Introduction: Antibody-drug conjugates (ADCs) trastuzumab-deruxtecan (T-DXd) and sacituzumab-govitecan (SG) provided significant progression-free survival (PFS) and overall survival (OS) improvements over chemotherapy (CT) in pretreated hormone receptor-positive (HR+) and triple-negative (TN)/HER2-low metastatic breast cancer (MBC). However, no direct comparison between the two exists, nor with the more recent datopotamab-deruxtecan (Dato-DXd).
Methods: We conducted a network meta-analysis (NMA) to compare efficacy and safety of T-DXd and SG in CT-pretreated HR+ and TN/HER2-low MBC and assess their benefit over standard CT, exploring also a comparison with Dato-DXd. Hazard ratios (HRs) with 95 % confidence intervals (CI) were calculated for PFS/OS. P-score was used for treatment ranking.
Results: Three RCTs (956 patients) were included in the primary analysis and 5 (1,445) in the exploratory NMA with Dato-DXd. In HR+/HER2-low, T-DXd showed no significant difference in PFS and OS when compared to SG. Similarly, in TN/HER2-low, PFS and OS did not differ significantly between the two ADCs. The P-score analysis favored T-DXd over SG in HR+/HER2-low in PFS (0.90 vs. 0.60) and OS (0.89 vs. 0.60). SG was favored over T-DXd in OS in TN/HER2-low (0.80 vs. 0.69). Similar results were obtained for HR+ MBC when including Dato-Dxd, which showed the worst performance, while T-DXd was the only ADC significantly outperforming CT in OS. The ADCs showed significantly better PFS and OS than CT in HR+/HER2-low and TN/HER2-low (all p < 0.001). SG had higher rates of neutropenia, diarrhea and alopecia vs. T-DXd, which showed more thrombocytopenia, fatigue and nausea. Pneumonitis and cardiotoxicity were typically T-DXd-related, and T-DXd showed more toxicity-related discontinuations.
Conclusions: Similar efficacy with T-DXd and SG in HER2-low MBC was observed, regardless of HR status. Safety profile, local drug-approval criteria and guidelines, patients' preferences and overall quality of evidence should ultimately guide therapeutic decision-making. Dato-DXd role remains uncertain.
Keywords: HER2-low; Metastatic breast cancer; Network meta-analysis; Sacituzumab govitecan; Trastuzumab deruxtecan.
Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Conflict of interest statement
Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: F. Schettini reports honoraria from Novartis, Gilead and Daiichy-Sankyo for educational events/materials and travel expenses from Novartis, Gilead and Daiichy-Sankyo. T. Pascual has received honoraria for speaker activities from Pfizer, AstraZeneca, Novartis, Veracyte and Argenetics and has held an advisory role with Novartis. O. Martínez-Sáez reports advisory/consulting fees from Reveal Genomics, Roche and Astrazeneca and lecture fees from Daiichi Sankyo, Pfizer, Novartis and Eisai and travel expenses from Gilead and Novartis. R. Sánchez-Bayona reported receiving travel grants from Pfizer, Gilead, AstraZeneca, and Novartis; receiving honoraria for speaker or advisory board participation from Novartis, Lilly, AstraZeneca, Daiichi Sankyo, Gilead, Roche, GlaxoSmithKline, Clovis Oncology, Seagen, and Accord; and having nonfinancial interests as a member of the ESMO YOC and scientific secretary of the Spanish Society of Medical Oncology. B. Conte reports speaker fees from Veracyte and payment for educational events from Medsite and Novartis.G. Buono received speaker’s honoraria, consulting honoraria, and advisory board honoraria from: Novartis, GSK, Eli-Lilly, Pfizer, AstraZeneca, Roche, Daiichi Sankyo, Seagen, Gilead, Exact Science and Genetic.M. Lambertini reported having an advisory role for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Menarini and Exact Sciences; receiving speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Takeda, Knight, Ipsen, Menarini and AstraZeneca; receiving travel grants from Gilead and Daiichi Sankyo; receiving research funding (to his institution) from Gilead; and having nonfinancial interests as the chair of the European Society for Medical Oncology (ESMO) Young Oncologists Committee (YOC) and as a member of the national council of the Italian Association of Medical Oncology. K. Punie reported receiving research grants (to his institution) from MSD and Sanofi; speaker fees and honoraria for consultancy and advisory board functions from AstraZeneca, Eli Lilly, Exact Sciences, Focus Patient, Gilead, Menarini, MSD, Novartis, Pfizer, Roche, and Seagen; speaker fees and honoraria for consultancy and advisory board functions (to his institution) from AstraZeneca, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pfizer, Roche, and Seagen; stock options from Need Inc; and travel grants from AstraZeneca, Novartis, Pfizer, PharmaMar, and Roche. J.M. Cejalvo reports speakers' fees from Daiichy Sankyo and Pfizer Inc. outside the submitted work.G. Arpino reports personal fees for research and medical writing: AstraZeneca; advisory boards, travel grants, activities as a speaker, consultancy: AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Exact Science, Novartis, Roche, Seagen, Viatris.D. Generali declares personal fees for educational events by Novartis, Lilly, Pfizer, Daiichy-Sankyo, Roche; research funds from AstraZeneca, Novartis and LILT. E. Ciruelos reports consulting fees from Novartis, Lilly, Pfizer, Roche, AstraZeneca, and Daiichi Sankyo; speaker's bureau from Lilly, Pfizer, AstraZeneca, and Daiichi Sankyo; and travel and accommodations from Pfizer and Roche. J. Cortés reports consulting for Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies; honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo.; research funding to the Institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F. Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; stock shares for MEDSIR, Nektar Pharmaceuticals, Leuko (relative); Travel, accommodation, expenses from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, Astrazeneca, Gilead; and Patents: Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés. US 2019/0338368 A1. LICENSED.A. Gennari received advisory role from AstraZeneca, Daiichi, Eisai, Lilly, Novartis, Pfizer, Roche, Seagen, Gilead, Teva, and Gentili; lecture honoraria from Novartis, Pfizer, Gilead, Roche, Eisai, Seagen, Teva, and Gentili; and research support from Roche, Eisai, Gilead, and Pharmanutra.M. Vidal has declared honoraria for presentations from Novartis, Roche, Pfizer, and Daichii, and travel expenses from Roche and Pfizer. Additionally, she has participated on a Data Safety Monitoring Board or Advisory Board for Novartis and Roche. S.M. Tolaney reports consulting or advisory roles for Novartis, Pfizer (SeaGen), Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Gilead, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corporation, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, and Arvinas; research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, NanoString Technologies, Seattle Genetics, and OncoPep; and travel support from Eli Lilly, Sanofi, Gilead, and Jazz Pharmaceuticals. A. Prat reports advisory and consulting fees from AstraZeneca, Roche, Pfizer, Novartis, Daiichi Sankyo, and Peptomyc, lecture fees from AstraZeneca, Roche, Novartis, and Daiichi Sankyo, institutional financial interests from AstraZeneca, Novartis, Roche, and Daiichi Sankyo; stockholder and employee of Reveal Genomics; patents filed PCT/EP2016/080056, PCT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369. G. Villacampa has received a speaker’s fee from Pfizer, MSD, GSK and Pierre Fabrer, has held an advisory role with AstraZeneca and received consultant fees from Reveal Genomics. The other authors have nothing to declare.
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