Emerging Toxicities of Antibody-Drug Conjugates for Breast Cancer: Clinical Prioritization of Adverse Events from the Fda Adverse Event Reporting System

Abstract

Aim. We critically appraised the safety of antibody-drug conjugates (ADCs) approved for breast cancer, using the FDA Adverse Event Reporting System (FAERS).  We prioritized adverse events (AEs) reported in FAERS (February 2013-March 2022) for trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), by scoring (max 8 points) four criteria: clinical relevance (e.g., the so-called designated medical events), the reporting rate, the reported case fatality rate, and stability of disproportionality signals (consistency of the reporting odds ratio across multiple analyses using three different comparators).  

Results. We retained 6589 reports (77.4% referring to T-DM1 as suspect), and 572 AEs generated a disproportionality signal in at least one analysis. The majority of these AEs (62%) were classified as moderate clinical priorities (e.g., interstitial lung disease with T-DXd, thrombocytopenia, peripheral neuropathy with T-DM1, febrile neutropenia and large intestine perforation with SG). Three AEs emerged as high clinical priorities (6 points): septic shock and neutropenic colitis with SG (N=8 and 13, with median onset 13 and 10 days, respectively), without co-reported immunosuppressive agents; pulmonary embolism with T-DM1 (N=31, median onset 109 days, 52% with reported metastasis).

Conclusion. The heterogeneous spectrum of toxicities for ADCs used in breast cancer is largely predictable from pre-approval evidence. We call oncologists for increased awareness about early onset of septic shock and neutropenic colitis with SG, and late emergence of pulmonary embolism with T-DM1. In the absence of clear patient- and drug-related risk factors, stringent monitoring, timely discontinuation and prompt treatment are key risk minimization strategies.

Note:
Funding declaration: This work was supported by the Italian Ministry of Health (Ricerca Corrente) [no grant number provided].

Conflict of Interests: CZ has received grants from Novartis, Roche, Eisai, AstraZeneca, Pfizer, PharmaMar, Tesaro, Pierre Fabre, Ist. Gentili, Teva, Seagen, Eli Lilly, Celgene, MSD, GSK, Amgen, and Daiichi; has received support for attending meetings and/or travel from Novartis, Roche, Pfizer, PharmaMar, Tesaro, Pierre Fabre, Ist. Gentili, and Celgene; and has participated in data safety monitoring or advisory boards for Novartis, Roche, Eisai, AstraZeneca, Pfizer, PharmaMar, Amgen, Tesaro, Quintiles IMS, Eli Lilly, Celgene, MSD, GSK, and Daiichi. LG reports serving as a consultant/advisor for Lilly, Novartis, AstraZeneca, GlaxoSmithKline, and Incyte. SC, SP, MF, MY, FDP, ER have no conflicts of interest that are directly relevant to the content of this article.

Keywords: Antibody-drug conjugates, adverse event, pharmacovigilance, trastuzumab-deruxtecan, trastuzumab-emtansine, Sacituzumab govitecan, disproportionality analysis