Sex-based differences in tolerability of developmental antibody-drug conjugates (ADCs) in non-small-cell lung cancer (NSCLC)

BACKGROUND: Sex-based differences in treatment-related adverse events (TRAEs) have been described across several anticancer therapies. However, sex-disaggregated safety data for antibody-drug conjugates (ADCs) in non-small-cell lung cancer (NSCLC) is lacking. PATIENTS AND METHODS: We conducted a monocentric cohort study including patients with advanced NSCLC treated with developmental ADCs within phase I-II clinical trials at Gustave Roussy (2018-2023). Clinically significant TRAEs (grade ≥2, Common Terminology Criteria for Adverse Events version 5.0), dose modifications, hospitalisations, and survival outcomes were analysed according to sex using univariate and multivariate analysis. RESULTS: Our population included 132 patients [women, 64 (48.5%); men, 68 (51.5%)] receiving ADCs targeting TROP2 (32.6%), ITGB6 (31.8%), HER2 (13.6%), CEACAM5 (13.6%), HER3 (5.4%), c-MET (2.3%), and Nectin-4 (0.7%). Overall, 100 (76%) and 39 (29%) patients experienced grade ≥2 and grade ≥3 TRAEs, respectively. Women had a higher incidence of grade ≥2 TRAEs than men [82.8% versus 69.1%; adjusted odds ratio (OR) 2.8, 95% confidence interval (CI) 1.03-7.84, P = 0.04)] and a higher median number of TRAEs (2 versus 1, P = 0.04). Metabolic TRAEs (anorexia, weight loss, ion and lipid imbalances) were significantly more frequent in women (29.7% versus 10.3%; OR 3.68, 95% CI 1.42-9.49, P = 0.009), as were dose reductions (37.5% versus 19.1%; OR 3.35, 95% CI 1.24-9.01, P = 0.02). CONCLUSIONS: Women treated with developmental ADCs for advanced NSCLC experience a higher burden of clinically relevant TRAEs. Our data suggest that sex may represent a key variable to integrate into safety reporting and monitoring strategies for developmental ADCs in NSCLC.