ESMO Open. 2025 Sep 4;10(9):105573. doi: 10.1016/j.esmoop.2025.105573. Online ahead of print.
ABSTRACT
BACKGROUND: Antibody-drug conjugates (ADCs) combine targeted monoclonal antibodies with cytotoxic payloads and are an emerging modality in systemic cancer therapy. Thirteen ADCs are Food and Drug Administration approved, with many more in development. However, design and use remain challenging, with issues including on/off-target toxicity, resistance from prior exposure to payload classes, and optimal target/payload selection.
PATIENTS AND METHODS: This pooled analysis included patients treated on 19 clinical trials (9 phase I, 10 phase II/III) of 14 novel ADCs at Sarah Cannon Research Institute, London (2012-2025). Patients who received one or more doses of the study drug were analyzed. Descriptive statistics and Cox regression were used to evaluate demographics, tumor characteristics, toxicity and outcomes, overall and in subgroups.
RESULTS: A total of 163 patients [median age 61 years (range 31-82 years); 46.8% male] were included. Most had breast (n = 53, 32.5%) or gynecological cancers (n = 36, 22.1%), with a median of 4 prior treatments (range 1-20). Payloads included alkylating agents (n = 3), microtubule inhibitors (n = 8), and topoisomerase inhibitors (n = 3). Four ADCs targeted an oncogene (HER2); others targeted tumor-associated antigens (TAAs). Treatment-emergent adverse events (TEAEs) occurred in 84% (grade 3-4 in 29%). Rates of any-grade colitis, interstitial lung disease (ILD), neuropathy, ocular toxicity, and hepatotoxicity were 2.4%, 6.0%, 25.1%, 18.0% and 22.8%, respectively. Most toxicities emerged within 6 weeks, except colitis (median 18.2 weeks), ILD (13.1 weeks), neuropathy (11.6 weeks) and thrombocytopenia (23.2 weeks). No significant difference in grade ≥3 AEs was seen across payload classes (P = 0.50), although HER2 targeting was associated with higher rates (P = 0.04). Overall objective response rate was 16%, higher with topoisomerase payloads (43%), HER2 targeting (49% versus 6% for TAAs), in breast cancer (39%), and at recommended phase II dosing (25%).
CONCLUSIONS: ADCs show activity across tumor types, with greater efficacy when targeting oncogenes. Toxicities are frequent and often early. Anticipating timing of toxicities is key to effective clinical management.
PMID:40912047 | DOI:10.1016/j.esmoop.2025.105573
