(A-229) A,B,Cs of ADCs (Antibody–Drug Conjugates) Post-Marketing Pharmacoepidemiology Planning

Background: A number of antibody–drug conjugates (ADCs), an innovative class of agents linking cytotoxic payloads to monoclonal antibodies targeting a specific cancer cell antigen, have been recently approved. These agents have proved highly effective in improving clinical outcomes. The full characterization of their real- world benefits and risks in the post marketing setting is ongoing.

Objectives: To describe the FDA and EMA regulatory approach to submission review, labelling, and post-marketing benefit-risk evidence generation individual ADCs approved for solid tumor indications.

Methods: ADCs approved in the US and/or EU with an indication for select solid cancers approved from 2011 (year of Brentuximab vedotin approval) to 31 January 2025 were identified through review of regulatory letters and documents (e.g., PMR/C database, Clinicaltrials.gov, Project ORBIS approvals list, SmPC, RMP EPARs, EMA-HMA Catalogue). Data was extracted from regulatory documents on main labelled AEs and post-marketing requirements relevant to safety or benefit risk evaluation using a pre-defined form.

Results: 7 ADCs, with 12 indications, are available in the US. All products initially received accelerated approval with 5 now fully FDA-approved. 6 products (11 indications) had at least 1 black box label warning and all 7 (12) had multiple warnings and precautions with the most common warnings listed being: embryo-fetal toxicity (6 products, 9 indications), peripheral neuropathy (5, 8), and myelosuppression (4, 9). At least one safety PMR was requested for 6 products, a PMC for 5. Of 15 PMR/Cs, 9 required data from new or ongoing trials while 6 were integrated analyses including existing trial and observational data. Two products were reviewed through Project Orbis. Two additional products have received FDA Breakthrough Therapy Designation. Among 6 ADCs available in the EU, for 10 indications, the most common important identified risks in the RMP as special warnings and precautions were embryo-fetal toxicity (5 products, 7 indications), myelosuppression (4, 8), and interstitial lung disease and serious skin reactions (both 4, 7). Of 11 PASS , 4 were category 2 - imposed (for 2 products) and 7 were category 3 - voluntary (5 products); 8 PASS required data from new or ongoing trials and 3 had observational design.

Conclusions: As ADCs indication expansions and further approvals are expected in the near future, resulting in a rapidly expanding population of patients exposed. It will be crucial to monitor measures required by health authorities to address or mitigate safety concerns to ensure effective and aligned risk management planning and to maximize the value of epidemiological data.