Learnings from Approved Antibody‐Drug Conjugates: Clinical Pharmacology Perspectives

Over the past decade, antibody-drug conjugates (ADCs) have emerged as promising anti-cancer therapeutics, with twelve ADCs approved by the FDA. This review evaluates trends in these ADCs, stratified by payloads on doses studied from first-in-human (FIH) trials through approval and post-marketing. It summarizes trends in pharmacokinetics (PK), drug-drug interactions (DDI), exposure-response analysis, immunogenicity, and organ impairment. Additionally, it provides perspectives on potential postmarketing requirements associated with clinical pharmacology attributes, and how this knowledge could inform efficient early clinical development of newer ADCs. Except for sacituzumab govitecan, which had a starting dose of 8 mg/kg, starting doses of ADCs ranged from 0.0067 to 0.8 mg/kg. All ADCs have been administered intravenously. Dose escalation generally progressed over four to eight distinct levels, with increments of 20% to 233% at the first three levels. The maximum tolerated dose was achieved by the fourth to seventh dose level in most cases. For 5/12 ADCs, the recommended phase 2 dose and the phase 3 dose were the same as the MTD. Approved doses ranged from 1.25-fold to 40-fold higher than the FIH starting dose levels. Generally, ADCs exhibited dose-proportional PK within the tested dose range. Exposure-response relationships have been reported for ADC/total antibody for efficacy and ADC/total antibody/payload exposures for safety. DDI potential has been reported for payloads associated with auristatins, maytansinoids, and camptothecin: SN38. At approved doses, immunogenicity assessments indicated low incidence of anti-drug antibodies. Organ impairment studies suggest no significant risk in patients with moderate hepatic or renal impairment.