Influence of antibody-drug conjugate cleavability, drug-to-antibody ratio, and free payload concentration on systemic toxicities: A systematic review and meta-analysis.

While in theory antibody drug conjugates (ADCs) deliver high-dose chemotherapy directly to target cells, numerous side effects are observed in clinical practice. We sought to determine the effect of linker design (cleavable versus non-cleavable), drug-to-antibody ratio (DAR), and free payload concentration on systemic toxicity. Two systematic reviews were performed via PubMed search of clinical trials published between January 1998-July 2022. Eligible studies: (1) clinical trial for cancer therapy in adults, (2) ≥ 1 study arm included a single-agent ADC, (3) ADC used was commercially available/FDA-approved. Data was extracted and pooled using generalized linear mixed effects logistic models. 40 clinical trials involving 7,879 patients from 11 ADCs, including 9 ADCs with cleavable linkers (N = 2,985) and 2 with non-cleavable linkers (N = 4,894), were included. Significantly more composite adverse events (AEs) ≥ grade 3 occurred in patients in the cleavable linkers arm (47%) compared with the non-cleavable arm (34%). When adjusted for DAR, for grade ≥ 3 toxicities, non-cleavable linkers remained independently associated with lower toxicity for any AE (p = 0.002). Higher DAR was significantly associated with higher probability of grade ≥ 3 toxicity for any AE. There was also a significant interaction between cleavability status and DAR for any AE (p = 0.002). Finally, higher measured systemic free payload concentrations were significantly associated with higher DARs (p = 0.043). Our results support the hypothesis that ADCs with cleavable linkers result in premature payload release, leading to increased systemic free payload concentrations and associated toxicities. This may help to inform future ADC design and rational clinical application.