Increased systemic toxicities from antibody-drug conjugates (ADCs) with cleavable versus non-cleavable linkers: A meta-analysis of commercially available ADCs.

Abstract

3032 Background: Though in theory ADCs should deliver high-dose chemotherapy directly to target cells with few systemic effects, in clinical practice numerous side effects have been observed. We hypothesized that ADCs with cleavable linkers would have more systemic toxicities than those with non-cleavable linkers due to the increased free payload released systemically. To compare their side effect profiles, we conducted a meta-analysis of adverse events (AEs) of commercially available ADCs. Methods: Systematic review yielded 12 phase II/III clinical trials that led to the FDA approval of commercially available ADCs. Polatuzumab vedotin was not included because it was only studied in combination with other agents. Any grade AEs and grade ≥3 AEs occurring in at least 5% of patients in each study were recorded. The estimated inverse variance weighted absolute average risk and 95% confidence interval (CI) were estimated for each AE. Absolute risk differences and 95% CIs were estimated by linker type. Results: Data from 2,417 patients treated with 9 ADCs were pooled. 7 ADCs had cleavable linkers (N = 1,082), and 2 had non-cleavable linkers (N = 1,335). At least half of studies reported thrombocytopenia, neutropenia, anemia, increased AST and ALT, nausea, vomiting, diarrhea, hypokalemia, headache, and fatigue, as well as rates of all grade and grade ≥3 AEs. AEs ≥ grade 3 occurred in 43% of patients overall, 47% in the cleavable linker arms and 34% in the non-cleavable arms. This was significantly different (weighted risk difference -12.9%; 95% CI -17.1% to -8.8%). There was also a significant difference favoring non-cleavable linkers for ≥ grade 3 neutropenia (-9.1%; 95% CI -12% to -6.2%) and ≥ grade 3 anemia (-1.7%; 95% CI -3.3% to -0.1%). Cleavable linkers were significantly associated with increased AST all grade (3.9%; 95% CI 0.3% to 7.5%) and increased ALT all grade (3.7%; 95% CI 0.2% to 7.3%), though notably the CI approached 0 on the low end of difference for each. There was no significant difference in rates of all grade AEs or in rates of discontinuation due to AEs. There was no significant difference in rates of all grade nausea, vomiting, diarrhea, hypokalemia, or headache. Finally, there was no significant difference in rates of grade ≥3 thrombocytopenia, increased AST/ALT, or fatigue. Conclusions: Cleavable linkers appear to have significantly higher rates of ≥ grade 3 AEs and neutropenia within the limitations of this non-randomized comparison and treatment of heterogeneous malignancies. The increased payload in the circulation likely accounts for this; however, it may also make them more efficacious, as suggested by the results of the DESTINY-Breast03 trial. In the final analysis, we will compare the efficacy of cleavable vs non-cleavable ADCs indirectly using the standard of care for each tumor and line of therapy, with the exception of breast cancer.

Exploration of the antibody–drug conjugate clinical landscape

“…In addition to cytosolic payload release, cleavable linkers have also been shown to be cleaved extracellularly due to the presence of cleaving agents in the blood and/or tumor microenvironment (TME). These linkers can be associated with both increased adverse events (due to systemic payload release) 19 and increased efficacy due to noted “bystander effects” (wherein released payload can diffuse across the plasma membrane of a higher tumor antigen expressing cell to adjacent tumor cells with lower antigen expression). 20 An ADC can also be created with a non-cleavable linker that only releases payload after proteolysis by lysosomal enzymes.…”