Clinical pharmacology of vc-MMAE antibody–drug conjugates in cancer patients: learning from eight first-in-human Phase 1 studies

Abstract

ABSTRACTvc-MMAE antibody–drug conjugates (ADCs) consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile valine-citrulline (vc) linker. The objective of this study was to characterize the pharmacokinetics (PK) and explore exposure–response relationships of eight vc-MMAE ADCs, against different targets and for diverse tumor indications, using data from eight first-in-human Phase 1 studies. PK parameters of the three analytes, namely antibody-conjugated MMAE (acMMAE), total antibody, and unconjugated MMAE, were estimated using non-compartmental approaches and compared across the eight vc-MMAE ADCs. Relationships between analytes were assessed by linear regression. Exposure–response relationships were explored with key efficacy (objective response rate) and safety (Grade 2+ peripheral neuropathy) endpoints. PK profiles of acMMAE, total antibody and unconjugated MMAE following the first dose of 2.4 mg/kg were comparable across the eight ADCs; the exposure differences between molecules were small relative to the inter-subject variability. acMMAE exposure was strongly correlated with total antibody exposure for all the eight ADCs, but such correlation was less evident between acMMAE and unconjugated MMAE exposure. For multiple ADCs evaluated, efficacy and safety endpoints appeared to correlate well with acMMAE exposure, but not with unconjugated MMAE over the doses tested. PK of vc-MMAE ADCs was well characterized and demonstrated remarkable similarity at 2.4 mg/kg across the eight ADCs. Results from analyte correlation and exposure–response relationship analyses suggest that measurement of acMMAE analyte alone might be adequate for vc-MMAE ADCs to support the clinical pharmacology strategy used during late-stage clinical development.

Impact of Physiologically Based Pharmacokinetics, Population Pharmacokinetics and Pharmacokinetics/Pharmacodynamics in the Development of Antibody‐Drug Conjugates

“…31,32 A recent publication showed that for multiple vc-MMAE antibody-drug conjugates, efficacy (objective response rate [ORR]), and safety (grade 2+ peripheral neuropathy [PN]) end points appeared to correlate well with conjugate (acMMAE) exposure, but not with unconjugated MMAE over the doses tested in the phase 1 studies. 12 Similar exposure-response findings were also observed for brentuximab vedotin. 33 Theoretically, the payload in the tissues can come from circulating antibody-drug conjugate and/or payloads, but the exposure-response results suggest that the circulating antibody-drug conjugate appears to play a more important role in delivering payloads to the tissues compared with circulating payloads, and thus its exposure correlated better with the efficacy and safety outcomes.…”

“…A recent publication showed that for multiple vc‐MMAE antibody‐drug conjugates, efficacy (objective response rate [ORR]), and safety (grade 2+ peripheral neuropathy [PN]) end points appeared to correlate well with conjugate (acMMAE) exposure, but not with unconjugated MMAE over the doses tested in the phase 1 studies 12 . Similar exposure‐response findings were also observed for brentuximab vedotin 33 .…”

“…However, exposure of unconjugated MMAE was reduced ∼46% by rifampin and increased ∼34% by ketoconazole coadministration. 10 As most of the vc-MMAE antibody-drug conjugates have similar PK characteristics for both conjugated and unconjugated MMAE, 11,12 it is conceivable that we could leverage the information learned from the brentuximab vedotin DDI study to inform DDI risk assessment for other vc-MMAE antibody-drug conjugates in clinical development.…”

“…Similar exposure‐response findings were also observed for brentuximab vedotin 33 . Theoretically, the payload in the tissues can come from circulating antibody‐drug conjugate and/or payloads, but the exposure‐response results suggest that the circulating antibody‐drug conjugate appears to play a more important role in delivering payloads to the tissues compared with circulating payloads, and thus its exposure correlated better with the efficacy and safety outcomes 12 . Given the high potency of the payloads, unconjugated payload exposures may correlate with some safety end points in some cases and may be included in exposure‐safety analysis.…”

“…In general, conjugate is considered the key analyte correlating with both efficacy and safety outcomes, for which exposure is often highly correlated with the antibody‐drug conjugate dose. Because there is a high correlation between conjugate exposure and total antibody exposure, 12 it is of limited value to perform exposure‐response analysis using both total antibody and conjugate. Thus, the key analyte for exposure‐response analysis is usually the conjugate 31,32 …”