Population pharmacokinetic analysis of raludotatug deruxtecan (R-DXd), a cadherin 6 (CDH6)–directed antibody–drug conjugate (ADC), in patients (pts) with advanced ovarian cancer (OC) or renal cell carcinoma (RCC).

Abstract

5571 Background: R-DXd is a CDH6–directed ADC under clinical investigation for the treatment of pts with advanced or metastatic solid tumors, including platinum-resistant OC (PROC). This analysis was done to characterize the population pharmacokinetics (PopPK) of R-DXd and its small-molecule payload, DXd, in pts with OC or RCC. The analysis used data from two clinical studies of R-DXd: the first-in-human Ph 1 study in pts with OC or RCC (DS6000-A-U101; U101) and an ongoing global, randomized Ph 2/3 study in pts with PROC (REJOICE-Ovarian01). Methods: A joint PopPK model was developed for R-DXd and DXd, based on pooled data from the dose-escalation and -expansion parts of U101 (156 pts with OC and 23 with RCC; 1.6–9.6 mg/kg IV Q3W) and the dose-optimization primary analysis of REJOICE-Ovarian01 (107 pts with OC; 4.8, 5,6, or 6.4 mg/kg IV Q3W). The analysis was performed using nonlinear mixed-effects modeling in NONMEM (version 7.5.1). The effect of key intrinsic/extrinsic factors on the PK of R-DXd was explored through preliminary covariate analysis. Results: The PK of R-DXd and unconjugated DXd were adequately captured by the PopPK model. R-DXd displayed time-varying clearance, resulting in an elimination half-life of approximately 8 days after the first dose and 14 days at steady state. The overall PK profile supports a Q3W dosing interval. Consistent with findings from other mAbs and DXd-based ADCs, covariate analysis identified body weight (BW) as an influential covariate affecting R-DXd and DXd exposure, with the largest effect seen at the extremes of the BW distribution; pts with high BW (101 kg; 95 th percentile) showed 26% and 66% higher R-DXd and DXd steady state area under the concentration–time curve (AUC), respectively, relative to a reference pt (61 kg; median BW). Post-hoc estimates of R-DXd and DXd AUC by BW quartiles showed that exposure in pts in the highest BW quartile (>75 kg) trended higher yet remained within the range of pts with average BW (53–74 kg; 25 th –75 th percentile). Other baseline covariates did not have a clinically important effect on R-DXd or DXd AUC, with effects falling within the predefined range of 80–125% vs reference. These covariates were CDH6 expression (total % membrane staining at any intensity); R-DXd formulation; hepatic function (mild impairment vs normal); renal function (mild-to-moderate impairment vs normal); tumor size; albumin level; number of prior lines of therapy (1 vs 2–3 vs ≥4); tumor type (RCC vs OC); Asian vs non-Asian race. Conclusions: R-DXd 5.6 mg/kg IV Q3W, the recommended Ph 3 dose, does not appear to warrant adjustment for any of the patient-specific covariates and clinical characteristics investigated. These findings support the adequacy of this dose for the global population of pts with PROC being recruited in the Ph 3 part of REJOICE-Ovarian01.