Exposure–response (E–R) analyses of efficacy and safety with raludotatug deruxtecan (R-DXd), a CDH6-directed antibod-drug conjugate (ADC), to inform dose selection for phase (Ph) 3 development in platinum-resistant ovarian cancer (PROC).

5570 Background: R-DXd, an ADC, comprises a humanized cadherin 6 (CDH6) IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload (DXd) via a tumor-selective cleavable linker. R-DXd monotherapy demonstrated promising antitumor activity and a manageable safety profile at doses up to 6.4 mg/kg IV Q3W in patients (pts) with heavily pretreated ovarian cancer (OC) in a Ph 1 study and in pts with PROC in an ongoing Ph 2/3 study. We report findings from E–R analyses of key efficacy and safety endpoints that supported R-DXd dose selection for Ph 3 clinical investigation in patients with PROC. Methods: Data were included from (i) the first-in-human Ph 1 study in pts with advanced OC (N=156) or renal cell carcinoma (RCC; N=23) evaluating R-DXd 1.6–9.6 mg/kg Q3W (NCT04707248), and (ii) the dose-optimization part of the Ph 2/3 REJOICE-Ovarian01 study in pts with PROC (N=107) (NCT06161025), in which pts were randomized 1:1:1 to receive R-DXd 4.8, 5.6, or 6.4 mg/kg Q3W. E–R analysis for efficacy was conducted based on pooled data from 241 pts with PROC using BICR-assessed endpoints: ORR (primary endpoint in the Ph 2 part of REJOICE-Ovarian01), best change in target lesion size, DOR, and PFS. Further, E–R analysis for safety was performed for 11 AEs of clinical interest using data from 286 pts treated with R-DXd across tumor types (OC, RCC). ORR and all safety endpoints, except interstitial lung disease (ILD), were analyzed by logistic regression; DOR, PFS, and ILD were analyzed using the Kaplan–Meier method. Numerous patient-specific covariates were evaluated. Results: E–R analyses demonstrated positive dose–response relationships for both efficacy and safety. Higher R-DXd exposure was associated with increased probability of achieving objective response, greater reduction in target lesion size from baseline, longer PFS, and longer DOR. Covariate analysis identified that baseline CDH6 expression was positively associated with ORR and tumor response. Higher R-DXd or DXd payload exposure was associated with an increase in drug-related TEAEs, including Grade ≥3 (G3+) AEs, any-grade ILD, G2+ gastrointestinal AEs (nausea/vomiting), G3+ cytopenias (anemia, neutropenia, thrombocytopenia), and AEs leading to dose reduction. While higher doses of R-DXd are predicted to maximize efficacy based on the E–R analysis, the 5.6 mg/kg dose provides an overall optimal balance of safety, tolerability, and efficacy compared to 6.4 mg/kg and 4.8 mg/kg. Conclusions: Integrated E–R analyses, combined with the totality of data from 286 pts, support selection of 5.6 mg/kg Q3W as the optimal R-DXd monotherapy dose for the Ph 2 extension and Ph 3 parts of REJOICE-Ovarian01, in accordance with the principle of benefit/risk for oncology dose optimization and guidelines from the FDA’s Project Optimus.