Abstract Background: R-DXd is a novel cadherin 6 (CDH6)-directed antibody-drug conjugate (ADC) under clinical investigation. In ongoing Phase 1 DS6000-A-U101 (NCT04707248) and Phase 2/3 REJOICE-Ovarian01 (NCT06161025) studies, preliminary data showed promising results in patients with platinum-resistant ovarian cancer (PROC). To support dose selection in PROC, a pharmacokinetic-tumor growth inhibition (PK-TGI) model was developed to investigate the effect of R-DXd exposure on tumor size and predict percent change from baseline in tumor size across R-DXd doses of interest (4.8, 5.6, and 6.4 mg/kg), as well as explore the effect of CDH6 expression levels on tumor response. Methods: The analysis dataset comprised 229 patients enrolled from either study who completed at least 18 weeks of follow-up (ie, 3 postbaseline tumor scans). Time-course data of PK (ADC and released payload DXd plasma concentration) and tumor size (sum of longest diameters SLD, assessed by blinded independent central review BICR) were collected from PROC patients treated with R-DXd monotherapy at 1.6-9.6 mg/kg IV Q3W in DS6000-A-U101 and the dose optimization part of REJOICE-Ovarian01. The PK-TGI model was developed using nonlinear mixed-effects modeling and adapted from previously published TGI modeling frameworks by Claret et al. Simulations accounting for parameter uncertainties were conducted to predict tumor response of R-DXd treatment across dose levels for a typical reference patient. Results: Model parameters were estimated with good precision, and goodness-of-fit plots showed that model predictions describe data appropriately. The final model was comprised of three components: 1) a drug-induced tumor killing rate () driven by R-DXd concentration, which is 2) attenuated over time by a resistance term (), and 3) tumor growth described as a saturated logistic function, , in which represents the intrinsic growth rate, tumor size, and the maximum tumor size. The simulations demonstrated a clear exposure-response relationship, with higher doses of R-DXd associated with stronger tumor shrinkage: predicted median tumor shrinkage at 24 weeks was −52%, −58%, and −64% for 4.8, 5.6, and 6.4 mg/kg, respectively. Additionally, baseline CDH6 protein expression was identified as a significant covariate on parameter, positively associated with tumor shrinkage, with its effect tending to plateau with increasing expression levels. Conclusions: The PK-TGI model could adequately characterize changes in tumor size as a function of R-DXd concentration as well as quantify the effect of target expression on tumor shrinkage. Combined with the totality of clinical data and an overall assessment of benefit-risk, the analyses supported the selection of 5.6 mg/kg Q3W as the optimal monotherapy dose of R-DXd for the Phase 3 part of the REJOICE-Ovarian01 study. Citation Format: YoungJun Yoo, Kevin Koloskoff, Sandra Re, Izna Ali, Felipe K. Hurtado, Raouf El Cheikh. Pharmacokinetic-tumor growth inhibition modeling of raludotatug deruxtecan (R-DXd) to support phase 3 dose selection in platinum-resistant ovarian cancer (PROC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1820.
Yoo et al. (Fri,) studied this question.