(T-072) Exposure–Response Relationship of Dostarlimab With Chemotherapy in Primary Advanced/Recurrent Endometrial Cancer: Results From Interim Analysis Two of Part 1 of ENGOT-EN6-NSGO/GOG-3031/RUBY Trial

Mita Kuchimanchi, M.S – Director, Clinical Pharmacology Modeling and Simulation, GSK, Waltham, MA, USA; Trine Lembrecht Jørgensen, MD, PhD – Clinical Oncologist, Odense University Hospital, Odense, Denmark; Eva Hanze, MSc – Senior Consultant, qPharmetra, Uppsala, Sweden; Angela Jain, MD – Medical Oncologist, Fox Chase Cancer Center, Philadelphia, PA, USA; Oskar Alskär, PhD – Consultant, qPharmetra, Uppsala, Sweden; Oleksandr Zub, PhD – Gynecologic Oncologist, Chernihiv Medical Center of Modern Oncology, Chernihiv Regional Council, Chernihiv, Ukraine; Mark S. Shahin, M.D. – Gynecologic Oncologist, Hanjani Institute for Gynecologic Oncology Abington Hospital-Jefferson Health, Asplundh Cancer Pavilion, Sidney Kimmel Medical College of Thomas Jefferson University, Willow Grove, PA, USA; Anthoula Koliadi, MD – Specialist physician, Uppsala University Hospital, Uppsala, Sweden; Bhavana Pothuri, MD – Gynecologic Oncologist, GOG Foundation and Departments of Obstetrics/Gynecology and Medicine, Division of Gynecologic Oncology, Laura & Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA; Tom Krivak, MD – Gynecologic Oncologist, Division of Gynecologic Oncology, The Western Pennsylvania Hospital, Pittsburgh, PA, USA; Mikalai Pishchyk, MD – Oncologist, Grodno Regional Clinical Hospital, Grodno, Belarus; Yakir Segev, MD MSc – Gynecologic Oncologist, Carmel Medical Center, Technion-Israel Institute of Technology, Haifa, Israel; Floor J. Backes, MD – Gynecologic Oncology Specialist, The Ohio State University College of Medicine, The James Cancer Hospital and Solove Research Institute, Columbus, OH, USA; Christine Gennigens, MD – Medical Oncologist, Department of Medical Oncology, CHU of Liège, Liège, Belgium, and Belgium and Luxembourg Gynaecological Oncology Group (BGOG); Sara Bouberhan, MD – Medical Oncologist, Massachusetts General Hospital, Boston, MA, USA; Stefan Zajic, PhD – Senior Director, Clinical Pharmacology Modeling & Simulation, GSK, Collegeville, PA, USA; Murad Melhem, PhD – Senior Director/ Clinical Pharmacology, Modeling and Simulation (Oncology), GSK, Waltham, MA, USA; Joseph Buscema, MD – Gynecologic Oncologist, Arizona Oncology, Tucson, AZ, USA

Objectives: Dostarlimab, an immune-checkpoint inhibitor, blocks the interaction between programmed cell death protein-1 (PD-1) and its ligands (PD-L1 and PD-L2). In the phase 3 RUBY trial (NCT03981796), dostarlimab+carboplatin-paclitaxel (CP) significantly improved PFS and OS vs placebo+CP in patients (pts) with primary advanced or recurrent endometrial cancer (pA/rEC). The first interim analysis (IA1) of RUBY Part 1 revealed no significant exposure–response (ER) relationship for PFS or for the 5 most common adverse events (AEs), except for rash (deemed not clinically relevant).1 Here, we report ER data from IA2 to assess the ER relationship between dostarlimab and OS, and between dostarlimab and dostarlimab-related AEs.

Methods: Due to limited pharmacokinetic (PK) sample accrual after IA12, no further PK analyses were performed at IA2. Population PK model predictions from IA12 were used at IA2. OS, defined as time from randomization to date of death by any cause, was analyzed using Cox regression. Covariates included mismatch repair status (mismatch repair deficient/microsatellite instability-high vs mismatch repair proficient/microsatellite stable), disease status in EC, prior external pelvic radiotherapy, baseline ECOG performance status, geographic location, and histology. Logistic regression was used to describe the relationship between the occurrence of dostarlimab-related AEs and dostarlimab exposure. Safety analysis was based on the 5 most common AEs of any grade at any time, assessed by investigators as related to dostarlimab (fatigue, nausea, rash, diarrhea, and arthralgia). AE analysis was completed for 3 periods: cycles 1–6 (chemotherapy phase [dostarlimab/placebo+CP]), cycle 7 and greater (monotherapy phase [dostarlimab/placebo alone]), and all cycles.

Results: In total, 232 pts treated with dostarlimab+CP with ≥2 quantified dostarlimab concentrations were included in the OS analysis. Cox regression of OS showed no significant ER relationship based on dostarlimab cycle 1 exposure. Geographic location, histology, and mismatch repair status were identified as significant covariates (P < 0.05) for OS; however, patient numbers were small in these exploratory analyses and should be interpreted with caution. Among the most common AEs, only rash and arthralgia exhibited significant (P < 0.05) ER relationships. The increase in predicted probabilities for rash and arthralgia for pts with high vs low exposure was limited, ranging from 5.6%–10.4% for rash and 4.3%–17.7% for arthralgia, depending on the exposure metric and time period assessed, making the relationship flat in nature.

Conclusions: Consistent OS benefits were demonstrated across the exposure metrics evaluated and no clinically meaningful ER relationships between dostarlimab exposure and safety were observed. Therefore, dose adjustment based on any covariate is not warranted. These data support the recommended therapeutic dose of dostarlimab in combination with CP in pts with pA/rEC.

Citations: [1] Kuchimanchi M, et al. ACoP 2023; Nov 5-8, 2023; National Harbor, MD. Poster PMX870.
[2] Melhem M, et al. ACoP 2023; Nov 5-8, 2023; National Harbor, MD. Poster PMX864.