ENGOT-ov65/KEYNOTE-B96: Phase 3, randomized, double-blind study of pembrolizumab versus placebo plus paclitaxel with optional bevacizumab for platinum-resistant recurrent ovarian cancer.

TPS5617 Background: Despite therapeutic advances in ovarian cancer, platinum-resistant recurrent ovarian cancer (PROC) remains an area of high unmet clinical need and there is an urgent need for new treatments to further improve clinical outcomes. Addition of bevacizumab to non-platinum-based chemotherapy significantly improved PFS in patients with PROC but did not show a clear OS benefit. Thus far, the combination of paclitaxel and bevacizumab has shown the most promise in treatment of PROC, although the proportion of patients eligible for bevacizumab is limited by treatment-associated toxicities. Combination of the anti-PD-1 antibody pembrolizumab with weekly paclitaxel showed antitumor activity and manageable toxicity in patients with PROC in a single-arm, phase 2 study (Wenham Int J Gynecol Cancer 2018). The current study ENGOT-ov65/KEYNOTE-B96 (NCT05116189) compares the efficacy and safety of the addition of pembrolizumab to standard of care chemotherapy (weekly paclitaxel) with/without bevacizumab vs placebo plus weekly paclitaxel with/without bevacizumab in patients with PROC. Methods: In this randomized, placebo-controlled, double-blind, phase 3 study, eligible patients are aged ≥18 y with histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with 1-2 prior lines of systemic therapy, including at least 1 prior platinum-based therapy with ≥4 cycles in first line. Patients must have platinum-resistant disease (radiographic evidence of PD ≤6 mo after last platinum-based therapy dose), be eligible for paclitaxel (with/without bevacizumab per investigator discretion), have ECOG PS ≤1, radiographically evaluable disease per RECIST v1.1, and have a tumor sample for central evaluation of PD-L1 status. Approximately 616 patients will be randomized 1:1 to receive pembrolizumab 400 mg IV or placebo Q6W for up to 18 cycles (̃2 y) plus paclitaxel 80 mg/m2 on days 1, 8, and 15 of each Q3W cycle (with/without bevacizumab 10 mg/kg Q2W per investigator discretion) until PD or unacceptable toxicity. Randomization is stratified by planned bevacizumab use (yes vs no), region (US vs Europe vs rest of world), and PD-L1 status (combined positive score [CPS] < 1 vs CPS 1- < 10 vs CPS ≥10). Tumor PD-L1 status is determined using the PD-L1 IHC 22C3 pharmDx (Investigational Use Only) diagnostic kit. Tumor imaging is performed Q9W from randomization to week 54 and Q12W thereafter. The primary endpoint is PFS per RECIST version 1.1 by investigator review in patients with tumor PD-L1 CPS ≥1 and in all patients. Secondary endpoints are OS in patients with tumor PD-L1 CPS ≥1 and in all patients, PFS per RECIST version 1.1 by blinded independent central review in patients with tumor PD-L1 CPS ≥1 and in all patients, safety, and patient-reported outcomes. Enrollment is ongoing. Clinical trial information: NCT05116189.