Efficacy and safety results from neopembrov study, a randomized phase II trial of neoadjuvant chemotherapy (CT) with or without pembrolizumab (P) followed by interval debulking surgery and standard systemic therapy ± P for advanced high-grade serous carcinoma (HGSC): A GINECO study.
Authors: Ray-Coquard Isabelle Laure , Savoye Aude Marie , Mouret-Reynier Marie-ange , Chabaud Sylvie , Derbel Olfa , Kalbacher Elsa , Leheurteur Marianne , Martinez Alejandra , Cornila Corina , Martinez Mathilde , Bengrine Leila , Priou Frank , Cloarec Nicolas , Venat-Bouvet Laurence , Selle Frederic , Berton Dominique , Collard Olivier , Joly Florence , Tredan Olivier 
Published: June 2021

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Background: To investigate whether adding Pembrolizumab (P) to neoadjuvant carboplatin-paclitaxel chemotherapy (CP) may increase the optimal debulking rate, assessed by Complete Resection Rate (CRR) after Interval Debulking Surgery (IDS) in patients (pts) with initially unresectable International Federation of Gynecology and Obstetrics (FIGO) stage IIIC/IV ovarian, tubal or peritoneal HGSC. Methods: Multicenter, open-label, non-comparative randomized phase II trial. Pts were randomized (2:1) to receive 4 cycles of CP ± P before IDS. After IDS, all patients received post-operative chemotherapy (2 to 4 cycles) and optional bevacizumab for 15 months in total ± P as maintenance therapy for up to 2 years. Randomization was stratified on center, FIGO stage, Bev planned after IDS and disease volume (<5cm/>5cm). Primary endpoint was the centrally reviewed CRR at IDS. 60 pts were planned in the CP+P arm (A'Hern's single-stage design P0=50%, P1=70%). Safety (particularly due to P addition), surgical morbidity, ORR, PFS and OS were secondary endpoints. Results: 91 pts were randomized from 02/18 to 04/19 with a median Peritoneal Cancer Index at 24 (range 7-39). 80 pts (88%) received Bev in combination with CP followed by bev ± P in maintenance. In the CP+P group (n=61), 58 (95%) pts had IDS and 78% achieved complete resection. The CRR in this group was 74%, statistically superior to the pre-defined hypothesis. In the CP group, CRR was 70% (29/30 pts underwent IDS). Complete resection after strictly 4 cycles of CP±P was obtained for 41 pts (71%) and 17 (58%) pts in CP+P and CP group, respectively (sensitivity analysis). For CP+P group, numerically higher ORRs were observed before IDS compared to CP group (76% vs 61%). Grade ≥3 adverse events (AE) occurred in 75% of the CP+P group and 67% in the CP group: mainly blood and lymphatic, gastrointestinal and vascular disorders. Postoperative AE (mainly infectious, vascular and gastrointestinal) occurred in 20% and 13% of the pts in CP+P and CP arm, respectively. No difference in the number of fatal events between the two arms: 2 in the experimental arm vs 1 in the control arm. Progression free survival rate at 18 months was 61% (95CI% [47-73]) and 57% (95CI% [37-72]) in CP+P and CP arm, respectively. Conclusions: P may be safely added to preoperative treatment in pts deemed non-optimally resectable. The primary objective was met with an improved CRR on CP+P arm. The CRR in the control group was higher than expected. Survival data and translational research including PDL1 status are ongoing to better define P as treatment option in this setting. Clinical trial information: 2016-004-163-39. Clinical trial information: NCT03275506.