Stage 1 results of BrUOG 354: A randomized phase II trial of nivolumab alone or in combination with ipilimumab for people with ovarian and other extra-renal clear cell carcinomas (NCT03355976).

Abstract

5598 Background: Clear Cell Carcinoma (CCC) outside the kidney is a rare tumor that can arise from multiple organs, including the ovary, endometrium and cervix. Extra-renal CCC is chemoresistant and has a poor prognosis. Data suggest that CCC of the gynecologic tract resembles the genomic profile of Renal Cell Carcinoma (RCC), which is responsive to immune checkpoint inhibition (ICI) therapy. We are conducting a two-stage phase 2 trial evaluating immunotherapy for extra-renal CCC. The primary objective is to assess overall rate of response (ORR); Progression-Free (PFS), Overall Survival (OS), and correlative biomarker studies are secondary. Here we present the results of Stage 1. Methods: This is a randomized two-stage non-comparative phase II study evaluating nivolumab (240mg IV every two weeks) alone (N) and in combination with ipilimumab (1mg/kg every six weeks, [N+I]) in patients with relapsed extra-renal CCC after at least one prior chemotherapy (no prior ICI), and measurable disease. Treatment was continued until disease progression or unacceptable toxicity. Stage 1 of this trial called for up to 30 volunteers (15 per arm) after which the study was closed. Consideration to reopen to stage 2 called for two or more responses in either arm. Here we present the completion of Stage 1; the release of results was approved by Brown University Oncology Group (BrUOG) Data Safety and Monitoring Committee. Results: Between July 2018 and October 2021, 30 patients were enrolled and 29 were treated (Table). The majority (83%) had CCC of the ovary (n=24). The ORR with N and N+I was 14.2 and 26.7%, respectively. The 6 month PFS rate was 19.1 and 43.8%; median PFS was 2.7 (95%CI 1.3-5.1) and 5.1 months (95%CI 0.9-NR), respectively. Grade ≥3 treatment-related toxicities occurred in 4 (28.6%) on N and 5 (33.3%) on N+I. There were no treatment-related deaths and no new safety signals. One volunteer enrolled on N+I stopped treatment after two years and remains in CR to date. Conclusions: Although sufficient activity was seen in CCC in both arms, the single-agent activity of N is similar to published reports in platinum-resistant epithelial ovarian cancer and decision made not to pursue it further. However, the combination of ipilimumab and nivolumab warrants additional investigation, and the second stage of this study will enroll 14 more patients to receive N+I. Clinical trial information: NCT03355976. [Table: see text]

Disparity in the era of personalized medicine for epithelial ovarian cancer

“…49 BrUOG 354 explored the activity of the PD-1 inhibitor nivolumab with and without ipilimumab (anti-CTLA4) in ovarian or extra-renal clear-cell pathologies; the stage 1 results of this study reported an overall response rate of 26.6% ( n = 4/15) in the combination arm compared to 16.7% ( n = 2/12) for nivolumab alone and so stage 2 will focus on dual treatment with nivolumab and ipilimumab. 50 In comparison to these two studies, MOCCA was a phase II study exploring the role of the PD-L1 inhibitor durvalumab against physicians choice of chemotherapy; this study was negative with an overall response rate to durvalumab of 10.7% and no significant difference in OS. 51 INOVA is a phase II study that is currently exploring the use of sintilimab (anti-PD1) in combination with bevacizumab in the treatment of recurrent CCOC; although this trial is still ongoing, preliminary results following the recruitment of 20 evaluable patients (out of a planned accrual of 38) have reported an overall response rate of 40%.…”