A phase II trial of combination nivolumab and bevacizumab in recurrent ovarian cancer

Abstract

Background: Single-agent trials of immune checkpoint inhibitors against PD1 or PD-L1 have demonstrated only modest effect in ovarian cancer, suggesting that these drugs are not likely to be effective as monotherapy. VEGF has demonstrated immune-suppressive functions through mechanisms such as impairment of dendritic cell function and maturation. As a result, anti-VEGF therapy may enhance immunotherapeutic responses when combined with immune checkpoint inhibitors. We conducted this Phase 2 trial to investigate the combination of the anti-VEGF agent bevacizumab and the PD1 inhibitor nivolumab in women with recurrent ovarian cancer. Methods: Women with epithelial ovarian, fallopian tube, or peritoneal cancer were eligible. Patients (pts) were required to have recurred within 12 months of their last dose of platinum-based chemotherapy; primary platinum-refractory disease was not allowed. All pts had measurable disease by RECIST 1.1. Prior bevacizumab was allowed unless there had been unacceptable toxicity. No prior treatment with drugs targeting T-cell co-stimulation or immune checkpoint pathways was allowed. All pts received bevacizumab 10mg/kg and nivolumab 240mg every 2 weeks until RECIST progression. Results: 38 pts were enrolled. 20 pts were platinum sensitive (ie, PFI 6-12 months) and 18 pts were platinum resistant. There were no complete responses and 10 partial responses (PR, 8 confirmed, 2 unconfirmed). Of these PRs, 8 (6 confirmed, 2 unconfirmed) occurred in platinum sensitive pts and 2 (both confirmed) in platinum resistant pts. Three pts in each group have had stable disease of at least 6 months. The median progression free survival (PFS) for all pts was 9.4 months. The most common treatment-related adverse events included fatigue (15 pts, all Gr 1), AST elevation (7 pts; 6 Gr 1/2, 1 Gr 3), ALT elevation (6 pts; 5 Gr 1/2, 1 Gr 3), myalgia (6 pts; all Gr 1/2), and skin changes (6 pts; 5 Gr 1, 1 Gr 3). 3 pts had pneumonitis (2 Gr 2, 1 Gr 1) and 1 pt had colitis (Gr 1). Conclusions: Combination nivolumab/bevacizumab demonstrated clinical activity in women with recurrent ovarian cancer, with an overall confirmed response rate of 21% and a median PFS of 9.4 months. Further studies of anti-angiogenic and immune checkpoint blockade combinations in ovarian cancer are warranted. Clinical trial identification: NCT02873962. Legal entity responsible for the study: Joyce Liu. Funding: Bristol Myers Squibb. Disclosure: R. Penson: Scientific Advisory boards: Genentech, Roche. P. Konstantinopoulos: Advisory boards: Merck, Pfizer, AstraZeneca. U.A. Matulonis: Consultant for Merck, Immunogen, 2x Oncology, Fujifilm, Geneos, Myriad Genetics. All other authors have declared no conflicts of interest.