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.
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.
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).
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
Legal entity responsible for the study
Bristol Myers Squibb.
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.