A Phase 2 Trial of Combination Nivolumab and Bevacizumab in Recurrent Ovarian Cancer
Single-agent trials of immune checkpoint inhibitors against programmed death-1 (PD-1) or its ligand, PD-L1, have demonstrated only modest effect in ovarian cancer, which has driven investigation into a variety of combination therapies.1 Vascular endothelial growth factor (VEGF) has demonstrated immune-suppressive functions through mechanisms such as impairment of dendritic cell function and maturation.2 As a result, anti-VEGF therapy may enhance immunotherapeutic responses when combined with immune checkpoint inhibitors. In this phase 2 trial, Liu and colleagues investigated the combination of the anti-VEGF agent bevacizumab and the PD-1 inhibitor nivolumab in women with recurrent ovarian cancer.3
Eligible patients included women with epithelial ovarian, fallopian tube, or peritoneal cancer. They were required to have cancer recurrence within 12 months of their last dose of platinum-based chemotherapy, and primary platinum-refractory disease was not allowed. All patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Only in the case of unacceptable toxicity was prior bevacizumab use disallowed. However, no prior treatment with drugs targeting T-cell co-stimulation or immune checkpoint pathways was allowed. All patients received bevacizumab 10 mg/kg and nivolumab 240 mg every 2 weeks until RECIST progression.
Of the 38 enrolled patients, 20 were platinum sensitive, with a platinum-free interval of 6 to 12 months, and 18 patients were platinum resistant. There were no complete responses and 10 partial responses (PRs). Among the patients with PR, 8 were platinum sensitive and 2 were platinum resistant. Three patients in each group have had stable disease for at least 6 months. The median progression free survival (PFS) for all patients was 9.4 months. The most common treatment-related adverse events included fatigue (15 patients, all grade 1), aspartate aminotransferase elevation (7 patients; 6â€‰grade 1/2, 1â€‰grade 3), alanine transaminase elevation (6 patients; 5â€‰grade 1/2, 1â€‰grade 3), myalgia (6 patients; all grade 1/2), and skin changes (6 patients; 5â€‰grade 1, 1â€‰grade 3). Three patients had pneumonitis (2â€‰grade 2, 1â€‰grade 1) and 1â€‰patient had colitis (grade 1).
Together, these results demonstrate that combination nivolumab/bevacizumab has 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 antiangiogenic and immune checkpoint blockade combinations in ovarian cancer are warranted.
- Castellano T, et al. Clin Ther. 2018;40(3):372-388.
- Oyama T, et al. J Immunol. 1998;160(3):1224-32.
- Liu JF, et al. ESMO 2018. Abstract 937PD.