Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer: A Phase 2 Nonrandomized Clinical Trial

Abstract

Importance: Treatment options for recurrent ovarian cancer are of limited clinical benefit and adversely affect patient quality of life, representing an unmet need for tolerable effective therapies.

Objective: To assess the efficacy and safety of a combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Design, setting, and participants: This open-label, single-arm phase 2 cohort study enrolled patients from September 6, 2016, to June 27, 2018, at a single institution in the United States. Eligible patients had recurrent ovarian cancer, measurable disease per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status of 0 to 1. Data were analyzed from September 6, 2016, to February 20, 2020.

Interventions: Patients received intravenous pembrolizumab, 200 mg, and bevacizumab, 15 mg/kg, every 3 weeks and oral cyclophosphamide, 50 mg, once daily during the treatment cycle until disease progression, unacceptable toxic effects, or withdrawal of consent.

Main outcomes and measures: Primary outcomes were objective response rate (ORR) and progression-free survival (PFS).

Results: Of the 40 women enrolled, 30 (75.0%) had platinum-resistant and 10 (25.0%) had platinum-sensitive ovarian cancer with a mean (SD) age of 62.2 (9.4) years. Three women (7.5%) had complete responses, 16 (40.0%) had partial responses, and 19 (47.5%) had stable disease in response to treatment based on irRECIST criteria, with an ORR of 47.5%, clinical benefit in 38 (95.0%), and durable response in 10 (25.0%). Median PFS was 10.0 (90% CI, 6.5-17.4) months. The most common grade 3 to 4 treatment-related adverse events were hypertension (6 [15.0%]) and lymphopenia (3 [7.5%]). The most frequently reported adverse events included fatigue (18 [45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]).

Conclusions and relevance: In this phase 2 nonrandomized clinical trial, the combination of pembrolizumab with bevacizumab and oral cyclophosphamide was well tolerated and demonstrated clinical benefit in 95.0% and durable treatment responses (>12 months) in 25.0% of patients with recurrent ovarian cancer. This combination may represent a future treatment strategy for recurrent ovarian cancer.

Trial registration: ClinicalTrials.gov Identifier: NCT02853318.

Figure 1.. Study Overview

Figure 2.. Tumor Response and Survival Data Among Evaluable Patients Receiving Combination Pembrolizumab With Bevacizumab and Oral Cyclophosphamide

irCR indicates complete response based on immune-related Response Evaluation Criteria In Solid Tumors (irRECIST); irPD, progressive disease based on irRECIST criteria; irPR, partial response based on irRECIST criteria; irSD, stable disease based on irRECIST criteria; and PD-L1, programmed cell death 1 ligand.

Figure 3.. Progression-Free Survival (PFS) Among Evaluable Patients Receiving Combination Pembrolizumab With Bevacizumab and Oral Cyclophosphamide

A, Among patients with 0% to 30% decrease in tumor burden, median 6-month PFS rate was 0.73 (90% CI, 0.45-0.89); median PFS, 10.3 (90% CI, 4.3-27.1) months. Among those with more than 30% to 100% decrease in tumor burden, 6-month PFS rate was 0.94 (90% CI, 0.72-0.99); median PFS, 17.4 (90% CI, 7.8-24.4) months (log-rank P = .47). B, Among patients with 3 or fewer prior lines of chemotherapy, median 6-month PFS rate was 0.79 (90% CI, 0.57-0.91); median PFS, 10.8 (90% CI, 7.6-24.4) months. Among patients with more than 3 prior lines of chemotherapy, median 6-month PFS was 0.54 (90% CI, 0.25-0.76); median PFS, 6.5 (90% CI, 4.3-10.2) months (P = .03).