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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Odunsi reported receiving grants from the National Cancer Institute, AstraZeneca, and TESARO, Inc, personal fees from ImmunoVaccine Technologies, Inc, and Genentech, Inc, and grants and personal fees from Kiyatek outside the submitted work; having a patent to PCT/US2014025673 issued; and being cofounder of Tactiva Therapeutics, Inc. No other disclosures were reported.

Figures

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).