Pembrolizumab Plus Bevacizumab and Oral Metronomic Cyclophosphamide for Recurrent Ovarian Cancer

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In a single-institution phase II trial reported in JAMA Oncology, Zsiros et al found that the combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide produced objective response in approximately half of women with recurrent ovarian cancer taking part in the study. Moreover, the combination produced clinical benefit in nearly all patients.

Study Details

In the trial, 40 women with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer were enrolled at Roswell Park Comprehensive Cancer Center between September 2016 and June 2018. Patients had to have measurable disease on immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Treatment consisted of pembrolizumab at 200 mg and bevacizumab at 15 mg/kg every 3 weeks plus oral cyclophosphamide at 50 mg once daily during the treatment cycle until disease progression or unacceptable toxicity.

Overall, 30 women (75%) had platinum-resistant disease, 14 (35%) had prior exposure to bevacizumab, and 19 (47.5%) had PD-L1–positive tumors (PD-L1 expression ≥ 1%).


  • Objective response was achieved in 47.5% of patients.
  • The clinical benefit rate was 95.0%.

Responses and Progression-Free Survival

Objective response on irRECIST was observed in 19 patients (47.5%), with complete response in 3 (7.5%). Responses were observed in 6 (60.0%) of 10 patients with platinum-sensitive disease and 13 (43.3%) of 30 (including the 3 complete responses) with platinum-resistant disease; responses were observed in 10 (52.6%) of 19 with PD-L1–positive disease and in 6 (35.3%) of 17 with PD-L1–negative disease. An additional 19 patients (47.5%) had stable disease, yielding a clinical benefit rate of 95.0%. The median duration of response was 8.3 months (interquartile range = 4.2–15.6 months) among patients with objective response and 5.9 months among all patients with clinical benefit, with response lasting > 12 months in 10 patients (25% of total population).

The median follow-up was 25.5 months. Median progression-free survival among all patients was 10.0 months (90% confidence interval [CI] = 6.5–17.4 months). Median progression-free survival was not reached in patients with complete response, 10.6 months in those with partial response, 20.2 months in those with platinum-sensitive disease, and 7.6 months in those with platinum-resistant disease.

Adverse Events

The most common treatment-related adverse events of any grade were fatigue (45.0%), diarrhea (32.5%), and hypertension (27.5%). Treatment-related grade ≥ 3 adverse events occurred in 32.5% of patients, with the most common being hypertension (15.0%) and lymphopenia (7.5%). Treatment-related adverse events led to discontinuation of treatment in 10% of patients, most commonly due to grade 2 skin toxicity. No treatment-related deaths were reported.

The investigators concluded, “In this phase II 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.”

Emese Zsiros, MD, PhD, of the Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by Merck & Co through the support of the Merck Investigator Studies Program. For full disclosures of the study authors, visit

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