Pembrolizumab/Bevacizumab Regimen Induces Durable Responses in Ovarian Cancer

Emese Zsiros, MD, PhD

Combination therapy with pembrolizumab (Keytruda), bevacizumab (Avastin), and metronomic cyclophosphamide induced a 95% disease control rate and 40% overall response rate among women with recurrent ovarian cancer, according to results from an open-label phase II study.

“Tumor responses (in our study) are higher and more durable compared to those reported for pembrolizumab monotherapy or patients treated with combination bevacizumab and oral cyclophosphamide alone,” Emese Zsiros, MD, PhD, FACOG, assistant professor of oncology, Department of Gynecologic Oncology, Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, said during her presentation at the 2019 SGO Annual Meeting.

At a median follow-up of 14.7 months, 16 patients (40%) experienced a partial response, 22 (55%) had stable disease, and only 2 patients (5%) had progressive disease. “More than 77% of our patients had decreases in their tumor size from baseline,” Zsiros added.

At 6 months, or after 8 cycles of treatment, the disease control rate was at least 62%; however, 3 patients still have not reached the 6-month follow-up time. “I would like to point out that 30% of the patients derived an especially long-term clinical benefit over 12 months or 12 cycles of treatment, and many of them are still on clinical trial without any major progression or toxicity,” said Zsiros.

Ten patients (25%) were platinum-sensitive and declined platinum-based therapy, with a median of 5 prior lines of chemotherapy. The 6-month progression-free survival (PFS) rates for the platinum-sensitive and nonsensitive patients were 100% and 59%, respectively (P = .024).

In addition, the regimen appeared safe and well tolerated. The most common adverse events (AEs) were fatigue, hypertension, diarrhea, nausea, vomiting, stomatitis, decreased white blood cells, decreased lymphocyte counts, arthralgia, musculoskeletal pain, and rash. The most common grade 3 AEs included hypertension (n = 5), decreased lymphocyte counts (n = 3), and decreased white blood cells (n = 1).

According to quality of life (QoL) analysis, patients showed high physical, emotional, cognitive, and social functioning throughout the clinical trial, as well as significantly improved body image.

Given single-agent immune checkpoint inhibitors are largely ineffective treating recurrent ovarian cancer, the researchers aimed to determine the efficacy and safety of the triplet regimen—designed to enhance pembrolizumab by combining it with bevacizumab to improve lymphocyte endothelial trafficking and restore DC function, and oral metronomic cyclophosphamide to selectively deplete circulating regulatory T cells and restore the cytotoxic potential of T cells and NK cells.

To be eligible, patients had to have recurrent, advanced-stage epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer; platinum-resistant disease or refuse retreatment with a platinum agent; ECOG of 0 or 1; and no prior immunotherapy received. Exclusion criteria included no active autoimmune disease and no central nervous system involvement.

Forty patients received 200 mg of pembrolizumab intravenously (IV) combined with 15 mg/kg of bevacizumab IV every 3 weeks and 50 mg of oral cyclophosphamide every day until disease progression or unacceptable toxicity. Eleven patients are still on treatment.

The researchers also gather blood, tumor tissue biopsy, and microbiome collections, as well as QoL assessments and microbiome questionnaires throughout treatment.

Primary objectives include safety, clinical benefit (CR plus PR plus SD >6 months), response rate, PFS, quality of life, and translational objectives.

The median age was 62 years (range, 44-88), and the majority of patients were white (95%). Patients had a median of 3.2 prior lines of chemotherapy, and only 14 (35%) and 5 (12.5%) received prior bevacizumab or oral cyclophosphamide, respectively. Overall, 33 patients (82.5%) had high-grade serous disease, 2 (5%) had low-grade serious, 2 (5%) had clear cell, 2 (5%) had mixed clear cell and serous, and 1 (2.5%) had endometrioid.

“Further analyses of predictive biomarkers are currently ongoing to understand the association between angiogenic treatment and immune checkpoint inhibition,” Zsiros said. “This includes analyses of tumor tissue biopsies, peripheral blood, as well as vaginal microbiome. We are interested in finding out who are those 30% of patients who derived a long-term clinical benefit.”

Zsiros E, Frederick PJ, Akers SN, et al. A phase II trial of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. Presented at: 2019 SGO Annual Meeting. March 16-19, 2019; Honolulu, HI. Abstract LBA4.

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