Triplet Combo Yields Durable Responses in Recurrent Epithelial Ovarian Cancer

Treatment with the combination of Keytruda (pembrolizumab), Avastin (bevacizumab) and metronomic cyclophosphamide appeared safe and effective in women with recurrent epithelial ovarian cancer, according to results from an open-label phase 2 study.

In particular, the triplet regimen induced a 95 percent disease control rate and 40 percent overall response rate.

“Tumor responses (in our study) are higher and more durable compared to those reported for (Keytruda) monotherapy or patients treated with combination (Avastin) and oral cyclophosphamide alone,” Emese Zsiros, M.D., Ph.D., FACOG, assistant professor of oncology in the Department of Gynecologic Oncology at the Center for Immunotherapy at Roswell Park Comprehensive Cancer Center, said during her presentation at the 50th SGO Annual Meeting, held March 16-19 in Honolulu, Hawaii.

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 Keytruda by combining it with Avastin to improve lymphocyte endothelial trafficking and restore dendritic cell function, and oral metronomic cyclophosphamide to selectively deplete circulating regulatory T cells and restore the cytotoxic potential of T cells and natural killer cells, which play a role in the host-rejection of both tumors and virally infected cells.

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

The researchers also gathered blood, tumor tissue biopsy, and microbiome collections, as well as quality of life assessments and microbiome questionnaires throughout treatment.

Primary objectives included safety, clinical benefit, response rate, progression-free survival, quality of life, and translational objectives.

The median age was 62 years, and the majority of patients were white (95 percent). Patients had a median 3.2 prior lines of chemotherapy, and only 14 (35 percent) and five (12.5 percent) patients, respectively, received prior Avastin or cyclophosphamide. Overall, 33 patients had high grade serous disease (82.5 percent), two with low grade serious (5 percent), two with clear cell (5 percent), two with mixed clear cell and serious (5 percent) and one with endometrioid (2.5 percent).

After follow-up of about 14.7 months, 16 patients experienced a partial response (40 percent) to the treatment regimen, 22 had stable disease (55 percent) and only two patients ended up with progressive disease (5 percent). “More than 77 percent of our patients had decreases in their tumor size from baseline,” Zsiros added.

At six months, or after eight cycles of treatment, the disease control rate was at least 62 percent; however, three patients still have not reached the six-month follow-up time. “I would like to point out that 30 percent 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 percnt) were platinum-sensitive and declined platinum-based therapy, with a median of five prior lines of chemotherapy. The six-month progression-free survival (PFS) rates for the platinum-sensitive and non-sensitive patients were 100 percent and 59 percent, respectively.

In addition, the regimen appeared safe and well tolerated. The most common side effects were fatigue, hypertension, diarrhea, nausea, vomiting, stomatitis (inflammation of the mouth and lips), decreased white blood cells, decreased lymphocyte counts, arthralgia, musculoskeletal pain and rash. The most common grade 3 side effects included hypertension (five patients), decreased lymphocyte counts (three patients) and decreased white blood cells (one patient).

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

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