A team from Roswell Park Comprehensive Cancer Center has detailed striking findings on the effectiveness of a previously untried combination of old and new drugs as treatment for recurrent ovarian cancer.
In a new article in JAMA Oncology, the researchers report that one-quarter of patients who received the combination of pembrolizumab (brand name Keytruda), bevacizumab (brand name Avastin) and a pill form of cyclophosphamide (brand name Cytoxan) experienced long-term disease control along with excellent quality of life -; far outpacing the effectiveness of either existing approved therapies or newer immunotherapies alone.
The idea to combine the two widely used systemic chemotherapy agents with pembrolizumab, an immune checkpoint inhibitor, grew out of the desire to improve immune response while preserving quality of life, notes Emese Zsiros, MD, PhD, FACOG, a staff physician and faculty member with the Department of Gynecologic Oncology and Center for Immunotherapy at Roswell Park.
Pembrolizumab works by activating immune cells against cancer, but checkpoint inhibitors haven't worked well in ovarian cancer because the T cells often can't get to the tumor. We combined bevacizumab, to normalize the tumor microenvironment and achieve better penetration of T cells into tumor tissue, and oral cyclophosphamide, which can deplete 'bad' regulatory T cells that actually help cancer cells to avoid immune attack, with checkpoint blockade in order to activate the 'good' killer T cells to fulfill their function."
Dr. Emese Zsiros, first author on the new paper
The results of the team's phase 2 clinical study suggest a significant benefit for patients receiving this combination regimen.
Among 40 patients with recurrent or treatment-resistant ovarian, fallopian-tube or peritoneal cancer -; which together represent the most-fatal gynecologic cancers -; 95% experienced clinical benefit from this treatment. Progression-free survival nearly doubled, from an expected survival of 5-6 months to 10 months. And the combination generated durable responses, with 47.5% of patients on the study responding to the treatment and 25% demonstrating long-term disease control.
The team assessed participants' quality of life at several junctures. Patients on the study maintained high and stable functioning throughout the study. Some indicators -; body image and emotional/social functioning -; actually improved overall over the course of the trial.
"The quality of life of our patients who took part in this clinical trial was excellent," says Dr. Zsiros. "Most of them were able to travel, spend good time with their families and resume their hobbies -; cooking, hiking, things that they were not doing before. And approximately 30 percent of our patients were still living more than a year and a half after going on this combination, which we did not anticipate. These are very striking results."
Approximately 70% of people diagnosed with ovarian cancer will experience a recurrence. Studies have shown that the available "second-line" chemotherapies for those whose cancers return are associated with limited clinical benefit, with overall response rates ranging from 10-25%, and result in significant treatment-related toxicities. And only 8% of patients with recurrent ovarian cancer have been shown to respond to pembrolizumab alone.
"This clinical trial represents a significant conceptual advance in the use of combination therapy to enhance the efficacy of immunotherapy, demonstrating that we can generate long-term disease control in ovarian cancer without compromising quality of life," says the paper's senior author, Kunle Odunsi, MD, PhD, FRCOG, FACOG, who is Deputy Director, the Robert, Anne & Lew Wallace Endowed Chair in Cancer Immunotherapy, Executive Director of the Center for Immunotherapy, and the M. Steven Piver Professor of Gynecologic Oncology at Roswell Park. "The combination assessed in our trial is an option that should be considered for many patients with recurrent ovarian cancer based on its high tolerability and strong signal of efficacy."
Zsiros, E., et al. (2020) 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. JAMA Oncology. doi.org/10.1001/jamaoncol.2020.5945.