Phase 2 Trial Reports Positive Outcomes with Treatment Combination for Ovarian Cancer

A phase 2 nonrandomized clinical trial published in JAMA Oncology found that the combination of pembrolizumab (Keytruda) with bevacizumab (Avastin) and oral cyclophosphamide (Cytoxan) was well tolerated and demonstrated clinical benefit and durable treatment responses in patients with recurrent ovarian cancer.¹

Based on these study findings, researchers suggested that this combination may represent a future treatment strategy for this patient population.

“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,” senior author, Kunle Odunsi, MD, PhD, FRCOG, FACOG, 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 Comprehensive Cancer Center, said in a press release.² “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.”

In this open-label, single-arm, cohort study, researchers enrolled patients with recurrent ovarian cancer, measurable disease per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at a single institution in the US from September 6, 2016 to June 27, 2018. Participants received 200 mg pembrolizumab intravenously, 15 mg/kg bevacizumab every 3 weeks, and 50 mg oral cyclophosphamide once daily during the treatment cycle until disease progression, unacceptable toxic effects, or withdrawal of consent.

The dual primary end points were objective response rate (ORR) and progression-free survival (PFS).

“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,” first author Emese Zsiros, MD, PhD, FACOG, a staff physician and faculty member with the department of Gynecologic Oncology and Center for Immunotherapy at Roswell Park, said in the release. “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.”

Among a total of 40 women enrolled in the trial, 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. The ORR was 47.5%. In total, 3 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.

Moreover, median PFS was 10.0 (90% CI, 6.5-17.4) months. Clinical benefit was also observed in 38 patients (95.0%) and durable responses were observed in 10 (25.0%).

Regarding safety, the most common grade 3 to 4 treatment-related adverse events (AEs) were hypertension (6 [15.0%]) and lymphopenia (3 [7.5%]). Further, the most frequently reported AEs included fatigue (18 [45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]).

“The quality of life of our patients who took part in this clinical trial was excellent,” Zsiros added. “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.”

Of note though, an important limitation of the current study was its single-center, 1-arm design lacking a comparison arm to characterize the effect of each trial drug versus a dual regimen or traditional second-line therapy. Moving forward, these results are being followed up with further analysis of biospecimens to determine the synergistic mechanisms among immune checkpoint inhibitor, antiangiogenic therapy, and regulation T-cell depletion, thus allowing more patients to benefit from immunotherapy treatments in the future.

References:

1. Zsiros E, Lynam S, Attwood KM, et al. Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer. JAMA Oncology. doi: 10.1001/jamaoncol.2020.5945

2. Roswell Park Reports Positive Outcomes from New Combination Treatment for Ovarian Cancer [news release]. Buffalo, NY. Published November 19, 2020. Accessed November 20, 2020. https://www.roswellpark.org/newsroom/202011-roswell-park-reports-positive-outcomes-new-combination-treatment-ovarian-cancer?utm_source=Cision&utm_medium=Email&utm_term=Nov-20&utm_content=Immunotherapy%2c+chemotherapy%2c+Keytruda%2c+pembrolizumab%2c+ovarian%2c+cancer%2c+research