Expert Reviews Potential for Triplet Regimen in Recurrent Gynecologic Cancers

Emese Zsiros, MD, PhD

Emese Zsiros, MD, PhD

In an open-label phase II trial presented at the Society of Gynecologic Oncology (SGO) 50th Annual Meeting on Women’s Cancer, the combination of pembrolizumab (Keytruda) plus bevacizumab (Avastin) with metronomic cyclophosphamide led to a 95% disease control rate and 40% overall response rate (ORR) in women with recurrent epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer.

After a safety lead-in cohort, 40 patients were given 200 mg of pembrolizumab intravenously (IV) plus 15 mg/kg of bevacizumab IV every 3 weeks and to 50 mg of oral cyclophosphamide daily until disease progression or unacceptable toxicity. All patients had platinum-resistant, recurrent ovarian cancer or had declined platinum retreatment, and had no evidence of active autoimmune disease. The median patient age was 62 years (range, 44-88) and patients had received a median of 5 prior lines of chemotherapy. Primary objectives included safety, clinical benefit rate, objective response rate, progression-free survival (PFS), and quality of life (QoL).

At a median follow-up of 14.7 months, 37.5% of patients had experienced a partial response (PR), 55% had stable disease, and 5% had progressive disease. In addition, at 6 months, or after 8 cycles of treatment, the disease control rate was at least 62%, while 3 patients still have not reached the 6-month follow-up. The overall 6-month PFS rate was 70% and 12 patients were still on treatment at the time of data cutoff.

Patients with platinum-sensitive disease experienced a 6-month PFS rate of 100% while patients with nonsensitive disease had a PFS rate of 59% (P= .024). A QoL analysis also showed patients on the clinical trial had high physical, emotional, cognitive, and social functioning, in addition to a significantly improved body image.

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

In an interview withTargeted Oncology,Emese Zsiros, MD, PhD, a gynecologic oncologist at Roswell Park Comprehensive Cancer Center, discussed the findings from this phase II trial investigating the triplet regimen in patients with recurrent disease. In addition, she shared details for the next steps planned for this regimen.

TARGETED ONCOLOGY:What was the rationale for exploring this triplet regimen of pembrolizumab, bevacizumab, and cyclophosphamide in women with gynecologic cancers?

Zsiros:The rationale for this clinical trial was to understand whether we can enhance the efficacy of single-agent checkpoint inhibitor pembrolizumab by combining it with 2 other agents, an anti-angiogenic drug bevacizumab and also oral cyclophosphamide. The rationale for this combination was that we believe that by blocking the VEGF pathway using bevacizumab, we will be able to normalize the tumor vessels in regard to anatomy and function, attract more T cells to the tumor microenvironment, and decrease the local immunosuppression. We also understand that low-dose metronomic cyclophosphamide depletes the regulatory T cells, thus tipping the balance toward more cytotoxic activity and potentially augmenting immunotherapeutic agents.

TARGETED ONCOLOGY:How was this trial designed, and what were the main findings?

Zsiros:The study design was a single-institution phase II trial that started in 2016. At that time, we enrolled 5 patients in the safety lead-in cohort to make sure that the triplet combination was safe and had no major toxicity. Once those 5 patients showed no concerning signs of toxicity, we continued to enroll, and we enrolled a total of 40 patients, 11 of which are still on the clinical trial and are doing quite well.

The findings of the clinical trial showed that by using the triplet combination, the overall response rate in this clinical cohort was 40%, so 16 out of 40 patients had a PR, and 2 patients essentially had a near complete response. We also saw that 55% of our patients had stable disease, thus our disease control rate was 95% in this heavily pretreated ovarian cancer patient population.

TARGETED ONCOLOGY:What does the safety profile look like for this combination?

Zsiros:During the clinical trial, we were collecting AEs and making sure that the triplet regimen was well tolerated. The most common grade 2/3 toxicity was bevacizumab-induced hypertension, which was expected. Other toxicities included grade 1/2 fatigue, nausea, diarrhea, joint pain, and rash. This only happened in a minority of the patients, and most of the time, it was grade 1 and was overall not bothersome and still well tolerated for the patients.

TARGETED ONCOLOGY:What are the next steps with this research?

Zsiros:In our clinical trial, we collected a lot of translational specimens, including tumor tissue biopsy, blood collection, as well as microbiome collections besides the quality of life questionnaires. Our next step is to analyze these biospecimens to understand how anti-angiogenic therapy combines with an immune checkpoint inhibitor and to be able to understand from those 30% of our patients who have done exceptionally well on this clinical trial, what were the biological factors that contributed to this great tumor response and durable disease control?

TARGETED ONCOLOGY:Is there any biomarker research ongoing to determine who might be best to receive this regimen?

Zsiros:Because we collected a lot of biospecimens in our clinical trial, our next step is to analyze the tumor tissue, as well as the peripheral blood and the microbiome samples, to look for any kind of predictive biomarkers or signatures that we could use to predict, or even modify, to enhance our response to future immunotherapeutic agents.

Reference:

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.