Expert Discusses Immunotherapy Potential in Ovarian Cancer

Bradley J. Monk, MD

Results of the phase III JAVELIN 200 Ovarian trial could have a practice-changing impact on the field of ovarian cancer, according to Bradley J. Monk, MD, as immunotherapy could finally make its mark on management of this disease.

The randomized phase III study is comparing the PD-L1 inhibitor avelumab (Bavencio) alone or combined with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in patients with platinum-resistant/refractory ovarian cancer (NCT02580058). The coprimary endpoints of the trial, which is estimated to be completed in March 2018, are progression-free survival (PFS) and overall survival (OS).

Earlier findings of a phase Ib study, which were presented during the 2016 American Society of Clinical Oncology Annual Meeting, showed that the objective response rate for avelumab was 9.7%, with partial responses observed in 12 of the 124 patients on the trial. Additionally, the disease-control rate was 54%, the median PFS was 11.3 weeks, and the median OS was 10.8 months.

OncLive: Please provide an overview of your discussion of immunotherapy in ovarian cancer.

During the 2017 OncLive^® State of the Science Summit on Ovarian Cancer, Monk, professor and director of the Division of Gynecologic Oncology at Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center in Phoenix, and a gynecologic oncologist with Arizona Oncology, shared his insight on the potential of immunotherapy in ovarian cancer, as well as what promise it might hold in other gynecologic malignancies.Monk: Immunotherapy is an emerging treatment in all solid tumors and is approved in many: head and neck, bladder, melanoma, lung, and kidney, but not ovarian cancer. Five randomized phase III trials are ongoing of avelumab and atezolizumab (Tecentriq), combining checkpoint inhibitors with chemotherapy either in the frontline setting or in platinum-resistant patients, or in the relapse of platinum-sensitive patients. We are excited about these trials.

How far along are some of these trials?

We combine immunotherapy agents with chemotherapy for 2 reasons. Tumor-infiltrating lymphocytes (TILs) are not present in about 40% of newly diagnosed epithelial ovarian cancers, and without TILs, checkpoint inhibitors are not likely to work. PD-L1 expression is also not there in about 30% of patients. We are hoping that by adding chemotherapy to checkpoint inhibition, we will be able to cause immunogenic cell death. As the cells die as a result of the chemotherapy, it will auto-immunize the patient, and then checkpoint inhibitors will help the patient’s immune system fight the cancer. We have a number of early phase I and phase II studies, but we are probably going to need a randomized trial to gain FDA approval of a checkpoint inhibitor in ovarian cancer. There are some early signals that may appear in some of these early trials; for example, the rate of pathologic complete response after neoadjuvant chemotherapy would be 1 potential accelerated approval mechanism.

Could immunotherapy agents have similar potential in other gynecologic cancers?

The first randomized phase III study to report will be the JAVELIN 200 Ovarian trial, which is avelumab versus pegylated liposomal doxorubicin versus the combination of pegylated liposomal doxorubicin and avelumab. It’s a 3-arm trial; the study has targeted to enroll 550 patients and it is almost at 500. Again, these are platinum- resistant patients who recur within 6 months of platinum-based therapy. The endpoint, which is a coprimary one of PFS and OS, could report out relatively soon. We are excited about it. Immunotherapy is not only important in ovarian cancer, but also in cervical and endometrial cancer. In cervical cancer, there is a randomized phase III trial of a checkpoint inhibitor getting ready to start. I can’t tell you the details quite yet, but it’s imminent.

We are most excited about the use of checkpoint inhibitors, particularly pembrolizumab (Keytruda) in microsatellite instability (MSI)-high recurrent endometrial cancer. This is for second-line endometrial cancer. Loss of expression of these mismatched-repair proteins that have MSI-high mutational burden have shown exceptional responses to single-agent pembrolizumab. There's a Prescription Drug User Fee Act date for pembrolizumab, as reported by Merck, in early June 2017. This could be the first checkpoint inhibitor approved in a gynecologic cancer.

Disis ML, Patel MR, Pant S, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase Ib trial: Safety and clinical activity. J Clin Oncol 34, 2016 (suppl; abstr 5533).