Expert Discusses Immunotherapy Across Gynecologic Malignancies

Dmitriy Zamarin, MD, PhD

Immunotherapy is slowly evolving in the gynecologic malignancies landscape and has moved beyond only having a role in ovarian cancer, according to Dmitriy Zamarin, MD, PhD.

For example, pembrolizumab (Keytruda) has shown promise in patients with microsatellite-instability high (MSI-H) endometrial cancer, yet this remains to be a small subset of patients.

Preliminary data for pembrolizumab in combination with lenvatinib (Lenvima) from the phase Ib/II Study 111 trial showed a median progression-free survival (PFS) of 9.7 months (95% CI, 4.2-not evaluable). Study 111 investigated 23 patients with both MSI-H and non—MSI-H endometrial cancer.

“The response rate was around 50%, which is much higher than what we typically see—even with chemotherapy,” said Zamarin. “There is certainly a lot of promise from these agents.”

OncLive: Beyond ovarian cancer, in what other gynecologic malignancies has immunotherapy shown potential?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Treatment of Ovarian Cancer, Zamarin, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the role of immunotherapy for patients with gynecologic malignancies.Zamarin: Ovarian cancer is not the only cancer that we treat with immunotherapy. Immunotherapy has also been shown to be effective in endometrial cancer. We already have a very effective drug, pembrolizumab, approved for MSI-H endometrial cancers or for any MSI-H tumor. It could encompass some of the patients with ovarian cancer, but it is specific to the endometrial histology.

Unfortunately, this is still a minority of the tumors; therefore, the cancers of the endometrium could use further evaluation, even with the same drugs. We already have some preliminary evidence that was presented, demonstrating that even in a non—MSI-H population, these immune checkpoint inhibitors can work.

There have been some preliminary data presented at the 2017 ASCO Annual Meeting presenting the combination of an immune checkpoint inhibitor with a targeted agent. In that case, it was lenvatinib (Lenvima) that demonstrated promising response rates in endometrial cancer. The response rate was around 50%, which is much higher than what we typically see, even with chemotherapy. There is certainly a lot of promise from these agents.

There is also cervical cancer. Again, we could start with the immune checkpoint inhibitors in this disease. The response rates have also been around 50%. Cervical cancer presents itself as a good candidate for a vaccine type of therapy because the majority of these are HPV-driven tumors. There are several vaccines that have been designed to elicit specific immune responses. There is a vaccine from Inovio called VGX-3100 that was effective in the precancerous setting in patients with CIN 2/3. We believe that this vaccine could have some efficacy in an advanced setting; if not by itself, then perhaps in combination with some of these immune checkpoint inhibitors.

There is also a Listeria-based vaccine that is currently being explored in advanced clinical trials for patients with cervical cancer. There is a large, multi-institutional study that is currently ongoing.

Another interesting thing about cervical cancer, and perhaps other gynecologic malignancies, is the potential for cellular-based therapies—meaning adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapies and the therapies that are using engineered T-cell receptor (TCR). There have been some exciting data reported for cervical cancer, specifically from the NIH, demonstrating that adoptive cell therapy can be effective. There are some studies that are ongoing in the NIH and other centers that use engineered T cells expressing a TCR that is specific for the HPV proteins. We are anxiously awaiting the results of these studies.

Can you discuss the NIH data regarding the adoptive T-cell therapy?

Some of the studies will combine adoptive T-cell transfer with immune checkpoint inhibitors which will hopefully make these T cells even more beneficial. There is a lot of room for development, but the studies are ongoing and we are anxiously awaiting these results.There was a clinical trial published in the Journal of Clinical Oncology in 2014 or 2015 on the first cohort of patients. They have some updated trials that are currently ongoing.

What is the rationale for exploring lenvatinib in combination with pembrolizumab for patients with endometrial cancer?

That was a multi-cancer type trial. The endometrial cancer data were reported at the 2017 ASCO Annual Meeting. They also presented the data at the 2017 ESMO Congress for the combination of lenvatinib with pembrolizumab with the renal cell carcinoma population, which also demonstrated promising response rates and PFS.

What does the future hold for the treatment paradigm of gynecologic malignancies?

The rationale for combining these drugs was not completely clear initially. This highlights how little we understand about the immunologic potential of some drugs that were not initially developed to target the immune system. The first drug that will probably be approved will be more of the standard off-the-shelf treatments, such as immune checkpoint blockade or some vaccines that are more common to different patients.

The adoptive T-cell therapies are more involved. They will probably be more expensive. The product (tisagenlecleucel) that was approved from Novartis for the treatment of patients with leukemia costs a lot of money per treatment, which may become a limitation of choosing some of these therapies. If the therapies result in long-term disease stabilization, or even cures of these patients, perhaps these types of treatments will justify the costs.

A problem that puts these adoptive cell therapies further in the future is that we don't necessarily have an effective target in ovarian cancer for an off-the-shelf type of use. There is currently an ongoing clinical trial at Memorial Sloan Kettering Cancer Center that is using adoptive cell therapy with CAR T cells targeting MUC16. MUC16…secretes CA 125, which is common to many patients with ovarian cancer. If that turns out to be effective, that could potentially be a nice off-the-shelf treatment approach for patients.

Further in the future are also TCR types of therapies, especially with the therapies that are targeting specific mutations unique to individuals. This will not happen for some time and will come later than some of these other treatments.

Makker V, Rasco DW, Dutcus CE, et al. A phase Ib/II trial of lenvatinib (LEN) plus pembrolizumab (Pembro) in patients (Pts) with endometrial carcinoma. J Clin Oncol. 2017;35 (suppl; abstr 5598).