Panagiotis A. Konstantinopoulos, MD, PhD, director of Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the role of immunotherapy in the treatment of patients with ovarian cancer.

Unlike cervical and uterine cancers where there are FDA-approved indications for pembrolizumab (Keytruda), there are not yet any approved uses for immunotherapy in ovarian cancer. With that being said, it is important to note that pembrolizumab is still a reasonable treatment strategy for the rare subset of patients whose tumors are microsatellite instability—high (MSI–H).

The incidence of MSI—H is very low in high-grade serous ovarian cancer, Konstantinopoulos explains, appearing in just 1% to 2% of cases. MSI–H is also observed in the low-grade endometrioid subtype of ovarian cancer, as well as in clear cell ovarian cancer, which is a highly aggressive and unique subtype of the disease.

In a study conducted at Dana-Farber Cancer Institute, investigators found that in 30 patients with clear cell disease, 3 of them had MSI—H tumors, which was also associated with high PD-L1 expression. There is rationale to test every patient with clear cell ovarian cancer for MSI–H using immunohistochemistry, Konstantinopoulos notes. Although these tumors are very rare, they can be matched with effective therapies.

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Dr. Konstantinopoulos on Immunotherapy in Ovarian Cancer

Panagiotis A. Konstantinopoulos, MD, director, Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the role of immunotherapy in the treatment of gynecologic cancers.

Although immunotherapy has not made much headway in this space overall, there are 2 types of gynecologic malignancies for which there have been FDA approved agents, namely checkpoint inhibitors. In endometrial cancer, about 28% of tumors express microsatellite instability (MSI), and a tumor agnostic has been approved by the FDA for pembrolizumab (Keytruda) for use in gynecologic cancers that express MSI. This is very applicable for patients with endometrial cancer who relapse on standard chemotherapy, Konstantinopoulos notes.

Pembrolizumab is also FDA approved for the treatment of patients with cervical cancer, specifically those who have a combined tumor proportion score of at least 1. This score takes into account PD-L1 expression in the tumor cells as well as the immune cells.

Panagiotis A. Konstantinopoulos, MD, PhD, director, Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses immunotherapy in gynecologic cancers.

Dr. Konstantinopoulos on Immunotherapy in Gynecologic Cancers

Panagiotis A. Konstantinopoulos, MD, PhD, director, Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the combination of PARP inhibitors and immunotherapy.

Konstantinopoulos explains that PARP inhibitors can induce double-strand breaks, which can lead to activation of the immune system either through increased neoantigens or activation of the STING pathway. The STING pathway is involved in innate immunity, he adds. Additionally, PARP inhibitors can also upregulate PD-L1 through the activation of a double-strand break in ATM- and ATR-Chk1.

Immune activation as a result of PARP inhibition paired with PD-L1 overexpression provides necessary immune priming for the cancer cells to respond to immunotherapy, according to Konstantinopoulos. This was the preclinical evidence for the phase I/II TOPACIO/KEYNOTE-162 study (NCT02657889), which is evaluating the combination of the PARP inhibitor niraparib (Zejula) and the PD-1 inhibitor pembrolizumab (Keytruda) in patients with recurrent ovarian cancer.

Panagiotis A. Konstantinopoulos, MD, PhD, director, Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the combination of PARP inhibitors and immunotherapy.
 

Dr. Konstantinopoulos Discusses PARP Plus Immunotherapy

Panagiotis A. Konstantinopoulos, MD, PhD, director, Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the rationale behind the TOPACIO trial for the treatment of patients with recurrent ovarian cancer (ROC).

Treatment for patients with platinum-resistant or platinum-refractory ovarian cancer is an important unmet need as these patients have very limited treatment options, says Konstantinopoulos. Bevacizumab (Avastin) paired with chemotherapy is currently FDA approved for the treatment of patients who have had up to two prior lines of chemotherapy.

At the 2018 ASCO Annual Meeting, Konstantinopoulos presented data from the TOPACIO trial which focused on a difficult-to-treat patient population. The trial combined the PD-1 inhibitor pembrolizumab (Keytruda) with the PARP inhibitor niraparib (Zejula). Data indicated the immunotherapy combination resulted in a 25% objective response rate (ORR) for all patients with platinum-resistant ovarian cancer and an ORR of 45% in the subgroup with 

Panagiotis A. Konstantinopoulos, MD, PhD, director, Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the rationale behind the TOPACIO trial for the treatment of patients with recurrent ovarian cancer.

Panagiotis A. Konstantinopoulos, MD, PhD

Articles

Dr. Konstantinopoulos on Immunotherapy in Ovarian Cancer

Dr. Konstantinopoulos on Immunotherapy in Gynecologic Cancers

Dr. Konstantinopoulos Discusses PARP Plus Immunotherapy

Dr. Konstantinopoulos on Rationale for TOPACIO Trial in Ovarian Cancer