Matthew Powell, MD
Although enthusiasm remains for developing immunotherapies for patients with ovarian cancer, phase II studies evaluating the treatment’s efficacy in the recurrent population have been disappointing thus far, explained Matthew Powell, MD.
Currently, the majority of the microsatellite instability–high (MSI-H) tumors in gynecologic malignancies are seen in patients with endometrial cancer; however, there is a small cohort of patients with ovarian cancer with MSI-H tumors who are candidates for checkpoint inhibitor therapy. Still, the low response rates observed in ovarian cancer with single-agent checkpoint inhibition have promoted investigators to look at combinations.
In a presentation during the 2018 OncLive®
State of the Science Summit™ on Ovarian Cancer, Powell, associate professor of obstetrics and gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, Siteman Cancer Center, discussed the promise of immunotherapy in ovarian cancer despite its challenges.
“We are understanding now how the immune system interacts with the cancer cell or the abnormal cell, how the cancer cell can hide from the immune system, and some of the tricks we can do to unmask the cancer to the immune system—and try to avoid some of the resistance mechanisms that have been developing,” said Powell.
The correlation between tumor-infiltrating lymphocytes (TILs) and survival is supported by multiple clinical studies in ovarian cancer, according to Powell. However, the clear majority of ovarian cancer tumors are “cold,” meaning they have low tumor mutational burden.
“Understanding tumor biology is important,” Powell said. “We know that there are unique antigens on an ovarian cancer cell that we can capitalize on. There have been a lot of studies looking at these different antigens. Unfortunately, most of them have been negative. However, we know that these are targets that we can be using.”
Powell said that if a patient has low levels of PD-1, they will do better regarding overall survival (OS) and progression-free survival (PFS). PD-L1 expression may represent a tumor resistance mechanism to TILs in ovarian cancer, meaning patients who have high levels of PD-L1 expression do worse with immunotherapy.
The phase I/II data available for single-agent PD-1/PD-L1 inhibitors have demonstrated encouraging but modest activity in recurrent ovarian cancer, suggesting an opportunity for combinations. Thus far, atezolizumab (Tecentriq), avelumab (Bavencio), nivolumab (Opdivo), and pembrolizumab (Keytruda) have been evaluated as monotherapy for these patients.
NRG-GY003 (NCT02498600) is a randomized, open-label, phase II trial evaluating the safety and efficacy of nivolumab with or without ipilimumab (Yervoy) as a therapy for patients with persistent or recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.
Patients in arm 1 are being administered 3 mg/kg of nivolumab once every 2 weeks for 4 cycles in the induction phase and then the same dose every 2 weeks for up to 42 weeks or until disease progression or unacceptable toxicity. In arm 2, patients will receive 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab once every 3 weeks for 4 cycles, followed by nivolumab 3 mg/kg every 2 weeks for up to 42 doses. This 2-arm trial has already completed accrual (N = 96), with data expected in late 2020 or early 2021.
Combining checkpoint inhibitors with chemotherapy induces neoantigens, according to Powell, making it a compelling option for investigation. Preclinical evidence for chemotherapy and PD-L1 inhibitors showed synergism of nab-paclitaxel (Abraxane) plus PD-L1 inhibition in MC38 mouse tumor models. Treatment with platinum agents or taxanes increased the percentage of CD8-positive TILs in immunocompetent mouse models, said Powell.
“Looking across both platinum and taxanes, they seemed to have increasing TILs within the tumor when we used this approach,” he explained. “You are killing the cancer with the cytotoxic agent, releasing neoantigens, allowing that immune system to recognize the tumor.”
There are several studies of chemoimmunotherapy in the works. JAVELIN 100 (NCT02718417) is a phase III study of the combination of avelumab and chemotherapy in the frontline setting. In the study, 951 patients are being randomized to either chemotherapy and observation, chemotherapy with maintenance avelumab every 2 weeks, or chemotherapy plus avelumab every 3 weeks with maintenance avelumab every 2 weeks. The primary endpoint is PFS, with secondary endpoints of OS, overall response rate (ORR), duration of response (DoR), pathologic complete response, pharmacokinetics (PKs), patient-reported outcomes, and safety.