Combinations Could Lead to Bright Future for Immunotherapy in Ovarian Cancer

Matthew Powell, MD

Matthew Powell, MD

While there is still enthusiasm for developing immunotherapies for patients with ovarian cancer, phase II studies thus far have had disappointing results in the recurrent population, explained Matthew Powell, MD.

There is a small cohort of patients with ovarian cancer with microsatellite instability—high (MSI-H) tumors who are candidates for checkpoint inhibitor therapy, however, the low response rates observed with single-agent checkpoint inhibition have promoted investigators to look at combinations.

Powell, associate professor of obstetrics and gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, Siteman Cancer Center, recently 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.

JAVELIN 200 (NCT02580058) is evaluating the combination as well, but in patients with platinum-refractory/-resistant ovarian cancer. In the study, 550 patients are being randomized to either 10 mg/kg of avelumab every 2 weeks, 10 mg/kg of avelumab every 2 weeks plus 40 mg/m²of pegylated liposomal doxorubicin (PLD) every 4 weeks, or 40 mg/m²of PLD alone every 4 weeks. The primary endpoint of this study is OS, with secondary endpoints of ORR, PFS, DoR, disease control, safety, quality of life, PKs, tumor biomarkers, and immunogenicity of avelumab. Powell said the estimated primary endpoint should be reported by the end of 2018.

VEGF inhibitors and PARP inhibitors in combination with immunotherapy are also being investigated, Powell said. The rationale for combining immunotherapy with VEGF inhibitors is that the latter induce abnormal tumor vasculature, directly inhibit T-cell function, stimulate immunosuppressive regulatory T cells, and inhibit dendritic cell function. There are several trials in development evaluating immunotherapy in combination with VEGF inhibitors, as well as with PARP inhibitors.

The NRG GY009 study (NCT02839707) is a 3-arm randomized study in patients with platinum-resistant recurrent ovarian cancer who have had 1 to 2 prior lines of therapy. Patients randomized to arm 1 will receive 40 mg/m²of PLD for 4 weeks plus 800 mg of atezolizumab every 2 weeks. Arm 2 mirrors arm 1, with the addition of 10 mg/kg of bevacizumab (Avastin) every 2 weeks. Patients randomized to arm 3 will receive 40 mg/m²of PLD every 4 weeks and 10 mg/kg of bevacizumab every 2 weeks.

Additional trials include ATALANTE (NCT02891824) and IMaGYN050 (NCT03038100). ATALANTE is a phase III, randomized, double-blinded study of atezolizumab versus placebo in patients with late relapse of epithelial ovarian, fallopian tube, or peritoneal cancer treated by platinum-based chemotherapy and bevacizumab.

IMaGYN050 is a double-blinded, randomized, placebocontrolled, multicenter study of atezolizumab versus placebo in combination with paclitaxel, carboplatin, and bevacizumab in previously untreated patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients enrolled on this trial are either stage III or stage IV or are in the adjuvant setting with advanced disease.

Early data support the combination of PARP inhibitors and immunotherapy, Powell added. “Preclinical models indicate synergy between PARP inhibitors and PD-1 inhibitors regardless ofBRCAmutation status or PD-L1 status,” he said. “We can damage the DNA and keep it from repairing and probably increase the amount of neoantigens seen; hopefully it will allow the immune system to better recognize them.”

The phase I/II TOPACIO/KEYNOTE-162 study (NCT02657889) is a dose-finding combination trial of niraparib (Zejula) plus pembrolizumab in patients with metastatic triple-negative best cancer or recurrent platinum-resistant epithelial ovarian cancer. Preliminary activity has been encouraging, said Powell, with responses observed in patients withBRCAwild-type and PD-L1—negative tumors. In the 60 evaluable patients, there was an ORR of 25% and a disease control rate of 67%. Powell said that these results warrant further development of this combination in ovarian cancer.

Other studies include FIRST (ENGOT-ov44/GINECO), which is a randomized phase III trial evaluating niraparib with the PD-L1 in inhibitor TSR-032 in patients with newly diagnosed advanced stage III/IV ovarian cancer. Patients in arm 1 will receive carboplatin, paclitaxel, and bevacizumab and then move onto a chemotherapy treatment break, after which they will receive placebo plus bevacizumab. Arm 2 mirrors arm 1, except patients will receive niraparib in place of placebo. Lastly, arm 3 will receive carboplatin, paclitaxel, TSR-042, and bevacizumab, move onto a chemotherapy treatment break, and then receive niraparib plus TSR-041 and bevacizumab. The primary endpoint of this study is PFS.

Additionally, the ATHENA trial (NCT03522246) is a phase III randomized trial of rucaparib (Rubraca) and nivolumab as maintenance treatment following response to first-line platinum-based chemotherapy. There are currently 1012 patients enrolled on this trial, and they are being randomized to either rucaparib plus nivolumab, rucaparib plus placebo, placebo plus nivolumab, or oral placebo plus intravenous placebo.

Overall, Powell predicted that the future of immunotherapy in ovarian cancer will be bright if investigators continue to pursue combination approaches. “When we look at immunotherapy, there is good biologic plausibility. There is a lot of room for promise and moving forward with these appropriate combinations makes sense,” he concluded.

Reference:

Konstantinopoulos PA, Waggoner SE, Vidal GA, et al. TOPACIO/KEYNOTE-162 (NCT02657889): a phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—results from ROC cohort.J Clin Oncol. 2018;36 (suppl; abstr 106). http://ascopubs. org/doi/abs/10.1200/JCO.2018.36.15_suppl.106.