Harnessing Immune Response in Advanced Ovarian Cancer

Mian M. Shahzad, MD, PhD

Preliminary research has shown that harnessing the immune system can lead to potentially viable and efficacious therapies for patients with advanced ovarian cancer; therefore, combination approaches with checkpoint inhibitors could have an impact on outcomes.

"If we can wake up the immune system to recognize a foreign [entity] and attack it, we may be able to make a big dent in [treatment],” said Mian M. Shahzad, MD, PhD. “There are also ongoing studies with oncolytic virotherapy."

In a presentation during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer, Shahzad, a gynecologic oncologist in The Center for Women’s Oncology, Moffitt Cancer Center, discussed the use of checkpoint inhibition in advanced ovarian cancer.

Initial studies with immunotherapy were done to assess the antitumor activity and safety of single-agent checkpoint inhibitors, said Shahzad. In the phase II KEYNOTE-100 trial, patients with recurrent disease were given 200 mg of pembrolizumab (Keytruda) every 3 weeks until progression or unacceptable toxicity for a maximum of 2 years. Results showed that the overall response rate (ORR) was 4.1% for those with PD-L1 expression (combined positive score [CPS]) <1, 5.7% in CPS ≥1, and 10.0% in patients with CPS >10.1

Given the insufficient single-agent activity, investigators turned to combination studies. Perhaps the most notable combination trial was the phase I/II TOPACIO/KEYNOTE-162 study,² which tested the combination of niraparib (Zejula) and pembrolizumab in patients with recurrent disease (n = 62). Although the ORR with the combination was modest at 18% (90% CI, 11%-29%), the disease control rate (DCR) was 65% (90% CI, 54%-75%) and 47% of patients achieved stable disease. Notably, responses were consistent across the study population, irrespective of BRCA status or platinum sensitivity.

In the phase II NRG-GY003 trial,³ patients with recurrent disease were randomized to nivolumab (Opdivo) monotherapy or in combination with ipilimumab (Yervoy). Investigators reported a significant improvement in ORR from 12.2% with nivolumab alone to 31.4% with the addition of ipilimumab. This translated to a 47.2% reduction in the risk of progression or death and a trend toward improved overall survival (OS).

Subsequently, the phase III JAVELIN Ovarian 100 trial was launched in treatment-naïve patients with stage III/IV ovarian cancer. Patients were randomized to receive chemotherapy, chemotherapy and avelumab (Bavencio) maintenance, or the combination of chemotherapy and avelumab followed by avelumab maintenance. However, the study was discontinued due to a lack of benefit, said Shahzad.

Avelumab was also evaluated in the platinum-resistant/refractory setting in the phase III JAVELIN Ovarian 200 trial.⁴ In the first randomized phase III trial to evaluate the role of checkpoint inhibition in ovarian cancer, patients were randomized to receive avelumab, pegylated liposomal doxorubicin (PLD), or the combination of avelumab and PLD. As in the JAVELIN 100 trial, patients were not preselected based on PD-L1 expression and had received ≤3 prior lines of therapy. Neither avelumab alone or in combination with PLD induced a statistically significant improvement in OS or progression-free survival (PFS), failing to meet the study’s coprimary endpoints.

In terms of other combinations, pembrolizumab and bevacizumab (Avastin) induced a 95% disease control rate, with a ORR of 40% in an open-label phase II trial presented during the 2019 SGO Annual Meeting.⁵ The combination acts similarly to the combination of pembrolizumab and weekly paclitaxel, which was studied in a phase II trial in the platinum-resistant setting. At a median follow-up of 6.7 months, the chemoimmunotherapy combination resulted in an overall DCR of 86.5%, with a partial response rate of 51.4%.⁶

There are several other ongoing trials exploring novel combinations, said Shahzad, including the phase III JAVELIN Ovarian PARP 100 trial (NCT03642132), and the phase II/III NRG-GY009 trial (NCT02839707). In the JAVELIN Ovarian PARP 100 trial, previously untreated patients will be randomized to receive avelumab and chemotherapy or avelumab and talazoparib (Talzenna) maintenance. In the NRG-GY009 trial, patients with platinum-resistant disease will be randomized to receive PLD and atezolizumab (Tecentriq); PLD, atezolizumab, and bevacizumab; or PLD and bevacizumab alone. Both trials are in the monitoring phase.

The phase III ATHENA (NCT03522246) and ATALANTE/ENGOT OV29 trials (NCT02891824) are actively accruing. In ATHENA, previously untreated patients will be randomized to 1 of 4 arms: rucaparib (Rubraca) and nivolumab; rucaparib and placebo; nivolumab and placebo; or placebo alone. In ATALANTE, patients in late relapse with a PFS >6 months will be randomized to receive either atezolizumab, bevacizumab, and chemotherapy, or bevacizumab and chemotherapy alone.

Finally, Shahzad discussed the multicenter phase III DUO-O trial (NCT03737643), which will evaluate the use of durvalumab (Imfinzi) in combination with chemotherapy and bevacizumab, followed by maintenance durvalumab, bevacizumab, and olaparib (Lynparza) in patients following primary debulking surgery or neoadjuvant chemotherapy.

References

1. Matulonis UA, Shapira-Frommer R, Santin AD, Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase 2 KEYNOTE-100 study [published online ahead of print May 2, 2019]. Ann Oncol. doi: 10.1093/annonc/mdz135.
2. Konstantinopoulos PA, Waggoner S, Vidal GA, et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 2019. doi: 10.1001/jamaoncol.2019.1048.
3. Burger R, Sill M, Zamarin D, et al. NRG oncology phase 2 randomized trial of nivolumab with or without ipilimumab in patients with persistent or recurrent ovarian cancer. Presented at: the Biennial Meeting of the International Gynecological Cancer Society; September 14-16, 2018; Kyoto, Japan. Abstract OC11.
4. Merck KGaA, Darmstadt, Germany, and Pfizer Provide Update on Avelumab in Platinum-Resistant/Refractory Ovarian Cancer [news release]. Merck KGaA and Pfizer. Published November 19, 2018. https://bit.ly/2PGGzPB. Accessed November 19, 2018.
5. Zsiros E, Frederick PJ, Akers SN, et al. A phase II trial of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. Presented at: 2019 SGO Annual Meeting. March 16-19, 2019; Honolulu, HI. Abstract LBA4.
6. Wenham R, et al. Trial of pembrolizumab following weekly paclitaxel for platinum-resistant ovarian, fallopian tube, or peritoneal cancer (PROMPT). Presented at: the Biennial Meeting of the International Gynecological Cancer Society; September 14-16, 2018; Kyoto, Japan. Abstract 1482.