Immunotherapy Combos on Horizon for Ovarian Cancer

Camille Gunderson, MD

Several phase III studies are exploring immunotherapy combinations for patients with ovarian cancer, with the potential to disrupt the systemic treatment paradigm for these patients, according to Camille Gunderson, MD, who spoke at the SGO 2018 Annual Winter Meeting in Snowmass, Colorado.¹

These larger studies for patients with ovarian cancer are testing combinations of immunotherapy with chemotherapy or anti-VEGF agents. These studies were preceded by small trials exploring monotherapy with immunotherapy. If findings from the smaller single-agent trials are proven and improved in larger phase III studies, these combinations could result in lasting treatment changes.

Immunotherapy Combinations

“There are a number of agents which enhance antigen presentation and T-cell activation, including conventional chemotherapy agents, radiation treatments, and newer, targeted agents such as PARP inhibitors,” said Gunderson, an assistant professor at the University of Oklahoma Health Sciences Center, Stephenson Cancer Center. “Antiangiogenic agents such as bevacizumab [Avastin] increase T-cell trafficking and infiltration into tumors. [Also], immunomodulatory agents block immunosuppression within the tumor microenvironment and enhance tumor cell death.”As a single agent, the PD-1 inhibitor nivolumab (Opdivo) showed responses in 15% of patients with platinum-resistant ovarian cancer in findings published in 2015.² Overall survival (OS) in this group reached 20 months. To push this efficacy further, several studies are assessing the combination of 2 immune checkpoint inhibitors.

Although 2 immune checkpoint inhibitors might seem like overkill, Gunderson said in this case “more is more.” She cited results published in The New England Journal of Medicine by Wolchock et al showing that 3-year overall survival (OS) for patients with previously untreated advanced melanoma was 58% for those who received a combination of nivolumab and ipilimumab compared with 52% for those assigned to nivolumab monotherapy and 34% for those assigned to ipilimumab monotherapy.³

NRG-GY003 (NCT02498600) is a randomized, open-label, phase II trial evaluating the safety and efficacy of nivolumab with or without the CTLA-4 inhibitor ipilimumab (Yervoy) in treating patients with persistent or recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer (n = 96).

One group of patients in the study was assigned to 3 mg/kg of nivolumab once every 2 weeks for 4 doses in the induction phase, then the same dose every 2 weeks for up to 42 weeks, until disease progression or unacceptable toxicity. The other group was assigned the same dose of nivolumab plus 1 mg/kg of ipilimumab once every 3 weeks for 4 doses, followed by nivolumab 3mg/kg every 2 weeks up to 42 doses.

That study has finished recruiting, with results eagerly anticipated. The estimated primary completion date for the study is December 2020.

“Although immune checkpoint inhibition has really changed the treatment for many solid tumors, particularly for melanoma and microsatellite unstable tumors, it looks like combining them really does provide a much stronger tumor kill than either agent alone,” she said.

Similarly, the phase II, single-arm DART trial (NCT02834013) is exploring the combination of nivolumab and ipilimumab in 31 rare cancers, such as nonepithelial tumors of the ovary, including germ cell tumor and Mullerian mixed tumor and adenosarcoma. The primary endpoint is overall response rate. Secondary endpoints include progression-free survival (PFS), clinical benefit rate, estimated immune-related ORR, and immune-related PFS by unidimensional immune-related response criteria.

Chemotherapy Plus Immunotherapy

DART’s expected completion date is August 2020.Two phase III studies, JAVELIN 100 (NCT02718417) and JAVELIN 200 (NCT02580058), are evaluating avelumab (Bavencio) in combination with chemotherapy. In a prior study,⁴ single-agent avelumab, a PD-L1 inhibitor, shored an objective response rate (ORR) of 9.7% for patients with heavily pretreated recurrent or refractory ovarian cancer. Median OS reached 10.8 months.

JAVELIN 100 is enrolling women with treatment-naïve histologically confirmed stage III-IV epithelial ovarian, fallopian tube cancer, or primary peritoneal cancer (N = 951). The 3-arm trial will compare single-agent avelumab in the maintenance setting following frontline chemotherapy; avelumab in combination with carboplatin/paclitaxel followed by avelumab maintenance; or, platinum-based chemotherapy alone followed by observation.

The primary endpoint is PFS, with OS as a secondary endpoint. Completion is scheduled for December 2021.

JAVELIN 200 is a phase III, multicenter, randomized, open-label study of avelumab alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in patients with platinum-resistant/refractory ovarian cancer. The study is fully enrolled, with 550 participants.

Immunotherapy Plus Anti-VEGF Agents

The estimated completion date for the primary endpoint of OS is March 2018, and Gunderson said the results are “eagerly awaited.”The VEGF molecule is considered immunosuppressive because it directly and indirectly inhibits T-cell function, Gunderson said. Also, VEGF stimulates immunosuppressive regulator T cells, inhibits dendritic cell function, reduces the adhesion of lymphocytes to vessel walls, and induces abnormal tumor vasculature. Therefore, inhibition of VEGF could positively impact the immune system.

Investigators are currently recruiting 1300 women into the global, phase III, multicenter, 2-arm randomized IMaGYN050 trial (NCT03038100). Those in the primary tumor-reductive surgery group will receive paclitaxel, carboplatin, and the PD-L1 inhibitor atezolizumab (Tecentriq) on day 1 of each 21-day cycle for a total of 6 cycles, and bevacizumab starting with cycle 2 for a total of 5 cycles. Patients will then receive bevacizumab with atezolizumab for a total of 22 cycles of atezolizumab and 21 cycles of bevacizumab as maintenance therapy.

Participants in the neoadjuvant therapy group will initially receive paclitaxel, carboplatin and atezolizumab for 6 cycles and bevacizumab for four 21-day cycles. Interval surgery will occur between cycles 3 and 4. After 6 cycles, participants will start maintenance therapy of bevacizumab and atezolizumab for an additional 16 cycles.

In the ATALANTE trial (NCT02891824), investigators are studying atezolizumab plus bevacizumab in women with epithelial ovarian cancer (including primary peritoneal and/or fallopian tube adenocarcinoma) who have platinum-sensitive relapse. Investigators are recruiting roughly 405 patients into this phase III, randomized, double-blinded, comparative, multicenter study assessing the efficacy of atezolizumab in combination with platinum-based chemotherapy plus bevacizumab administered concurrent to chemotherapy and in maintenance.

References:

1. Gunderson C. Selection of Novel Agents for Combination Therapy with Gynecologic Cancers. Presented at: 2018 SGO Annual Winter Meeting; February 8-10, 2018; Snowmass, CO.
2. Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti—PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. doi:10.1200/JCO.2015.62.3397
3. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377:1345-1356. doi: 10.1056/NEJMoa1709684.
4. Disis ML, Patel M, Pant S, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with recurrent/refractory ovarian cancer from the JAVELIN Solid Tumor phase Ib trial: Safety and clinical activity. J Clin Oncol 34, 2016 (suppl; abstr 5533).

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