Additional Studies Needed for Immunotherapy Combinations in Clear Cell Ovarian Carcinoma

In a phase 2 trial (NCT03602586) of patients with recurrent clear cell carcinoma of the ovary, the use of pembrolizumab (Keytruda) plus the IDO1 inhibitor epacadostat led to an inconclusive effect on efficacy despite observed objective responses, according to results presented at the 2022 Annual Global Meeting of the International Gynecologic Cancer Society.¹

At a median duration of follow-up of 6.6 months, the objective response rate was 21% (95% CI, 0.05-0.51) in 14 patients with recurrent clear cell carcinoma of the ovary and the median duration of response was 6.9 months. All 3 responders had a partial response. Additionally, 4 patients had stable disease for a disease control rate of 50%.

“There was an inconclusive effect [on efficacy with the] additional attribution of an IDO1 inhibitor. However, there was a rapid accrual of patients in the first stage that exceeded expectations. This demonstrated the enthusiasm and need for future trials of this rare tumor,” Lilian Gien, MD, affiliate scientist at Sunnybrook Health Sciences Centre in Toronto, Canada, said during the presentation.

Previous studies have shown dramatic and durable responses, specifically with immune checkpoint inhibitors, in clear cell ovarian cancer. In a phase 2 study published in the Journal of Clinical Oncology in 2015, 2 out of 20 patients with platinum-resistant ovarian cancer who were treated with nivolumab (Opdivo) had complete responses to therapy. Histologic subtypes garnering a complete response included 1 with clear cell histology and recurrent disease and another with peritoneal carcinomatosis.²

Similarly, results from a subset of the NRG-GY003 study which tested nivolumab plus ipilimumab (Yervoy) vs nivolumab alone in patients with recurrent epithelial ovarian cancers showed a 5-fold increase in the odds of response in patients with clear cell histology, a fact Gien called both “hypothesis-generating and thought-provoking.”³

As such, the investigators of the trial aimed to improve response rates with immunotherapy for this patient population by adding an inhibitor of indoleamine 2, 3-dioxygenase 1 (IDO1), the use of which is known to increase cell-mediated antitumor immune responses. Early data in solid tumors indicate that the combination of pembrolizumab and epacadostat is generally safe and feasible, with notable efficacy in melanoma.⁴ Unfortunately, results from a phase 3 trial on the efficacy of the combination in melanoma that was published after the ovarian cancer study’s initiation failed to show a benefit vs single-agent checkpoint inhibition.⁵

For the current trial, the median patient age was 65 years (range, 44-89) and a majority had not received prior radiation therapy (78.6%). The number of prior of lines of chemotherapy was 1 for 28.6% and 2 or 3 lines for 35.7% each. Additionally, 21.4% of patients received prior bevacizumab (Avastin) and 64.3% had unknown mismatch repair status.

Patients were given pembrolizumab at 200 mg intravenously every 3 weeks plus epasadostat at 100 mg orally twice a day. The primary end point was the objective response rate with secondary end points of progression-free survival (PFS), overall survival (OS), and safety.

The median PFS was 4.8 months (95% CI, 1.9-9.6) and median OS was 18.9 months (95% CI, 1.9-not reached). The most common grade 3 or greater adverse effects (AEs) were bowel obstruction (21.4%) and electrolyte abnormalities (21.4%). There were 3 grade 5 serious AEs, including 1 case of bowel perforation, 1 treatment-unrelated death due to disease, and 1 death likely related to both drugs.

References

1. Gien LT, Enseroo DM, Block MS, et al. Phase II trial of pembrolizumab and epacadostat in recurrent clear cell carcinoma of the ovary: an NRG Oncology Study (NRG-GY016). Presented at: 2022 Annual Global Meeting of the International Gynecologic Cancer Society; New York, NY; September 29-October 1, 2022. Abstract O014.
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. 2015;33(34):4015-4022. doi:10.1200/JCO.2015.62.3397
3. Zamarin D, Burger RA, Sill MW, et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG Oncology study. J Clin Oncol. 2020;38(16):1814-1823. doi:10.1200/JCO.19.02059
4. Gangadhar TC, Hamid O, Smith DC, et al. Preliminary results from a phase I/II study of epacadostat (incb024360) in combination with pembrolizumab in patients with selected advanced cancers. J Immunother Cancer. November 4, 2015;3(suppl 2):O7. doi:10.1186/2051-1426-3-S2-O7
5. Long GV, Dummer R, Hamid O, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019;20(8):1083-1097. doi:10.1016/S1470-2045(19)30274-8