Ovarian clear cell carcinoma (OCCC) is a rare histologic subtype accounting for <10% of epithelial ovarian cancers in North America and Europe [1]. OCCC has a worse prognosis and survival compared to high grade serous ovarian cancer with a response rate of <10% in recurrent disease with platinum-based chemotherapy [2]. There is an unmet need for effective therapies in this disease type, given the particularly poor prognosis of OCCC upon recurrence, the lack of effective treatment, and the rarity of this disease. Future treatment of this disease may rest on novel therapies.

Immune checkpoint blockade is increasingly being used as a therapeutic option in gynecologic malignancies. In epithelial ovarian cancer, response to single agent programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors has ranged from 8 to 13% [3,4] in studies that include all histologic subtypes. Notably, small studies have suggested that immune checkpoint inhibitors may be of particular benefit in those with clear cell histology. In a phase 2 study by Haminishi et al. [4], 20 patients with heavily treated platinum-resistant ovarian cancer were given nivolumab. Two patients (10%) had a durable complete response (CR), one of whom had clear cell carcinoma with peritoneal dissemination which disappeared after two cycles of nivolumab. In a phase 1b study of avelumab in recurrent or refractory ovarian cancer, two patients with OCCC had partial responses [5]. In a phase 2 randomized trial of nivolumab versus nivolumab and ipilimumab for recurrent ovarian cancer, a subset analysis demonstrated those with clear cell histology were five times more likely to respond to nivolumab and ipilimumab compared to other histologic subtypes, though clear cell histology represented only 12% of the study cohort [6]. Although these early studies have shown promise, in order to improve upon these results, strategies incorporating combinations of immunotherapy are needed. Furthermore, with the small number of clear cell patients in these previous studies, histotype-specific trials specifically for patients with OCCC are also needed.

Indoleamine 2, 3-dioxygenase 1 (IDO1) is an enzyme that catalyzes oxidative catabolism of the amino acid tryptophan (Trp) to kynurenine [7], which results in the inhibition of antitumor cell–mediated immune responses. IDO1 is prevalent in approximately 56% of ovarian tumors and correlates with a reduced number of CD8+ tumor infiltrating lymphocytes (TILs) [8]. High IDO expression is associated with impaired overall and progression-free survival, with a trend across all histologic subtypes, including clear cell cancer [8].

Epacadostat (INCB024360) is a potent, selective oral inhibitor of IDO1. Inhibiting IDO1 leads to decreased kynurenine, and downstream downregulation of regulatory T-cells (Tregs), thereby increasing the antitumor immune response. Results from a phase I/II study of epacadostat in combination with MK-3475 (pembrolizumab), an anti-PD-1 antibody, were reported in patients with advanced cancers [9] with an overall response rate of 53% with 3 complete responses and a disease control rate of 74%. Promising anti-tumor activity was reported in patients with advanced renal cell carcinoma with response rates of 37%.

With poor outcomes related to recurrent OCCC, early studies demonstrating durable objective responses with PD-1 inhibition with this histologic subtype, and the need for a combination approach to improve response rates even further, we sought to examine the efficacy of pembrolizumab and epacadostat (IDO1 inhibitor) in recurrent OCCC.