Results from a phase I/II dose-escalation and dose-expansion study of epacadostat (incb024360; Incyte Corporation)*, a potent, selective inhibitor of indoleamine 2,3-dioxygenase 1 (also known as IDO1), in combination with pembrolizumab (Keytruda®; formerly known as MK-3475 and lambrolizumab; Merck & Co., Inc) were reported earlier today during the 30th Anniversary Annual Meeting Late-Breaking Abstract Session of the Society for Immunotherapy of Cancer’s (SITC).
In preclinical studies and initial data from a dose-escalation study in patients with unresectable metastatic melanoma epacadostat showed increased anti-tumor efficacy when epacadostat was administered in combination with ipilimumab and supported evaluation of additional combination dosing regimens.
These results are very promising and once again demonstrates the potential for combination regimens in immunotherapy...
The study, with a 3+3+3 Phase I design, which, as of August 21, 2015, included 54 patients, is a new combination immunotherapy regimen that was generally well tolerated. Patients participating in the study were diagnosed with Stage IIIB, IV or recurrent non-small cell lung cancer (NSCLC), advanced melanoma, renal cell carcinoma (RCC), transitional cell carcinoma (TCC), endometrial adenocarcinoma (EA), or squamous cell carcinoma of the head and neck (SCCHN).  Patients previously treated with either an anti-PD-1 or anti-CTLA 4 therapy were excluded.
Very few patients experienced dose limiting toxicity (DLT) or grade 3 treatment-related adverse effects. No grade 4 treatment-related adverse effects or deaths were reported. Furthermore, the study showed a low discontinuation rate for treatment-related adverse effects (2%). Efficacy results included an overall response rate of 53% and a disease control rate of 74%, with an especially profound effect in patients with melanoma.
"I think the results are very promising and once again demonstrates the potential for combination regimens in immunotherapy. In this case pembrolizumab was combined with an IDO inhibitor and demonstrated responses in more than half of the subjects with different types of cancer. The study, I think, needs to be interpreted cautiously because the numbers of patients treated are still small, but if this can be replicated in a larger population, this could be very significant for bringing immunotherapy to a larger number of patients with cancer," noted Howard L. Kaufman, MD, FACS, SITC President.
The goal is increased response rates, and the way to get more people to respond to checkpoint inhibitors is to target different pathways related to immune stimulation and/or blocking immune suppression. IDO is an enzyme that may inhibit local T cell response in the tumor microenvironment. While prembrolizumab is approved for the treatment of melanoma and non-small cell lung cancer, IDO inhibitors are still in experimental study as a method for restoring local T cell response within the tumor microenvironment. Enrollment in the clinical trial is ongoing to further evaluate efficacy. A phase III study for patients with advanced melanoma is planned, with initiation expected in 2016.
Combination Therapy Task Force
SITC continues to support the field via the Combination Therapy Task Force. The task force was established in response to the increasing number of therapeutic options for a variety of cancers, and to highlight the potential opportunity to bolster encouraging clinical findings for single agents by combining immunotherapy approaches with complementary treatments. A forthcoming white paper will define the state of the science and strategically focus dialogue regarding key issues likely to influence the future course of combination immunotherapy, including responses of depth and duration not previously observed nor believed possible, and also the concerns of both toxicity and cost to the healthcare system.
* Epacadostat (INCB024360) is an orally available hydroxyamidine and inhibitor of indoleamine 2,3- dioxygenase (IDO1), with an IC50 of 10 nM. It shows little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). Epacadostat displays potential immunomodulating and antineoplastic activities. Epacadostat has been reported to restore and increase the proliferation of various immune cells including dendritic cells, NK cells, and T cells in vitro and in vivo.
 Gibney GT, Hamid O, Gangadhar TC, Lutzky J, Olszanski AJ, Gajewski T, Chmielowski B, Boasberg PD, et al. Preliminary results from a phase 1/2 study of INCB024360 combined with ipilimumab (ipi) in patients (pts) with melanoma. J Clin Oncol 32:5s, 2014 (suppl; abstr 3010)
 Gibney GT, Hamid O, Smith DC, Bauer TM, Wasser JS, Luke JJ, Balmanoukian AS, et al. Preliminary results from a Phase I/II study of epacadostat (incb024360) in combination with pembrolizumab in patients with selected advanced cancers. Journal for ImmunoTherapy of Cancer 2015, 3 (sup 2): o7
 A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of MK-3475 in Combination With INCB024360 in Subjects With Selected Cancers (INCB 24360-202 / MK-3475-037 / KEYNOTE-037) - NCT02178722. Clinicaltrials.gov.
Last editorial review: November 6, 2015. Copyright © 2015 Sunvalley Communication, LLC. All rights reserved. Republication or redistribution of Sunvalley Communication content, including by framing or similar means, is expressly prohibited without the prior written consent of Sunvalley Communication. Sunvalley Communication shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Onco'Zine and Oncozine are registered trademarks and trademarks of Sunvalley Communication around the world.