PD-1 and IDO Inhibitor Combo Slated to Change Practice in Melanoma

Gina Columbus @ginacolumbusonc
Published Online: Wednesday, Mar 22, 2017

Thomas F. Gajewski, MD, PhD

Thomas F. Gajewski, MD, PhD

Mature data from the ongoing phase III KEYNOTE-252/ECHO-301 trial could lead to an exciting FDA approval and a new, less toxic frontline standard of care in melanoma, according to Thomas F. Gajewski, MD, PhD.

The pivotal study is exploring the combination of the PD-1 inhibitor pembrolizumab (Keytruda) with the first-in-class IDO1 inhibitor epacadostat (INCB024360) in patients with stage III/IV unresectable or metastatic melanoma (NCT02752074). Six hundred patients across more than 120 locations will be randomized to the novel combination or pembrolizumab plus placebo.

Phase I findings for the combination presented at the 2016 ESMO Congress demonstrated that 11 of 19 evaluable treatment-naïve patients achieved an objective response (58%), including 5 patients (26%) with a complete response and 6 participants (32%) with a partial response. The disease control rate was 74%.

Moreover, the median progression-free survival (PFS) had not yet been reached at the median follow-up of 56 weeks. The PFS rate was 74% at 6 months and 57% at 12 months.

During the 2017 OncLive® State of the Science Summit on Melanoma and Immuno-Oncology, Gajewski, professor of medicine at The University of Chicago Medicine, discussed how the combination of PD-1 and IDO inhibitors could change the standard of care for patients with melanoma, and highlighted other emerging targets on the horizon.

OncLive: Can you provide an overview of your talk at this State of the Science Summit?

Gajewski: I discussed how we are using patient samples to try and discover new targets for novel immunotherapies. Many people are aware that the anti–PD-1 drugs nivolumab (Opdivo) and pembrolizumab are having a remarkable impact not just in melanoma, but in many cancer types. What we know is that, despite this remarkable advance, only a subset of patients respond.

Therefore, we are using tumor biopsies and blood-based assays to try to figure out why some patients are responding and others are not. As we explore those variables, we’re finding new therapeutic targets that we then investigate experimentally. Then, we have new therapeutic approaches that are already back in the clinic to try and make PD-1 better. 

What are some of these new targets?

One of the fundamental observations that we made in our group that has been confirmed by multiple others is that a subset of patients already has an ongoing immune response in their tumors. The immune system is trying to attack the tumor and get it rejected, but it is failing. PD-1 is one of the pathways keeping that immune response in check. As0 we study that subset of tumors more, we realize that there are other negative regulators in that same tumor set.

One of them is called IDO. This is a target that can be hit with a small molecule inhibitor. PD-1 is hit with antibodies that block PD-1 interactions with ligands; that has gone from basic experiments all the way from early-phase clinical trials. Now, there is a large phase III trial nearly accrued in metastatic melanoma treating patients with anti–PD-1 versus anti–PD-1 plus an IDO inhibitor.

Secondly, we have a lot of thoughts about what is going on in the non–T-cell inflamed tumors. There are tumors that don’t generate any spontaneous immune response to the anti–PD-1 drugs; they usually don’t work. None of those targets are even present in those tumors.

We have done a lot of basic research to figure out what’s going on in those tumors. We have multiple strategies to try and wake up those tumors to get the immune response going, and then render those patients response to anti–PD-1, or PD-1/IDO combinations down the road.

Could we see any of this combination data at the 2017 ASCO Annual Meeting?

The first phase II data from the PD-1 plus IDO regimen were presented at the 2016 ESMO Congress. Some more advanced data from that same trial—not just in melanoma, but in other tumor types—are being presented at ASCO this year. The phase III trial, which is already nearly accrued, is going to take a year to a year-and-a-half to mature to a point where there are enough events to say whether the combination is better than the single agent. 




View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Clinical Vignette Series: 34th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow®Feb 28, 20182.0
Community Practice Connections™: 13th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®Apr 28, 20182.0
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