Pembrolizumab Plus Epacadostat Active in RCC

Primo N. Lara Jr, MD

The combination of the PD-1 inhibitor pembrolizumab (Keytruda) and the IDO-inhibitor epacadostat induced a response rate of 47% in patients with advanced renal cell carcinoma (RCC), according to results from the phase I/II KEYNOTE-037 study presented at the 2017 ASCO Annual Meeting.

Patients had received 1 or no prior lines of treatment. The complete response rate was 5% and responses occurred regardless of PD-L1 expression. The median duration of response was 26.8+ weeks (range, 18.1+ to 53.1). The safety profile for the combination was, in general, similar to prior research with single-agent pembrolizumab.

OncLive: Can you give an overview of the study investigating epacadostat and pembrolizumab?

In an interview with OncLive during ASCO, Primo N. Lara Jr, MD, an associate director for Translational Research and co-leader of the Cancer Therapeutics Program at the UC Davis Comprehensive Cancer Center, discussed the KEYNOTE-037 pembrolizumab/epacadostat findings in patients with advanced RCC, and how the combination could change treatment in this population.Lara: The epacadostat/pembrolizumab trial was a phase Ib/II trial testing the IDO inhibitor epacadostat in combination with the PD-1 inhibitor pembrolizumab in a variety of solid tumors. The subset that we presented at ASCO this year was in metastatic renal cell carcinoma.

Of this subset of RCC patients, 46 patients were evaluable for safety and 30 were evaluable for efficacy. We saw encouraging response rates and safety signals with this combination, specifically in patients who had minimally pretreated disease of 0 to 1 prior therapies. The confirmed response rate was 47%, which is in line with many prior studies of combination immuno-oncology therapies. However, taken in the context of a favorable safety signal in this study, only 15% of patients experienced grade 3 or higher toxicity, which is what one expects with a single-agent checkpoint inhibitor therapy.

We believe that this combination of the IDO inhibitor epacadostat plus pembrolizumab ought to be studied further in a phase III clinical trial. Epacadostat is a modulator of the tumor micro-environment, which allows T cells to become more active because the suppressive environment is alleviated by this IDO inhibitor. An advantage of epacadostat is that it is an oral drug which would provide an extra level of convenience for patients should it become a standard therapy in the future.

How do you think a combination like this will fit into the treatment paradigm?

Again, the drug needs to be put through its paces. We need to get this drug in combination with a PD-1 inhibitor in the phase III setting in metastatic RCC. In general, the combination appears to have encouraging clinical activity, particularly in patients who are minimally pretreated with 0 to 1 prior therapies and overall, it has an encouragingly manageable and tolerable safety signal. Presently, there are several ongoing or recently completed phase III clinical trials of either combinations of immuno-oncology agents or standard therapies plus an immuno-oncology agent versus a standard of care. In most of those trials, the control arm is sunitinib (Sutent). There are at least 5 of those trials that are ongoing or recently completed.

If you think about the role of epacadostat plus pembrolizumab in this very crowded field of ongoing or completed trials, you need to think about how advantageous an IDO inhibitor would be in the context of the other drugs being tested in this space. The advantages of an IDO inhibitor, such as epacadostat, is it appears to be a well-tolerated new immuno-oncology agent, at least in the initial phase Ib/II experience. It does not seem to increase the toxicity of the PD-1 inhibitor, which in this instance is pembrolizumab.

That is a contrary distinction with many other ongoing evaluations of combination regimens where there is clearly an additive or even synergistic level of toxicity when you put one drug together with another drug.

The other advantage is the oral bioavailability of epacadostat. That gives patients another level of convenience instead of getting a second intravenous drug. They will benefit from having pills to take at home.

I think in the context of a crowded field, this combination of epacadostat plus pembrolizumab offers a different angle and if positive, may provide an option for patients in the future.

Lara P, Bauer TM, Hamid O, et al. Epacadostat plus pembrolizumab in patients with advanced RCC: Preliminary phase I/II results from ECHO-202/KEYNOTE-037. J Clin Oncol. 2017;35 (suppl; abstr 4515).