Epacadostat/Pembrolizumab a Promising, Timely Combo for Melanoma, Expert Says

Omid Hamid, MD

The exciting data being presented at the upcoming 2017 ESMO Annual Congress will not only be a step toward bringing new melanoma treatment regimens from bench to bedside, but will also benefit patients with other solid tumors, says melanoma expert Omid Hamid, MD.

In an interview withTargeted Oncology, Hamid, chief of translational research and immunotherapy and director of melanoma therapeutics at The Angeles Clinic and Research Institute, recently shared the top melanoma abstracts to look out for at the meeting, which is taking place September 8 to 12 in Madrid, Spain, as well as some background on the promising phase I/II results he will be presenting for the combination of epacadostat plus pembrolizumab (Keytruda) in patients with advanced melanoma.

The combination is being evaluated in the phase I/II ECHO-202/KEYNOTE-037study of multiple tumor types, with Hamid et al presenting efficacy and safety data for patients with advanced melanoma. A phase III study evaluating the combination in patients with treatment-naïve advanced melanoma is ongoing.

“This is a combination that is extremely interesting and extremely timely as we are looking for combinations that can translate from the bench to bedside, from the research clinic into community clinics,” Hamid said.

TARGETED ONCOLOGY:Can you provide some background on the ECHO-202/KEYNOTE-037 study?

Hamid:This is a phase I/II trial of pembrolizumab plus an IDO1 inhibitor, epacadostat. IDO is in the tumor microenvironment, and it's immunosuppressive. In some tumors, it indicates a poorer prognosis. We had done phase I studies that showed it was tolerable without significant side effects. We went forward with it in this idea of checking to see if it was tolerable, which it was, and seeing what the response rates were.

Early on, we saw a very high response rate in patients with melanoma in the first-line setting. That led to this trial going on to become a randomized, phase III trial that has accrued over 600 patients. It is important to understand how far this is going. Also, IDO has shown good, early responses in other solid tumors. At the 2017 ASCO Meeting, we presented data of the same combination in triple-negative breast cancer, as well as cancer of the head and neck, lung, and renal cell.

In this trial, we looked for tolerability, and what we found was that it is a very tolerable regimen. Initially, what we have seen is response and durability of response amongst all the responding patients with melanoma. What we see is a more than 50% response rate. We also see rapid, deep, and durable responses. We don't see any significant toxicity.

TARGETED ONCOLOGY:Why is this regimen especially beneficial for patients with melanoma?

Hamid:We've seen combination immunotherapy get high response rates. But, we've also seen combinations have specific toxicities, and this does not have that. The toxicities are very mild. There's no real increase in grade 3 or 4 toxicity, except for rash.

TARGETED ONCOLOGY:What are the next steps with this study?

Hamid:The results were significant enough, because single-agent first-line response rates with pembrolizumab are around 35% to 40% and this combination had a 55% response rate and above.

These studies are moving along and, by moving along, I mean that they are becoming more and more complex. We are now combining this combination with chemotherapy. As far as with lung cancer, chemotherapy/PD-1 regimens have become a standard. Now, we are doing chemotherapy/PD-1 and IDO inhibitors. We are doing epacadostat combinations in trials for patients who have failed PD-1, so some of the trials are going to start to accept patients with melanoma that have been on PD-1 therapy and have then subsequently progressed.

TARGETED ONCOLOGY:What other melanoma clinical trials are you particularly excited about at this year’s ESMO Congress?

Hamid:This year's meeting is going to be a real tour de force on adjuvant therapy for melanoma. Some significant, practice-changing abstracts include [Editor’sNote:Full abstract names inserted for clarity]:

Adjuvant therapy with nivolumab (Opdivo) versus ipilimumab (Yervoy) after complete resection of stage III/IV melanoma: a randomized, double-blind, phase III trial (CheckMate-238)

We already know that nivolumab is showing benefit over ipilimumab in relapse-free survival. We're interested in seeing what else and how much. Also, we know there is an ongoing trial, CheckMate-915, which is looking at the combination of ipilimumab and nivolumab. Although, it's a much smaller dose of ipilimumab than in the metastatic setting. Let's say the relapse-free survival is significant and this is going to the FDA for approval, then many patients in the future who will have metastatic disease will have already seen PD-1 in the adjuvant setting. Then the question becomes, “What do we do from there?”

COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K—mutant melanoma

This combination has less toxicity. The other thought is that we are pushing up cost. You must see what kind of benefit you receive with combination versus single-agent therapy. We're taking everything and putting it earlier. 

I'd also say that, again, it's going to bring this question of whether the BRAF/MEK shows any benefit. What do you give first in the adjuvant setting? There's another choice to be made.

TARGETED ONCOLOGY:You are also presenting a poster on the safety, pharmacokinetics, and pharmacodynamics data from a phase I dose-escalation study of the OX40 agonistic monoclonal antibody PF-04518600 (PF-8600) in combination with utomilumab, a 4-1BB agonistic monoclonal antibody.

Hamid:This is a great trial. Basically, most of what we have seen in combination checkpoint has been based on a PD-1 or CTLA-4 platform. For example, Paolo Ascierto, MD, presented the LAG-3 nivolumab and PD-1 failures at the 2017 ASCO Annual Meeting, but that was still based on a PD-1 backbone. This is an OX40 and 4-1BB compound that's in phase I/II. In the phase I study and early on, there were a couple of patients who had some benefit and we will present that. It's the first time you've seen that data presented on a trial with 2 checkpoints that are not PD-1 or anti—CTLA-4. That's the first part. The second part is there are some great response data, and the third part is it's in multiple solid tumors. It tells us that there is a promise in the combination of other checkpoints. It's going to be a great one. It's a poster, but everyone should look at it. 

TARGETED ONCOLOGY:Overall, why is this year’s ESMO congress going to be so exciting?

Hamid: