Paradigm-Shifting Change May Be Coming in Melanoma


An ongoing trial studying Keytruda (pembrolizumab) with the first-in-class IDO1 inhibitor epacadostat (INCB024360) can mean drastic change for patients with melanoma.

An exciting FDA approval can be the result of mature data from the ongoing phase 3 KEYNOTE-252/ECHO-301 trial, changing the standard of care for patients with melanoma, says Thomas F. Gajewski, M.D., Ph.D.

The pivotal study is exploring the combination of the PD-1 inhibitor Keytruda (pembrolizumab) with the first-in-class IDO1 inhibitor epacadostat (INCB024360) in patients with stage 3/4 unresectable or metastatic melanoma (NCT02752074). Six hundred patients across more than 120 locations will be randomized to the novel combination or Keytruda 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 percent), including 5 patients (26 percent) with a complete response and 6 participants (32 percent) with a partial response. The disease control rate was 74 percent.

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 percent at 6 months and 57 percent at 12 months.

Can you provide an overview of the topic?

During an interview with CURE, 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. 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 Opdivo (nivolumab) and Keytruda 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.

What are some of these new targets?

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. 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. As 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 3 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.

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

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.The first phase 2 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 3 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.

We are obviously still early with this research. What are the biggest questions researchers hope to answer first?

We will see a little bit at the 2017 ASCO Annual Meeting, but the mature data — if positive — could lead to FDA approval. But we won’t see it until at least 2018. One of the major fundamental questions is, how do you turn a cold tumor into a hot tumor? Here, we’re really working hard from multiple angles. We’re taking that problem, turning it around, and hacking it from different angles. That is really a question of primary resistance—patients who walk in and they’re resistant to anti—PD-1 therapy from the get-go.

Secondary resistance is also something that’s starting to become a clinical issue that we have to address. Many patients treated with PD-1 or other immunotherapies respond, do well, have durable tumor control, and are perhaps chronically controlled or even cured. We hate to use the “C-word” liberally, but maybe some of those patients are cured.

However, in a fraction of those patients, their tumors start to grow again. This is what has happened with the targeted therapies in melanoma, such as the BRAF inhibitors. Now, we are starting to get a sense that a subset of patients treated with PD-1 also develops secondary resistance.

How do we figure out what those mechanisms are? We have to rebiopsy the tumor, and this requires patient cooperation, funding, and the infrastructure to process the samples. We have all of this set up at The University of Chicago Medicine for that discovery platform.

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