Expert Discusses IDO/PD-1 and Other Emerging Combos in Melanoma

Adil Daud, MD

At the 2017 ASCO Annual Meeting, promising results were presented for combining the IDO inhibitor epacadostat with the PD-1 inhibitor nivolumab (Opdivo).

In the phase I/II ECHO-204 study, the combination of epacadostat and nivolumab demonstrated an objective response rate of 63% and a complete response rate of 5% for patients with treatment-naive melanoma.

OncLive: Can you provide an overview of your presentation on immunotherapy for patients with melanoma?

In an interview with OncLive at the 2017 European Post-Chicago Melanoma/Skin Cancer Meeting in Munich, Germany, Adil Daud, MD, a clinical professor, Department of Medicine at UCSF Helen Diller Family Comprehensive Cancer Center, discussed combination regimens and biomarkers being explored to advance immunotherapy in the field of melanoma.Daud: One of the things I focused on was IDO inhibitors, such as epacadostat, but others are in testing right now. Everything is starting to come together for these IDO inhibitors. For the last few years, there has been a lot of basic science research done showing that IDO is a fundamental mechanism that keeps pregnancy going, is involved in the immune system, and senses the tumor microenvironment.

Now, this current generation of inhibitors is in testing and they seem to be relatively non-toxic when they’re added to PD-1. I think that's something exciting considering all the immune checkpoint combinations that people are talking about. It seems like they can be combined and have a reasonable rate of activity with the caveat that, currently, we are just talking about phase II trials. We haven’t seen that phase III data, but it seems like in squamous cell cancer of the head and neck, kidney cancer, melanoma, and many other tumor types, they’re being studied.

High-dose staining is a stable kind of staining that can be looked at in the tumor microenvironment so I think having a marker is helpful for drug development in order to target that certain type of cell.

What combinations are currently being investigated that you think could be practice changing?

I think that a patient with better immune checkpoints has an advantage. It’s not clear that you can predict those patients in advance and in the years to come I'm not sure we can just combine them all since there is so many of them. It would be difficult to see how drug development is going to proceed unless we can find some better markers.There is the LAG-3 combination with PD-1. There was a certain amount of response to patients who had progressed on PD-1 previously. There was some interesting data with the TLR-9 agonist. These have been in development for over a decade now, and I think we are looking at just the latest generation of drugs. Some have fallen by the wayside for toxicity reasons.

Can you discuss the development of biomarkers further?

Additionally, there are some interesting 4-1BB antibodies that look like they can at least be combined and have some activity. However, going forward, we need a way to predict if those will work for individual patientsThere are clearly differences between immune checkpoints, sensitive patients, and nonsensitive patients. I feel like you can’t look at the whole field and think that we’ve made no progress. When it comes to that critical patient decision biomarker, I think we are almost there.

What other challenges still exist in the immunotherapy treatment landscape for patients with melanoma?

There was a study that was presented by Doug Johnson, MD, at Vanderbilt, which was combining IDO plus PD-L1 and that seemed like it was better than just PD-L1 alone. That study looked at 100 patients, but if that could be validated in different data sets, I think that could be exciting. I hear a lot of skepticism for the biomarker field. Personally, I am a believer. I think that if you look at many of these nonresponder patients to PD-1, you can tell they have very few T cells.At this meeting, we discussed a clinical trial with interleukin 12 electroporation along with PD-1. We showed some patients who had increased T cells after the electroporation and PD-1 but still did not respond. Additionally, there were other patients who still had increases in T cells and responded. One of the issues is that we don’t know for sure if all T-cell infiltrated patients are the same as having high numbers of exhausted T cells.

Are there any ongoing trials that you are excited to see the results of?

You can see PD-L1 expression or exhausted T cells being present but if you see 20% in one tumor versus 20% in another tumor, is that the same thing or are they just differences in levels of activation or a difference in the microenvironment? This makes the whole biomarker field more complicated.I saw in that LAG-3 trial that Paolo Ascierto, MD, showed at ASCO that said the LAG-3 biomarker actually did correlate with some of the responses to the LAG-3 plus PD-1. I thought that was an interesting finding and could be important if it holds out for 4-1BB.

What are the key points from your talk that you hope the audience took with them?

What I found surprising is that people who are developing IDO inhibitors are not looking at IDO expression, which is a very reproducible biomarker. This may be something that is done retrospectively to determine whether you are seeing activity.Immunotherapy is at a pretty exciting point. There are many interesting discoveries. I was thinking last year that patients who are refractory to PD-1 are refractory to ipilimumab (Yervoy) plus nivolumab. At ASCO this year, there were a number of combinations where people were showing responses in those progressed or nonresponsive patients. Just because one PD-1 combination doesn’t work that doesn't necessarily mean that a patient is spent in terms of their T cells.

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