Questions Remain About Immunotherapy in Melanoma

Questions still remain regarding immunotherapy in melanoma, even as agents such as Keytruda (pembrolizumab), Opdivo (nivolumab) and Yervoy (ipilimumab) have shown to be quite successful in recent years.

“There is still a lot to do in melanoma,” says Jason Luke, M.D., an assistant professor of Medicine at The University of Chicago Medicine. “This is why we really need patients to participate in clinical trials.”

There is a lot happening currently in melanoma. What are you most excited about?

In an interview with CURE, Luke discusses some of the exciting research that is happening across the field of immunotherapy in melanoma, including combination strategies, novel agents, and next-generation diagnostics.One area that is exciting in melanoma therapeutics right now is combination immunotherapies to build on checkpoint blockade, where we have seen the success with PD-1.

How do IDO inhibitors differ from other types of immunotherapies?

We are very excited about the idea that combination strategies might double down on T-cell inflammation where it is present. Our research suggests that between about 50 percent to 70 percent of patients with advanced melanoma have active inflammation in their tumor microenvironment, which we think is the rationale for why PD-1 antibodies are so effective. Along that same sort of approach is the addition of other tumor microenvironment factors or inhibitors, such as the IDO pathway, which also looks quite exciting.This again goes to the concept that some patients have an immune infiltrate in their tumor. When that is present, we see that the T cells drive an inflammatory phenotype in which the tumor cells react to the immune cells that are in the tumor microenvironment, upregulating certain molecules—one of them obviously being PD-L1, the important one for PD-1 antibodies.

However, it turns out there are a number of other molecules that are actually activated in parallel with PD-L1, one of them being IDO. That molecule is a suppressive enzyme that catabolizes tryptophan into kynurenine. Tryptophan is the amino acid we all get from turkey at Thanksgiving time, and kynurenine being an inhibitory or immune-suppressive amino acid.

Where are we right now in terms of understanding which patients should receive immunotherapies as a single agent, or in combination?

The tumor will upregulate this molecule to block those immune cells that have come into the tumor microenvironment to kill the cancer. By blocking both of the mechanisms at once, IDO and PD-1 or PD-L1, we have seen quite a dramatic increase in the efficacy of the treatment. Importantly, the IDO molecule does not have enormous impact on your normal physiology so, by blocking it, you really don’t induce any toxicity. The combination thus far of IDO and PD-1 antibodies have had no increase in toxicity relative to the PD-1 antibody alone, and that is quite exciting in the context of combination therapies, where we’ve seen some increase in toxicities between combining agents so far. There are several different lines of evidence and hypotheses that are starting to drive those considerations, the most obvious one being PD-L1 immunohistochemistry [IHC]. Obviously, in melanoma, the drugs have been approved without the requirement of doing PD-L1 IHC, and that has been the case in most cancers.

The rationale is that even in patients who are negative for PD-L1, these drugs still often work better than the other drugs that we have. That doesn’t really help us yet. However, there are other translational analyses that are coming toward prime time, which might get us closer to that answer. On the basic biology side, what we have observed with gene expression profiling is knowing which genes are expressed can really stratify patients. We believe it will be very soon that gene expression profiling analyses will be available for melanoma to help answer this question.

Other things, such as the mutational load in the cancer, also show promise. Some groups have found that if tumors have a very high mutational rate in the cancer, the likelihood of response is very high. That has not quite come forward yet, but with next-generation sequencing in the clinic, we are starting to be able to pick out which patients those might be.

Another group has looked specifically in the tumor microenvironment, where T cells have shown signs of being in the tumor microenvironment and inhibited but ready to go with the expression of PD-1 and CTLA-4.

What considerations should be made when selecting between targeted immunotherapies for patients who are BRAF positive?

That approach is a little more nuanced but, again, has been able to pick up patients very clearly who will benefit. The long and the short of it is we are still not quite there and we are doing this empirically in clinic, but I don’t think it is going to be very long — six months to one year — before we really do have that next generation of immunotherapy diagnostics to let us hone in on each individual patient and be able to select monotherapy or combination — and which combination.There is a role for all of these drugs. They have all been shown to improve overall survival so it is important that we use them all in a smart manner. To date, we have used them individually and the standard of care is still to use them until progression, and then use the next one—whether it be a BRAF inhibitor and then immunotherapy, or vice versa. We don’t truly know which of those is the best approach.

There are some phase 1 clinical trials that are now starting to be reported in which all of these drugs are being given at once, including BRAF and MEK inhibitors plus PD-1 antibodies. The rationale for doing that is not totally clear. These are the questions we need to sort out. With this multi-dimensional biomarker analysis, we will eventually be able to hone in on which patients will derive the most benefit.

There is some concern that, as we are starting to study resistance in patients, we unfortunately are starting to find some overlapping phenotypes between targeted therapy and immunotherapy. This is a little bit disconcerting because that could suggest that patients most likely to benefit from targeted therapy are also those who are most likely to benefit from immunotherapy. If we give them all at once and get resistance, they might be resistant to everything. We don’t know that answer yet, and this is where the research will go. There is still plenty to accomplish in melanoma and we really need patients to participate in clinical trials.