Anti-PD-1 Therapy Poised to Take the Next Step in Melanoma

The development of agents targeting the PD-1 immune checkpoint in the treatment of patients with advanced melanoma is progressing rapidly, with optimal sequencing and combinations emerging as the most pressing questions that researchers are seeking to answer in ongoing clinical trials, according to Jason J. Luke, an assistant professor of Medicine in the Melanoma and Developmental Therapeutics Clinic at the University of Chicago.

Luke believes the recently approved anti-PD-1 monoclonal antibodies Opdivo (nivolumab) and Keytruda (pembrolizumab) will move quickly from second-line to frontline settings. Both agents currently are indicated for patients with unresectable or metastatic melanoma whose disease has progressed after treatment with the CTLA-4 inhibitor Yervoy (ipilimumab) and who are not candidates for drugs targeted at BRAF V600 mutations.

Luke offered context to the clinical implications of these immunotherapies during the 11th Annual International Symposium on Melanoma and Other Cutaneous Malignancies in early March.

What impact do the approvals of Keytruda and Opdivo have on the treatment paradigm for melanoma?

Luke: The approval of PD-1 agents is highly exciting. Put it in a historical perspective where, before 2011, median life expectancy was only 9 to 12 months. We now have six or seven drugs or combinations approved. PD-1 agents are exciting because response rates are over 40 percent in melanoma, and there is the potential for long-term survival.

The question now becomes: What line of therapy is most appropriate? Currently, the FDA label indication is in second-line therapy after ipilimumab or a BRAF inhibitor if the patient is BRAF-mutant. There is a lot of debate in the field on whether that is the appropriate indication. Ongoing clinical trials are likely to modify it; there are several phase 3 trials comparing PD-1 agents with ipilimumab. I think all of us believe that, very quickly, PD-1 antibodies will transition to frontline therapy.

The question will become: Is that enough, or will combinations of CTLA-4 and PD-1 be even better? We have to include the caveat that there appears to be more toxicity, but there are a number of other molecules in development as well that could be combined with PD-1. It is unlikely the current indication will be the case a year from now, and it’s very unknown what the case will be two years from now. Hopefully, there will be something even better.

Do the adverse events differ between Yervoy and PD-1 agents and, if so, are they managed differently?

Qualitatively, the answer is no. They are the same adverse events. Quantitatively, the answer is absolutely yes. With CTLA-4 antibodies, up to 30 percent of patients may have worrisome or high-grade events; in clinical trials those are more at 10 percent to 20 percent, although in clinical practice we see that high-grade adverse events might be somewhat higher.

With PD-1 antibodies, however, the rates of high-grade toxicity are much lower at about 10 percent. Though the adverse events are the same adverse events, which can be rash, dermatitis, colitis and pneumonitis, they don’t happen nearly as often. The management of them is the same, and the take-home point is to be aware that there are signs of side effects, and try to get on them very quickly. Adverse events will escalate if they are not managed properly.

Please discuss sequencing considerations in using Yervoy, followed by a PD-1 inhibitor, as the labels for the new PD-1 agents indicate.

This is an area of controversy. The FDA approval indicates that ipilimumab should be given as frontline therapy, followed by a PD-1 antibody. Which approach is the best is sort of a moot point at the current time in clinical practice, in that we’re essentially required to give ipilimumab first.

It is worth noting that the NCCN (National Comprehensive Cancer Network) has already suggested that consideration of frontline treatment with anti-PD-1 is appropriate. Whether or not payers will agree with that, given the growing and astronomical cost of these agents, is a wholly separate issue. Based on what we have seen in clinics, I would think most investigators in the field believe that PD-1 antibodies deserve to be frontline treatment already. Clinical trials will help us to understand whether or not you should give ipilimumab first. Those clinical trials actually are ongoing and accrued; we just don’t have the results yet. This is an area where we are just at the beginning.

You explored Yervoy's mechanism of action and recently published a case report detailing the antitumor responses and toxicities experienced by a 61-year-old woman with unresectable metastatic melanoma who underwent treatment (J Clin Oncol. 2015;33(6):e32-35). Can you elaborate on your findings?

It appeared that the patient’s disease was getting worse after the first few doses of ipilimumab. This does highlight patient education, which is very important with this drug. Going into it, patients need to understand that this is not chemotherapy or targeted therapy, where the drug will start to kill the cancer after it is infused. This is trying to modify the patient’s immune system and that process can take time.

Therefore, we sometimes see that the tumors can look worse before they get better. That can be because it can take some time for the immune system to kick in to start to fight the tumor. Alternatively, what we are actually seeing as the tumor grows is it is swelling with immune cells. The tumor itself is not getting better, but on a scan it looks larger because there are immune cells in it that are killing the tumor and, over time, you see the resolution of that. It can look like there is an increase in disease burden, but then it goes away over time.

The consideration was that the patient had metastatic disease involving the skin, which can actually be much worse for the patient than cancer of the brain or liver because they can actually see it. Every day, they look at it and say, ‘Is it better today?’ In reality, we need to know if it is better in three months. That can be very difficult on a day-to-day level for a person; it is totally understandable. Really, it is just about education and trying to communicate with the patient to hang in there with the treatment.

Are there emerging drug developments or translational therapeutic advances you would like to discuss?

The point to emphasize is that what we have seen in melanoma is just the tip of the iceberg for all cancers. PD-1 or PD-L1 antibodies have significant activity in a number of different types of cancers, but almost across the board there is somebody somewhere with almost every kind of cancer, who has responded to these drugs. The question becomes: Why is it just the one guy, as opposed to all patients?

In melanoma, it is clear. We have a 40 percent response rate to anti-PD-1 and that is incredible. In colon cancer, it is probably less than a 5 percent response rate. Can we change something about the patient’s tumor to make them immunotherapy responsive? This is a wholesale shift in the way we have thought about cancer treatment. Historically, we’ve thought, “give treatment, kill cancer.” Now what we need to think about is how to alert the body that the cancer is there, so it can attack the cancer. My research centers on drug development and combination approaches that try to do that.

There are a number of other immune molecules that are being investigated that have the potential to change the immune microenvironment. These can be immune checkpoints such as LAG-3, 4-1BB, and OX40. There are other approaches like T-VEC [talimogene laherparepvec], which is the modified herpes virus attenuated for viral replication. Any of these in combination could potentially be the next step in two ways. One is to boost the benefit we already know from anti-PD-1, and the other is to try to turn patients who otherwise would not respond into responders.

Where do you see the treatment of melanoma in five years?

To me, the major issue in melanoma still is: Why is that 60 percent of patients don’t respond to anti-PD-1? It dovetails with my previous comments about the next steps in research, which is to try to better understand the tumor microenvironment in such a way that we can predict ahead of time which patients will respond.

What is the next iteration or therapeutic approach to treat patients who are not going to respond to anti-PD-1 alone? Do we add the combination of CTLA-4 and anti-PD-1? Do we need radiation with anti-PD-1 to try and change the tumor microenvironment? There are a number of other approaches, and there are lots of other drugs that could potentially be given in sequence.

We’re right at the beginning of anti-PD-1, even in melanoma. People get the sense that now we have these great drugs, and we do, except they don’t even benefit half of the patients yet. We certainly have not cured melanoma. We have a small subset of patients who have long-term survival, but that is not good enough. We need to get that upped to everybody who has melanoma with long-term survival.