Expert Anticipates Exciting Advances in Adjuvant Melanoma

Jason J. Luke, MD

Experts in the melanoma field are aware of the rapid progress made over the last 5 years, but the explosion of ongoing research—especially with combination regimens—signals that the work is far from done.

For example, in the adjuvant space, the phase III CheckMate-915 trial that is expected to begin recruitment in the future is exploring the PD-1 inhibitor nivolumab (Opdivo) with the CTLA-4 inhibitor ipilimumab (Yervoy) versus nivolumab or ipilimumab alone after complete surgical resection in patients with stage IIIB/C/D to IV melanoma (NCT03068455). This is exploring the potential and safety of the regimen in patients who are at high risk for relapse.

Additionally, there are methods under investigation to bridge the gap between targeted therapies and immunotherapy in melanoma. This year, the community could see data from longer follow-up on patients with melanoma who were given a triplet regimen of a PD-1 antibody plus a BRAF/MEK inhibitor combination, explains Jason J. Luke, MD.

OncLive: What is important to highlight regarding adjuvant therapy in melanoma?

Luke, an assistant professor of Medicine at The University of Chicago Medicine, who also chaired the 2017 OncLive^® State of the Science Summit on Melanoma and Immuno-Oncology, lectured on adjuvant therapy for patients with melanoma, as well as the future of targeted agents and immunotherapy. In an interview during the meeting, he explained these topics a few steps further, sharing what’s next for the ever-evolving field.Luke: Adjuvant therapy for melanoma is becoming more exciting with the approval of ipilimumab a few years ago and, now, the readout of an improvement in OS for patients. We now, for the first time, truly have a drug that improves the overall survival (OS) and outcomes for patients.

That being said, the use of it in standard medical practice is a little complicated. The NCCN still supports observation as opposed to any therapy as a reasonable alternative. Consideration can be given to some patients for observation, while some physicians still advocate the use of interferon, biochemotherapy, and then ipilimumab.

In the study of ipilimumab, it was clear that most of the benefit was derived by the patients who had ulcerated primary lesions or more than 4 lymph nodes that were bad regional melanoma; those are really the patients for whom I prioritize ipilimumab.

Are there other agents being studied in the adjuvant setting?

It certainly is not the case that all patients should get ipilimumab for stage III melanoma, but rather a discussion should be given about risks and benefits. This is because there is about a one-third chance that a patient will get severe toxicity from ipilimumab, all which is reversible. However, that’s under consideration—especially for patients at a more advanced stage. There is an explosion of clinical trials that are ongoing now. We haven’t had the readouts yet, but clinical trials are going to be coming soon with results. These include comparisons of CTLA-4 blockade with ipilimumab as compared with PD-1 blockade, either with nivolumab or pembrolizumab (Keytruda). The gut feeling is that most oncologists think that those will be positive trials and, given the preferred safety profile of PD-1 antibodies, we’re excited about that to eventually move into the adjuvant setting.

Beyond that, there’s even some discussion around combination immunotherapy with CTLA-4 and PD-1 immunotherapy in the adjuvant setting. That will be a rather toxic adjuvant therapy, so I’m sure there will be much debate about that.

It sounds like we could potentially have several options in a few years. How will choices be made?

When speaking to patients, what do you tell them regarding risks and benefits with adjuvant therapy?

Finally, what about BRAF inhibitors? Everything in the field was about BRAF inhibitors a few years ago. It just takes a while for adjuvant trials to be performed, but those trials are going to be reading out in the next year or 2, as well. That will further complicate the landscape because if those trials are positive, then we will have several active agents that may improve the long-term outcomes in patients. This will be a confusing landscape in the future, with the presumption that all of these trials are positive. It will then just be a discussion with the patient about the pros and cons. There are toxicity differences between all of these different approaches, and presumably differences in the relative improvement in OS. Some patients may say, “I don’t really want to come in for these visits every few weeks for infusions,” or, “I like the profile of toxicity of this agent versus this one.” It will be a patient-level conversation between doctors and their patients about what is best. When I talk about risks and benefits regarding checkpoint blockade, either for metastatic or adjuvant disease, I start from a place of the mechanism at first and talk about how it’s the reverse from chemotherapy. You’re not going to lose your hair or get nausea. Rather, if your immune system kicks in, it can kill the cancer but also could cause autoimmune-like problems. That can make more sense to patients.

Do you notice that patients underreport immune-related adverse events for fear of discontinuing therapy?

I explain that it could be similar to what you’ve heard about with rheumatoid arthritis, Lupus, or inflammatory bowel disease. Hopefully it would never be so bad, but that can give people a spectrum of what to think bout. The most important thing about these toxicities is to know that they’re happening and getting on them really quickly. If we initiate steroids rapidly, they usually don’t become severe in the first place. Absolutely. The toxicities are underreported and it’s becoming clear that there is a chronic fatigue syndrome associated with checkpoint blockade. Patients, fortunately, do well for a long time but, in that setting, they do progressively get more fatigued. They are hesitant to report that or not as robustly as they would if they had 10 bowel movements a day.

What about the debate over the potential combination of PD-1 agents with CTLA-4 inhibitors?

Similarly, there is an arthralgia-like syndrome, or joint achiness, that patients get especially with PD-1 antibodies. That’s underreported over time. They’re either scared to tell a doctor or think that it’s normal. That information is emerging, and so there’s a lot of work to do in terms of a quality-of-life analysis as we move into the future. One could imagine that, if most of the benefit from these immunotherapies is upfront, maybe we don’t need to keep giving them for so long. We don’t have that answer yet. It’s hard to know so far. Based on the toxicity we see in the metastatic setting, more than 50% of patients get high-grade toxicity that, for all intents and purposes, will put them in the hospital. Now, if you’re cured of melanoma, some patients will take that trade-off. We are going to need to wait to see how much benefit there is for the combination relative to any monotherapy.

You also spoke on the future of targeted therapies and immunotherapies. Could you elaborate?

It is interesting to note that, in the metastatic setting, we know that there is a subpopulation of patients who seem to get the same benefit from PD-1 alone as they do from the combination. That kind of biomarker stratification is going to be essential, because none of us in the physician world are going to be excited about having a 50% chance of putting our patients in the hospital—especially if we know that there is a subset of patients who don’t need to take that risk. We will only know after we get the results from these clinical trials. There have been updates in BRAF-targeted therapy recently and, over the last year and a half, we have seen the long-term follow-up from the COMBI-d and COMBI-v studies, suggesting that at 3 years, more than 50% of patients are still alive and even 20% to 30% of them are actually still on the combination of BRAF/MEK inhibitors. That is somewhat counter to the dogma in the field that all patients progress on targeted therapy. Clearly, that’s not the case.

More than that, we are learning about the clinical factors that really dictate who is likely to do the best with that therapy. Honestly, it’s somewhat counter to the way we have previously been using the drugs. It seems that the patients who have the least amount of cancer and the best performance status are most likely to have long-term benefit.

The way we had been using the drugs, for the most part, is we were giving it to the patients with the worst cancers that were growing fast. We need to reexamine that and think about using BRAF inhibitors earlier in their therapy curse.

There has been a third set of BRAF/MEK inhibitors that have now come through phase III trials. The COLUMBUS trial investigated encorafenib plus binimetinib and that study actually showed, very interestingly, a further improvement in progression-free survival (PFS) of the patients relative to what we’ve seen with previous combinations.

It is worth noting that, in that combination, they were actually able to dose-escalate the BRAF inhibitors slightly higher than even in a more potent dose than the other 2 FDA-approved regimens. That is most likely the reason we see a benefit, but that may imply that the dose of the encorafenib/binimetinib combination is actually more effective than any other combinations that are approved.

Most importantly, it’s the least toxic profile. The preliminary results just came out at the 2016 Society for Melanoma Research Annual Meeting, so we’ll wait for more robust data. However, it is exciting that, even in this field that we thought we had completely squared off, we now understand it even further.

In the immunotherapy space, we are also continuing to see quite marked and rapid improvement in the research around what we have been doing. PD-1 antibodies were obviously a revelation, and the combination with ipilimumab is exciting in that we see a higher response rate—it’s looking like good, long-term PFS.

That being said, we have this toxicity issue with more than 50% of patients having grade 3/4 events. There are a number of other combinations coming forward and initial data sets from the PD-1/IDO inhibitor trials have now been presented at a few meetings. In preliminary fashion, that combination looks like it might be as potent as the nivolumab/ipilimumab combination.

Excitedly, where that combination has a lot of side effects, adding the IDO inhibitor to PD-1 monotherapy does not increase the side effect profile at all—as far we can tell. It is very early data, but suggestive of a very potent regimen that might allow us to defer that risk of side effects that come with the CTLA-4 antibody.

Further than that, the approval last year of talimogene laherparepvec (T-VEC)—an injectable, modified oncologic herpes virus—was exciting in and of itself, but in combination with checkpoint blockade, it is interesting. A phase III trial has now been launched with T-VEC and pembrolizumab versus pembrolizumab alone.

We are just a few months away from the 2017 ASCO Annual Meeting. What melanoma data are you anticipating?

Again, that’s exciting for patients who have cutaneous lesions; perhaps we can amplify the benefit because giving T-VEC outside of the injection site doesn’t really cause a lot of side effects. There’s still more to do in immunotherapy. There are a lot of novel approaches—intratumor things like STING agonists or TLR agonists, and a host of other immune molecules that we are yet to explore. The future of immunotherapy is quite bright both in melanoma and, more broadly, across all of cancer. We expect at least to see the first readout from the ECOG 1609 study, which is the adjuvant study of ipilimumab against interferon. Ipilimumab, in that trial, was given in 2 different doses: the metastatic dose at 3 mg/kg as well as the FDA-approved 10 mg/kg dose. That will be very interesting, because we are hoping to see that ipilimumab has a clear survival advantage to interferon. If that’s not the case, it really muddies the water quite a bit.

What ongoing clinical trials at The University of Chicago Medicine are you a part of?

There have been preliminary data presented with the triplet combinations of BRAF/MEK/PD-1. I’m sure those will be updated as well, and it’s a way to start to merge the fields of targeted therapy and immunotherapy. We have a very robust melanoma program and, while we participate in many—if not all—of the major industry trials, we’ve had a few pillars of our research program that we’ve been the most interested in. In the immunotherapy space, we’ve really been leaders in the idea of inflamed tumors and non-inflamed tumors. Our group was one of the first to advocate for IDO inhibitors with PD-1. And, we helped to lead the trial of pembrolizumab and epacadostat; we’re quite excited that it’s gone to phase III. We have other IDO inhibitors that we’re working on, as well, so it is really the biology around the T-cell inflamed microenvironment and trying to create combinations that will go after that inflammation.

Vice versa, there are going to be patients who do not have T-cell inflammation. The inflammation surrogate for that might be PD-L1 staining, which is one component of the inflammation. Patients who are PD-L1—negative or are non-inflamed need to do something completely different.

In that space, we have been looking at injectable approaches to try to change the tumor microenvironment, like STING agonists. We were also 1 of the first groups to advocate for the use of the modulation of the microbiome, specifically the gut-fecal microbiome, and we are about to launch a phase II trial of modulated-gut microbiome in addition to a PD-1 antibody.

You chaired this State of the Science Summit. Why should community oncologists attend this type of meeting?

Finally, we are interested in this idea that we might be able to sequence PD-1—based therapy followed by CTLA-4–based therapy, with the hope that we can reduce toxicity and yet maintain that benefit—so we can do it in serial fashion and not expose patients to the toxicity of ipilimumab. If we can show that the benefit is roughly similar with sequential therapy in that regard, it might allow us to save patients from being exposed to toxicity that they might not need to face. Attending the State of the Science Summit and disease-specific working groups like this are important to better inform your general understanding of any 1 disease. Melanoma may seem like skin cancer, but it’s really quite complicated.

At The University of Chicago Medicine, we have a weekly team meeting where we go over all of the cases of atypical melanistic lesions and sometimes it can be difficult. Is that melanoma or is it not melanoma? There are a lot of controversies around surgery in melanoma for complete lymph node dissection, and discussion even from the dermatologist all the way to the medical oncologist of the utility of adjuvant therapy. With all of the caveats of the toxicity with ipilimumab and long-term outcomes in clinical trials, we really value perspectives from many parts of the team in that regard.

These kinds of forums can really help to better inform in the totality of understanding a disease. I would really advocate that community oncologists attend this type of symposium.