Welcome to our new interview series called Clinical Trials Catch Up, an article delivered in a question-and-answer format designed to help patients understand what’s happening in the clinical trials world, what researchers are excited about, and what information future trials may seek.
Our guest today is Joshua M.V. Mammen, M.D., Ph.D., F.A.C.S.; Merle M. Musselman Centennial Professor of Surgery; Chief, Division of Surgical Oncology; Vice-Chair for Academic Affairs, Department of Surgery, University of Nebraska, interviewed by Alicia Rowell, Vice President of AIM at Melanoma.
While there are various types of clinical trials, such as prevention or behavioral trials, today we will focus on treatment trials. Why are treatment clinical trials important for melanoma researchers?
Clinical trials are important for both researchers and for patients because this is how we learn. This is how we learn how to be more effective in our treatments. And trials don’t just look at new, additional treatments. Trials also help us figure out when to stop treating, because sometimes we are treating individuals more than we need to be treating them. Indeed, one of the strategies we’ve taken in more recent clinical trials is looking at what things we can stop doing rather than just thinking of what treatments we can add on.
Why are they important for patients?
There are theoretical and societal benefits of trials: They help to advance the field and help outcomes for individuals later on. But there’s also the question—which is a very fair question—that a patient might ask, which is, “Should I participate in a clinical trial—what’s the benefit to me as an individual?” And we have numerous studies that have shown that individuals who participate in trials tend to do better than those who don’t. And that in a sense may seem counterintuitive because trials are, frankly, experimental—we’re testing one group against another. But individuals who are participating in clinical trials are watched a lot more closely and by more people than individuals who are not in trials, and we think that’s one reason individuals who are on trials have better outcomes in general than those who are not on trials.
Approximately how many melanoma treatment clinical trials are going on at this time in the U.S.?
That’s a really hard number to get your arms around, but there are hundreds. A lot of trials are smaller—being done at one institution, for example. One way to answer this question is to look at how many trials are being done just by the cooperative groups—these are the large groups that are funded by the National Cancer Institute in the U.S.—and there are about a dozen trials that either are focused just on melanoma or that include individuals with melanoma.
Your field is surgical oncology. Would you explain what that is and the types of clinical trials that a surgical oncologist might run?
One of the interesting things about surgical oncology, which is similar to medical oncology and radiation oncology, is that we have a tremendous amount of overlap with each other and work so closely with each other. So while my focus is on the surgery part of the treatment of cancer—the actual removal of the melanoma, the resection, the cutting it out—we really rely on our fellow oncologists, our partners. The type of trials we tend to lead are trials that are really focused on the surgery part—the removal of the cancer at the local site, the lymph nodes, or elsewhere it may have spread—but also we tend to lead trials where some of the medications are done first, prior to surgery. Those trials are typically called neoadjuvant trials. The reason we might lead these types of trials is that the medications or radiation can affect the type of surgery we can perform, and the length of the treatment may affect the ability to have surgery. Or the surgery may change depending on the effect of the neoadjuvant treatment. And I want to be very clear that although a surgeon may be leading a trial, there are always medical oncologists who are partners, just like for a medical oncology-focused trial there are always surgical oncologists on the team as well.
(Read more about the history and current state of neo-adjuvant treatment in the In Plain English article, here.)
Are you involved with any trials at this time?
I am involved in helping to lead some of the trials at my own institution, the University of Nebraska. In that role as a primary investigator, I make sure that we identify the best trials for our patients, make sure they get through the approval process at our institution, and, once they’re approved, that we find individuals who might benefit from those trials and offer them the opportunity to participate in the trial. There are several trials at our institution, both in melanoma and my other expertise, which is sarcoma.
Nationally there are two trials that I’m involved in. The major group that I work with is SWOG, one of the four large National Cancer Institute-funded cooperative groups in the U.S. In SWOG, I had been initially involved in breast cancer trials. There is a trial that is closed now called SWOG 1418, which looked at the neoadjuvant treatment of triple-negative breast cancer with what was at that time a really new agent called pembrolizumab, which many people know now as Keytruda, either through television ads or because they’ve experienced cancer. The trial attempted to figure out whether that drug would be helpful in individuals who had already received neoadjuvant treatment but who had residual disease—whether pembrolizumab would help to improve survival if they received it and had residual disease. Those results aren’t out yet but should be out in the next year or so. I was the surgical primary investigator for that trial and co-primary investigator. The primary investigator was Lajos Pusztai at Yale.
The other trial I’ve been quite involved in is SWOG 2015. I’m a primary investigator for this trial and head of this trial in the US. It’s an international trial. The name it typically goes by is MelMarT. It’s a melanoma margins trial that is trying to understand whether we can do a smaller surgery than we’ve been doing for certain types of early-stage melanomas. The amount we’ve removed is based on trials over the last 30-40 years, and it can be an incision anywhere from 9cm in size to 15cm in size, which is quite large—several inches long. And different countries take different margins, even though we’re all looking at the same data from the past 30-40 years.
It’s a large trial—there are 2998 people in the trial. We have groups from the U.S. and also patients and investigators from the United Kingdom, Australia, New Zealand, Canada, Sweden, The Netherlands, and other countries. Many countries are participating in this trial, as it takes a tremendous effort to conduct a trial this large. I hope to have results in the next five years—maybe preliminary results—but it may take up to ten years to have the final results. Depending on the results, we may be able to decrease the size of incisions, and also decrease the chance of needing a skin graft or complex plastic surgical reconstructions, which all have increased morbidity, scar size, and healing implications. Once we have this trial completed, I expect we’ll be able to have a single answer for the world for recommended margin size.
The International primary investigators for this trial are Mark Moncrieff and Michael Henderson. Dr. Moncrieff is in the United Kingdom, and Dr. Henderson is in Australia.
Which trial(s), besides your own, are you most excited about? Why?
I think there are some really great trials out there. Another trial that is active right now is called SWOG 2000. It’s for individuals whose melanoma has spread to their brains—those who have brain metastases. It’s looking at whether a targeted approach with three medications—encorafenib (Braftovi), binimetinib (Mektovi), and nivolumab (Opdivo)—is better than the current two-agent regimen, which is very commonly used, which is nivolumab and ipilimumab (Yervoy). It’s a smaller trial—certainly not 3000 people—but having the answer for brain metastases, which act differently than metastases elsewhere, is really important.
Another interesting trial is from ECOG-ACRIN, another of the cooperative groups, called EA6192. It’s one of those trials that I alluded to earlier about stopping treatment because maybe you don’t need as much treatment as we’ve been giving. The typical treatment that is given for melanoma that has spread is immunotherapy, and the question this trial asks is, if the cancer stops showing up on a PET scan as active, and you do a biopsy and it shows no obvious cancer—even though you don’t know 100% for sure it’s all gone—can you stop treatment? In this trial, if the patient’s PET scan looks good, and the biopsy shows no obvious cancer, treatment is stopped after one year and patients are just watched really carefully. Right now, we recommend treating indefinitely, but this trial asks which is better: stopping after one year or treating indefinitely? The answer to this question is important from cost perspective, a time perspective, and a toxicity perspective. There are tremendous benefits if we are able to stop treatment, so this is a very exciting trial from my standpoint.
The other interesting trial is a registration trial called 151804—it’s an Alliance for Clinical Trials trial, yet another cooperative group. It’s not trying a new treatment or stopping a treatment, but a trial that is gathering information about immunotherapy side effects. As we know, immunotherapy has side effects, and trying to understand those side effects is really important. This trial collects information from those who have had side effects to try to learn more about these side effects and about that individual; we hope to collect tissue from that individual as well. The hope is that we will eventually be able to predict who will have side effects and who will not, and who will benefit from the treatment and who will not. The ideal of course, would be to combine those pieces of information—who’s going to have a side effect and who’s going to benefit—and stop treating those individuals who have a really high risk of side effects with very little chance of benefit from the treatment, and really focus on those individuals with a low chance of side effects and a high chance of benefit. That’s the sweet spot we’re trying to identify, and this registration trial will hopefully allow us to understand that a bit better.
Are there any trial results expected soon that you and others are eagerly awaiting?
The results that we had been eagerly anticipating came out last year: Dr. Sapna Patel’s SWOG 1801. It was probably the most important trial result to come out recently. And that trial will continue to mature. As you know, that trial compared individuals who had Stage III melanoma or resectable (can be removed by surgery) Stage IV melanoma, and they were treated either neoadjuvantly—meaning prior to surgery—with three doses of pembrolizumab (Keytruda) or just adjuvantly. And the trial showed that there was a superior event-free survival rate in giving immunotherapy upfront (neoadjuvantly). I think the results have already shifted practice, where we are starting to do more immunotherapy first rather than doing surgery then immunotherapy only afterwards. In fact, I had a call yesterday with a medical oncologist who was not as familiar with these results and together we came up with a plan to do exactly that—immunotherapy first and then surgery. Certainly event-free survival is important, but also showing that overall survival was improved—showing that folks actually lived longer using the neo-adjuvant strategy—will be important as well. So those overall survival results are anticipated but not available yet.
The other trial (not a cooperative trial) that we would like overall survival results on is Keynote 716. It’s a trial that looked at earlier-stage melanoma and treating those individuals who did not have melanoma that spread to lymph nodes. We know that some high-risk Stage II melanomas (Stage IIB and IIC) unfortunately have worse survival than early Stage III melanomas. The results of the Keynote trial had shown improved disease-free survival, but we still do not have overall survival results, and I’m eagerly anticipating those. Disease-free survival is important as an outcome, but showing that folks actually lived longer is important because, as we’ve already discussed, immunotherapy has side effects, so we don’t really know, just because disease-free survival is better, if we could have just given the treatment later and had the same overall survival results. Are we exposing too many individuals to immunotherapy toxicities that we didn’t need to? I really want that result before we say that immunotherapy should be the standard of care for high-risk Stage IIB and IIC patients.
Thank you for all of this information. One more question: What would you like to make sure our readers understand about clinical trials?
I think that one important point that we sometimes fail to convey during our appointments with patients is that they should take the time they need to make the decision about clinical trials. Patients should never feel rushed or feel like they don’t have an option. I’d encourage patients to ask all the questions they have. Also, if a physician is mentioning a clinical trial, don’t feel compelled to participate just because it was mentioned. Whether you participate in a trial or not is your choice, and we respect that. Our ultimate goal is to care for you as an individual and to provide you the greatest benefit possible in your cancer treatment journey.
Learn more about clinical trials here.