The Melanoma Research Edition, July 2023

From the Desk of Sam Guild, President

AIM at Melanoma Foundation

Notes from the Lab: Novel Targets for Immune Checkpoint Inhibitors

By Paul Bunk, Ph D candidate, Cold Springs Harbor Laboratory

In Plain English: Neoadjuvant Therapy for Melanoma, and How We Got Here

By Kim Margolin, M D , FACP, FASCO

Clinical Trials Catch Up An Interview with Joshua

M.V. Mammen, M.D., Ph.D., F.A.C.S.

By Alicia Rowell, Vice President, AIM at Melanoma

FROM THE DESK OF SamGuild

PRESIDENT | AIM AT MELANOMA FOUNDATION

Without research there can be no cure

That’s one of AIM’s guiding principles, and why we created and fund the Melanoma Tissue Bank Consortium and other unique research initiatives

But what we repeatedly hear is that the melanoma community wants more information on the wide range of research being performed and they want to understand how it may help them or future patients The first series we introduced In Plain English has been incredibly popular with our community, and each article is widely and repeatedly read In this series, Dr Kim Margolin, Medical Director, Melanoma Program, Saint John’s Cancer Institute, explains a selected melanoma concept and the current research around it in language that patients and families can easily understand

Last year we debuted the first article in a series called Notes from the Lab, which was also widely read Paul Bunk, a Ph D candidate at Cold Spring Harbor Laboratory, has been our guest writer for this series, which seeks to explore topics in research that’s in its early stages to help the melanoma community understand what might be important in treatment in the upcoming years. Today we introduce another series called Clinical Trials Catch Up, designed to help melanoma patients and their families better understand what kind of treatments are currently in the clinical trial and what looks promising Dr Joshua Mammen, Merle M Musselman Centennial Professor of Surgery, and Chief, Division of Surgical Oncology, University of Nebraska, is our guest writer for this series.

As always, let us know what you think of our newsletters and the information therein We appreciate your feedback and always, your support.

Our focus for this month’s newsletter is research and treatment.

NOTES FROM THE LAB

Novel Targets for Immune Checkpoint Inhibitors

By Paul Bunk, Ph.D. candidate, Cold Springs Harbor Laboratory

Survival rates of patients with melanoma have drastically improved in the last two decades. In the early 2000s, patients with Stage IV melanoma had a median life expectancy of about seven months. This number has now risen to just over six years, according to long-term follow up from the CheckMate 067 study. What is behind this significant progress for patients and families? The answer is immunotherapy—and more precisely immune checkpoint inhibitors (ICIs). The first two drugs of this class, ipilimumab (Yervoy) and nivolumab (Opdivo), were approved for the treatment of melanoma in 2011 and 2014, respectively, and overall, eight more ICIs were approved in the ten-year span between 2011 and 2021 In March 2022, the FDA approved a completely novel type of ICI, relatlimab, in combination with nivolumab—which together are known as Opdualag--for a total of 11 ICIs approved since 2011

What makes this drug novel? Why is it exciting? And why do researchers keep looking for new ICIs if our existing drugs have had so much success already?

IMMUNE CHECKPOINTS AND CANCER

To answer these questions, we should first review the immune system in general Our immune system consists of a group of cells that are tasked with defending the body against all kinds of threats. These threats include viruses and other pathogens, as well as mutated cells that could become cancer Our immune cells are very effective at getting rid of dangers; however, their activity needs to be tightly regulated so that they do not overreact and hurt our own bodies. If the immune system goes awry, the effects can range from uncomfortable, as in the case of allergies, to debilitating and even life-threatening, as in the case of autoimmune conditions

This balance between reacting but not overreacting is where immune checkpoints come into play. As the name suggests, immune checkpoints keep immune responses in check—or, regulate them In general, they work like this: When an immune cell gets activated (when it reacts to a threat), it will start expressing immune checkpoint proteins

These proteins are basically emergency “off buttons ” If these proteins find their counterparts (called ligands) nearby, the checkpoint gets activated and starts shutting the immune response off—the presence of the ligands sends a message to the immune system that there is not actually a threat after all. But if these proteins do not find ligands nearby, the checkpoint is not activated, and the immune system launches an immune response designed to destroy the threat

These regulatory mechanisms are important for us to stay healthy because they allow the body to keep immune cells “ on ” when needed and to turn immune cells “off” if they are activated inappropriately. Unfortunately, these same mechanisms are exploited by cancer cells. Cancer cells often express the ligands of immune checkpoints, allowing them to turn off immune cells that should be attacking the growing tumor. This so-called “immune evasion” can be seen with melanoma

You might be familiar with the immune checkpoint protein called PD-1, which can be expressed when immune cells encounter melanoma cells and sense the threat. Inside of the melanoma tumor, the tumor cells will express the ligand of PD-1— called PD-L1, and the immune checkpoint PD-1 will be tricked into stopping the immune response This means the body’s own immune system is not able to fight the cancer, and tumors are allowed to grow uncontrolled Another immune checkpoint protein called CTLA-4 may also be familiar to patients with melanoma. Like PD-1, CTLA-4 can be expressed when immune cells encounter melanoma cells In this case, the cancer cells trick the immune system in a slightly different way

While expressing PD-L1 allows cancer cells to inhibit activated Tcells that are trying to destroy the melanoma cells, engaging the CTLA-4 checkpoint halts the immune response at an even earlier point. When patrolling Tcells first recognize the threat of cancer cells stimulation of CTLA4 leads to the immune response being stopped in its track before immune cells can even be fully activated.

Immune checkpoint inhibitors (ICIs) can tackle this issue. ICIs are antibodies that can bind to either the immune checkpoint molecule or its ligand, and by doing so will disrupt the activation of immune checkpoints and reinvigorate immune cells. The first ICI to be approved was ipilimumab (Yervoy), which blocks CTLA-4, in 2011 for melanoma.

In 2014, nivolumab (Opdivo) and pembrolizumab (Keytruda), which both block PD-1 on immune cells binding to PD-L1 on cancer cells and other nearby cells that suppress immune responses in cancer, were approved in melanoma Besides the subsequent FDA approval of eleven single ICIs, there have been a number of approvals for combinations of ICI with other immunotherapy or other ICI, and ICI plus traditional cell-killing chemotherapy or so-called molecularly-targeted therapy, which blocks very specific chemical pathways in cancer cells with unique genetic mutations

RELATLIMAB TARGETS A NOVEL IMMUNE CHECKPOINT CALLED

LAG-3

Ten of the currently approved ICIs target either CTLA-4 or PD-1/PD-L1. With the 2022 approval of relatlimab + nivolumab (together called Opdualag), the FDA has added a new target to the ICI arsenal Relatlimab inhibits LAG-3, which is another immune checkpoint besides CTLA-4 and PD-1 Relatlimab was the first LAG-3targeting ICI to be approved, but it is not the only one under development: others include Immutep, Fianlimab (which is currently in phase III clinical trials against melanoma), and MK-4280

LAG-3, similar to CTLA-4 and PD-1, can be found on the surface of activated immune cells It has multiple binding partners, one of the most important being the protein responsible for compatibility between different tissues in the case of organ or bone marrow transplantation. Upon interaction with any of these ligands for LAG-3, inhibitory signals are sent into the immune cell

Again, this process is an important part of immune homeostasis, meaning the day-to-day balance of our immune system, highlighted by the fact that genetic loss of LAG-3 in newborn mice predisposes them to the development of autoimmune diseases (loss of CTLA-4 causes severe autoimmune diseases, while loss of PD1 is associated with only mild disease)

LAG-3 has also moved into the limelight due to research that showed when tumors were treated with PD-1/PD-L1 inhibitors, other immune checkpoint molecules, including LAG3, were upregulated as a compensatory response These findings indicate that when we tackle one of the mechanisms cancer uses to suppress our immune system, cancer can utilize other mechanisms as back-up to escape from control by our immune systems. This information led researchers to further explore combination therapies and novel ICI targets.

In clinical trials, relatlimab was tested in combination with the anti-PD-1 inhibitor nivolumab ICIs have already been proven to be more effective in combination than as single agents For example, it has been shown that the combination of two different ICIs nivolumab and ipilimumab was more effective than either ICI alone at treating melanoma that has metastasized to the brain. However, this increased efficacy comes with more frequent and serious side effects. Side effects can be a huge burden to patients and can lead to discontinuation of treatment. When relatlimab was combined with nivolumab, adverse events occurred about twice as frequently as when patients received nivolumab alone. However, the relatlimab + nivolumab adverse event rate appears to be about three times lower than with other ICI combinations such as nivolumab and ipilimumab. Therefore, using combination therapies including relatlimab or potentially other LAG-3 targeting ICIs may offer a safer and better tolerated option for treatment of cancer

NOVEL IMMUNE CHECKPOINT

INHIBITORS MAY HAVE HIGHER EFFICACY OR BETTER SAFETY PROFILE

The search for new ICIs has accelerated, in the hope that novel ICIs may have fewer side effects, in combinations or alone, or be more effective—or both Immunotherapies come with many side effects that can limit treatment options for patients. Alternatives that are better tolerated could significantly enhance patient lives and lead to better treatment outcomes as well.

Additionally, 50% of patients with melanoma still do not respond to current immunotherapies Novel therapeutic approaches are therefore needed to expand the success of immunotherapies. LAG-3 is just one of several promising targets for novel ICIs. Others include TIM-3, TIGIT, VISTA, B7-H3, and BTLA Additional molecules that are immunomodulatory and may synergize with one or more ICIs include ICOS, CD40L, OX40, 4-1BB and CD47 Many clinical trials are trying to determine whether blocking these other checkpoints, either alone or in combination with existing ICIs, could lead to better results than current treatment regimes

Similar to LAG-3, these novel ICI targets hold a lot of therapeutic promise. For example, there is currently a phase III trial evaluating the blockade of TIGIT in combination with the PD-1 inhibitor pembrolizumab in patients with resected high-risk melanoma Another example is VISTA, which is still in early clinical trials. VISTA may be particularly interesting to patients with melanoma because about one third of melanomas show high levels of this immune checkpoint protein, which is associated with advanced disease and worse prognosis Additionally, similar to what has been shown with LAG-3, treatment of melanomas with PD-1 blockade leads to increased levels of VISTA, indicating that tumors use immune suppression via VISTA as a back-up mechanism to escape the antitumor effects of blocking the PD-1/PD-L1 interaction. The efficacy of these and other novel ICIs remains to be seen, but patients should look out for new developments in this field

Overall, the discovery of immune checkpoints and their therapeutic blockade has had significant impact on many thousands of melanoma patients, extending survival by years and potentially curing as many as 35-40% of patients with metastatic melanoma Nonetheless, a substantial proportion of patients still does not reap the benefits of immunotherapy, and too many recipients of immunotherapy struggle with debilitating side effects that require treatment discontinuation Therefore, it is important that more research is done on novel immune checkpoint inhibitors and new combination treatments that show increased efficacy and tolerability.

Paul works in the group of Semir Beyaz and focuses his research on the impact of metabolism on immune cells and their ability to fight cancer. With this research, the Beyaz Lab sits at the cutting edge of cancer immunology and hopes to help make better immunotherapies for the future

Paul Bunk is a Ph D candidate at Cold Spring Harbor Laboratory, a New York-based research institute world-renowned in the fields of cancer biology, neuroscience, and plant biology.

IN PLAIN ENGLISH

NEOADJUVANT THERAPY FOR MELANOMA, AND HOW WE GOT HERE

BY KIM MARGOLIN, M.D., FACP, FASCO

UNDERSTANDING THE PRINCIPLES OF ADJUVANT THERAPY FOR ADULT CANCERS SO WE CAN APPLY THIS UNDERSTANDING TO NEOADJUVANT THERAPY

Until the modern era of cancer immunotherapy which really began in 2011 with the first approval of ipilimumab (Yervoy) for unresectable (inoperable) Stage III or Stage IV, or what is called “advanced,” melanoma we were taught by the giants of immunology who worked in experimental animal cancers that it was almost impossible to cure an animal once the cancer had grown to the point of detection. Thus, when the cancer was easy to feel or see, or there was evidence that the animal was sick, such as weight loss, slowed movements or ruffled fur, the cancer was too advanced for any treatment to save the animal from death.

However, other experiments showed that it was sometimes possible to cure animals that had very little cancer in the body. Many animal cancer experiments featured a socalled three-day model and ten-day model, where three and ten referred to the number of days that had passed after the researcher had injected tumor cells into the animal or had implanted an experimental tumor and then removed it surgically at different sizes of growth.

The upshot of these experiments was that effective treatments could eradicate the few cancer cells present in the three-day model or early after transplantation of the experimental tumor, while the animal would more likely die despite therapy in the tenday model or following more delayed removal of the implanted experimental tumor

The newest and possibly most beneficial approach—currently undergoing randomized trials Is to give immunotherapy prior to surgery to patients with a single site of melanoma that can be safely removed. This strategy is termed “neoadjuvant” therapy.

This concept of basing adjuvant therapy trials on successful drugs for patients with an advanced case of the same cancer has been widely used and has led to many approvals for adjuvant therapy in adult cancers. Indeed, the most common cancers (lung, breast, colorectal), which are also responsible for the highest number of deaths from cancer, have approved adjuvant therapies that increase the time it takes to relapse and, in some cases, increase the average lifespan of patients who receive these drugs following surgical removal of the primary tumor

Until the last decade, melanoma was not a part of the adjuvant therapy conversation, because melanoma was almost completely impervious to the various drugs used in the adjuvant setting, which is not surprising, since those drugs were also inactive for patients with advanced melanoma Nevertheless, desperate diseases [sic] call for desperate measures, and patients with advanced melanoma were among the first to benefit from the new generation of immunotherapies and targeted drugs that were first approved by the FDA in 2011

Once these drugs were shown to be effective in advanced melanoma, researchers began studying whether they would also be effective in the adjuvant setting for patients whose melanoma is removed surgically and who have no evidence of disease but might have micrometastases And they were! Both immunotherapy using immune checkpoint blocking antibodies like ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda) and targeted therapy using one of the three pairs of oral drugs that are approved for melanoma with a BRAF mutation can reduce the rate of relapse and prolong the average time to relapse The standard of care now is to offer adjuvant treatment (drug treatment after surgical removal of detectable melanoma) to Stage III patients, and adjuvant treatment has also been approved for Stage IIB and IIC melanoma These adjuvant treatments have shown great success in preventing or delaying relapse of melanoma, but their impact on overall lifespan may be less dramatic, since most patients who relapse can then get the same drugs and potentially the same degree of benefit.

PRINCIPLES AND PRACTICE OF NEOADJUVANT THERAPY IN MELANOMA AND OTHER CANCERS

The newest and possibly most beneficial approach currently undergoing randomized trials—is to give immunotherapy prior to surgery to patients with a single site of melanoma that can be safely removed. This strategy is termed “neoadjuvant” therapy. The number of treatments given before surgery is usually limited to one to three cycles so that the removed tumor can then be studied for microscopic features, but it is likely that some forms of neoadjuvant therapy will be so compelling as to make surgery unnecessary some of the time.

Animal studies showed survival (lifespan) benefits to the neoadjuvant approach and opened the field to human patients with various cancer types. While neoadjuvant treatment uses drugs that are already known to be effective against Stage IV melanoma, the drugs are not formally FDA-approved for neoadjuvant treatment, since the drug approvals specify treatment for “advanced (surgically unresectable) melanoma.” Nevertheless, this strategy is already used in other settings and has become part of standard practice for malignancies such as with radiation in patients with rectal cancer (in large part to avoid the need for huge surgeries and colostomy bags), and a similar approval has been given for the most dangerous form of breast cancer using chemotherapy, radiation and immunotherapy.

These tumors are particularly amenable to this approach as a result of their moderate sensitivity to chemotherapy and radiation and the decrease in surgical complications and organ dysfunction resulting from surgery on smaller tumors. Further, not only does the neoadjuvant approach reduce local tumor and potentially eliminate the need for surgery or reduce the amount of surgery required, the systemic therapy can also eradicate microscopic metastases at other sites and thus prolong the survival of these patients. As in the postoperative adjuvant treatment setting, the most critical determinant of the benefit from neoadjuvant therapy is the level of antitumor activity of the drug balanced against its toxicities, which could even have an unfavorable impact on surgical risks.

Fortunately, most cancers now have at least one drug approved for adjuvant therapy, so that drug becomes the comparator, or control group, instead of placebo or close observation.

The most definitive trial, with the largest number of patients and the most commonlyused immunotherapy pembrolizumab (Keytruda) for melanoma was reported in the last year and published in the New England Journal of Medicine Based in part on a very small trial in Philadelphia and subsequent laboratory analyses at UCLA, this randomized study (commonly referred to by its trial number, S1801), which was led by Dr. Sapna Patel of M.D. Anderson and chair of the SWOG (U.S. cooperative clinical trials group) melanoma committee, recruited 313 patients with a resectable but bulky single site of melanoma.

Most patients had a large single node or group of nodes involved with the tumor, and patients were randomly assigned to receive three cycles of neoadjuvant pembrolizumab prior to surgery and 15 more cycles after surgery OR to have surgery first, followed by 18 cycles of traditional postoperative adjuvant pembrolizumab. The trial was completed in record time and demonstrated a large benefit of the neoadjuvant treatment over all-adjuvant treatment in delaying or even preventing relapse.

In melanoma, the neoadjuvant approach came as a natural consequence of the emergence of today’s highly-active drugs, particularly immunotherapy agents that can provide durable remissions to a substantial proportion of patients with melanoma.

It was too early to know if overall lifespan would also be longer in this group, since measuring overall survival requires a substantial number of patients to have died in each group in order to detect a meaningful difference. Also, despite the seemingly large number of patients more than 300 total this trial was designed at a level of precision that would require further validation with an even larger number of patients. Such a trial will most likely be performed soon in order to provide data to the FDA in support of its approval of neoadjuvant therapy for similar patients with resectable melanoma.

Clinical investigators (researchers whose “experiments” consist of patients going on important trials of novel therapies in hopes of improving upon the current standard for their disease) are now excited about several elements in this arena. First of these is the basic science underlying the clinical observations: Using the same drugs that are given to patients with advanced melanoma, who are sometimes biopsied to see if there is evidence of immune attack against melanoma, it has been shown that neoadjuvant therapy can enhance the number and function of the particular immune cells that are inside the tumor and are responsible for killing melanoma cells and producing remissions.

It is believed that this phenomenon is responsible for the high rate of complete and near-complete remissions resulting from pre-surgical therapy, which appear to occur more frequently than for advanced melanoma treated with the same drugs. Many researchers are currently working on the detailed mechanism of these effects so that we can understand it better. Secondly, there is a strong chance that some, many, or even all of the patients who go into a complete or near-complete remission including the absence of any residual aliveappearing melanoma cells under the microscope may not need any postoperative adjuvant therapy This question is another one that will need to be answered by well-designed and randomized clinical studies Finally, the choice of agents to be used in the neoadjuvant setting (and, if necessary, in the postoperative adjuvant setting) will also need to be studied in trials designed to compare the antitumor effects and toxicities of the best-known drug regimens for melanoma

In conclusion, not only do neoadjuvant studies allow clinicians and researchers to pick the best and safest drugs for inducing remissions in patients with melanoma but they also appear to improve the average time to any relapse that might occur It is sincerely hoped that this approach will result in lengthening the average survival time and thus enhancing the likelihood of cure for a higher percentage of patients with melanoma than are currently cured without neoadjuvant therapy.

Dr. Margolin is a Medical Director of the SJCI Melanoma Program, St John’s Cancer Institute She worked at City of Hope for 30 years and also held faculty positions at the Seattle Cancer Care Alliance/University of Washington and at Stanford University Her academic achievements include long-term leadership of the Cytokine Working Group, leadership involvement in the Cancer Immunotherapy Trials Network, participation in the Southwest Oncology Group’s Melanoma Committee, and many positions in the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer Dr Margolin has reviewed grants for many cancer-related nonprofit organizations and governmental agencies She has also served as a member of the Oncology Drugs Advisory Committee to the FDA, the American Board of Internal Medicine’s Medical Oncology certification committee, and the Scientific Advisory Committee of the European Organization for the Research and Treatment of Cancer

Dr Margolin collaborates with AIM at Melanoma to write our “In Plain English” articles to provide timely updates on new developments for patients, caregivers, and other individuals with an interest in medical advances in melanoma

IN PLAIN ENGLISH ARTICLES

HAVE YOU MISSED ANY OF THE PREVIOUS IN PLAIN ENGLISH ARTICLES? CLICK ON ANY TITLE BELOW TO READ THEM.

TUMOR-INFILTRATING LYMPHOCYTE (“TIL”) THERAPY FOR ADVANCED MELANOMA

PART I IN PLAIN ENGLISH WHEN, HOW, AND WHERE MELANOMA SPREADS

PART II IN PLAIN ENGLISH WHEN, HOW, AND WHERE MELANOMA SPREADS

IN PLAIN ENGLISH: THE RESULTS OF DREAMSEQ

VACCINES 2021—MAJOR ADVANCES IN PREVENTING DEATH FROM INFECTION AND MALIGNANCY

WHAT IS TRANSLATIONAL MEDICINE?

WHAT ARE ACRAL MELANOMAS AND HOW ARE THEY SIMILAR TO AND DIFFERENT FROM COMMON CUTANEOUS MELANOMAS?

CLINICAL TRIALS CATCH UP

Welcome to our new interview series called Clinical Trials Catch Up, an article delivered in a question and answer format that is 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 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

Joshua M V Mammen, M D , Ph D , F A C S

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, also in this newsletter.)

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 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’s 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 would 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 low chance of side effects and 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 eventfree 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 neoadjuvant 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

If you want to learn more about clinical trials, you can go to AIM’s website here.