International Consortium Defines Guidelines for Conducting Neoadjuvant Trials in Melanoma

Rodabe N. Amaria, MD

Rodabe N. Amaria, MD

The use of neoadjuvant therapy prior to surgery has been impactful in breast cancer and other cancer types, but investigators are working to further the reach of neoadjuvant treatment in the melanoma landscape. Over 200 researchers joined forces as the International Neoadjuvant Melanoma Consortium (INMC) to define the best practices for running neoadjuvant clinical trials in melanoma.

The INMC, including medical oncologists, pathologists, radiologists, and translational scientists from around the world, came together to define recommended patient inclusion criteria and treatment duration for neoadjuvant clinical trials. They also defined the role of genomic testing in this space to further improve the drug development process. These recommendations have been published in theLancet Oncology.¹

In order to collaborate most efficiently, the INMC recommends limiting enrollment of clinical trials to patients with clinical stage IIIB, IIIC, and IIID melanoma who have been determined as surgically resectable by RECIST criteria. It is also recommended that treatment range between 3 and 12 weeks to prevent the disease from progressing and becoming unresectable.

The key endpoints for neoadjuvant clinical trials were also defined by the INMC as safety, radiographical and pathological response, and survival. Standard quality-of-life assessments may also be included as a key secondary endpoint.

By aligning the designs of neoadjuvant trials, the results of the trials in small patient populations can then be pooled to be more widely impactful in this setting, Rodabe N. Amaria, MD, explained. By harmonizing these clinical trials across the globe, future drug and biomarker development can be accelerated to best benefit patients with high-risk melanoma.

Another important part of neoadjuvant trials includes the collection of blood and tumor samples. The INMC recommends that all trials collect baseline samples, on-treatment samples, and surgical samples. The collection of these biospecimens can help in determining biomarkers that can predict response to treatment in the future. Evidence also suggests that samples from the gut microbiome may be important in predicting response to therapy in melanoma.

The identification of biomarkers through genomic testing can play a large role in drug development. Although phase III clinical trials on the way to getting FDA approvals can be costly, identifying patient populations that respond to therapy early on in small neoadjuvant trials can help phase III trials target more specific patient populations and prevent these trials from resulting in negative data.

In an interview withTargeted Oncology, Amaria, of the Department of Melanoma Medical oncology, Division of Cancer Medicine, MD Anderson Cancer Center, discussed the guidelines and recommendations outlined by the INMC. She also highlighted the importance of genomic testing in the neoadjuvant setting of melanoma.

TARGETED ONCOLOGY: How did the INMC get started and who is in attendance?

Amaria:Our first formal meeting was in November of 2016 at the Society of Melanoma Research Meeting in Boston. At that point, that was a big meeting, and we had assembled investigators that we knew were interested in participating in or were already doing neoadjuvant therapy trials. Predominantly, it’s been MD Anderson, Melanoma Institute of Australia, and the NKI, which is the big center in the Netherlands, those were the initial groups, but we’ve obviously had a lot of newer people [join]. For example, the University of Pennsylvania published a trial, there’s a trial at the Mayo Clinic, etc., but those were the initial 3 groups. With that, what we are trying to do is have a multidisciplinary collaboration of people that were interested worldwide in neoadjuvant [therapy in melanoma]. I am a medical oncologist, but we also work with surgical oncologists, pathologists, radiologists, as well as translational scientists.

In that initial meeting, we actually had a representative from the FDA, and we also had Monica Bertagnolli, MD, who is a famous breast surgeon who has done a lot of neoadjuvant work in breast cancer. Obviously, we draw a lot from breast cancer because that’s where they’ve been doing a lot in neoadjuvant therapy for many, many years.

That was our first meeting, where when we engaged with the FDA, they basically said melanoma has the ability to learn what other cancer groups have gone through. For example, breast cancer and their neoadjuvant trials. They stressed the importance of having trial designs that could be relatively comparable. You don’t want to have 10 different trials with 10 different designs. You want to be able to have trial designs that are relatively comparable so that data can be pooled. In melanoma, it is very difficult to do any 1 trial that would be big enough to produce data that are going to [lead to]an FDA approval in this subset of patients because the patients that would be eligible for this kind of therapy only represent about 10% to 15% of the melanoma cases we see a year. It’s a relatively small number of patients to start with. 

That meeting really drove home the point that we need to be organized, and that’s what we have tried to do. Again, we’ve had the idea of trying to engage people across the globe in multiple different disciplines within melanoma to have us thinking along the same lines in terms of how these trials should be designed, which patients should be treated, what kind of treatments we should do, what we do with the blood and tumor we collect, and that kind of thing.

TARGETED ONCOLOGY: What are the recommendations that came out of this?

Amaria:The idea here is that we are looking for a specific patient population that we define as clinical stage III melanoma, which is basically defined as people that have palpable lymph nodes. There are other disease characteristics that could be included in clinical stage III, but the focus in this paper is on this population because it’s the biggest group of patients. For this specific group of patients, we wanted people that had clinical disease or a palpable lymph node that follows RECIST criteria. This basically means it has to be over a certain size, over 15 mL in the smallest diameter, needs to be isolated to 1 nodal basin, and has to be surgically resectable, meaning a surgeon has to be able to look at it and say, “I can take that out.” If it’s too big, too involved, or has too many sites, then the patient wouldn’t qualify for this therapy. We were trying to homogenize the patient population so that these are people that have RECIST measurements and clinical nodal disease.

That was the first thing, the patient population, but the next thing was that we are not trying to say specifically what kind of treatment to give but rather to say the intent would be to give this therapy for over a 6- to 9-week period of time. We didn’t want to be giving therapy for 3 months or 6 months, like they sometimes do in breast cancer. Melanoma is a very different kind of cancer than breast cancer; it can be aggressive. So the intent was to limit the duration of neoadjuvant treatment so that even if the disease grows a little, it would still be amenable to surgery as opposed to growing to be not surgically acceptable. [That’s why] we defined the duration of treatment.

We also defined principles of surgery, how the surgery needs to be done. What we also want to do in a future exploration is to try and get some metrics on how the neoadjuvant therapy affects the surgery at all. Does it make the surgery easier? Does it make the surgery less easy? That’s difficult to calculate because it is a subjective assessment, but we are trying, as a group, to come up with a uniform surgical respectability survey that can be standardized so all neoadjuvant trials will collect some kind of metric, and we can understand more about the effect of the neoadjuvant therapy, not the surgery itself.

Also, 1 thing that is critical in neoadjuvant therapy is the ability to collect blood and tumor across time points to get a baseline sample, a sample on-treatment, and a surgical sample, so you can get at least 3 sets of samples. What we like to do is interrogate the blood and tumor to figure out if there are specific changes in the blood or tumor, or even at a molecular or immunologic level, that is going to predict either a good or poor response to the applied therapy. Now, how do you collect those specimens? And what assays do you do? Those are other things that we focused on in the paper, because again, these patients are relatively rare, so we have to make sure that the trials being designed are maximally impactful. That includes collecting blood and tumor that can be analyzed for the use of molecular and immunologic study.

TARGETED ONCOLOGY: What types of assays do you recommend using in the neoadjuvant setting?

Amaria:It depends a little bit on the type of study that you are running—if you are doing a targeted therapy study or an immunotherapy study. In general, we would usually do some type of molecular testing, which would be either DNA sequencing, RNA sequencing, or whole-exome sequencing to look for specific changes in the DNA or transcriptional changes in the RNA level. Those are the molecular kinds of changes.

There are also immunologic changes, so you can do immunohistochemistry and look for different cell populations. Are the CD8 T cells upregulated by treatment, for example. You can also do gene expression changes. There you can do flow cytometry or T-cell receptor sequencing. There’s any number of things you can do. You can also build in microbiome, that’s something we have done and we do see that people who do have various microbiome profiles may respond better or worse to therapy, for example. There are a number of things that can be done, and a lot of times you should tailor it to the type of treatment.

One thing people always talk about is circulating tumor DNA. Well we have a good assay to do circulating levels forBRAF, so that would be an assay you include on any clinical trial targetingBRAF-specific patients, for example. That would only be specific for a therapy that includes BRAF inhibition.

TARGETED ONCOLOGY: What is the current value of identifying biomarkers through genomic testing in melanoma?

Amaria:I feel like our clinical trials have changed within the last few years. We are trying to pay attention and trying to determine mechanisms of response or resistance to therapy. Obviously, the issue we have with immunotherapy in general is that it can really be curative, but you never know who that population of patients is that could be cured. That becomes a big problem, and that has sparked this very detailed analysis plan that has been incorporated into a number of trials.

In the neoadjuvant space, it’s easy to do these studies because you have patients that have, by definition, tumor that is accessible in the lymph nodes. A lot of these kinds of studies have already been done in our metastatic patients, but it’s harder to do, say, a bunch of lung biopsies or a bunch of liver biopsies. Those are obviously much more invasive procedures than just biopsying lymph nodes. Already, we do a lot of these same kind of analyses in patients with metastatic melanoma, but we think this is a great population of patients just due to the ease of doing the biopsies. They are a lot, safer and you can do a bunch of them. The more tumor and blood you collect, potentially the more assays you can do to try and find these answers.

TARGETED ONCOLOGY: In what other ways can genomic testing in the neoadjuvant space be useful in melanoma?

Amaria:[Genomic testing for] neoadjuvant therapy in breast cancer, for example, can be used as a platform for drug development. What I mean by that is you know how much it costs to do new drug development. It’s a ton of money. If a drug company has a new drug or drug combination, a lot of times in order to get those drugs FDA approved, you start with the phase I study to find the dose, use that in the phase II study to figure out how effective it is, then you usually do a phase III study where you compare your new drug or combination against the standard of care. These studies, the phase III, are usually huge. You have to enroll hundreds of patients, and they are super expensive. Sometimes, those phase III studies fail, and that’s the worst thing that kills drug development.

A lot of times if you can do a neoadjuvant study, which is a small study by definition, you are usually enrolling maybe 20 to 30 patients. If you get the biospecimens throughout, you can actually figure out in a small number of patients over a short period of time which patients are going to respond or which patients you think are going to respond or not. It gives you a little bit of that biomarker information that may be helpful to a drug company in saying maybe we need to focus these clinical trials in X patient population that is going to provide the best results to help with drug registration in the future.

The idea is that you can use [neoadjuvant therapy trials] as a drug development platform because you can get a lot of answers about the mechanisms of action of the drug, is the drug hitting the intended target, and a lot of times it can help drug companies get information that helps them with the go/no-go decision about whether to launch bigger, more expensive trials.

They do that in breast cancer pretty effectively. We are obviously not there in melanoma, but that is something we can aspire to.

TARGETED ONCOLOGY: What does the community oncologist need to know in regard to neoadjuvant therapy in melanoma?

Amaria:It takes a lot to make something a new standard of care. What we are trying to do is make neoadjuvant therapy the new standard of care, but in order to do that, we have to be organized. I think we have done a great job in organizing ourselves and assembling the INMC. I feel like melanoma oncologists—at least the academic ones that go to our meetings and read the medical journals—know that neoadjuvant therapy is now a viable option. We need to affect a cultural change, not only amongst us who see melanoma every day, but also among the community oncologists who are seeing tons of different cancers, they need to know in that situation, they should refer [patients] to a neoadjuvant clinical trial as opposed to doing the old tried-and-true method of upfront surgery then adjuvant therapy. We are just trying to educate the oncology community as a whole to recognize that this is a viable option. Patients in this scenario should be referred to centers that have experience in neoadjuvant therapy and should potentially consider neoadjuvant therapy trials.

TARGETED ONCOLOGY: What is your main take home message from this?

Amaria:Our group pooled the data from our initial clinical trials that have matured data. That ended up being presented at ASCO this year, and I think it was a sign of what we can do by pooling our data together. Alexander M. Menzies, BSc, MBBS, FRACP, PhD, was the first author on this presentation in the melanoma session. I think that’s a sign of what we can do when we organize ourselves, cooperate, and collaborate with each other.

Reference:

Amaria RN, Menzies AM, Burton EM, et al. Neoadjuvant systemic therapy in melanoma:recommendations of the International Neoadjuvant Melanoma Consortium.Lancet Oncol.2019;20:e378-389.