Deeper Understanding of Disease Biology Needed in Melanoma to Move the Needle Forward

Jason J. Luke, MD, FACP

Despite the recent advancements with BRAF-targeted therapies and PD-1 checkpoint inhibitors, there is still much to learn in the field of melanoma, especially with regard to disease biology, according to Jason J. Luke, MD, FACP, who added that this understanding is needed to inform development and sequencing strategies, as emphasized during the 2020 SMR Virtual Congress.

“We need to gain a better understanding of the biology of melanoma. Over the past decade, we have seen tremendous progress with the development of BRAF-targeted therapies, the identification of CTLA-4, and PD-1 checkpoint blockade; however, this is not enough for at least half of our patients,” said Luke. “We need to better understand some of the differences in these melanoma tumors to know what kinds of combination therapies should be developed or what sequence of treatment would be needed to optimize treatment for each patient. Over the years, we've learned a lot from several large clinical trials. Even so, I believe we need to go back to the basic translational realm to learn more about the biology of this disease to identify new targets and improve the way that we use the treatments that we have available now.”

In an interview with OncLive®, Luke, an associate professor of medicine in the Division of Hematology/Oncology, who is also the director of the Cancer Immunotherapeutics Center Immunology and Immunotherapy Program at the University of Pittsburgh Medical Center Hillman Cancer Center, highlighted key research presented during the 2020 SMR Virtual Congress and beyond.

OncLive®: Could you spotlight some of the key topics that were discussed during the SMR meeting?

Luke: Due to this very unusual year, the SMR meeting was conducted virtually. However, even so, the agenda was very exciting. Some of the research that I am most excited about has to do with how melanoma develops and evolves over time, especially in relation to the treatments we administer in the metastatic setting. This research could lead to the next generation of therapeutic targets.

We see the progression of melanoma from very early, dysregulated melanocytes, all the way through to refractory metastatic disease. Understanding what those biological processes are help that transition might nominate a place where we can intervene, even before people develop melanoma. A number of the talks during the meeting focused on that biology; [by understanding this better, we will] hopefully be able to push the field into new directions.

What is currently known about the molecular pathogenesis of melanoma?

We have seen a number of elegant studies conducted by investigators like Boris C. Bastian, MD, and Hunter A. Shain, MD, that have looked at the progression of melanocytes, picking up serial dysregulated oncogenes, and the overexpression of certain pathways.

One of the surprising features about melanoma is that BRAF, which we target with BRAF-targeted therapies, actually develops very early in melanocytes. Even moles harbor BRAF mutations, although we know that moles are not melanoma.

It's now becoming clear that there's a series of stages that these lesions go through, which points to our ability to potentially intervene therapeutically. We continue to learn more about this.

One of the talks dissected the melanoma tumor. As we continue to learn about which cells, and at which stages, are developing dysregulated pathways, this may help us better understand when different treatments are needed to avoid the development of metastatic melanoma over time.

Could you expand on the importance of testing for BRAF mutations?

BRAF is a foundational mutation that is discovered in about half of the melanomas that arise. However, it has to happen in conjunction with some other mutations or dysregulations in the tumor. Even so, it’s considered foundational because it was one of the targets in early targeted therapy drug development. In melanoma, half of our treatment paradigm is targeting BRAF mutations with the 3 FDA approved BRAF and MEK inhibitor combinations. We now also have the combination of BRAF/MEK inhibitors and PD-1 antibodies.

BRAF is very important, biologically, in the sense that it drives the development of about half of the melanoma cases out there. It’s also important therapeutically because it’s integrated into the treatment paradigm in half of our patients and truly dictates how we select and sequence therapies.

What is the significance of HLAs in melanoma?

HLAs are genes that help the immune system to show within the immune system to different parts of the immune system, molecules come that it comes into contact with. As such, having a diversity of HLA is important in terms of having a diverse immune response. It has become quite clear after analyzing immune checkpoint blockade, or PD-1–blocking antibody clinical trials, that patients who have diversity of their HLA status are more likely to benefit from immunotherapy. This is presumably because the immune system is able to show more cancer particles to different cells of the immune system.

Melanoma is a diverse cancer type, which often develops from sun damage. As such, many different molecules could be present, which is both good and bad. A patient might be more likely to have a better immune response against the tumor if their HLA is more diverse. It will be interesting to hear new data that will hopefully answer a few questions for us, such as how HLA relates to patient outcomes, along with the implications of therapeutic strategies like BRAF inhibitors and PD-1 antibodies.

Could you provide some background on the COMBI-AD trial? How have these data impacted your own personal practice?

The COMBI-AD trial was a randomized, phase 3 clinical trial in the adjuvant, stage III setting.

Patients with melanoma who had lymph node involvement were randomized to receive either placebo or the combination of dabrafenib plus trametinib (Mekinist).

Notably, there was some skepticism with regard to this clinical trial when it initially started because, at that time, there were no reports of long-term benefit with targeted therapy in the adjuvant setting. Over the past couple of years of follow-up, however, it has become clear that in the patients who received the combination, there has been a real and stable improvement in relapse-free survival (RFS) compared with those who received the placebo.

As we expected, there's an initial tremendous benefit over the first year of treatment; however, this starts to drop around years 2 and 3, similar to [what we see with] the placebo. Once you get a few years out, then you see a stable difference, meaning that patients who were treated with this approach had an absolute improvement in RFS. We believe this is very meaningful because, in the adjuvant setting, we're hoping to decrease relapses.

Although there is some initial toxicity with this regimen, once patients get past the initial fever, they are able to tolerate this very well. This could be an important foundational treatment in melanoma, and we plan to build upon this in the future.

You are currently involved in the KEYNOTE-716 trial examining adjuvant pembrolizumab (Keytruda) in stage II disease. Could you speak to the goals of this research?

An area that I've been interested in is investigating earlier stages of melanoma. [Patients with] stage II melanoma are those who have deep, primary disease on the skin but do not have lymph node involvement. For a long time, these patients have not been treated with adjuvant therapy.

We recently completed accrual of the KEYNOTE-716 trial, which was a randomized, phase 3 trial that evaluated pembrolizumab in patients with stage II melanoma. I helped design and lead that study.

The risk for patients with the stage II melanoma is actually as high as some of the patients who already have FDA approval for the use of immunotherapy. As such, this has been a jarring clinical problem that we aren’t able to treat these patients. I'm very excited to see the results of KEYNOTE-716 as they become more mature, because those patients deserve to have the option at least to consider treatment in that setting. This trial would potentially be the first to offer that opportunity.

How has melanoma treatment been impacted by the coronavirus disease 2019 (COVID-19) pandemic?

With the approvals of checkpoint inhibitors at extended schedules, such as nivolumab (Opdivo) to 1 month and pembrolizumab to 6 weeks, at least in the academic community, we’ve been pushing to create less visits for patients. So, we have shifted to more extended schedules.

Also, accrual to clinical trials really slowed down in light of the pandemic, especially large, randomized, phase 3 studies and adjuvant studies. My hope is that, as we near the end of the year, we will see an improvement in the COVID-19 pandemic and these trials will pick back up again. These trials are very important in terms of advancing the field and moving toward the next generation of treatments.

What challenges are faced in the field of melanoma?

A major challenge, especially for metastatic melanoma, is trying to identify which patients need an aggressive approach up front, versus those for whom we can serially use the therapies that we already have.

We can use some clinical biomarkers such as lactate dehydrogenase or the presence of brain metastases to look at that; they could be very powerful in terms of stratification. However, on a molecular level, it's out there and we could understand it.

Data presented during the SMR meeting provided insight on who could benefit from an aggressive approach, and future analyses will continue to expand on this. Fully understanding this is important because aggressive approaches are associated with more toxicities.

Finally, there is still a whole segment of the melanoma population that doesn't do well. Those patients need new treatments and we need to better understand what the therapeutic targets are for this subset. I'm very excited though because we have the tools to find this information.

What are some of the ongoing research efforts being made that are generating excitement?

There is so much going on. Currently, we have 4 randomized, phase 3 trials in the frontline setting for immunotherapy, 2 randomized trials in the second-line setting, as well as another single-arm trial [that may lead to the] potential approval of another therapy. So, we have 7 new therapies that could potentially become available in the next couple of years.

While we've made tremendous progress with our treatments over the past 10 years, the next 10 years look very bright, as well. This emphasizes the importance of continued clinical trial participation. With participation, we could expand the benefits of therapy and improve overall survival for our patients in the long term.