Despite high response rates and durable outcomes with existing frontline immunotherapy regimens for metastatic melanoma, significant unmet needs remain—namely, improving frontline combinations, identifying predictive biomarkers to better individualize therapy and extend the benefit of current regimens, and developing more effective second-line strategies, according to Douglas B. Johnson, MD, MSCI.
“Frontline therapy may or may not change all that dramatically [in the next few years]…although hopefully, we’ll get a little bit better at biomarkers,” Johnson said in an interview with OncLive®. “What is likely to change is having some of these [novel treatment approaches] either in an adjuvant setting, [in the case of oncolytic vaccines], or in the second and later lines, [in terms of next-generation] cellular therapies.”
During the interview, Johnson highlighted the need for improved frontline strategies, more effective second-line options, and greater biomarker precision in melanoma. He also pointed to investigational platforms such as tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR)–based therapies, and neoantigen vaccines as promising modalities that may eventually broaden immunotherapy’s reach within the melanoma treatment paradigm.
“My prognostication is that some of those therapies will potentially be on the cusp of being tested in the frontline setting, but we’re probably not there quite yet,” Johnson added.
Johnson, a professor of medicine and leader of the Melanoma Clinical Research Program at Vanderbilt University Medical Center in Nashville, Tennessee, expanded on the importance of Cancer Immunotherapy Awareness Month in a concurrent interview.
OncLive: What are some of the most critical unmet needs with immuno-oncology today in your field, and where do current agents fail to provide durable benefit?
Johnson: Melanoma has certainly been at the forefront of immunotherapy advances, so we’ve been very fortunate to have high response rates in the metastatic setting and long-term responses in many cases. Unfortunately, we’re still seeing 10% to 30% response rates in the frontline setting. We’ve come a long way, but there’s still a long way to go.
We still don’t have great biomarkers either, so we’re not able to predict which patients are going to respond ahead of time and which are not. Improving our frontline options so that more patients can respond, as well as developing better options in the second-line setting, is really an unmet need.
There are a number of ways that people are trying to address these challenges. [With] TILs or other cellular therapy options, we’re seeing somewhere between 30% to 50% response rates in patients who have [progressed on] immune checkpoint inhibitors, with either lifileucel [Amtagvi], which is the FDA-approved TIL product, or some newer products. There’s one from a company called Obsidian [called OBX-115], which is sort of the next-generation TIL. [It is] very early, but [the agent appears] very promising, and it doesn’t require high-dose IL-2.
There’s also something called TCR-T therapy, which is sort of a cousin to tumor-infiltrating lymphocytes, but the cells can be harvested from the peripheral blood, so patients don’t have to undergo surgery. If that agent pans out—there’s one from a company called [IMA203]—that so far has shown somewhere around a 50% response rate, although it’s only applicable to patients who have HLA-A*02:01 positive [disease].
[Despite these advances], we still have a ways to go in melanoma and in many other tumor types. There are still a lot of challenges.
What are some of the current challenges and considerations with utilizing TIL therapy in clinical practice, and how could these be addressed?
Lifileucel is an incredible step forward. TILs in general are an incredible step forward. [However,] there are some significant downsides to TILs. High-dose IL-2 is required at the moment for TILs; [to tolerate that therapy] patients have to have excellent performance status, excellent cardiac function, lung function. A lot of patients don’t tolerate that.
Patients also have to have a tumor that’s accessible for surgery. Patients with brain-only metastases or bone-only disease are not candidates for treatment.
The patient also has to have time. That is probably the biggest issue at this moment, because in general, it’s going to take several weeks for insurance approval to get done. When centers are just starting out, it could take quite a bit longer. Patients have to have 2 to 3 months for insurance approval, surgery scheduling, and product manufacturing, which takes about 5 weeks. Many patients don’t have the time to wait around for therapy. For some patients, there could be some bridging options—perhaps BRAF/MEK inhibitor therapy, as an example.
However, that’s the biggest challenge right now. The key needs going forward are reducing IL-2, reducing lymphodepletion chemotherapy, and then [reducing the overall] turnaround time—not just the manufacturing part, but the insurance plus surgery plus manufacturing part.
What are some of the ongoing clinical trials or emerging treatment approaches that could shift the treatment paradigm for melanoma?
There’s a lot [of exciting research] going on in melanoma. There were some nice data presented at the 2025 ASCO Annual Meeting looking at the triplet combination of ipilimumab [Yervoy], nivolumab, and relatlimab-rmbw [Opdalaug].
What was interesting is they also combined that with sarilumab [Kevzara], which is the IL-6 blocker, to potentially mitigate some of the toxicities that would be associated with triplet therapy. Interestingly, they saw [an approximately] 60% response rate, which is [typical of] a triplet like that, but only a 12% rate of high-grade toxicities in the first 12 weeks, which is dramatically lower than what we would expect.
That kind of approach, where we’re treating the patient aggressively with multi-agent checkpoint inhibitors, but then potentially having an agent on top of that to mitigate some of the toxicities, is very interesting.
Some of these next-generation cellular therapies are quite interesting, and there are a number of trials going there. As I mentioned, [OBX-115] is quite interesting in that it removes the need for high-dose IL-2, allows for lower-dose lymphodepleting therapy, and allows for TIL harvest based on biopsies.
There is also the TCR-T therapy [IMA203], which recognizes the PRAME antigen expressed in HLA-A*02:01. [For this therapy to be effective, the tumor must] have the PRAME antigen and the right HLA type, which is only about 40% of patients. However, there’s [an approximately] 50% response rate [with this agent] in cutaneous melanoma. [Moreover,] at least among the first 15 patients with uveal melanoma, 10 of those patients responded—[this] is a very challenging subset of melanoma.
The last [emerging therapy of interest to me] is the Moderna-Merck mRNA vaccine that’s being looked at in the adjuvant setting. There are some interesting randomized phase 2 data that showed the vaccine plus pembrolizumab [Keytruda] was significantly better than pembrolizumab alone in terms of decreasing relapse rates in stage III melanoma. A phase 3 study is ongoing.
Novel approaches like TILs, TCR-T therapy, and these neoantigen vaccines are proving grounds in melanoma, but could expand across a variety of cancer types.
How do you expect the melanoma treatment paradigm, and the role of immunotherapy in it, to evolve in the next few years?
Frontline therapy may or may not be all that different. I could see us potentially using a triplet or some sort of other immunomodulator, but we do have a couple of regimens right now that do cure about half of patients, so I kind of see that probably continuing. Hopefully, we’ll get a little bit better at biomarkers and things like that, but so far, that’s been a little bit frustrating.
What is likely to really dramatically change is having some of these therapies that I just mentioned, either in an adjuvant setting, like the vaccine, as well as some of these cellular therapies in the second- and later-lines of therapy. There are other agents [that could fill this role], including oncolytic viruses, like the drug RP1, which is under FDA review.
If some of these cellular therapies show enough activity in the second-line setting, it’s possible they’ll get moved toward the frontline. Thinking about a new patient with newly diagnosed metastatic disease waiting that long to get started—if the data look good enough, that’s certainly possible, and that would be very exciting. However, it’s a high bar in the frontline, especially when you’re dealing with cellular therapies that take weeks and weeks to produce.
My prognostication would be that some of those therapies will potentially be on the cusp of being tested in the frontline setting, but probably not be there quite yet.
