Treatment Gaps Persist in Advanced Melanoma as Trials Explore Options Beyond Standard Checkpoint and BRAF/MEK Inhibitors

Vincent Ma, MD

Although dual checkpoint inhibition remains the preferred frontline approach for patients with BRAF-mutated, advanced-stage melanoma, there is a significant need for effective treatment alternatives for those who are refractory to, ineligible for, or did not respond to standard checkpoint blockade or BRAF/MEK inhibitors, according to Vincent Ma, MD, who adds that a variety of ongoing clinical trials are exploring novel strategies to address this gap.

When managing patients who do not respond to or benefit from checkpoint inhibitors, BRAF/MEK targeted therapy should be considered in those with a BRAF V600 mutation, Ma explained. Additionally, the 2024 FDA approval of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel (Amtagvi) as a third-line treatment for patients with BRAF mutations and a second-line option for broader melanoma populations represents a feasible treatment option for those who are sufficiently healthy and fit to tolerate next-line therapy. However, many patients may be ineligible for BRAF/MEK targeted therapy due to the absence of a BRAF mutation, Ma noted. Furthermore, many patients are not sufficiently healthy or fit enough for TIL therapy, which has its own logistical and biological challenges.

“There are a lot of novel and emerging therapies currently being explored in the advanced-stage setting…and I anticipate that multiple new agents will be approved in the next few years,” Ma said in an interview with OncLive®. “[However,] there's still a continual unmet need for therapies for patients who are, in general, not eligible for checkpoint inhibitors, including patients with autoimmune conditions and transplant recipients. There's also an ongoing need for developing better biomarkers [to determine] which patients [are unlikely] to respond well to immunotherapy and [for whom] we should be thinking about alternative treatment options.”

In the interview, Ma discussed how molecular profiling supports the initial use of dual checkpoint blockade over frontline BRAF/MEK targeted therapy in BRAF V600–mutant advanced melanoma; new and emerging strategies for patients who progress on standard checkpoint inhibition; and ongoing efforts to address persistent unmet needs in melanoma care for patients who are ineligible for current therapies due to comorbidities or tumor characteristics.

Ma, who is an assistant professor in the Division of Hematology, Medical Oncology and Palliative Care within the Department of Medicine, and a faculty affiliate of the Department of Dermatology at the University of Wisconsin Carbone Cancer Center in Madison, also discussed the rising incidence of melanoma, advances in immunotherapy, and the growing utility of individualized neoadjuvant strategies in stage II and III disease in another article.

OncLive: How is molecular profiling shaping treatment selection and sequencing strategies in melanoma?

Ma: With the publication of the phase 3 DREAMseq study (NCT02224781), which I believe was a significant, practice-changing trial, we gained important insights into the optimal treatment sequencing for patients with previously untreated advanced-stage melanoma. This phase 3 study enrolled patients with advanced-stage melanoma harboring a BRAF V600 mutation. Patients were [randomly assigned] to receive either initial immune checkpoint blockade with ipilimumab [Yervoy] and nivolumab [Opdivo] followed by BRAF/MEK targeted therapy upon progression, or the reverse sequence: starting with BRAF/MEK inhibitors followed by immune checkpoint therapy.

What we understood from the study was that patients who were initially treated with ipilimumab [Yerboy] and nivolumab [Opdivo] and then developed progression and went on to receive BRAF/MEK targeted therapy had an overall survival benefit compared with patients who [received] the converse sequence, meaning they started with BRAF/MEK inhibitors followed by immune checkpoint therapy. Nowadays, [the current thinking is that], in the majority of cases, if patients have a mutation, it is still preferable to start with checkpoint inhibitor therapy, if possible.

Of course, there are some caveats. For example, this [recommendation] may not apply to all patients, because we know that patients with active brain metastases were excluded from the DREAMseq trial. [Additionally], for patients with rapidly progressive disease who may not have sufficient time to respond to immunotherapy, BRAF/MEK targeted therapy may be [more appropriate] if they possess a BRAF V600 mutation.

In the DREAMseq trial, standard dosing of ipilimumab at 3 mg/kg and nivolumab at 1 mg/kg was used. However, in current clinical practice, the toxicity associated with the standard dose may [render this regimen] unfeasible. [As a result,] there is an alternative, flipped dosing regimen of ipilimumab at 1 mg/kg and nivolumab at 3 mg/kg. Another alternative option is the combination of nivolumab and relatlimab-rmbw [Opdualag]—a LAG-3 inhibitor plus anti–PD-1 agent. [The recent introduction of this regimen] also raises important questions about how this newer dual checkpoint therapy fits into the treatment landscape.

It is also worth noting that [the DREAMseq study] focused primarily on patients who received dabrafenib [Tafnilar] and trametinib [Mekinist] as the BRAF/MEK inhibitor combination. How these results translate to other FDA-approved BRAF/MEK inhibitor regimens [remains to be determined].

[There are] still limitations right now in regards to the appropriate treatment selection and sequencing for patients with a BRAF V600 mutation. We also can’t discredit the fact that other mutations also exist in melanoma. The presence of NRAS and KIT mutations [for example], should not impact decisions regarding the use of dual checkpoint therapy. However, identifying these mutations is still important, as ongoing studies are evaluating the potential role of molecular therapies targeted against them.

Overall, molecular profiling [remains] a relevant and important area of ongoing research in the melanoma treatment space.

For patients who relapse after immune checkpoint blockade or BRAF-targeted therapy, what investigational options are being studied to address acquired resistance, and are there any actionable biomarkers emerging from this research?

There are a lot of novel and emerging therapies currently being explored in the advanced-stage setting. [An important question] is how to manage patients who do not respond to or derive benefit from checkpoint inhibitors. [For patients with] a BRAF V600 mutation, we should certainly consider BRAF/MEK targeted therapy. There’s also been a lot of excitement about the FDA approval of the TIL therapy lifileucel, which is a feasible treatment option for patients who are healthy and fit enough to be able to tolerate next-line therapy following progression on checkpoint inhibitors.

[However,] a considerable proportion of patients may be ineligible for BRAF/MEK targeted therapy due to lack of a BRAF mutation. [They also might not be] healthy or fit enough for TIL therapy. [In this context,] a variety of clinical trials are investigating novel strategies in the advanced-stage setting.

For example, last year there [was a study] evaluating triplet immunotherapy [using] the combination of nivolumab, relatlimab, and ipilimumab. Although [this combination was] evaluated in the frontline setting, we saw numerically higher response rates and 3-year progression-free survival [with the triplet] compared with historical benchmarks from [phase 3] trials such as RELATIVITY-047 [NCT03470922] and CheckMate 067 [NCT01844505]. It remains to be seen whether this triplet approach could [be utilized as] a later-line therapy.

Beyond PD-1 and CTLA-4 inhibition, other immune checkpoint pathways are under investigation, as well as cytokine-based therapies. More recently, there's been a lot of interest, in genetically modified herpes simplex viruses designed to express immune-stimulating proteins and enhance immunogenic cell death. There are also several great bispecific T-cell engagers being investigated right now.

There's been a lot of excitement [surrounding] the role of individualized neoantigen therapy, also known as vaccine therapy, and antibody-drug conjugates. We also can't also forget about other molecularly-targeted therapies for non-BRAF mutations, such as NRAS and KIT alterations.

Something that I've also been very interested in keeping an eye on is theragnostic approaches, which essentially integrate imaging to locate where cancer cells are and then deliver radiation therapy to kill those cells. In parallel, biomarker studies are underway to elucidate some of the mechanisms of resistance to immune checkpoint inhibition. There are a lot of things to look forward to over the next few years. and I anticipate that multiple new therapies will be approved.

What are some of these most pressing unmet needs in melanoma care today, and how is the field really working to address them?

The biggest unmet need right now is finding better or novel therapies for patients who are refractory to the standard immune checkpoint inhibitors. We have an FDA-approved TIL therapy as of last year, but we also know that a substantial number of patients are just not eligible for this therapy. Patients often experience [clinical deterioration] following progression on standard first-line regimens and may be ineligible for additional [cytotoxic or intensive therapies] such as high-dose interleukin-2 [IL-2], which is associated with considerable morbidity and mortality.

TIL therapy also poses logistical and biological challenges. The procedure requires the availability of a sufficiently large tumor specimen to enable successful TIL harvest and expansion. Moreover, the manufacturing process typically requires several weeks, a timeframe that may not be clinically feasible for patients with rapidly progressive disease. In addition, patients with active brain metastases were excluded from the pivotal TIL studies, further limiting the generalizability of this approach.

TIL therapy also requires that patients have a large enough tumor specimen to access for tumor harvesting. For patients who have rapidly progressive disease, this therapy requires TIL expansion [to occur] over a matter of several weeks, and some patients just can't wait. We also know that patients with active brain metastases were excluded from the pivotal TIL studies, further limiting the generalizability of this approach. There's also an unmet need for treating patients with uveal melanoma and mucosal melanoma as those patients are also [commonly] excluded from major clinical trials.

To address these limitations, several strategies are currently under investigation. [One approach is] to introduce TIL therapy earlier [in the treatment course]. A phase 3 trial is evaluating the combination of anti–PD-1 therapy with TIL to determine whether earlier integration may lead to improved survival outcomes while patients are still healthy enough. Another study is looking at an investigational TIL therapy [engineered to] help produce IL-15. This may potentially eliminate the need for high-dose IL-2 administration, thereby reducing treatment-related toxicity.

Then there are some studies [assessing] the role of autologous T-cell receptor (TCR)–engineered T-cell therapies, an alternative cellular therapy–based treatment. [This approach involves] collect peripheral blood T cells through leukapheresis rather than isolating the TIL therapy through surgery, which may facilitate quicker turnaround in terms of TIL expansion.

There's still a continual unmet need for novel therapies for patients who are, in general, not eligible for immune checkpoint inhibitors. This includes patients with autoimmune conditions and transplant recipients. There's also an ongoing need for developing better biomarkers [so we can determine] which patients [are unlikely] to respond well to immunotherapy, and [for whom] we should be thinking about alternative treatment options.

Reference

FDA approves first cellular therapy to treat patients with unresectable or metastatic melanoma. News release. FDA. February 16, 2024. Accessed May 22, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-unresectable-or-metastatic-melanoma