Melanoma Clinical Trials: Current Options and How to Enroll

Key Takeaways

• Every major advance in melanoma treatment, ipilimumab, pembrolizumab, nivolumab, BRAF inhibitors, TIL therapy, was first proven in a clinical trial. Today’s standard of care is yesterday’s experimental treatment.

• Clinical trials give you access to promising treatments before they are widely available, and they are often the best option, not a last resort.

• Active areas of melanoma trial research include new checkpoint inhibitor combinations, next-generation TIL therapy, personalized mRNA cancer vaccines, and approaches to overcome treatment resistance.

• Lifileucel (Amtagvi), the first FDA-approved tumor-infiltrating lymphocytes therapy for any cancer, was approved in February 2024 and further evolved TIL approaches are now in active trials.

• Eligibility criteria vary by trial; some are designed for newly diagnosed patients, others for people who have progressed on prior treatment.

• Melanoma trials rarely use placebo alone, most compare a new treatment against the current best standard of care.

Why Consider a Melanoma Clinical Trial?

Every approved melanoma treatment that exists today, including the immunotherapy drugs that have saved thousands of lives, was proven in a clinical trial before it was widely available. Patients who enrolled in those trials gained access to those treatments years before anyone else. For some, it made the difference between a durable remission and running out of options. A clinical trial is not a last resort. For many patients with melanoma, especially advanced disease, it may be the best available option and is worth exploring at every stage of treatment planning.

What Melanoma Trials Are Currently Being Studied?

The melanoma trial landscape is one of the most active in oncology. Here are the major areas of current investigation:

New Immunotherapy Combinations

Dual checkpoint inhibitor blockade, targeting two immune checkpoints simultaneously, has become a major strategy for improving on the efficacy of single-agent immunotherapy. The combination of nivolumab plus ipilimumab (PD-1 + CTLA-4) set the standard for combination immunotherapy in metastatic melanoma with its 5-year and 7-year survival data. Now, researchers are investigating additional checkpoint targets to build on that foundation.

Relatlimab is a LAG-3 checkpoint inhibitor that works on a different immune pathway than PD-1 or CTLA-4. The combination of relatlimab plus nivolumab (brand name Opdualag) received FDA approval in March 2022 for unresectable or metastatic melanoma in adults and children 12 and older, based on data showing improved progression-free survival compared to nivolumab alone, with a more favorable tolerability profile than nivolumab plus ipilimumab. Trials are now testing relatlimab-nivolumab in additional settings including adjuvant use and earlier-stage disease.

Additional checkpoint targets being investigated in melanoma trials include TIM-3, TIGIT, and VISTA. Trials testing new three-drug combinations, such as PD-1 + CTLA-4 + LAG-3, are underway. The goal is to find combinations that increase the proportion of patients achieving durable responses while managing cumulative toxicity.

Tumor-Infiltrating Lymphocyte (TIL) Therapy

TIL therapy is a form of adoptive cell therapy in which tumor-infiltrating lymphocytes: T cells that have already entered the tumor and are capable of recognizing it, are harvested from the patient’s own tumor, expanded in the laboratory to billions of cells, and reinfused into the patient after lymphodepletion chemotherapy.

Lifileucel (Amtagvi), developed by Iovance Biotherapeutics, became the first TIL therapy approved by the FDA for any cancer in February 2024. It is indicated for adult patients with unresectable or metastatic melanoma who have progressed on prior anti-PD-1 therapy and, if BRAF V600-mutated, a BRAF inhibitor. Response rates in the pivotal trial (C-144-01) were approximately 31% in a heavily pretreated population, with responses that were often durable.

The approval of lifileucel opens a new class of treatment, and next-generation TIL approaches are now advancing through trials. These include genetically engineered TIL products designed to persist longer, overcome immunosuppressive signals in the tumor microenvironment, and target specific tumor antigens. Trials are also studying whether TIL therapy is effective earlier in the treatment sequence, before or instead of combination immunotherapy.

Cancer Vaccines

Personalized cancer vaccines represent one of the most exciting frontiers in melanoma treatment. Unlike traditional vaccines that prevent infection, cancer vaccines train the immune system to recognize and attack the patient’s own tumor cells.

mRNA-4157/V940 (developed by Moderna in partnership with Merck) is a personalized mRNA neoantigen vaccine. Each vaccine is individually designed based on the specific mutations present in a patient’s tumor, sequencing the tumor and using the resulting data to encode up to 34 neoantigens in a single mRNA vaccine. The vaccine is designed to prime T cells to recognize and attack cells bearing those tumor-specific mutations.

In the KEYNOTE-942 Phase 2b randomized trial, mRNA-4157/V940 combined with pembrolizumab significantly improved recurrence-free survival compared to pembrolizumab alone in patients with resected high-risk Stage III/IV melanoma. At 18 months, the combination reduced the risk of recurrence or death by approximately 44% relative to pembrolizumab alone. These results triggered rapid advancement to Phase 3 trials (V940-001), which are now enrolling. If the Phase 3 data confirms the Phase 2 signal, this could become a new standard of care for high-risk resected melanoma.

Other cancer vaccine platforms, including dendritic cell vaccines, peptide vaccines, and oncolytic viral therapies, are also under investigation.

Adjuvant and Neoadjuvant Approaches

Adjuvant therapy: systemic treatment given after surgery to reduce the risk of recurrence, is now standard of care for resected Stage IIB through Stage III melanoma. Trials continue to refine which patients benefit most, what duration of treatment is optimal, and whether new agents outperform current standards.

Neoadjuvant therapy: systemic treatment given before surgery, is an increasingly studied approach in Stage III disease. The logic is compelling: giving immunotherapy before resection may shrink the tumor, make surgery easier, provide an in vivo assessment of treatment responsiveness, and train the immune system against tumor antigens present in a fully intact tumor. Trials are demonstrating that pathologic complete response (complete disappearance of tumor at surgery) after neoadjuvant immunotherapy is a strong predictor of excellent long-term outcomes. The NADINA trial showed that neoadjuvant ipilimumab plus nivolumab followed by surgery was superior to adjuvant nivolumab after surgery in Stage III melanoma, a result that is reshaping how Stage III disease is approached.

Targeted Therapy Combinations

For patients with BRAF mutation-positive melanoma, BRAF plus MEK inhibitor combinations are highly effective but commonly face resistance within 6–12 months. Trials are investigating strategies to prevent or overcome this resistance, including:

• Triple combinations adding a third agent (such as an ERK inhibitor, MEK inhibitor dose adjustment, or an immunotherapy agent) to BRAF + MEK inhibitors

• Sequencing strategies, whether to start with targeted therapy or immunotherapy, and how to sequence them optimally

• Combinations targeting alternative resistance mechanisms such as the PI3K pathway

Who Can Participate in a Melanoma Trial?

Each clinical trial has specific eligibility criteria, requirements that define who can and cannot participate. These criteria exist to protect participants and to ensure that the trial generates meaningful scientific results.

Common eligibility factors include:

• Stage and prior treatment. Some trials are designed for newly diagnosed patients; others require progression on specific prior therapies (for example, prior anti-PD-1 therapy for lifileucel). Knowing your treatment history precisely is important.

• BRAF mutation status. Many trials stratify participants by BRAF status or require a specific BRAF status for enrollment.

• Performance status. Trials typically require participants to be well enough to undergo treatment, usually an ECOG performance status of 0 or 1.

• Organ function. Blood tests, liver function, kidney function, and cardiac assessments are part of the screening process.

• Brain metastases. Some trials exclude patients with active, untreated brain metastases; others are specifically designed for this population.

• Prior treatments. Maximum number of prior regimens, specific agents received, and time since last treatment can all affect eligibility.

Not meeting criteria for one trial does not mean there is no trial for you, it means that specific trial is not the right fit. Eligibility criteria vary substantially across trials, and a thorough search often identifies multiple options.

How to Find Melanoma Clinical Trials

ClinicalTrials.gov is the official U.S. registry of clinical trials. You can search by disease (melanoma), location, phase, and other filters. Listings include eligibility criteria, sponsor contact information, and study locations. It is comprehensive but can require time to navigate.

Ask your oncologist. Your treating oncologist is a critical resource. They may know of trials available at your institution or at nearby centers, and they can evaluate your eligibility based on your medical history. If your oncologist practices at a community hospital, asking for a referral to an NCI-designated cancer center, which typically has more trials available, is entirely reasonable.

NCI-designated cancer centers. Centers designated by the National Cancer Institute maintain active research programs and typically have a broader portfolio of active trials than community practices. There are over 70 NCI-designated cancer centers across the United States. A list is available at cancer.gov.

North’s trial finder. North’s trial finder allows you to search for current melanoma trials matched to your diagnosis. North can help you identify options and navigate the process of finding a trial that fits your situation.

What to Expect When You Enroll

The clinical trial process has several distinct phases:

Informed consent. Before any trial-related procedures begin, you will receive an informed consent document that describes the study’s purpose, the experimental treatment, potential benefits and risks, your rights as a participant, and what participation involves. You can take time to review it, ask questions, and consult with family or your physician before signing. Signing the informed consent does not lock you into the trial, you can withdraw at any time without affecting your standard medical care.

Screening. Before enrollment is confirmed, the trial team will perform screening assessments, blood tests, imaging, tumor biopsy if needed, to verify that you meet eligibility criteria. This process can take days to weeks.

Treatment. Once enrolled, you will follow the study protocol: the specific treatment schedule, monitoring visits, and assessments defined in the trial plan. This typically involves more frequent medical appointments than standard care, which serves both monitoring and data-collection purposes.

Monitoring and follow-up. Trials include scheduled assessments to evaluate treatment response and safety. Imaging is typically performed at regular intervals; blood work and symptom assessments are frequent. This intensive monitoring is one of the practical benefits of trial participation.

Leaving a trial. You can choose to leave a clinical trial at any time. If the treatment is not working, if the side effects are not tolerable, or if you simply change your mind, you can withdraw. Leaving a trial does not affect your eligibility for other treatments or your ongoing care relationship with your medical team.

About placebos. In cancer clinical trials, placebo-only arms are uncommon. Most melanoma trials compare the experimental treatment against the current best standard of care, or add the experimental agent to the existing standard. You will not be denied established treatment to receive a sugar pill. When placebo is used, it is usually added to an active control treatment so that neither group goes without a meaningful intervention. Your informed consent document will clearly describe the trial’s design.

Questions to Ask Before Joining a Melanoma Trial

Use this checklist when evaluating a trial with your care team:

• What phase is this trial, Phase 1, 2, or 3? What does that mean for what is known about the treatment?

• What is the experimental treatment, and how is it given?

• How does this compare to the standard treatment I would receive outside the trial?

• What are the most common or serious side effects?

• How often do I need to come in for treatment or monitoring visits?

• Is travel reimbursement or housing assistance available?

• What happens if I respond well, can I stay on the treatment?

• What happens if the treatment stops working, what are my options then?

• Will this trial affect my eligibility for other trials in the future?

• Can I continue to see my regular oncologist while enrolled?

Frequently Asked Questions

Are there clinical trials for melanoma?

Yes, melanoma is one of the most actively researched cancers in oncology. Hundreds of clinical trials for melanoma are actively enrolling at any given time, spanning all stages from early (adjuvant after surgery) to advanced (Stage III and IV). Trials are studying new immunotherapy combinations, personalized cancer vaccines, TIL cell therapies, targeted therapy combinations, and strategies to overcome treatment resistance. ClinicalTrials.gov and North’s trial finder are the best starting points for finding current options.

What is TIL therapy for melanoma?

TIL therapy (tumor-infiltrating lymphocyte therapy) is a type of cell therapy in which T cells are harvested from the patient’s own tumor, expanded to large numbers in the laboratory, and reinfused into the patient after preparatory lymphodepleting chemotherapy. Lifileucel (Amtagvi) became the first TIL therapy approved by the FDA for any cancer in February 2024, indicated for unresectable or metastatic melanoma after progression on anti-PD-1 therapy. Next-generation TIL approaches, including genetically modified TIL products, are being studied in active trials.

What is the melanoma vaccine trial?

The most advanced cancer vaccine trial in melanoma involves mRNA-4157/V940, a personalized mRNA neoantigen vaccine developed by Moderna and Merck. In the KEYNOTE-942 Phase 2b trial, this vaccine combined with pembrolizumab significantly reduced the risk of recurrence or death compared to pembrolizumab alone in patients with resected high-risk Stage III/IV melanoma. A Phase 3 trial (V940-001) is currently enrolling. This adjuvant approach, given after surgery, could represent a new standard of care for high-risk early-stage melanoma if the Phase 3 results confirm the Phase 2 data.

Can I join a trial if I’ve already tried immunotherapy?

Possibly, it depends on the specific trial. Some trials are designed specifically for patients who have progressed on prior anti-PD-1 immunotherapy (lifileucel was approved specifically for this population). Others study combinations that include immunotherapy as part of a new regimen, regardless of prior exposure. Your prior treatment history, what you received, how long ago, and how you responded, is one of the factors the trial team will assess during screening. Having received prior immunotherapy does not disqualify you from all trials, and the trial team can clarify eligibility for the specific study you are interested in.

How do I find melanoma clinical trials near me?

The most practical steps: (1) Ask your oncologist what trials are available at your institution or in your area. (2) Search ClinicalTrials.gov for melanoma trials filtered by your location. (3) Use North’s trial finder, which is designed to match your diagnosis to current available trials. (4) Consider requesting a consultation at an NCI-designated cancer center if your current institution has limited trial options, these centers maintain broad trial portfolios and often have more flexibility to evaluate patients remotely or in consultation.

References

1. National Cancer Institute. Melanoma Clinical Trials. https://www.cancer.gov/about-cancer/treatment/clinical-trials/disease/melanoma/treatment

2. ClinicalTrials.gov. Search: Melanoma. https://clinicaltrials.gov/search?cond=melanoma

3. Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. 2021;39(24):2656-2666. https://pubmed.ncbi.nlm.nih.gov/33979178

4. Weber JS, Carlino MS, Khattak A, et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet. 2024;403(10427):632-644. https://pubmed.ncbi.nlm.nih.gov/38246194

5. Lucas MW, Versluis JM, Rozeman EA, Blank CU. Personalizing neoadjuvant immune-checkpoint inhibition in patients with melanoma. Nat Rev Clin Oncol. 2023;20(6):408-422. https://pubmed.ncbi.nlm.nih.gov/37147419

6. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma (RELATIVITY-047). N Engl J Med. 2022;386(1):24-34. https://pubmed.ncbi.nlm.nih.gov/34986285.