Rare Melanoma Trial Serves as Model for Advancing Cancer Immunotherapy

Immunotherapy has dramatically changed the prognosis of many cancers, and now attention is turning to rare disease states where clinical trials are more challenging to run. Desmoplastic melanoma, once considered one of the most resistant and difficult-to-treat subtypes of skin cancer, has emerged as exceptionally responsive to single-agent immune checkpoint inhibitors (ICIs) in both the advanced and neoadjuvant setting.

The results of the SWOG S1512 trial (NCT02775851) validate the work that goes into targeting rare tumor types and also serves as a model of an approach that can apply to many other types of cancer and reach patients in need.

Research into rare subtypes has relevance beyond the patients who directly benefit. Because of the unique mutation profile that develops in each individual cancer, even more commonly occurring cancers have the potential to be treated as rare.

“Ultimately, every patient who progresses…develops a rare cancer,” argued Karen E. Knudsen, PhD, MBA, CEO of the Parker Institute for Cancer Immunotherapy (PICI), in an interview with Targeted Oncology. “They’ve developed mutations that are specific to their cancer type that are hard to compare to someone who might have started off at the same stage of disease, but whose cancer took a different evolutionary path. Every [cancer], ultimately, becomes a rare disease for an advanced cancer.”

Knudsen and PICI, whose mission is to accelerate the development and deployment of cancer immunotherapies, see the success of the study in desmoplastic melanoma as a sign of the continued value of focusing on immunotherapy in the right patient population to maximize the capabilities of these therapies. She described it as “a perfect example of the kind of study that we’d like to see move forward.”

Bringing Immunotherapy to Desmoplastic Melanoma

Desmoplastic melanoma has traditionally been managed with surgery and radiotherapy and is considered a difficult-to-treat subtype in contrast with cutaneous melanoma because of its deep penetration into the skin and nerves that requires more invasive surgery and makes recurrence more difficult to prevent. However, it has proven to be highly responsive to single-agent ICIs in both the advanced and resectable settings.

“People have said for years that in desmoplastic cancers that antibodies don’t penetrate, that the immune system doesn’t penetrate, and that’s not true,” said Antoni Ribas, MD, PhD, in an interview. “If you have a very immunogenic cancer, the T cells go in, kill the cancer cells, and then all of the fibrosis and tumor microenvironment disappears.”

Ribas, director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center (JCCC) and director of the PICI Center at UCLA in Los Angeles, California, led the multicenter phase 2 SWOG S1512 study of pembrolizumab (Keytruda) in 2 separate desmoplastic melanoma cohorts.

Results were first reported in 2025 from the metastatic cohort, including an objective response rate (ORR) among 27 evaluated patients of 89%, a 3-year melanoma-specific progression-free survival (PFS) rate of 84%, and 3-year overall survival (OS) rate of 96%.¹

Success in the Neoadjuvant Setting

Likewise, the other cohort of patients with stage I to III disease treated with neoadjuvant pembrolizumab had highly favorable results. The current standard of care for localized disease is surgical excision with or without radiotherapy, followed by adjuvant anti–PD-1 therapy if stage IIB or higher.² When 3 doses of pembrolizumab were given prior to resection, investigators observed a 71% pathological complete response rate before surgery and only a single melanoma-specific survival event at 3 years after resection.³

Although it is an uncommon subtype, Ribas is proud of the success of these findings. “This is a cancer where we’ve really changed the natural course. It doesn’t matter when it’s diagnosed. It doesn’t matter how deep it is, if there’s metastasis or not, as long as we give a little bit of anti–PD-1, those patients do well,” he said.

The strong response means there is less concern about needing a large surgical excision; the immunogenicity of the cancer and selecting the right patient population for immunotherapy is now the leading factor.

“I think that this disease is no longer a surgical disease,” he added. “This is a disease to be treated with anti–PD-1 therapies, and the rest would be for the rare cases that don’t respond, or if there’s something left over after the immunotherapy.”

These results should be considered in the context of the SWOG S1801 trial (NCT03698019), in which patients with high-risk cutaneous, acral, or mucosal melanoma who received both neoadjuvant and adjuvant pembrolizumab had significantly improved event-free survival vs adjuvant therapy alone.⁴

Because the tumor is still present when ICI is given, the neoadjuvant approach is uniquely effective, Ribas suggested. Previous standard-of-care adjuvant treatment in cutaneous melanoma would only give immunotherapy after removing the bulk of the tumor. However, Ribas pointed out that “the tumor that’s taken out by the surgeon has the immune cells that recognize the cancer accumulated there, because they have receptors that attract them to where the antigen is. By taking the tumor out, you take away the effectors of the immune response.”

Expanding Use of Immunotherapy in Trials

Knudsen explained how this trial, also funded by the National Cancer Institute (NCI), represents PICI’s focus on accelerating cancer immunotherapy research. “Our thesis is to not just fund game-changing cancer therapeutic research but to curate discoveries and follow them all the way through to patient testing and commercialization,” she said. “That’s how patients are going to get access to game-changing therapy. We love this study because it’s such an area of significant unmet clinical need.”

She said that in the current immuno-oncology space, we are seeing the fruits of the science that is demonstrating now just how immunotherapy works, but when to deploy it. The next step is to learn from these discoveries and move forward with the knowledge about how to achieve the greatest efficacy with ICIs.

Vaccines Present Early Intervention Potential

A key area of research that could build on ICIs is cancer neoantigen vaccines, which Knudsen says is one of PICI’s 4 major scientific priorities going forward. The vaccines currently in trials are often used in combination with ICIs, and results from phase 1 studies have built confidence that this approach has great potential to complement existing immunotherapies. Like ICIs, vaccines can be easily deployed in community oncology and rural settings.

Vaccines in development include tumor-specific vaccines as well as genetically driven ones that can be applied tumor-agnostically, such as in all BRCA-deficient cancers. Ultimately, Knudsen thinks the goal could be the capability for cancer prevention in those at high risk due to BRCA1/2 and other mutations. “We hear from patients regularly who know due to modern technology that they are not of average risk, but what do they do about it?” she asked. “Thinking through how immunotherapy and vaccination strategy works in those patients is key.”

Patients in remission are also increasingly seeking solutions to prevent disease recurrence, illustrating the need for powerful targeted therapies that don’t interfere with quality of life. Knudsen sees immunotherapy and vaccines as filling this role as well.

Promoting Access to Therapies

Although ICIs are widely accessible to patients, other immune-based treatments such as chimeric antigen receptor (CAR) T-cell therapies can only be given with strict monitoring at designated academic centers. “On the one hand, cell-based therapy and CAR T-cell therapy is expensive and challenging to deliver across a wide geography, but on the other hand, it is curative,” Knudsen noted. Because of the strong benefit of cellular therapies, it is essential that all eligible patients have access.

Because the extraction, manufacturing, and infusion of CAR T cells creates delays and barriers to availability, in vivo engineering is an approach that Knudsen said is attracting a great deal of interest and investment from PICI. The ongoing phase 1 inMMyCAR trial (NCT07075185) demonstrated preliminary efficacy for KLN-1010, an in vivo CAR T product targeting B-cell maturation antigen in patients with multiple myeloma.⁵

“We have a lot of faith that that’s going to reduce the complexity and increase the accessibility,” she said. Taking the curative technology of CAR T-cell therapy and making it more accessible is where the field is heading.

Learning From Rare Disease Trials

Knudsen and Ribas emphasized the role of the NCI’s funding and support and the cooperation of multiple centers through SWOG that made it possible to enroll sufficient patients with desmoplastic melanoma in SWOG S1512 and carry out the trial successfully.

Electronic health records have made it more efficient to identify potential patients for clinical trials both of rare diseases and molecular targets across all cancers, and Knudsen feels that artificial intelligence can go beyond this and guide decisions on how a particular cancer center or group can successfully build a trial in an area of great need. It can also aid in synchronizing data collection between hospital records and clinical trial investigators. This can solve the bottlenecks that can form and allow more trials to open.

Initially, the decline in cancer mortality that has been observed in the United States since 1991 was largely attributed to cancer prevention strategies. Now, Knudsen said, declines in mortality from lung cancer, liver cancer, multiple myeloma, and melanoma are instead reflections of the role of therapy in prolonging survival.⁶ “What’s the common denominator in all of those? Immunotherapy.”

Moving Forward

In addition to supporting focused research into the most effective applications of medicines and investigating new mechanism to target cancer, another priority is ensuring that no areas of investigation get overlooked. “There’s a lot of great research out there that’s just not getting to the point where it ever gets to clinical trial, because we don’t have great mechanisms for that yet,” said Knudsen. The pharmaceutical industry may not support certain research if it doesn’t quickly yield strong clinical signals to support their investment.

Government and philanthropic sources can fund studies like SWOG S1512 that would have been ignored otherwise, and one of PICI’s goals is to help “connect the science to the people” to streamline the often long and slow process of getting lifesaving treatments to patients. “Encouraging others to take on that role and join us is something that we feel like is an important component of what we do moving forward the pace,” said Knudsen. “We’ve got this mismatch. The pace of discovery has never been faster, but the ability to convert that over into clinical trial has never been more challenging.”

REFERENCES

1. Kendra KL, Bellasea SL, Eroglu Z, et al. Anti-PD-1 therapy in unresectable desmoplastic melanoma: the phase 2 SWOG S1512 trial. Nat Med. 2025;31(11):3668-3674. doi:10.1038/s41591-025-03875-5

2. Hughes TM, Williams GJ, Gyorki DE, et al. Desmoplastic melanoma: a review of its pathology and clinical behaviour, and of management recommendations in published guidelines. J Eur Acad Dermatol Venereol. 2021;35(6):1290-1298. doi:10.1111/jdv.17154

3. Kendra KL, Bellasea SL, Eroglu Z, et al. Neoadjuvant PD-1 blockade in surgically resectable desmoplastic melanoma: cohort A of the phase 2 SWOG S1512 trial. Nat Cancer. Published online January 29 2026. doi:10.1038/s43018-025-01113-y

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