Pre-surgery pembrolizumab has success clearing tumours in most patients with desmoplastic melanoma, trial reports

Investigators have reported that three doses of the anti-programmed cell death protein 1 immunotherapy pembrolizumab – given prior to surgery – left no detectable cancer at time of operation in almost three-quarters of patients with resectable desmoplastic melanoma, a rare subtype that often demands extensive and disfiguring procedures

Researchers co-led by the University of California, Los Angeles (UCLA), USA, have reported clinical trial results that could alter surgical decision-making for desmoplastic melanoma, a rare and often aggressive form of skin cancer that can infiltrate deeply and prove difficult to remove. The investigators said that using the immunotherapy drug pembrolizumab – prior to surgery – had shrunk tumours substantially and had eliminated detectable cancer in many patients at the time of operation.

The study team has described the results from a multicentre trial that the SWOG* Cancer Research Network conducted with funding from the US National Cancer Institute. The trial – known as SWOG S1512 – evaluated programmed cell death protein 1 (PD-1) blockade, an approach that aims to restore anti-tumour immune activity by inhibiting a checkpoint pathway that cancers can exploit to evade immune attack.

Pembrolizumab – an anti-PD-1 antibody – has already seen wide use across melanoma and other cancers but this programme sought to test the drug in a melanoma subtype that clinicians have managed surgically and with radiotherapy.

Desmoplastic melanoma tends to arise in chronically sun-exposed skin, commonly on the head and neck, and it can extend along nerves or into deeper soft tissue. These anatomical patterns can make complete excision difficult and can raise the risk of functional impairment or disfigurement. Historically, surgeons have often relied on wide local excision, sometimes followed by radiotherapy, while clinicians have tended to reserve systemic therapy for more advanced disease.

The study team said that the latest analysis focused on patients whose tumours surgeons could remove at diagnosis. In this cohort, 28 patients with surgically resectable desmoplastic melanoma received three infusions of pembrolizumab across nine weeks before surgery. The research team collected tumour samples before treatment, during therapy and at operation to track biological response and pathology.

The researchers reported that 71 per cent of patients who received pembrolizumab had no detectable cancer remaining at the time of surgery, a finding that suggests a high rate of pathological complete response. They also reported that adverse effects were generally mild, a point that could matter for a pre-operative strategy that must preserve fitness for surgery and avoid delay.

“At the time of surgery, we often saw no viable tumour left to remove,” said Dr Antoni Ribas, senior author, professor of medicine at the David Geffen School of Medicine at UCLA and director of the Tumor Immunology Program at the UCLA Health Jonsson Comprehensive Cancer Center. He said the findings supported the use of pembrolizumab before surgery as a strategy to reduce the need for invasive operations and improve outcomes.

The investigators also reported follow-up outcomes that suggested durable benefit. At three years, they said that 95 per cent of patients had not died from desmoplastic melanoma and that 74 per cent had remained cancer-free. Such outcomes matter in a subtype where local recurrence can drive repeat operations, where spread arounds nerves can complicate further surgeries and where radiotherapy can impose long-term morbidity.

“Giving pembrolizumab before surgery led to very high rates of tumour clearance, few serious side effects and excellent three-year survival,” Ribas said. He argued that, taken together with earlier SWOG S1512 findings in advanced disease, the results indicated a shift away from repeated surgery and radiotherapy towards a systemic approach that could offer durable control and better quality of life.

The broader SWOG S1512 programme has aimed to test whether desmoplastic melanoma, despite its dense fibrous supportive tissue, might prove unusually sensitive to single-agent PD-1 blockade. Earlier work from the trial and from retrospective studies has suggested that the subtype often carries a high mutational burden linked to ultraviolet damage and may already have immune cells in and around the tumour, features that align with response to checkpoint inhibition. The study team has framed the trial as an attempt to translate those biological clues into a practical treatment strategy for this hard-to-treat disease.

The first author of the report was Dr Kari Kendra, a SWOG investigator and medical oncologist at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. The investigators have said that the multicentre design and the systematic tissue collection helped them to link clinical outcomes to tumour response at operation, an endpoint that can provide clear treatment outcomes in a neoadjuvant setting.

Neoadjuvant immunotherapy has attracted increasing attention across several cancers because it can expose an intact tumour to immune attack, potentially expand tumour-reactive T cells before resection and – in some settings – correlate pathological response with longer-term outcomes. For desmoplastic melanoma, the appeal is also practical in that if the therapy can shrink a deep, infiltrative lesion before surgery then less tissue will need to be removed. This could translate into fewer reconstructions and less functional loss, especially in presentations at the face and neck.

The researchers have cautioned that desmoplastic melanoma remains uncommon and that the cohort was modest in size, so further work will be needed to refine patient selection, to confirm outcomes in larger groups and to define how to integrate surgery and radiotherapy when patients do not achieve complete pathological response. Even so, the data have strengthened the case that single-agent anti-PD-1 therapy can play a central role in a melanoma subtype that clinicians have often treated with extensive local measures.

If the approach sees broader adoption, it could also affect how teams plan care pathways, with earlier involvement from medical oncology, tighter coordination around surgery dates and a stronger emphasis on pathological assessment at operation to guide subsequent management.

• * Previously the Southwest Oncology Group

For further reading please visit: 10.1038/s43018-025-01113-y