Desmoplastic melanoma is a rare and dangerous form of skin cancer typically diagnosed in older patients with chronically sun-damaged skin, and it affects more men than women. Although it accounts for less than 4 percent of all skin cancers, its incidence has been increasing steadily over the past 25 years. The disease is characterized by cancerous cells and fibrous tissue with large amounts of collagen, and it is associated with poor survival rates.
A previously published retrospective review suggested this type of cancer may be highly responsive to PD-1 or PD-L1 immune checkpoint blockade therapy (Nature 2018; doi: 10.1038/nature25187). The study found that patients with advanced desmoplastic melanoma derive substantial clinical benefit from this type of therapy due to the high tumor mutational burden (TMB) and frequent pre-existing adaptive immune response limited by PD-L1 expression.
Based on these findings, Kari Kendra, MD, PhD, and colleagues conducted a prospective Phase II clinical trial (NCT02775851) to evaluate the efficacy of pembrolizumab, an inhibitor of the PD-1/PD-L1 immune checkpoint, in patients with both resectable and unresectable desmoplastic melanoma. While pembrolizumab is already approved for the first-line treatment of patients with unresectable metastatic melanoma, this is the first trial testing the immune checkpoint inhibitor specifically in patients with the desmoplastic melanoma subtype. The researchers emphasized the importance of identifying the best treatment strategies for patients with different types of melanomas.
"Not all melanomas are the same and they don't respond to treatments in the same degree. Identifying the best treatment strategies for these unique patients can improve outcomes, which is our continual goal," noted principal investigator Kari Kendra, MD, PhD, a medical oncologist specializing in melanoma treatment at The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.
Study Details
The study involved two cohorts of patients with resectable or unresectable desmoplastic melanoma, and pembrolizumab was administered to patients as neoadjuvant treatment before surgery. The results of Cohort A showed a 59 percent complete pathologic response rate with neoadjuvant pembrolizumab in patients with resectable desmoplastic melanoma. The results from Cohort B of the study, which focused on patients with metastatic desmoplastic melanoma, were presented at the 2023 AACR Annual Meeting.
The study enrolled 27 patients with histologically and genetically confirmed desmoplastic melanoma who had not received prior systemic therapy. The median age was 75 and 93 percent of patients were male. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years with a median of 15 cycles received. The primary endpoint was complete response rate assessed per RECIST 1.1. Secondary endpoints included progression-free survival, overall survival, and safety/toxicity assessment.
The study met its primary endpoint with a complete response rate of 33 percent, exceeding the prespecified threshold of 20 percent. Twenty-four patients had a clinical response to pembrolizumab for an objective response rate of 89 percent (9 complete responses and 15 partial responses). The 2-year progression-free survival rate was 74 percent and the 2-year overall survival rate was 89 percent.
"With responses this high with single-agent pembrolizumab, combination therapy-with its increased potential for toxicity-is not needed as first-line therapy for patients with unresectable desmoplastic melanoma," Kendra stated. "Many advances in the treatment of melanoma have resulted in improvement in overall survival. There are many treatment options available. Now our focus is on how we decide the best approach for each given patient."
There were 10 patients who reported Grade 3 or higher adverse events, but there were no Grade 5 treatment-related adverse events. The most common were fatigue, diarrhea, and maculopapular rash.
The primary site of disease was the head or neck in 63 percent of patients. Whole exome sequencing analysis was available for 16 patients. Researchers evaluated genetic drivers of melanoma in baseline and on-treatment biopsies from 10 and 12 patients, respectively. They found that seven patients had tumors with loss of function mutations in NF1 and all had mutations in TP53. No cases had activating mutations in BRAF or NRAS, which is consistent with the known genetic alterations in desmoplastic melanoma. The median TMB in baseline biopsies was 79.4 mut/Mb (range: 34.3-159).
The findings from this study suggest that pembrolizumab may provide a promising and effective treatment option for patients with desmoplastic melanoma, potentially avoiding the need for more toxic combination therapies. "This study makes us truly question whether combination therapy is necessary for these patients, and it presents important knowledge that could help us further tailor treatment based on characteristics of the patient's unique tumor and reduce the potential for toxicity from combination therapies," Kendra concluded.
Dibash Kumar Das is a contributing writer.