Neoadjuvant Pembrolizumab Achieves 71% pCR in Resectable Desmoplastic Melanoma

Neoadjuvant therapy with pembrolizumab led to pathologic complete responses in 71% of patients with resectable desmoplastic melanoma, meeting the primary end point of cohort A of the phase 2 SWOG S1512 trial. The benefit of neoadjuvant pembrolizumab was largely comparable across all subgroups, irrespective of age, sex, performance status, lactate dehydrogenase level, disease status, and desmoplastic histologic subtype.

The trial enrolled 30 patients with resectable, stage I to III desmoplastic melanoma across 10 sites in the United States between July 2017 and May 2021. A total of 28 patients were included in the analysis after 1 refused protocol therapy and another was deemed ineligible following pathologic assessment. The median age was 75 years, and most patients were male (75%) and White (96%). The most common primary disease site was the head and neck area (68%). Most patients had primary (82%) as opposed to recurrent (18%) disease at enrollment, and 5 patients had positive nodes.

Patients received three 200-mg infusions of pembrolizumab every 3 weeks before surgery at week 9. Those who did not achieve a clinical response were permitted to undergo an optional fourth cycle of neoadjuvant therapy and up to 15 cycles of adjuvant therapy. Most patients (89%) received the intended 3 cycles of neoadjuvant pembrolizumab; 1 patient discontinued treatment due to colitis, and 2 others received the fourth dose of neoadjuvant pembrolizumab. Of the 28 patients who started neoadjuvant therapy, 27 underwent resection. The remaining patient elected not to undergo surgery and did not have a pCR with pembrolizumab.

The 3-year relapse-free survival and overall survival rates were 74% and 87%, respectively. Neither the median relapse-free survival nor the overall survival was reached at 42 months of median follow-up. The median time from start of therapy to surgery was 80 days. Mostly grade 1/2 adverse events occurred with the regimen, and no patients developed surgically unresectable disease.

Desmoplastic melanoma is a rare form of melanoma that is traditionally amelanotic and stems from sun-exposed areas. Although it is one of the most genetically mutated cancers, it lacks common drivers of cutaneous melanoma, such as BRAF and NRAS mutations. Standard treatment for localized disease consists of surgical excision with or without radiation and adjuvant PD-1 inhibition with nivolumab or pembrolizumab if stage IIB or higher. However, the full extent of lesions is often not entirely captured clinically or by imaging, leading to additional surgeries and excisions, which may result in clinical defects. Moreover, surgical morbidity presents a challenge for older and frail individuals.