Neoadjuvant Pembrolizumab Shows Pathological Complete Response in Desmoplastic Melanoma

In the challenging landscape of melanoma treatment, a new beacon of therapeutic promise has emerged.

Results from cohort A of the phase 2 SWOG S1512 trial (NCT02775851) reveal that neoadjuvant pembrolizumab—a PD-1 inhibitor—elicits a remarkably high pathological complete response (pCR) in patients with resectable desmoplastic melanoma, a rare and immunologically distinct melanoma subtype.

The study enrolled 28 eligible individuals, all diagnosed with surgically resectable desmoplastic melanoma. Each participant received three doses of pembrolizumab, 200 mg intravenously every three weeks, prior to undergoing surgical excision. This neoadjuvant approach—administering immunotherapy before surgery—was evaluated for its ability to eradicate tumor cells at the pathological level, aiming to halt the disease in its tracks before it could take firmer hold.

The findings are compelling: a pCR rate of 71% was achieved, with a 95% confidence interval ranging from 51% to 87%, and a P value of less than 0.001. This primary endpoint met the trial’s prespecified statistical threshold, offering persuasive evidence that PD-1 blockade can induce robust tumor regression in this melanoma subtype before surgery.

Desmoplastic melanoma, while less common than other cutaneous melanomas, is characterized by a dense fibrous stroma and a high mutational burden, which often translates into increased immunogenicity. These biological features may explain its apparent sensitivity to PD-1 blockade. The clinical implications of a high pCR rate are significant—historically, pCR in melanoma has correlated with improved long-term outcomes, including relapse-free and overall survival.

Beyond the primary endpoint, safety and survival outcomes were closely monitored. The toxicity profile of neoadjuvant pembrolizumab proved manageable, with only two grade 3 treatment-related adverse events reported across the cohort—representing 7% of participants. After three years of follow-up, four patients had died, but notably, none of the deaths were attributed to melanoma progression or treatment-related toxicity. These survival data, while preliminary and limited by cohort size, lend further weight to the therapeutic value of preoperative immunotherapy in this context.

Pathological assessments were conducted using tissue samples collected at baseline, shortly after treatment initiation (3 to 5 weeks), and at the time of surgery. This allowed investigators to observe dynamic changes within the tumor microenvironment, underscoring the rapid and potentially durable impact of PD-1 inhibition at the cellular level.

While the study's scope was focused and the sample size modest, the magnitude of response positions pembrolizumab as a potentially transformative agent in the neoadjuvant setting for desmoplastic melanoma. Importantly, the trial reinforces the broader oncologic principle that tailoring immunotherapy to the biological nuances of tumor subtypes can yield outsized benefits.

These findings may also stir renewed interest in the design of future melanoma trials, particularly those exploring the timing and sequencing of immune checkpoint blockade. For clinicians managing desmoplastic melanoma—a disease that often defies conventional therapeutic patterns—this study delivers a new tool with proven efficacy, grounded in immunologic rationale and clinical data.

As research continues to refine the use of immunotherapy in rare melanoma subtypes, SWOG S1512 offers a timely and hopeful reminder: even within the fibrous, elusive borders of desmoplastic tumors, immunotherapy can strike a decisive blow.