Responses to PD-1 Blockade Approach 90% in Rare Melanoma

ORLANDO -- Exceedingly high response rates were seen with pembrolizumab (Keytruda) in patients with unresectable metastatic desmoplastic melanoma, according to results from the SWOG S1512 phase II trial presented here.

Among a cohort of 27 patients with metastatic desmoplastic melanoma -- a deeply invasive, rare melanoma subtype with a high tumor mutation burden -- nine achieved a complete response to the single-agent anti-PD-1 immunotherapy (P<0.001), meeting the study's primary endpoint of a complete response ≥20%, reported Kari Kendra, MD, PhD, of the Ohio State University Comprehensive Cancer Center in Columbus.

Another 15 patients had partial responses, contributing to an overall response rate of 89% (95% CI 71-98), Kendra said during a session at the American Association for Cancer Research (AACR) annual meeting.

Moreover, the safety profile of pembrolizumab monotherapy was consistent with what has been previously reported in trials using single-agent anti-PD-1 therapies for metastatic melanoma.

"The response rates were dramatic," Kendra noted. "Patients with desmoplastic melanoma are exceptional responders to single-agent PD-1 blockade with pembrolizumab. Based on these data, single-agent anti-PD-1 immunotherapy should be considered the first-line treatment of choice for most patients with unresectable desmoplastic melanoma."

AACR discussant Zeynep Eroglu, MD, of the Moffitt Cancer Center in Tampa, Florida, lauded Kendra and her colleagues for championing a study in such a rare tumor, adding, "I think we can say desmoplastic melanoma has one of the highest tumor response rates we've seen in any cancer to anti-PD-1 therapy."

As explained by Kendra, desmoplastic melanoma is extremely rare, making up just 4% of all cutaneous melanomas. It is amelanotic (lacking the dark pigment more typical of melanoma), usually found in highly sun-exposed areas, and is more common in the elderly and among men.

Looking at secondary endpoints, the 2-year progression-free survival rate was 74%, and the 2-year overall survival rate was 89%. Eight patients had died at the time of the analysis, with six due to other comorbidities, one due to progression in the central nervous system, and one from an unknown cause.

"Keep in mind our patient population had a median age of 75 years old, going up to 90, all with multiple comorbidities," Kendra pointed out.

During her discussion, Eroglu noted that the field is currently turning to combination immunotherapy for the first-line treatment of unresectable metastatic melanoma. However, she suggested that de-escalating therapy should be considered with desmoplastic melanomas, "considering these very high response rates to PD-1 alone, and given the elderly age of many of these patients."

"Perhaps PD-1-based combinations can be reserved for those rare desmoplastic melanoma patients who are resistant to PD-1 alone," she added.

Turning to early-stage disease, Eroglu pointed out that patients with desmoplastic melanoma are primarily treated with surgery.

"But we know that surgery for desmoplastic melanoma can be quite morbid," she said. "These tumors tend to infiltrate quite deeply into a patient's face or scalp, and require very extensive surgery -- sometimes multiple surgeries for complete excision. Given how disfiguring surgery can be for patients with early-stage desmoplastic melanoma, I wonder if it's possible in the near future to de-escalate the surgical approach for patients with early-stage disease following neoadjuvant PD-1 therapy."

This prospective study enrolled patients into one of two cohorts. Kendra had previously reported results from cohort A, evaluating those who had cancer that was considered to be treatable with surgery. Here, she reported findings from cohort B.

The median age of patients in this cohort was 75, and 93% were men. The primary site of disease was the head or neck in 63% of patients, an extremity in 19%, and torso in 19%. Patients received pembrolizumab 200 mg intravenously every 3 weeks for 2 years.

Responses to therapy were rapid, with some observed in most patients within 9 weeks, including complete responses.

As for safety, Kendra said that adverse events were similar to those seen previously with PD-1 blockade, the most common of which were fatigue, diarrhea, maculopapular rash, pruritus, anemia, arthralgia, and decreased lymphocyte count.

There were two grade 4 adverse events -- increased lipase in one patient, and lung infection and sepsis in a second patient.

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