Patients with Rare Type of Skin Cancer May Benefit from Single-agent Pembrolizumab

Monotherapy with pembrolizumab (Keytruda®; Merck & Co) led to clinical responses in 89% of patients with unresectable metastatic desmoplastic melanoma, according to results from a phase 2 clinical trial presented at the annual meeting of the American Association for Cancer Research (AACR), being held April 14-19, 2023 at the Orange County Convention Center in Orlando, Florida. [1].

The study was supported by the SWOG Cancer Research Network and Merck & Co.

Desmoplastic melanoma is an extremely rare but dangerous subtype of melanoma with a high tumor mutation burden (TMB).[2] The disease is characterized by cancerous cells and fibrous tissue with large amounts of collagen.

Desmoplastic melanoma is often difficult to identify, not only clinically but also histologically, because it usually lacks pigmentation, and is commonly mistaken for a variety of benign growths, malignant non-melanocytic spindle cell tumors or less dangerous skin cancers such as basal cell- or squamous cell carcinomas.

Pathology findings have shown that desmoplastic melanoma manifest significant variation with respect to the extent of intratumoral cellularity, fibrosis and/or perineural invasion. In addition, some tumors present with a pure desmoplastic invasive component (>90%) while, in contrast, other tumors display only mixed features of desmoplastic and non-desmoplastic melanoma. [2]

The disease is generally diagnosed in older patients (the average at diagnosis is 66 years of age) with chronically sun-damaged skin, caused by natural or artificial exposure to natural or artificial exposure to ultraviolet (UV) light. On average, more men are diagnosed with the disease than women (with a ratio of approximately 2:1). The distribution pattern seen  shows that approximately half of desmoplastic melanoma is found on the head and neck (51%), extremities (30%), and trunk (17%) [4]

And while cancer of the skin is by far the most common of all cancers, according to the American Cancer Society (ACS), melanoma accounts for only 1% of all skin cancers. Of these melanomas, desmoplastic melanoma accounts for less than 4% of primary cutaneous melanomas.[2][3][5]. However, over the last 25 years the incidence of desmoplastic melanoma has been increasing steadily. The disease is generally associated with poor survival.[4]

Treatment options
Standard, first-line treatment of any form of primary cutaneous melanoma, including desmoplastic melanoma, is surgical management.[2] The recommended approach consists of surgical excision, completely removing the lesion along with margin from 1 to 2 cm for lesions 1.01 to 2.0 mm in thickness and 2 cm margins for melanomas greater than 2.0 mm. The amount of healthy tissue removed is individualized and based on the depth and thickness of the patient’s melanoma. For lesions that are more advanced (usually greater than 4 mm), radiation therapy may also be recommended.

A previously published retrospective review of patients with PD-1 blockade treated desmoplastic melanoma suggested this type of cancer may be highly responsive to PD-1 blockade. [6]. Although desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma, the authors of this study concluded that patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy. They noted that this benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression. [6]

The study results presented at this years AACR-meeting  are first prospective study investigating PD-1 blockade with pembrolizumab in patients with desmoplastic melanoma.

Advances in treatment options
“Recent advances have led to a variety of treatment options for patients with melanoma, whether it be single drug therapy or combination therapies,” explained Kari Kendra, MD, Ph.D., a professor of medicine and the director of cutaneous oncology at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

“The question clinicians are now posed with is how we decide the best approach for any given patient, which requires an understanding of which patient populations and/or tumor types respond to different treatments,” she added.

Retrospective analysis
Previous studies have shown that desmoplastic melanoma is characterized by high levels of tumor mutational burden, a characteristic that led Kendra and colleagues to hypothesize that this subtype may be uniquely sensitive to immune checkpoint inhibition. A prior retrospective analysis found high response rates among 60 patients with desmoplastic melanoma who had been treated with an immune checkpoint inhibitor.

Based on these findings, Kendra and colleagues conducted the prospective phase II S1512 clinical trial to evaluate the efficacy of pembrolizumab, an inhibitor of the PD-1/PD-L1 immune checkpoint, in patients with desmoplastic melanoma.

While pembrolizumab is approved for the first-line treatment of patients with unresectable metastatic melanoma, Kendra noted that this is the first prospective trial testing the immune checkpoint inhibitor in patients with the desmoplastic melanoma subtype.

Study design
The trial enrolled patients with histologically and genetically confirmed desmoplastic melanoma who had not received prior systemic therapy. Patients were assigned to one of two cohorts: Cohort A of the trial evaluated neoadjuvant pembrolizumab in patients with resectable disease, while Cohort B evaluated pembrolizumab in patients with unresectable metastatic disease. Previously reported results of neoadjuvant treatment showed a 59% pathologic complete response rate among patients in Cohort A.

Here, the researchers reported findings from Cohort B. Twenty-seven (27) patients with unresectable metastatic desmoplastic melanoma were enrolled in Cohort B and received 200 mg pembrolizumab monotherapy every three weeks (Q3W) for two years or until disease progression or unacceptable toxicity. Ninety-three (93%) were male, 70%
had Zubrod PS 0, and the median age of patients was 75 years of age (range 59–90). Median number of treatment cycles received was 15 (range 1–34).

The primary endpoint, reported here, was complete response rate (CR) assessed per RECIST 1.1.

Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety/toxicity assessment. Twenty-four (24) patients had a clinical response to pembrolizumab, for an objective response rate (ORR) of 89% (nine complete responses and 15 partial responses). The study met its primary endpoint with a complete response rate of 33%, exceeding the prespecified threshold of 20%. Six patients experienced grade 3 or higher adverse events.

“This study identified a subgroup of melanoma patients, those with desmoplastic melanoma, who had an exceptionally high response rate to pembrolizumab monotherapy,” Kendra concluded, adding that the response rates to pembrolizumab observed in this study exceeded those of historical data from patients with other melanoma subtypes.

Predictive biomarker
Kendra suggested that the diagnosis of desmoplastic melanoma could be used as a predictive biomarker to identify patients with melanoma likely to respond to pembrolizumab. In addition, the results suggest that patients may be able to undergo monotherapy with pembrolizumab instead of combination therapies, which are commonly employed as first-line treatment for desmoplastic melanoma, according to Kendra.

“The high responses to pembrolizumab monotherapy indicate that first-line combination therapy may not be necessary for patients with desmoplastic melanoma, which could help patients avoid unnecessary toxicities,” she explained.

“It is important to keep studying rare diseases and rare subsets of more common diseases so that we can better tailor therapy to each individual,” Kendra noted.

Kendra and colleagues continue to evaluate the long-term efficacy of pembrolizumab in this trial, specifically its impact on progression-free survival (PFS) and overall survival (OS). Additional ongoing studies are examining molecular features of the tumors that progressed following pembrolizumab treatment to identify biomarkers of treatment resistance.

The authors of the study acknowledge that one of the limitation of the study was its small sample size.

Clinical trials
Pembrolizumab in Treating Patients With Desmoplastic Melanoma That Can or Cannot Be Removed by Surgery – NCT02775851

Highlights of prescribing information
Pembrolizumab (Keytruda®; Merck & Co) [Prescribing Information]

Reference
[1] Kendra K, Bellasea S, Eroglu Z, Hu-Lieskovan S, Campbell KM, Carson III W, Wada D, Plaza JA, Sosman J, IN GK, Ikeguchi A, Hyngstrom J, Brohl A, Khushalani NI, Markowitz J, Negrea G, Kasbari S, Doolittle GC, Swami U, Roberts T, Patel SP, Sharon E, Moon J, Wu NC, Ribas A. High response rate with single agent anti-PD-1 in patients with metastatic
desmoplastic melanoma. In: Proceedings of the 114th Annual Meeting of the American Association for Cancer Research; 2023 April 14-19; Orlando, FL. Philadelphia (PA): AACR; 2023. Abstract nr CT009 – S1512
[2] Chen LL, Jaimes N, Barker CA, Busam KJ, Marghoob AA. Desmoplastic melanoma: a review. J Am Acad Dermatol. 2013 May;68(5):825-33. doi: 10.1016/j.jaad.2012.10.041. Epub 2012 Dec 23. PMID: 23267722; PMCID: PMC4703041.
[3] Key Statistics for Melanoma Skin Cancer, About Melanoma Skin Cancer. American Cancer Society (ACS). Online. Last accessed on April 16, 2023.
[4] Feng Z, Wu X, Chen V, Velie E, Zhang Z. Incidence and survival of desmoplastic melanoma in the United States, 1992-2007. J Cutan Pathol. 2011 Aug;38(8):616-24. doi: 10.1111/j.1600-0560.2011.01704.x. Epub 2011 Apr 26. PMID: 21518379.
[5] Quinn MJ, Crotty KA, Thompson JF, Coates AS, O’Brien CJ, McCarthy WH. Desmoplastic and desmoplastic neurotropic melanoma: experience with 280 patients. Cancer. 1998 Sep 15;83(6):1128-35. PMID: 9740077.
[6] Eroglu Z, Zaretsky JM, Hu-Lieskovan S, Kim DW, Algazi A, Johnson DB, Liniker E, Ben Kong, Munhoz R, Rapisuwon S, Gherardini PF, Chmielowski B, Wang X, Shintaku IP, Wei C, Sosman JA, Joseph RW, Postow MA, Carlino MS, Hwu WJ, Scolyer RA, Messina J, Cochran AJ, Long GV, Ribas A. High response rate to PD-1 blockade in desmoplastic melanomas. Nature. 2018 Jan 18;553(7688):347-350. doi: 10.1038/nature25187. Epub 2018 Jan 10. PMID: 29320474; PMCID: PMC5773412.

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