BACKGROUND Antibodies inhibiting the programmed death receptor 1 (PD-1) have shown significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized. METHODS 58 stage IV uveal melanoma patients received PD-1 or PD-L1 antibodies between 2009 and 2015 at nine academic centers. Patients who were evaluable for response were eligible for analysis. Imaging was performed every 12-weeks and at the investigators’ discretion. Safety and clinical efficacy outcomes including best overall response (BOR), progression-free survival (PFS), overall survival (OS) were determined retrospectively. RESULTS Of 56 eligible patients, 48 (86%) had received prior therapy and 35 (63%) had been treated with ipilimumab. Three patients had an objective response to ipilimumab and 8 patients had stable disease as the best response. 38 (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in two patients for an overall response rate of 3.6% (95% CI 1.8-22.5%). Stable disease (≥ 6 months) was observed in 5 (9%) patients. The median PFS was 2.6 months (95% CI 2.4-2.8 months) and the median OS was 7.6 months (95% CI 0.7-14.6 months). There was no association between prior treatment with ipilimumab or liver directed therapy and PFS or OS. Treatment was well tolerated and only 1 patient discontinued treatment due to toxicity. CONCLUSIONS PD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population.

Background Therapeutic antibodies against programmed death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described. Methods A multi-institutional retrospective cohort analysis identified adults with advanced acral and mucosal melanoma treated with nivolumab or pembrolizumab as standard clinical practice, via expanded access programs, or published prospective trials. Objective responses were determined utilizing investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progression-free (PFS) and overall survival (OS) were assessed using Kaplan-Meier methods. Results 60 individuals were identified; 25 (42%) with acral and 35 (58%) with mucosal melanoma. Fifty-one (85%) patients had received prior therapy, including 77% with prior ipilimumab. Forty patients (67%) received pembrolizumab at 2mg/kg or 10mg/kg and 20 (33%) received nivolumab at 1mg/kg or 3mg/kg every 2–3 weeks. ORR (95% confidence interval, CI) was 32% (15–54%) in acral and 23% (10–40%) in mucosal melanoma. After a median follow up of 20 months in acral and 10.6 months in mucosal, median PFS was 4.1 months and 3.9 months, respectively. Only two patients (3%) discontinued treatment due to toxicity. Conclusions Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to published rates in cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice. Further investigation is needed to identify the mechanisms of response and resistance to therapy in these subtypes.

Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, but is highly associated with ultraviolet light DNA damage.1 We analysed 60 patients with advanced DM treated with programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1) blocking antibody therapy. Objective tumour responses were observed in 42 of the 60 patients (70%, 95% confidence interval 57–81%), including 19 patients (32% overall) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF-1 mutations (14 out of 17 cases). Immunohistochemistry (IHC) analysis from 19 DM and 13 non-DM revealed a higher percentage of PD-L1 positive cells in the tumour parenchyma in DM (p = 0.04), highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced DM derive significant clinical benefit from PD-1/PD-L1 immune checkpoint blockade therapy despite being a cancer defined by its dense desmoplastic fibrous stroma. The benefit is likely derived from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.

Background. Subtypes of melanoma, such as mucosal, uveal, and acral, are believed to result in worse prognoses than nonacral cutaneous melanoma. After a diagnosis of distant metastatic disease, however, the overall survival of patients with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma has not been directly compared. Materials and Methods. We conducted a single-center, retrospective analysis of 3,454 patients with melanoma diagnosed with distant metastases from 2000 to 2013, identified from a prospectively maintained database. We examined melanoma subtype, date of diagnosis of distant metastases, age at diagnosis of metastasis, gender, and site of melanoma metastases. Results. Of the 3,454 patients (237 with mucosal, 286 with uveal, 2,292 with nonacral cutaneous, 105 with acral cutaneous, and 534 with unknown primary melanoma), 2,594 died. The median follow-up was 46.1 months. The median overall survival for those with mucosal, uveal, acral,