A Study to Estimate the Anti-Tumor Activity and Identify Potential Predictors of Response in Patients With Advanced Mucosal or Acral Lentiginous Melanoma Receiving Standard Nivolumab in Combination With Ipilimumab Followed by Nivolumab Monotherapy

Immunotherapy with HD-IL-2 has produced durable benefit in 10% of patients with metastatic cutaneous melanoma. The antitumor activity of IL-2 has been limited at least in part by immunosuppressive and immune-regulatory forces within the tumor microenvironment. Antibodies against CTLA4 (e.g. ipilimumab), PD1 and its ligand (PD-L1) produced long-term benefit in approximately 20-40% of patients with advanced melanoma. In addition, the combination of ipilimumab with the anti-PD1 antibody, nivolumab, has shown tumor responses in up to 60% of patients with advanced melanoma. These findings have led to FDA approval of ipilimumab and nivolumab as an indication for treatment of patients with advanced melanoma and nivolumab for other cancers. While these data are exciting, only a few patients enrolled to the prior studies had metastatic MCM or ALM. There is no prospective immunotherapy studies conducted in MCM or ALM-specific population. Therefore the activity of the ipilimumab + nivolumab combination in these subsets or patients remains unknown

Reliable predictive biomarkers for the use of immune checkpoint inhibitors are needed to identify pretreatment those patients most likely to respond and early on in treatment assays could help identify mechanisms of tumor response and resistance necessary to improve therapy. Although tumor PD-L1 expression in tumor confers higher treatment response rate, responses to nivolumab or nivolumab + ipilimumab alone were noted in 55% and 41% of patients, respectively, with PD-L1- tumors. Therefore, more reliable predictive biomarkers are needed.

Recently, extensive studies on metastatic colorectal cancer have demonstrated that a new scoring system as well as density of immune cells infiltrates at the center of the tumor and its invasive margin, described as Immunoscore, could accurately separate a group of patients with high Immunoscore with improved DFS, and OS from those with low Immunoscore where the histopathological staging system cannot. A recent study has also demonstrated relationship between degree of pre-treatment CD8+ tumor infiltrating lymphocytes (TILs) infiltration and PD-L1 expression at the invasive margin of the advanced cutaneous melanoma and improved long-term clinical benefits in patients with advanced melanoma who received pembrolizumab monotherapy. Further, there appeared to be an association between tumor response and clonality of the immune infiltrate based on a next-generation sequencing method used to evaluate T-cell receptor rearrangement pre- and in response to checkpoint inhibitor therapy. Also, high mutational burden correlated with overall survival in patients with cutaneous melanoma treated with ipilimumab or lung cancer treated with anti-PD1. However, the biology of MCM and ALM are distinct from cutaneous melanoma at multiple levels. Consequently, the utility of predictive biomarkers developed for cutaneous melanoma remains unknown.