Purpose: Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in GNAQ or GNA11 which lead to downstream signaling through the MAPK pathway. Ulixertinib (BVD-523) is a potent and reversible small molecule ATP-competitive inhibitor of both ERK1 and ERK2 protein kinases.
Patients and methods: We performed a phase II study to determine the efficacy and safety of BVD-523 in patients with metastatic uveal melanoma. This was conducted as a Simon two-stage design with a sample size of 25 patients (pts) and an initial evaluation of efficacy after 13 pts.
Results: From April 2018 to April 2019 thirteen pts were enrolled. Pts were predominantly female (69%) with a median age of 64 years (34 -76). Sites of metastases included liver (84.6%) and lung (30.8%). Grade 3 and 4 toxicities associated with therapy were consistent with ERK inhibitors and included LFT elevation, hyponatremia, pruritis, amylase elevation, anemia and rash. The best response, per RECIST 1.1, was stable disease in 4 pts, and disease progression in 7 patients. Two patients were unevaluable for response due to withdrawal from study. Median time to progression was 2.0 months. There were eight deaths due to disease progression with a median overall survival of 6.9 months.
Conclusions: ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed were consistent with what would be expected with MAPK pathway inhibition.