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Published on: January 25, 2015
A Phase II Study of ERK Inhibition by Ulixertinib (BVD-523) in Metastatic Uveal Melanoma
Elizabeth I Buchbinder1,2,3, Justine V Cohen1,2,3, Giuseppe Tarantino1,2,3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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.
Materials 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 and an initial evaluation of efficacy after 13 patients.
Results:
From April 2018 to April 2019, 13 patients were enrolled. Patients 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 liver function test (LFT) elevation, hyponatremia, pruritis, amylase elevation, anemia, and rash. The best response, per RECIST 1.1, was stable disease in 4 patients, 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.
Significance:
Uveal melanoma is a difficult to treat disease with minimal therapy options. The majority of uveal melanomas have mutations in GNAQ or GNA11 leading to activation of the MAPK pathway. Efforts to target MEK in uveal melanoma has had mixed results. This phase II trial of ERK inhibition with BVD-523 examined the potential role of this agent in uveal melanoma therapy.
Insights
Ulixertinib (BVD-523) showed no efficacy in treating metastatic uveal melanoma. The ERK inhibitor did not demonstrate significant activity, and toxicities were consistent with MAPK pathway inhibition.
Area of Science:
- Oncology
- Melanoma Research
- Molecular Targeted Therapy
Background:
- Uveal melanoma is a rare, aggressive cancer with limited treatment options.
- Mutations in GNAQ or GNA11 drive MAPK pathway activation in over 80% of uveal melanomas.
- Ulixertinib (BVD-523) is an ERK1/2 inhibitor investigated for its therapeutic potential.
Purpose of the Study:
- To evaluate the efficacy and safety of ulixertinib (BVD-523) in patients with metastatic uveal melanoma.
- To assess the role of ERK inhibition in a patient population with GNAQ/GNA11-driven disease.
Main Methods:
- A Phase II, Simon two-stage study design was employed.
- 13 patients with metastatic uveal melanoma were initially enrolled and evaluated.
- Treatment involved ulixertinib (BVD-523), an ERK1/2 inhibitor.
Main Results:
- No objective responses were observed; best response was stable disease in 4 patients.
- Median time to progression was 2.0 months, with 7 patients experiencing disease progression.
- Median overall survival was 6.9 months, with 8 deaths due to disease progression.
Conclusions:
- Ulixertinib (BVD-523) did not demonstrate clinical activity in metastatic uveal melanoma.
- Observed toxicities were consistent with known side effects of ERK inhibitors.
- Targeting the MAPK pathway via ERK inhibition may not be an effective strategy for this patient group.
