A combination of two protein kinase inhibitors that has shown promise in patients with metastatic uveal melanoma is being evaluated in a phase 2/3 clinical trial at Roswell Park Comprehensive Cancer Center. The study builds on the results of a previous phase 2 clinical trial showing that the dual therapy of darovasertib (IDE196) and crizotinib (Xalkori) resulted in a disease-control rate of 90% in 20 patients who received it as a first-line therapy. Even among 63 patients who received the treatment in any line, the regimen achieved a disease-control rate of 87% (55 patients).
Benjamin Switzer, DO, MHSA, MS,
Assistant Professor of Oncology
Those numbers offer a ray of hope for patients diagnosed with this rare cancer, particularly for those with an HLA-A*02-01-negative genetic subtype. They face a grim five-year survival rate of approximately 16%.
Benjamin Switzer, DO, MHSA, MS, Assistant Professor of Oncology in the Department of Medicine at Roswell Park, serves as Site Principal Investigator for the clinical trial, “IDE196 (Darovasertib) in Combination with Crizotinib as First-Line Therapy in Metastatic Uveal Melanoma” (NCT05987332), sponsored by IDEAYA Biosciences.
About 90% of patients with metastatic uveal melanoma have a genetic mutation in GNAQ/GNA11 genes that is hypothesized to cause increased activity of protein kinase C (PKC), which is found on the surface of uveal melanoma cells. Darovasertib works by blocking PKC, which prevents the cancer cells from growing and migrating. Crizotinib functions similarly by inhibiting the c-Met receptor tyrosine kinase.
“Early signals of this combination therapy indicate that it is well-tolerated while offering a novel and synergistic treatment approach that focuses on the biology of advanced HLA-A*02-01-negative uveal melanoma,” says Dr. Switzer. “Currently there is no widely accepted standard of care for this diagnosis, so we are very excited to offer this new treatment option to our patients.”
This study will first establish the optimal dose of the dual therapy and then compare its effectiveness against the investigator’s choice of the immune checkpoint inhibitor pembrolizumab (Keytruda); a combination of the immune checkpoint inhibitors ipilimumab (Yervoy) plus nivolumab (Opdivo); or the chemotherapy dacarbazine (DTIC-Dome).
Investigators will primarily evaluate progression-free and overall survival achieved with the dual therapy vs. the investigator’s choice of treatment. Secondarily, it will focus on the safety, tolerability and pharmacokinetics of the combination therapy as well as the dose-exposure relationship and anti-tumor activity.
Worldwide, uveal melanoma affects about 7,000 people annually. The multi-center study aims to enroll 420 patients across 13 countries.
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