Phase 1/2 trial of Darovasertib With or Without Binimetinib Is Feasible, Safe for Metastatic Uveal Melanoma

April 16, 2021
Audrey Sternberg

Darovasertib as monotherapy for the treatment for patients with heavily pretreated metastatic uveal melanoma induced responses and promising rates of overall survival, according to preliminary data from a phase 1/2 trial.

Treatment with the selective inhibitor of protein kinase C darovasertib (IDE196) as monotherapy in patients with heavily pretreated metastatic uveal melanoma (MUM) resulted in a 1-year overall survival (OS) rate of 57% (95% CI, 44%-69%), according to Ideaya Biosciences, Inc. who is responsible for developing the agent.

Clinical data released from the phase 1/2 trial (NCT03947385) also show the agent’s activity in combination with the MEK inhibitor binimetinib (Mektovi), which was able to induce responses in certain patients.

“The darovasertib single-agent 1-year survival data in MUM is encouraging and compares favorably to historical survival rates in this indication, where a therapy has yet to be approved,” Meredith McKean, MD, MPH, associate director of Melanoma and Skin Cancer Research for Sarah Cannon Research Institute at Tennessee Oncology in Nashville, Tennessee, said in a press release.

In total, 81 patients with MUM and 7 patients with skin melanoma were enrolled to the monotherapy arm. The safety population was comprised of 88 patients, with 81 evaluable for efficacy. The reported data are considered preliminary and follow-up to the monotherapy portion of the trial remains ongoing. The safety profile of the monotherapy was consistent with prior reports and included mostly low-grade gastrointestinal events and hypotension.

The OS rate at 1 year was derived from a patient population who were in predominantly their second or third line of therapy, with some patients having received as many as 7 or 8 prior lines of treatment. This compared favorably with historical data in this group of patients with MUM who have a 1-year survival rate of 37%. The median OS in this group was 13.2 month (95% CI, 10.7-not reached), which surpasses historical data at approximately 7 months.

Out of 75 patients evaluable for response, 46 (61%) had a reduction in their tumor size per RECIST 1.1 including 15 (50%) with 30% or greater reduction in their target lesion and 1 confirmed complete response. In skin melanoma, 80% of 5 evaluable patients had tumor reduction per RECIST 1.1, which included 1 partial response.

For the combination with binimetinib, 24 patients had been enrolled at the data cutoff of April 13, 2021 including 8 who were treated in the dose-expansion cohort of the study. Out of 9 patients with MUM, there was 1 confirmed and 1 unconfirmed partial response in those with at least 2 post-baseline scans (22%) per RECIST 1.1. In patients with at least 1 post-baseline scan, 79% showed reduction in their tumor size.

Treatment-related adverse events with the combination occurring in more than 10% of population included nausea, vomiting, diarrhea, rash, edema, aspartate aminotransferase/alanine aminotransferase increase, and creatinine kinase increase.

“The early partial responses observed in the darovasertib and binimetinib combination in MUM are exciting where historical response rates have been from 0 to low-to-mid, single-digit percent, and we look forward to seeing the data set mature,” Richard Carvajal, MD, co-leader of the Precision Oncology and Systems Biology Program and director of Experimental Therapeutics and of the Melanoma Service at Columbia University Irving Medical Center, said in a press release.

In addition to the above trial, a separate clinical trial with darovasertib plus crizotinib (Xalkori) is being performed in patients with MUM.

Reference

IDEAYA reports darovasertib (IDE196) monotherapy overall survival data and observes early partial responses in binimetinib combination in metastatic uveal melanoma. News release. Ideaya Biosciences, Inc. April 16, 2021. Accessed April 16, 2021. https://bit.ly/3siPULO