Darovasertib Shows Encouraging Activity in Metastatic Uveal Melanoma

Darovasertib (IDE196), both as a single agent and in combination with binimetinib (Mektovi), has demonstrated promising early activity in patients with metastatic uveal melanoma, according to preliminary data from an ongoing phase 1/2 trial (NCT03947385).¹

Single-agent darovasertib resulted in a 1-year overall survival (OS) rate of 57% (95% CI, 44%-69%) in heavily pretreated patients with metastatic uveal melanoma who received the agent as second- or third-line treatment. The historical 1-year OS rate in similar patient populations is 37%, according to IDEAYA Biosciences, Inc. The median OS in these patients was 13.2 months (95% CI, 10.7–not reached) with darovasertib vs a historical median OS of about 7.0 months.

Moreover, 61% of evaluable patients with metastatic uveal melanoma (n = 46/75) experienced tumor reduction per RECIST v1.1 assessment; 20% (n = 15) of these patients reported a reduction in target lesion of 30% or more, with 1 confirmed complete response. Eighty percent of evaluable patients in the skin melanoma cohort of the trial (n = 4/5) experienced a reduction in tumor size per RECIST v1.1 evaluation; this included 1 confirmed partial response (PR).

“The darovasertib single-agent 1-year survival data in metastatic uveal melanoma are encouraging and compare 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 at Sarah Cannon Research Institute, stated in a press release.

Darovasertib, when paired with binimetinib, elicited 2 PRs in 9 patients with metastatic uveal melanoma who had at least 2 post-baseline scans in accordance with RECIST v1.1 guidelines; this comprised 1 confirmed PR and 1 unconfirmed PR (-40.5%) awaiting confirmation. Moreover, 79% of evaluable patients with metastatic uveal melanoma with at least 1 post-baseline scan experienced tumor reduction, although follow-up for overall response remains immature.

“The early PRs observed in the darovasertib and binimetinib combination in metastatic uveal melanoma 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 Precision Oncology and Systems Biology Program, director of Experimental Therapeutics and director of the Melanoma Service at Columbia University Irving Medical Center, added in the release.

In the multicenter, open-label basket trial, investigators set out to examine the safety and antitumor activity of IDE196 in patients with solid tumors that harbor GNAQ or GNA11 mutations or PRKC fusions, including metastatic uveal melanoma, cutaneous melanoma, colorectal cancer, and other solid tumors.²

To be eligible for enrollment, patients had to be at least 18 years of age, measurable disease, an ECOG performance status of 0 to 1, a life expectancy of more than 3 months, and acceptable organ function at screening. Additional inclusion criteria for the darovasertib/binimetinib combination were to have acceptable cardiac function represented by left ventricular ejection fraction of 50% or greater.

A total of 81 patients with metastatic uveal melanoma and 7 patients with skin melanoma were given darovasertib monotherapy twice daily were enrolled to the trial at the time of the data and analysis cutoff of April 13, 2021. Eighty-eight patients were determined to be evaluable for safety, while 81 were noted to be evaluable for efficacy, based on RECIST v1.1 criteria. The data reported are based on an unlocked database and investigators will continue to follow the monotherapy arm as the trial continues.

Twenty-four patients with metastatic uveal melanoma were enrolled to the combination study as of the April 13, 2021 data cutoff; this included 8 patients who were dosed in the expansion cohort of the combination study. Here, findings are also based on an unlocked database. Enrollment to this doublet arm is ongoing.

Regarding safety, the toxicity profile of single-agent darovasertib was found to be consistent with previous reports of the agent. Gastrointestinal toxicities are reported with the agent, as well as hypotension, although they are primarily low grade.

Treatment-related toxicities observed in patients with metastatic uveal melanoma who received darovasertib plus binimetinib comprised nausea, vomiting, diarrhea, rash, edema, increased liver enzymes, and hypotension, among others.

References

1. IDEAYA reports darovasertib (IDE196) monotherapy overall survival data and observes early partial responses in binimetinib combination in metastatic uveal melanoma. News release. April 16, 2021. Accessed April 19, 2021. https://bit.ly/3stVFq9
2. Study of IDE196 in patients with solid tumors harboring GNAQ/11 mutations or PRKC fusions. ClinicalTrials.gov. Updated February 17, 2021. Accessed April 19, 2021. https://clinicaltrials.gov/ct2/show/NCT03947385