Early Efficacy of Darovasertib +/- Binimetinib Better Than Historical Controls for Metastatic Uveal Melanoma

Darovasertib (IDE196), a selective protein kinase C inhibitor, demonstrated promising response rates, survival, and reduction in tumor size as treatment of patients with metastatic uveal melanoma (MUM) treatment both alone and in combination with binimetinib (Mektovi), according to preliminary results from a 7-armed phase 1/2 clinical trial (NCT03947385).

In a press release, IDEAYA Biosciences, Inc announced that 81 patients with MUM were evaluated in the darovasertib monotherapy twice daily arm of the study and evaluated for efficacy and safety. The coprimary end points of the ongoing study are dose-limiting toxicity (DLT), maximum-tolerated dose, recommended phase 2 dose, and plasma concentrations. The secondary end points included overall response rate, duration of response, disease control rate, and the number of patients with adverse events (AEs). Additional outcome measures include progression-free survival and overall survival (OS)

The treatment led to a 1-year OS rate of 57% (95% CI, 44%-69%) in patients who predominantly were on their second or third line of therapy. Some patients had as many as 8 lines of prior treatment. The historical 1-year OS rate for patients with MUM is 37%. The median OS observed with darovasertib was 13.2 months (95% CI, 10.7 months to not reached), compared with 7 months observed with historical controls.

Sixty-one percent of patients had a reduction in their tumor size out of 75 evaluable patients. Of those with tumor reduction, 20% had a ≥ 30% reduction in their target lesion, and there was one confirmed response to therapy in the study.

For the dose-expansion portion of the study, which is exploring darovasertib plus binimetinib as treatment of MUM, 24 patients have been enrolled in the study, thus far, and 8 have been dosed with the combination. The target enrollment in this cohort is 40 patients. Treatment-induced partial responses (PRs) were reported in 2 patients who had at least 2 post-baseline scans. One of the PRs was unconfirmed awaiting a confirmatory scan. Tumor reductions were observed in 79% of evaluable patients who had baseline scans. OS data are still immature in this cohort and were not reported.

Based on the activity seen with darovasertib/binimetinib so far in the trial, the doses of each drug in the combination have been decided and treatment will be expanded to a larger cohort of patients with MUM.

Safety was reported for the combination of darovasertib and binimetinib, showing treatment-related adverse events (TRAEs) in more than 10% of patients. TRAEs observed were nausea, vomiting, diarrhea, rash, edema, aspartate aminotransferase/alanine aminotransferase increase, and CK increase. In addition, less than 10% of patients in the cohort experienced hypotension.

The ongoing study will enroll an estimated 245 patients with MUM, advanced cutaneous melanoma, colorectal cancer, or other solid tumors who are at least 18 years of age or older. Treatment across the arms of the study include darovasertib monotherapy, darovasertib/binimetinib, and darovasertib/crizotinib (Xalkori), including in patients with non-MUM tumors harboring GNAQ or GNA11 mutations or PRKC fusions.

Patients are required to have measurable disease per RECIST v1.1 criteria, an ECOG performance status of at least 1, a life expectancy of at least 3 months, and adequate organ function at screening. To receive binimetinib in the study, additional criteria include adequate cardiac function represented by left ventricular ejection fraction ≥ 50%.

Patients were excluded from the study if they had another malignancy, received prior treatment with a PKC inhibitor, known microsatellite instability/mismatch repair deficient tumors who have not previously received immune checkpoint inhibitors, adverse events from prior anti-cancer therapy that have not resolved, untreated or symptomatic central nervous system metastases, human immunodeficiency virus, hepatitis B or C virus, recent surgery or radiotherapy, impaired cardiac function, or if they were pregnant or breastfeeding.

"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," said Meredith McKean, MD, MPH, associate director, Melanoma and Skin Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology, in a press release.

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

_Reference:

_{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 16, 2021. https://bit.ly/32mAEmE}