Approximately 5% of cutaneous melanoma patients harbor a GNAQ/11 mutation.

IDEAYA Biosciences, Inc. is initiating of a Phase 2 expansion of the darovasertib and crizotinib combination in GNAQ/11 metastatic cutaneous melanoma. 

There are currently no U.S Food and Drug Administration-approved therapies for this genetically-defined patient population. Darovasertib (IDE196) is a potent, selective small molecule inhibitor of protein kinase C (PKC). 

"The clinical efficacy observed in a GNAQ melanoma patient that progressed on immune checkpoint inhibitor therapies and treated in our clinic has been durable and well tolerated. This is a very important finding in this biomarker defined population," says Marcus Butler, MD, Medical Oncologist, Tumor Immunotherapy Program, Melanoma/Skin Oncology Site Lead at Princess Margaret Cancer Centre in Toronto, Canada, and Ocular Melanoma Physician Task Force of Canada Co-Lead, in a news release.

The Phase 2 darovasertib and crizotinib combination expansion is based on preliminary clinical efficacy observed in the GNAQ/11 metastatic cutaneous melanoma setting. Mutations in GNAQ or GNA11 (GNAQ/11) have been identified in approximately 90% of patients with metastatic uveal melanoma. These mutations are associated with activation of signaling pathways, including oncogenic RAS/RAF/MEK/ERK via PKC activation, driving tumor progression. 

The GNAQ/11 prevalence in cutaneous melanoma has been reported at approximately 5% in The Cancer Genome Atlas. 

The GNAQ/11 cutaneous melanoma estimated annual incidence is approximately 5,000 patients in the US and 8,000 patients in the EU28, and the estimated total prevalence of GNAQ/11 cutaneous melanoma is approximately 70,000 patients in the US and 110,000 patients in the EU28. It has been reported that approximately 12.5% to 15% of cutaneous melanoma patients have been reported to develop metastatic disease, whereas in uveal melanoma, a predominantly GNAQ/11 mediated cancer, the metastatic rate has been reported at approximately 50%. In addition, based on several metastatic cancer patient databases, including Memorial Sloan Kettering Cancer Center (MSKCC) Impact, we project GNAQ/11 metastatic cutaneous melanoma has the potential to double or more the annual addressable metastatic patient population of metastatic uveal melanoma alone. In addition, GNAQ/11 mutation patients are known to have low tumor mutational burden making these patients less likely to benefit from immune checkpoint inhibitor therapies.