Results for darovasertib in combination with crizotinib in first line HLA*A2:01-negative metastatic uveal melanoma met the study’s primary objective 

Data for darovasertib in combination with crizotinib presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago in first line metastatic uveal melanoma support a potential future targeted treatment option in a challenging patient population. Unfortunately, at this time there are no approved therapies for patients with HLA-A*02:0-negative disease. 

HLA-A*02:01 status is an important biomarker in uveal melanoma. Biomarkers are genes or other substances that show important details about a person’s cancer or cancer risk. Approximately 45% to 50% of patients with uveal melanoma carry this genetic subtype, which makes them eligible for treatment with tebentafusp (Kimmtrak), the first targeted therapy shown to significantly improve overall survival in unresectable or metastatic uveal melanoma. The other 50-55% of patients are not eligible for this treatment.  

Darovasertib is an oral inhibitor of protein kinase C. Mutations that activate protein kinase C are found in more than 95% of uveal melanomas, and this activation causes tumors to grow. Crizotinib is an oral inhibitor of the cMET pathway, which is believed to have a role in metastasis to the liver. 

In total, 313 patients with 1L HLA*A2:01-negative metastatic uveal melanoma in the Phase 2/3 OptimUM-02 trial received either darovasertib plus crizotinib or an investigator’s choice of therapy that included ipilimumab (Yervoy) plus nivolumab (Opdivo) (anti-CTLA-4/PD-1) or pembrolizumab (Keytruda) (anti-PD-1) alone.   

The results showed that the main goals of the study were met. Median progression free survival (the point when half of patients experienced disease progression or death) was 6.9 months with darovasertib plus crizotinib and 3.1 months with investigator’s choice of therapy, and there was a 58% reduction in risk of disease progression. The overall response rate (percentage of patients in a treatment group whose cancer shrinks or disappears after treatment) was 37.1% compared to 5.8% with investigator’s choice of therapy, and the disease control rate (the combination of responses and stable disease) was 73.3% compared to 31.1% with investigator’s choice of therapy. 

Darovasertib plus crizotinib was also well-tolerated with a manageable safety profile consistent with previous results and known side-effects of each therapy alone. 

The results of this trial suggest that darovasertib plus crizotinib may become a new standard of care for patients with metastatic uveal melanoma. It was noted that this combination therapy may also be an option for select patients who have HLA*A2:01-positive disease.