Darovasertib plus crizotinib more than doubles progression-free survival in HLA-A*02:01-negative metastatic uveal melanoma

Late-breaking ASCO 2026 data offer hope for a patients with HLA-A*02:01-negative metastatic uveal melanoma

ASCO 2026 delivered a wealth of late-breaking data across oncology, including several studies of interest to ophthalmologists. Among them was the phase 2/3 OptimUM-02 trial, which reported promising results for darovasertib plus crizotinib in patients with HLA-A*02:01-negative metastatic uveal melanoma. The findings address a significant unmet need in a disease where treatment options remain limited and outcomes are often poor once metastases develop. Although metastatic uveal melanoma is typically managed by multidisciplinary oncology teams, these findings are relevant to ophthalmologists involved in the diagnosis, long-term follow-up and referral of patients with this rare ocular malignancy.

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What did the study explore?

Uveal melanoma is the most common ocular cancer in adults, and up to 50% of patients develop metastases, which are associated with high mortality. While tebentafusp has changed the treatment landscape for patients with HLA-A02:01-positive disease, there are currently no FDA-approved systemic treatments for patients with HLA-A02:01-negative metastatic uveal melanoma, leaving a substantial group of patients with limited options.

The OptimUM-02 study investigated whether a combination of darovasertib, a first-in-class oral protein kinase C inhibitor, and crizotinib, a MET inhibitor, could improve outcomes in this patient population. The approach builds on encouraging clinical outcomes reported in a prior phase 1/2 study of the combination.

The open-label, nested phase 2/3 trial enrolled treatment-naïve patients with HLA-A*02:01-negative metastatic uveal melanoma. Patients were randomized 2:1 to receive darovasertib 300 mg plus crizotinib 200 mg twice daily or investigator’s choice of treatment, which included pembrolizumab, ipilimumab plus nivolumab or dacarbazine. Progression-free survival by RECIST, assessed by blinded independent central review, was the primary efficacy endpoint for the phase 2 portion of the study.

What does the data show?

Overall, 338 patients received at least one dose of study treatment and 313 comprised the efficacy population. Median progression-free survival by blinded independent central review was 6.9 months with darovasertib plus crizotinib compared with 3.1 months with investigator’s choice, representing a 58% reduction in the risk of disease progression or death (HR 0.42; p<0.0001).

Investigator-assessed progression-free survival was also improved, at 6.7 months versus 2.7 months, respectively (HR 0.36; p<0.0001). Response outcomes also favoured the combination. Objective response rate by blinded independent central review was 37.1% with darovasertib plus crizotinib compared with 5.8% with investigator’s choice, while disease control rates were 73.3% and 31.1%, respectively. Median duration of response was 6.8 months with darovasertib plus crizotinib and was non-evaluable in the investigator’s choice arm.

Preliminary overall survival was also reported to be trending favourably, although overall survival data remain immature and will be presented as they mature.

The most common treatment-emergent adverse events with darovasertib plus crizotinib were diarrhoea, nausea, peripheral oedema and vomiting. The most common grade 3 or 4 adverse events in the combination arm were diarrhoea and syncope. Treatment-related serious adverse events occurred in 9.2% of patients receiving darovasertib plus crizotinib and 25.3% of those receiving investigator’s choice treatment. One treatment-related fatal adverse event occurred in each arm.

What is the key clinical takeaway?

Darovasertib plus crizotinib significantly improved progression-free survival, objective response rate and disease control rate compared with investigator’s choice treatment in the first-line setting for patients with HLA-A*02:01-negative metastatic uveal melanoma. With no FDA-approved systemic treatments currently available for this population, the OptimUM-02 results support the combination as a potential new therapeutic standard for a disease with limited treatment options and poor prognosis.

Reference: Orloff MM, et al. Darovasertib plus crizotinib versus investigator’s choice as first-line treatment for patients with HLA-A2-negative metastatic uveal melanoma: Primary results from the OptimUM-02 trial. Presented at: ASCO Annual Meeting 2026, Chicago, IL, USA, June 1, 2026. Abstr LBA9503.