Darovasertib/Crizotinib Meets PFS End Point in Metastatic Uveal Melanoma

Darovasertib plus crizotinib (Xalkori) demonstrated a statistically significant improvement in the median progression-free survival (PFS) compared with investigator’s choice of therapy (ICT) for patients with first-line HLA-A*A2:01-negative metastatic uveal melanoma, according to results from the phase 2/3 OptimUM-02 trial (NCT05987332).

Darovasertib Plus Crizotinib Efficacy

The median PFS was 6.9 months in the combination arm vs 3.1 months in the ICT arm (HR, 0.42; 95% CI, 0.30-0.59; P <.0001), showing a 58% reduction in the risk of disease progression. Additionally, the overall response rate (ORR) was 37.1% in the combination arm, with 5 complete responses (CR) by BICR compared with 5.8% in the ICT arm (P <.0001), which had no CRs. In the darovasertib plus crizotinib arm, the median duration of response (DOR) was 6.8 months.

Currently, the overall survival (OS) data are not mature, but the press release noted there was an early trend in improvement in the combination arm compared with the ICT arm.

In the second half of 2026, a new drug application is planned to be submitted based on additional details from the OptimUM-02 trial that will be presented at an upcoming medical meeting.

"Metastatic uveal melanoma is an area of high unmet medical need with poor prognosis and short [OS], and there are currently no approved therapies for HLA-A*02:01-negative patients with [metastatic uveal melanoma]. The data from the OptimUM-02 study provides potential practice changing results for the treatment of first-line metastatic uveal melanoma," Meredith McKean, MD, MPH, director of the Melanoma and Skin Cancer Research Program at Sarah Cannon Research Institute, said in the press release.¹

OptimUM-02 Trial Design

A total of 420 patients is estimated to be enrolled in this trial and will receive either the treatment combination or ICT, which includes pembrolizumab (Keytruda), ipilimumab (Yervoy) plus nivolumab (Opdivo), or dacarbazine.²

The phase 2 primary end point was PFS, which has been met, and in phase 3, it was OS. Secondary end points included safety, ORR, DOR, and disease control rate.

Patients were enrolled if they had histologically or cytologically confirmed metastatic uveal melanoma, were HLA-A*02:01 negative, had no prior systemic therapy, had measurable disease per RECIST 1.1 guidelines, and could safely receive and absorb the study therapy.

Patients were excluded if they had previous treatment with a PKC inhibitor, an inhibitor directly targeting MET, or an inhibitor directly targeting GNAQ/11; concurrent malignant disease; adverse effects from prior anti-cancer therapy that was not resolved as grade 1 or higher; or symptomatic or untreated central nervous system (CNS) metastases, or CNS metastases that require corticosteroids.

OptimUM-01 Trial Results

In October 2025, results from the phase 1/2 OptimUM-01 trial (NCT03947385) were presented at the 2025 Society for Melanoma Research Congress.³ The median OS was 21.1 months (95% CI, 12.5-27.1) in the darovasertib and crizotinib arm vs 10 to 12 months with historical controls. The median PFS was 7.0 months (95% CI, 3.8-7.7) vs 2.8 months (95% CI, 2.7-3.4).

The ORR was 34.1% (95% CI, 20.1%-50.6%) in the darovasertib and crizotinib arm, with 56.1% of patients having stable disease and 9.8% experiencing disease progression. The median DOR was 9.0 months (95% CI, 3.8-12.0), and the disease control rate was 90.2% (95% CI, 76.9%-97.3%). Of note, 85% of patients had a reduction in target lesions.

The most common treatment-related adverse effects included diarrhea (all grades, 90.9%; grade 3 or higher, 2.3%), nausea (79.5%; 0%), peripheral edema (61.4%; 0%), vomiting (47.7%; 0%), dermatitis acneiform (43.2%; 0%), hypoalbuminemia (43.2%; 2.3%), and fatigue (38.6%; 0%).

References

1. IDEAYA Biosciences and Servier announce positive topline results from phase 2/3 registrational trial (OptimUM-02) of darovasertib in combination with crizotinib in first-line HLA-A*02:01-negative metastatic uveal melanoma. News release. April 13, 2026. Accessed April 13, 2026. https://tinyurl.com/ycy7vt4k
2. IDE196 (Darovasertib) in combination with crizotinib as first-line therapy in metastatic uveal melanoma. ClinicalTrials.gov. Updated February 17, 2026. Accessed April 13, 2026. https://tinyurl.com/bddub3rx
3. McKean M, Chmielowski B, Butler MO, et al. First reported overall survival results from a phase 1/2 study of darovasertib plus crizotinib as first-line treatment for metastatic uveal melanoma (OptimUM-01). Presented at: 2025 Society for Melanoma Research Congress; October 25-27, 2025; Erlangen, Germany.