IDEAYA Biosciences (Nasdaq: IDYA) and Servier reported that darovasertib plus crizotinib met the primary endpoint in the Phase II/III OptimUM-02 trial. The treatment - a combination of a PKC inhibitor and a MET/ALK/ROS1 inhibitor - was found to cut the risk of progression by 58% versus investigator choice of therapy in first-line HLA-A*02:01-negative metastatic uveal melanoma. The two firms are now planning to make a New Drug Application (NDA) filing for the indication, which currently has no FDA-approved systemic treatment option, in the second half of the year.
Trial specifics
OptimUM-02 is a global, randomized Phase II/III registrational trial enrolling patients with first-line HLA-A*02:01-negative metastatic uveal melanoma. The topline analysis covered 313 patients from the Phase IIb/III portion, with a data cutoff of January 23, 2026.
The darovasertib combination produced a median progression-free survival of 6.9 months by blinded independent central review versus 3.1 months for the investigator choice arm (HR: 0.42; 95% CI: 0.30–0.59; p<0.0001). The objective response rate by BICR was 37.1% versus 5.8% (p<0.0001), with five complete responses in the combination arm and none in the comparator arm. Overall survival data remain immature, though the company reported an early directional trend favoring the combination. Grade 3 or higher treatment-emergent adverse events included diarrhea, syncope, and hypotension; the treatment-related serious adverse event rate was in the single-digit percent range.
The comparator arm reflected real-world clinical practice: 76% of the 103 patients assigned to investigator choice received ipilimumab plus nivolumab, and 24% received pembrolizumab. Neither checkpoint regimen carries an FDA approval specifically for uveal melanoma, and the 5.8% response rate observed in OptimUM-02 is consistent with the historically poor activity of PD-1 and CTLA-4 blockade in this disease. The gap between arms — roughly a sixfold difference in response rate — reflects the mechanistic mismatch between checkpoint inhibition and a tumor type driven by constitutively active GNAQ/GNA11 mutations rather than high mutational burden or PD-L1 expression.
Uveal melanoma is biologically distinct from cutaneous melanoma. Approximately 95% of cases harbor activating mutations in GNAQ or GNA11, which drive downstream protein kinase C signaling and tumor proliferation independent of the MAPK pathway alterations that define most cutaneous disease. Darovasertib is a PKC inhibitor developed to suppress that signaling; crizotinib, a MET/ALK/ROS1 kinase inhibitor approved in other oncology settings, is combined with darovasertib based on preclinical and early clinical evidence suggesting complementary activity. The rationale for the combination, and early data supporting it, have been described in the published literature.
The HLA-A02:01 stratification is central to understanding where this combination fits in the treatment landscape. The only FDA-approved uveal melanoma-specific therapy, tebentafusp (Kimmtrak, Immunocore), is a bispecific T-cell engager that requires HLA-A02:01 expression for activity and is approved exclusively in HLA-positive patients. That population represents roughly 30–50% of metastatic uveal melanoma cases. The HLA-A*02:01-negative majority — estimated at 50–70% of patients — has no approved targeted option. OptimUM-02 was designed specifically for that unserved group, and the comparator arm's 3.1-month median PFS underscores the scale of the gap darovasertib is attempting to fill.