IDEAYA Reports Three-Trial Progress for Darovasertib in Uveal Melanoma

IDEAYA Biosciences and Servier announced updated data from three ongoing trials of darovasertib in uveal melanoma on October 19, 2026. The results, scheduled for presentation at the European Society for Medical Oncology (ESMO) Congress in Madrid, cover metastatic disease in HLA-A*02:01-positive and -negative patients and neoadjuvant treatment of primary tumors.

Darovasertib is an investigational oral protein kinase C (PKC) inhibitor designed to target signaling downstream of GNAQ and GNA11 mutations, which occur in nearly all uveal melanomas. It is being evaluated alone and with crizotinib, a c-MET inhibitor. Neither regimen is currently approved by the US Food and Drug Administration (FDA).

Three Trials, Different Clinical Questions

OptimUM-01 is a Phase 1/2 single-arm study evaluating darovasertib plus crizotinib in HLA-A02:01-positive metastatic uveal melanoma. OptimUM-02 is a randomized Phase 2/3 trial comparing the combination with investigator’s choice of therapy (ICT) in first-line HLA-A02:01-negative disease. OptimUM-09 is a Phase 2 study investigating single-agent darovasertib before local treatment of primary tumors.

Key Clinical Results

The three studies evaluated darovasertib across metastatic and primary uveal melanoma, with findings ranging from response activity after prior treatment to progression-free survival and potential eye preservation.

OptimUM-01: Darovasertib plus crizotinib in metastatic disease

• Treatment-naïve patients (n=13): The objective response rate (ORR) was 36.4% (4/11), with a disease control rate (DCR) of 90.9% (10/11). Median progression-free survival (PFS) was 7.4 months and median overall survival (OS) was 27.1 months.
• Patients previously treated with tebentafusp (n=15): ORR was 35.7% (5/14) and DCR was 85.7% (12/14). Median PFS was 5.7 months and median OS was 12.1 months.
• Overall population (n=101): ORR was 22.1% (19/86), DCR was 80.2% (69/86), median PFS was 5.4 months and median OS was 13.4 months. Response and disease control rates were calculated in 86 efficacy-evaluable patients.

OptimUM-02: First-line HLA-A*02:01-negative metastatic disease

• Median PFS by blinded independent central review: 6.9 months with darovasertib plus crizotinib versus 3.1 months with investigator’s choice of therapy (ICT).
• Median PFS by investigator assessment: 6.7 months versus 2.7 months, respectively.
• Additional subgroup analyses reportedly showed a consistent direction of benefit across baseline lactate dehydrogenase levels, ECOG performance status, lesion size and choice of ICT.

OptimUM-09: Neoadjuvant treatment of primary uveal melanoma

• Tumor shrinkage: Approximately 80% of patients experienced some shrinkage, while 57.8% (67/116) achieved at least 20% shrinkage.
• Eye preservation: The eye preservation rate was 57% in the cohort requiring enucleation.
• Radiation exposure: In the plaque brachytherapy cohort, 66% had a reduction in the planned radiation dose to critical eye structures.
• Metastasis-free status: Across both cohorts, 86.3% of patients were metastasis-free at 15 months.

The OptimUM-01 results reflect a March 23, 2026 data cutoff. OptimUM-09 figures are from the February 23, 2026 dataset of 116 patients; the ESMO poster is expected to include an updated dataset of 119 patients as of June 15, 2026.

Metastatic Disease: Evidence Varies by Trial Design

OptimUM-02 provides the strongest comparative evidence among the three updates. Its previously reported randomized results showed longer median PFS with darovasertib plus crizotinib than with ICT. The ESMO subgroup analyses reportedly showed consistent improvements in ORR and PFS across baseline lactate dehydrogenase levels, ECOG performance status, lesion size and choice of control therapy. Patients with higher tumor burden had poorer outcomes overall but still favored the combination.

OptimUM-01 adds evidence of activity in HLA-A*02:01-positive disease, including after tebentafusp. However, its single-arm design prevents direct comparisons with other treatments, while the small subgroups and wide confidence intervals limit the precision of the estimates. Findings across HLA groups also come from separate trials rather than a direct randomized comparison.

Neoadjuvant Treatment and Safety

In OptimUM-09, 66% of patients in the plaque brachytherapy cohort had a reduction in planned radiation dose to critical eye structures. Across both cohorts, 86.3% were metastasis-free at 15 months. These findings are encouraging, but the study does not establish that neoadjuvant treatment improves long-term vision or prevents metastasis compared with immediate local treatment.

Diarrhea (82%), nausea (76%), peripheral edema (70%) and vomiting (57%) were the most common treatment-related adverse events reported in OptimUM-01. Treatment-related adverse events led to discontinuation in 8.9% of patients. In OptimUM-09, treatment-related serious adverse events occurred in 6%, most commonly hypotension (3.4%); 9% discontinued treatment because of any adverse event.

Regulatory Outlook

IDEAYA expects to complete an NDA submission for darovasertib plus crizotinib in first-line metastatic uveal melanoma in the second half of 2026 under the FDA’s Real-Time Oncology Review program. The drug has received Fast Track designation for metastatic disease, Orphan Drug designation in primary uveal melanoma and Breakthrough Therapy designation for neoadjuvant treatment when enucleation has been recommended.

Clinical Interpretation

The findings support continued development of darovasertib, with OptimUM-02 providing the clearest comparative evidence in first-line HLA-A*02:01-negative metastatic disease. OptimUM-01 broadens the evidence of activity but remains limited by its single-arm design, while OptimUM-09 raises the possibility of preserving the eye in some patients before local treatment. Mature survival data, longer follow-up, quality-of-life outcomes and randomized neoadjuvant evidence are needed to establish the broader clinical benefit. Darovasertib remains investigational pending regulatory review.

Reference

IDEAYA Biosciences and Servier Announce Data from Three Clinical Trials at ESMO 2026 Supporting the Potential of Darovasertib to Become a Foundational New Therapy for Patients Across the Treatment Journey of Uveal Melanoma, IDEAYA Bioscience, 19 October 2026

Study of IDE196 in Patients with Solid Tumors Harboring GNAQ/​11 Mutations or PRKC Fusions, ClinicalTrials.gov ID NCT03947385

IDE196 (Darovasertib) in Combination with Crizotinib as First-line Therapy in Metastatic Uveal Melanoma, ClinicalTrials.gov ID NCT05987332

(Neo)Adjuvant IDE196 (Darovasertib) in Patients with Localized Ocular Melanoma, ClinicalTrials.gov ID NCT05907954