Darovasertib Plus Crizotinib Demonstrates Significant Clinical Benefit in First-Line HLA-A*02:01-Negative Metastatic Uveal Melanoma: Primary Results from the Registrational Phase 2/3 OptimUM-02 Trial

Metastatic uveal melanoma (mUM) is a rare but highly aggressive intraocular malignancy in adults, accounting for approximately 3-5% of all melanoma cases, with about 1,500 to 1,700 Americans diagnosed annually. Globally, approximately 30% to 50% of patients will eventually develop metastatic disease, primarily spreading to the liver. The annual incidence of uveal melanoma in Western populations is around 5–7 cases per million, with roughly half of patients ultimately developing metastatic disease, most commonly to the liver.[1]. Uveal melanoma arises from melanocytes within the uveal tract of the eye, and while the disease is often diagnosed at an early stage, local treatment modalities come with significant visual morbidity, and metastatic progression is not uncommon.[2]

Once metastasis occurs, the prognosis is poor, with median overall survival typically ranging from 6 to 12 months. Quality of life is often severely impacted due to the rapid progression of disease, liver dysfunction, and the limited effectiveness of available treatments. Standard treatment options for mUM have historically included systemic chemotherapy, liver-directed therapies, and immune checkpoint inhibitors, but these approaches provide only modest benefit for most patients.[2]

Unlike cutaneous melanoma, uveal melanoma is genetically distinct, with a small number of alterations and a low mutational burden, making it less responsive to immunotherapies that have transformed the care of cutaneous melanoma. Immune checkpoint inhibitors provide limited benefit and can result in serious immune-related adverse events.[2]]3][4]

Tebentafusp (Kimmtrak®; Immunocore), a bispecific fusion protein, has demonstrated a survival advantage in randomized trials but is approved only for HLA-A*02:01-positive patients and has a modest response rate. As a result, patients with HLA-A*02:01-negative mUM have no US Food and Drug Administration (FDA) approved systemic options, and management often relies on liver-directed therapies, which are palliative. These limitations underscore the urgent unmet medical need for effective systemic treatments for this underserved patient group. [1][2][3][4]

Study Design and Methods
The OptimUM-02 trial (NCT05987332) is a global, multicenter, open-label, registrational Phase 2/3 study evaluating the efficacy and safety of darovasertib*, a novel, oral, first-in-class protein kinase C (PKC) inhibitor also known as IDE196, in combination with crizotinib (Xalkori®; Pfizer), a MET inhibitor, versus the investigator’s choice of therapy (ICT) in first-line HLA-A*02:01-negative metastatic uveal melanoma. investigator’s choice of therapy comprised current standard options, including anti-PD-1 monotherapy pembrolizumab (Keytruda®, Merck & Co/MSD), combination checkpoint blockade, ipilimumab (Yervoy®, Bristol-Myers Squibb) plus nivolumab (Opdivo®; Bristol-Myers Squibb), and dacarbazine (DTIC-Dome; Dome Laboratories, a division of Bayer; Generic)[5][6]

A total of 313 patients were randomized 2:1 to receive darovasertib plus crizotinib or ICT. The primary endpoint for Phase 2 was progression-free survival (PFS) by blinded independent central review (BICR), with secondary endpoints including investigator-assessed PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety. Efficacy data were analyzed as of January 23, 2026.

Progression-Free Survival
The study met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in median PFS for the darovasertib combination arm:

• Median PFS by BICR was 6.9 months (95% CI: 5.6, 8.3) with darovasertib plus crizotinib, compared to 3.1 months (95% CI: 1.8, 4.2) for ICT (Hazard Ratio [HR]: 0.42, 95% CI: 0.30, 0.59; p<0.0001).
• Median PFS by investigator assessment was 6.7 months versus 2.7 months, respectively (HR: 0.36; 95% CI: 0.26, 0.50; p<0.0001).

The darovasertib combination reduced the risk of disease progression by 58% (BICR) and 64% (investigator assessment) relative to ICT. Subgroup analyses confirmed consistent benefit across age, gender, immune therapy type, LDH stratification, ECOG status, and metastatic site.

Objective Response Rate and Disease Control Rate

• ORR by BICR was 37.1% (78/210) with darovasertib plus crizotinib, compared to 5.8% (6/103) for ICT (p<0.0001).
• ORR by investigator assessment was 39.5% versus 1.9%, respectively.
• DCR by BICR was 73.3% (154/210) for the combination, versus 31.1% (32/103) for ICT.
• DCR by investigator assessment was 74.3% versus 27.2%.
• Median response duration was 6.8 months (BICR and investigator), with a median follow-up of 7.4 months.

Overall Survival
At the data cutoff, overall survival data remained immature, but early trends favored the darovasertib combination arm. OS will be evaluated in a pre-specified interim analysis and is the primary endpoint for the Phase 3 portion.[5][6]

Safety Profile
The darovasertib plus crizotinib regimen demonstrated a manageable safety profile. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 40.6% of patients in the combination arm versus 37.0% with ICT. The incidence of treatment-related serious adverse events (TR-SAEs) was notably lower in the combination arm (9.2%) compared to ICT (25.0%). Discontinuations due to TRAEs were infrequent: 2.5% for darovasertib and 10.0% for crizotinib, versus 19.0% for ICT. The most common Grade 3/4 TRAEs in the combination arm were diarrhea (10.0%), syncope (7.1%), and hypotension (3.8%).[5][6]

Significant advancement
These results mark a significant advancement for HLA-A*02:01-negative mUM, a population with historically limited treatment options and poor survival. The combination of darovasertib and crizotinib achieved robust, statistically significant improvements in PFS, ORR, and DCR compared to contemporary ICT, most of which included ipilimumab plus nivolumab. The observed benefit was consistent across all key subgroups and accompanied by a manageable safety profile, supporting the potential of this regimen as a new therapeutic standard.

The FDA is reviewing the new drug application for darovasertib plus crizotinib under the Real-Time Oncology Review (RTOR) program, with a full submission anticipated in the second half of 2026. Mature OS data are awaited and will be critical for potential full approval.

Darovasertib in combination with crizotinib represents the first targeted regimen to deliver significant clinical benefit in first-line HLA-A*02:01-negative mUM. The OptimUM-02 trial results support this novel combination as a promising new standard of care, addressing an urgent unmet need in this aggressive malignancy.[5][6]

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Note:* Darovasertib has received US FDA Breakthrough Therapy Designation as neoadjuvant therapy in enucleation-recommended primary uveal melanoma and Fast Track designation for darovasertib in combination with crizotinib in adult patients with metastatic uveal melanoma. Darovasertib has also been designated as an Orphan Drug by the US FDA in uveal melanoma, including in metastatic uveal melanoma.

Clinical trials
IDE196 (Darovasertib) in Combination With Crizotinib as First-line Therapy in Metastatic Uveal Melanoma – ClinicalTrials.gov ID NCT05987332

Highlights of Prescribing information
Crizotinib (Xalkori®; Pfizer)[Prescribing Information]
Tebentafusp (Kimmtrak®; Immunocore)[Prescribing Information]
Pembrolizumab (Keytruda®, Merck & Co/MSD)[Prescribing Information]
Ipilimumab (Yervoy®, Bristol-Myers Squibb)[Prescribing Information]
Nivolumab (Opdivo®; Bristol-Myers Squibb)[Prescribing Information]
Dacarbazine (DTIC-Dome; Dome Laboratories, a division of Bayer; Generic)[Prescribing Information]

References
[1] Eye Cancer (Ocular Melanoma). American cancer Society (ACS). Online. Last accessed on June 1, 2026.
[2] Krantz BA, Dave N, Komatsubara KM, Marr BP, Carvajal RD. Uveal melanoma: epidemiology, etiology, and treatment of primary disease. Clin Ophthalmol. 2017 Jan 31;11:279-289. doi: 10.2147/OPTH.S89591. PMID: 28203054; PMCID: PMC5298817.
[3] Koch EAT, Heppt MV, Berking C. The Current State of Systemic Therapy of Metastatic Uveal Melanoma. Am J Clin Dermatol. 2024 Sep;25(5):691-700. doi: 10.1007/s40257-024-00872-1. Epub 2024 Jun 22. PMID: 38907174; PMCID: PMC11358228.
[4] Piperno-Neumann S. Uveal Melanoma: Changing Paradigms of Treatment. Ocul Oncol Pathol. 2025 Dec 11. doi: 10.1159/000549994. Epub ahead of print. PMID: 41798271; PMCID: PMC12962742.
[5] Cao L, Chen S, Sun R, Ashby CR Jr, Wei L, Huang Z, Chen ZS. Darovasertib, a novel treatment for metastatic uveal melanoma. Front Pharmacol. 2023 Jul 28;14:1232787. doi: 10.3389/fphar.2023.1232787. PMID: 37576814; PMCID: PMC10419210.
[6] Orloff MM, Ramelyte E, Butler MO, et al. Darovasertib plus crizotinib vs investigator’s choice as first-line treatment for patients with HLA-A2 negative metastatic uveal melanoma: primary results from the OptimUM-02 trial. J Clin Oncol. 2026;44(suppl 17):abstr LBA9503. doi:10.1200/JCO.2026.44.17_suppl.LBA9503

Featured image: Chicago, IL – McCormick Place – 2023 ASCO Annual Meeting – during the 2023 59th ASCO Annual Meeting. Photo courtesy © 2023 – 2026 ASCO/Scott Morgan.

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