Darovasertib-Crizotinib Improves PFS in Metastatic Uveal Melanoma

The combination of darovasertib (IDE196) plus crizotinib (Xalkori) significantly improved progression-free survival (PFS) compared with investigator's choice of therapy (ICT) in patients with first-line HLA-A*02:01–negative metastatic uveal melanoma (mUM), according to topline data reported in a news release.¹

The phase 2/3 OptimUM-02 registrational trial (NCT05987332) met its primary end point with a median PFS of 6.9 months in the darovasertib combination arm vs 3.1 months with investigator’s choice of therapy (ICT), a 58% reduction in risk of progression or death (HR, 0.42; 95% CI, 0.30-0.59; P <.0001). The overall response rate (ORR) by blinded independent central review (BICR) was 37.1% vs 5.8% in favor of the combination (P <.0001), including 5 complete responses in the darovasertib arm and none in the ICT arm.

Disease Background and Unmet Need

Uveal melanoma is a rare and aggressive ocular malignancy affecting more than 3000 patients annually in the United States and more than 10,000 globally.^1,2 Approximately 50% of patients progress to metastatic disease, at which point prognosis is poor, with a median overall survival (OS) of 10 to 12 months and a 5-year survival rate of 15% to 20%. Liver metastases occur in approximately 90% of cases.

Currently, there are no FDA-approved systemic therapies for patients with HLA-A*02:01–negative mUM, who represent an estimated 50% to 70% of the metastatic uveal melanoma population. The only approved systemic therapy for mUM, tebentafusp-tebn (Kimmtrak), is restricted to HLA-A*02:01–positive patients, leaving the majority of patients without an approved treatment option. Existing approaches, including off-label checkpoint inhibitor therapy and invasive liver-directed treatments, have demonstrated limited efficacy.

Mechanism of Action

Darovasertib is an oral, selective inhibitor of protein kinase C (PKC), which represents the primary oncogenic driver in more than 95% of uveal melanoma cases. Activating mutations in GNAQ/11 GTPase proteins result in PKC overactivation and subsequent tumor cell growth. In this trial, darovasertib is combined with crizotinib, an oral inhibitor of the cMET pathway, which is believed to play a central role in metastatic spread driven by hepatocyte growth factor (HGF) in the liver microenvironment. This all-oral, targeted combination regimen was designed to address both the primary oncogenic pathway and the mechanisms of metastatic progression.

Trial Design

OptimUM-02 was a global, open-label, randomized phase 2/3 trial enrolling 437 patients in a 2:1 ratio. The trial compared darovasertib 300 mg twice daily plus crizotinib 200 mg twice daily against ICT, which consisted of ipilimumab (Yervoy) plus nivolumab (Opdivo) in 76% and pembrolizumab (Keytruda) in 24%. Topline results were drawn from 313 patients enrolled in the phase 2b/3 portion, with a data cutoff of January 23, 2026. The PFS analysis was based on 159 events. OS data remain immature, though an early trend toward improvement was observed in the combination arm.

Safety Profile

The darovasertib combination was generally well tolerated. The safety profile was consistent with previously reported adverse events for each agent. The most common grade 3 or higher treatment-emergent adverse events were diarrhea, syncope, and hypotension. Treatment-related serious adverse events occurred at a rate below 10%.

Implications and Next Steps

Based on these results, the trial sponsors plan to submit a new drug application (NDA) to the FDA in the second half of 2026.

“OptimUM-02 is the first randomized study to demonstrate a statistically significant and clinically meaningful benefit in PFS in the clinical setting of first-line HLA-A*02:01–negative metastatic uveal melanoma,” said Yujiro S. Hata, president and chief executive officer of IDEAYA Biosciences.

Beyond the metastatic setting, other trials are being planned or are already enrolling patients to be treated with darovasertib across the entire uveal melanoma disease continuum, including neoadjuvant (OptimUM-10; NCT07015190), adjuvant (OptimUM-11), and HLA-A*02:01–positive metastatic (OptimUM-01) indications. The compound has received FDA orphan drug designation, fast track designation in mUM, and breakthrough therapy designation.

Full data from OptimUM-02 are expected to be presented at a major medical conference later in 2026.

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. IDEAYA Biosciences. April 13, 2026. Accessed April 13, 2026. https://tinyurl.com/5b7y4f4a

2. Zahra FT, Ali H, Mohsin F, et al. Trends in mortality, incidence, and survival of uveal melanoma: A SEER-based retrospective analysis. J Clin Oncol. 2025;43(suppl 16):e21581. doi:10.1200/JCO.2025.43.16_suppl.e2158