Darovasertib Plus Crizotinib Shows Striking Efficacy in HLA-A2–Negative Metastatic Uveal Melanoma, OptimUM-02 Results Show

Primary results from the phase 2/3 OptimUM-02 trial now offer the first compelling evidence of a regimen that meaningfully changes that picture. Data presented at the 2026 American Society of Clinical Oncology Annual Meeting showed that adding darovasertib to crizotinib led to improved survival benefits for patients with HLA-A2-negative uveal melanoma.

The Uveal Melanoma Treatment Landscape

Uveal melanoma is a rare and aggressive cancer that has long resisted the immunotherapy advances that transformed treatment of cutaneous melanoma. For patients who develop metastatic disease—roughly half of all diagnoses—prognosis has remained grim, with no FDA-approved systemic options for those who are HLA-A2 negative.¹

Uveal melanoma arises from melanocytes in the eye and is driven by distinct biology from other melanoma subtypes, including frequent activation of the PKC signaling pathway. Checkpoint inhibitors, which have become a backbone of cutaneous melanoma treatment, show limited efficacy in uveal melanoma, leaving most patients with metastatic disease dependent on chemotherapy regimens with modest benefit.¹

“Currently, there are no FDA-approved treatments for HLA-A2 negative patients, and there are currently no approved targeted therapies,” said Marlana Orloff, MD, an associate professor of medicine and medical oncologist at Thomas Jefferson University Hospital—Sidney Kimmel Cancer Center in Philadelphia.¹

Darovasertib is a first-in-class oral PKC inhibitor developed specifically for this molecular context. Earlier phase 1/2 data suggested encouraging activity when combined with the MET inhibitor crizotinib, setting the stage for the randomized OptimUM-02 trial.^1,2

Investigating Darovasertib

OptimUM-02 is an open-label study that randomized 338 patients with HLA-A2–negative first-line metastatic uveal melanoma 2:1 to receive darovasertib 300 mg plus crizotinib 200 mg twice daily, or the investigator's choice of treatment—pembrolizumab, ipilimumab plus nivolumab, or dacarbazine. The phase 2 primary end point was progression-free survival (PFS) by blinded independent central review (BICR); overall survival (OS), the phase 3 primary end point, will be reported as data mature.²

“This trial aimed to evaluate the combination of darovasertib,” explained Orloff, “a first-in-class oral PKC inhibitor that had demonstrated clinical activity in both A2-positive and A2-negative patients, and crizotinib, an oral MET inhibitor that had shown complementary activity with darovasertib preclinically and clinically."¹

Darovasertib Improved Survival Outcomes

The results were striking across every efficacy measure. Median PFS by BICR was 6.9 months with darovasertib plus crizotinib versus 3.1 months with the investigator's choice—a hazard ratio of 0.42 (P < .0001). Investigator-assessed PFS showed an even sharper separation, with a hazard ratio of 0.36.²

Objective response rate by BICR was 37.1% with the combination versus 5.8% with the investigator’s choice, and the disease control rate was 73.3% versus 31.1%. Median duration of response in the investigator's choice arm was not evaluable, reflecting the paucity of responses. Preliminary overall survival data are also trending in favor of the combination.²

"Nearly 90% of patients in the darovasertib-crizotinib arm had some degree of tumor reduction,” said Orloff.¹

Darovasertib Was Safe, Tolerable

The safety profile was consistent with what had been observed in earlier studies. The most common adverse events with darovasertib plus crizotinib were gastrointestinal—diarrhea (89.5%), nausea (78.2%), and vomiting (53.6%)—along with peripheral edema (70.7%). Grade 3 or 4 events were relatively limited, most notably diarrhea (10.9%) and syncope (7.9%).²

Treatment-related serious adverse events occurred in 9.2% of patients on the combination, compared with 25.3% in the investigator's choice arm. Discontinuation due to adverse events was low for darovasertib at 3.8%, and one treatment-related fatal adverse event occurred in each arm.²

“Due to differing mechanisms of action of the drugs, there was an opportunity to dose-modify and dose-hold in darovasertib-crizotinib, whereas more patients in the investigator's choice arm, once they faced a serious adverse event, had their treatment often discontinued per protocol recommendation," Orloff explained.¹

Darovasertib Expands Patient Therapeutic Options

For a disease where no approved systemic options exist for HLA-A2–negative patients and immunotherapy has historically underperformed, OptimUM-02 represents a meaningful advance.

“The OptimUM-02 trial hopefully supports a potentially new therapeutic standard for a disease with limited treatment options and a poor prognosis,” Orloff concluded.¹

The combination of darovasertib and crizotinib more than doubled PFS, drove response rates far exceeding any available alternative, and did so with a manageable safety profile. These results make a compelling case for a new first-line standard in this underserved population, with overall survival data anticipated to further define the regimen's long-term impact.

REFERENCES

1. Chacon MR, Ma BT, Carlino M, et al. Melanoma/Skin Cancers. Presented at: ASCO 2026. May 28-June 2, 2026. Chicago, IL.

2. 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.Presented at: ASCO 2026. May 28-June 2, 2026. Chicago, IL. Abstract LBA9503