Frontline Sorafenib Shows Promising Outcomes in Metastatic Uveal Melanoma

First-line therapy with sorafenib (Nexavar) demonstrated promising activity among patients with metastatic uveal melanoma who received no prior chemotherapy, according to findings from the phase 2 STREAM trial (NCT01377025) published in iScience.¹

Data showed a median progression-free survival (PFS) of 5.5 months with sorafenib vs 1.9 months with placebo (HR, 0.53; P = .0083). The respective 12-month PFS rates were 28.2% and 8.4%. In each respective arm, the median overall survival (OS) was 14.8 months and 14.4 months (HR, 0.85; P = .51). Overall, 59.0% of patients initially assigned to placebo switched to treatment with sorafenib following unblinding due to disease progression; the median PFS in this group was 10 weeks.

Investigators noted that a short relapse-free interval, metastatic dissemination beyond the liver, elevated lactate dehydrogenase level, and elevated γ-glutamyl transpeptidase (GGT) level correlated with negative prognostic value for PFS. Additionally, GGT was more than 50 times higher than the upper limit (P < .0001) and S100 was higher than 0.105 μg/L (P = .00066), correlating with shorter OS.

“Taken together, the phase 2 STREAM study showed that sorafenib provided a significant PFS benefit for [patients without prior chemotherapy] with metastatic uveal melanoma. A subsequent realization of a phase 3 trial of sorafenib vs placebo is, in our view, not advisable in this orphan disease,” lead study author Halime Kalkavan, from University Duisburg-Essen, wrote with coauthors in the publication. “Instead, future studies may include multikinase inhibition in combination with other promising and rational therapeutic strategies to improve patient outcomes in this fatal disease.”

In this randomized trial, patients received sorafenib in a 56-day open-label run-in period at 400 mg twice daily. Patients who achieved a partial response (PR) per RECIST criteria were eligible to continue treatment with the agent; those with progressive disease were taken off the study, and those with stable disease were randomly assigned to receive sorafenib (n = 39) or a matched placebo (n = 39) without stratification.

The trial’s primary end point was PFS. Secondary end points included safety, OS, PFS among patients who crossed over from placebo to sorafenib, and plasma-based biomarkers.

Patients 18 years or older with histologically or cytologically confirmed metastatic uveal melanoma, an ECOG performance status of 0 to 2, and a life expectancy of more than 5 months were eligible for enrollment in the trial.² Another eligibility criterion included having adequate hematologic, renal, and hepatic function.

Among 78 patients who were randomly assigned, 59% in the sorafenib arm and 67% in the placebo arm were men; the median age in each respective cohort was 58 years (range, 23-79) and 66 years (range, 47-88). Additionally, most patients in each arm had an ECOG performance status of 0 (81% vs 77%), metastases localized in the liver only (51% vs 46%), and metastases in one organ site (51% vs 49%).

The median PFS was 7.2 months in patients with detectable circulating tumor DNA (ctDNA) vs 16.0 months in those without (HR, 2.33; P < .0001). The presence of ctDNA correlated with worse PFS at the univariable (HR, 2.38; 95% CI, 1.56-3.70; P < .0001) and multivariable levels (HR, 2.22; 95% CI, 1.35-3.57; P = .0017).

“One might argue that the [randomized discontinuation trial] design selects a more indolent, homogeneous group than the real-world patient population. Nevertheless, using a run-in phase and the option that patients who progress during the randomized phase might be crossed over to the investigational drug after unblinding enabled an ethically justifiable use of placebo as a comparator arm within an oncology trial,” the study authors noted.¹

References

1. Kalkavan H, Scheulen ME, Kämpgen E, et al. Sorafenib as first-line therapy for metastatic uveal melanoma: a multicenter, placebo-controlled randomized discontinuation study (STREAM). iScience. 2025;28(12):114045. doi:10.1016/j.isci.2025.114045
2. A study of sorafenib in patients with chemonaive metastatic uveal melanoma (STREAM). ClinicalTrials.gov. Updated December 3, 2014. Accessed January 2, 2026. https://tinyurl.com/37h3k6nb