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% vs 8.4%. In each respective arm, the median overall survival (OS) was 14.8 months vs 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 (LDH), and elevated gamma-glutamyl transpeptidase (GGT) 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) correlated 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 multi-kinase 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 and 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 on the trial.² Other eligibility criteria 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 male; 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 1 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, 1.56-3.7; P <.0001) and multivariable levels (HR, 2.22; 95% CI, 1.35-3.57; P = .0017).

“[O]ne 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