An analysis of data from the phase 3 FOCUS trial found that treatment of metastatic uveal melanoma using percutaneous hepatic perfusion with melphalan resulted in a favorable response rate and longer survival compared to using best alternative care options, prompting FDA approval of this drug for uveal melanoma in August 2023.
Study Design
This study was a multicenter prospective, single-arm, open-label clinical trial of percutaneous hepatic perfusion with melphalan. Patients with unresectable hepatic metastasis and limited extrahepatic disease were included. The study began as a randomized phase 3 trial comparing liver-directed melphalan to the best alternative care for hepatic-dominant ocular melanoma (investigator’s choice of transarterial chemoembolization, pembrolizumab, ipilimumab, or dacarbazine). However, it was amended to include only the 91 patients who received liver-directed melphalan after the best alternative care arm was halted due to enrollment concerns. The primary outcome was objective response rate (ORR).
Outcomes
The patients who received liver-directed melphalan had an ORR of 35.2% (n = 91) compared to 12.5% in the best alternative care group (n = 42). The median duration of response was 14 months in the liver-directed melphalan group, with a median overall survival of 20.5 months compared to 14.1 months in the best alternative care group. Although 42.6% of patients experienced treatment-associated adverse events during the trial, most were transient, and there were no reports of treatment-related deaths.
Limitations
Patients with metastases affecting more than half of the liver or with significant extrahepatic disease were excluded from this study. The single-arm design due to the halting of the best alternative care arm also limits the study for a randomized comparison.
Clinical Significance
Patients with uveal melanoma develop metastasis in half of cases by 15 years after the time of initial diagnosis, with metastatic disease occurring in the liver 90% of the time, which is associated with a poor prognosis.1 Few effective treatments for metastatic uveal melanoma are available to our patients. However, based on the results of this FOCUS study, the FDA approved liver-directed melphalan for metastatic uveal melanoma in August 2023.
Percutaneous hepatic perfusion with melphalan is the second FDA-approved treatment for metastatic uveal melanoma, after the approval of Tebentafusp in 2022, and the first approved liver-directed therapy for this disease. Although the overall survival benefit was modest in the FOCUS study, and liver-directed melphalan has a boxed warning for severe periprocedural complications (i.e., hemorrhage, hepatocellular injury, thromboembolic events), further improvement of this treatment modality has the potential to improve outcomes for our patients who otherwise have few effective therapeutic options.
Financial Disclosures: Dr. Michael Heiferman discloses no financial relationships.
Reference:
1 Kaliki S et al. Indian Journal of Ophthalmology. 2015;63(2):93-102.