Predictable clinical responses to sorafenib in stage IV uveal melanoma.

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e19032 Background: Uveal melanoma is an orphan disease with poor prognosis, once metastasized. There is currently no approved systemic treatment and all clinical trials so far failed to significantly improve OS in stage IV uveal melanoma patients (see results of the EORTC 18021 trial, abstract 95725). Sorafenib is a pleiotropic kinase inhibitor targeting tumor metabolism and related neoangiogenesis. Although sorafenib failed as monotherapy in metastasized melanoma, results from small phase II trials have indicated synergism with chemotherapy in some patients. We therefore offered compassionate use treatment with sorafenib to patients with documented progressive stage IV uveal melanoma after fotemustine iv or HIA treatment (EORTC 18021 trial). Methods: Sorafenib 400 mg orally bid was combined with fotemustine 100 mg/m² at 3 week intervals to treat a total of 7 patients with metastatic uveal melanoma. Patients were closely followed by repeated analyses of serum tumor markers and ultrasound scans of liver metastases. Complete staging by CT/MR scans was done every 3 months. Results: 3 of 7 patients with initially elevated tumormarkers showed an early rapid drop in serum MIA and/or S100 within two weeks of sorafenib treatment followed by partial responses and long term stabilization of the disease up to 20 months. Responder patients could also be identified by a rapid drop in tumorperfusion as shown by contrast enhanced ultrasound of liver metastases. Due to hematologic toxicity treatment had to be modified in all responder patients. Neither reduction of sorafenib dosage to 200 mg orally bid nor omittance of fotemustine treatment resulted in early disease progression, pinpointing potential high sorafenib responsiveness in uveal melanoma patients. Conclusions: Patients with stage IV uveal melanoma may benefit from treatment with the kinase inhibitor sorafenib. Our observations suggest selection of responder patients by early drop of elevated tumor markers S100 / MIA and early drop in tumor perfusion. Stimulated by these data a first phase II trial investigating sorafenib in uveal melanoma patients has been initiated in Germany (ClinicalTrials.gov NCT0137702: A Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma (STREAM).