Combined vemurafenib and fotemustine in patients with BRAFV600 melanoma progressing on vemurafenib.

// Paola Queirolo 1 , Francesco Spagnolo 2 , Virginia Picasso 1 , Laura Spano 1 , Enrica Tanda 1 , Valeria Fontana 3 , Laura Giorello 3 , Domenico Franco Merlo 3 , Ester Simeone 4 , Antonio Maria Grimaldi 4 , Marcello Curvietto 4 , Michele Del Vecchio 5 , Paolo Bruzzi 3 , Paolo Antonio Ascierto 4 1 Department of Medical Oncology, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy 2 Department of Plastic and Reconstructive Surgery, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy 3 Department of Epidemiology, Biostatistics and Clinical Trials, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy 4 Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione “G. Pascale”, Napoli, Italy 5 Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy Correspondence to: Francesco Spagnolo, email: francesco.spagnolo85@gmail.com Keywords: vemurafenib, BRAF, fotemustine, melanoma, treatment beyond progression Received: February 29, 2016      Accepted: June 30, 2016      Published: July 13, 2016 ABSTRACT Background: BRAF inhibitor vemurafenib achieves high response rate and an improvement in survival in patients with BRAF-mutated metastatic melanoma. However, median progression-free survival is only 6.9 months in the phase 3 study. Retrospective analyses suggest that treatment with BRAF inhibitors beyond initial progression might be associated with improved overall survival. We aimed to prospectively investigate the activity of prolonged treatment with vemurafenib and the addition of fotemustine in patients with systemic progression on prior single-agent BRAF inhibitor. Patients and Methods: In this two-centres, single-arm Phase 2 trial, we enrolled patients with systemic progressive disease during single-agent vemurafenib treatment. Participants received vemurafenib 960 mg twice daily or dose administered at time of disease progression with vemurafenib previous treatment and fotemustine 100 mg/m2 intravenously every three weeks. The primary endpoint was PFS. Results: Thirty-one patients were enrolled in the study; 16 patients had brain metastases at baseline. Median PFS was 3.9 months and 19 patients (61.3%) achieved disease control (1 CR, 4 PR, 14 SD). For patients achieving disease control, median duration of treatment was 6 months. Median OS was 5.8 months from enrolment and 15.4 months from start of previous vemurafenib. Five patients (16.1%) had a G3-4 AE, the most common being thrombocytopenia, which occurred in 3 patients. This trial is registered with ClinicalTrials.gov number NCT01983124. Conclusion: The combination of vemurafenib plus fotemustine has clinical activity and an acceptable safety profile in BRAF-refractory patients.