Fatal gastrointestinal toxicity with ipilimumab after BRAF/ MEK inhibitor combination in a melanoma patient achieving pathological complete response

// Maria Gonzalez-Cao 1 , Aram Boada 2 , Cristina Teixido 1,10 , Maria Teresa Fernandez-Figueras 3 , Clara Mayo 1,10 , Francesc Tresserra 4 , Jean Bustamante 5 , Santiago Viteri 1 , Enrique Puertas 6 , Mariacarmela Santarpia 7 , Aldo Riso 1 , Feliciano Barron 8 , Niki Karachaliou 1 , Rafael Rosell 1,9 1 Translational Cancer Research Unit, Instituto Oncologico Dr Rosell, Dexeus University Hospital-Quironsalud Group, Barcelona, Spain 2 Dermatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain 3 Pathology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain 4 Pathology Department, Dexeus University Hospital-Quironsalud Group, Barcelona, Spain 5 Albert Einstein Medical Center, Philadelphia, PA, USA 6 Radiotherapy Department, Hospital Quironsalud, Barcelona, Spain 7 Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy 8 Medical Oncology Unit, Insituto Nacional de Cancerologia, Mexico 9 Catalan Institute of Oncology, Cancer Biology & Precision Medicine Programme, Germans Trias i Pujol Hospital and Health Sciences Institute, Badalona, Spain 10 Pangaea Biotech, Laboratory of Oncology, Barcelona, Spain Correspondence to: Maria Gonzalez-Cao, email: mgonzalezcao@oncorosell.com Keywords: BRAF mutation, ipilimumab, melanoma, sequential treatment, toxicity Received: April 03, 2016       Accepted: May 29, 2016      Published: July 18, 2016 ABSTRACT Approximately 50% of metastatic melanoma patients harbor BRAF mutations. Several treatment options including the combination of BRAF and MEK inhibitors (BRAF/MEKi) and immunotherapy (mainly anti CTLA-4 and anti PD-1 antibodies), have been shown to improve survival in these patients. Although preclinical data support the synergistic effect of both modalities in combination, data confirming the activity and tolerability of these combinations are not yet available in the clinical setting. Herein, we report the case of a melanoma patient treated with sequential BRAF/MEKi (dabrafenib plus trametinib) followed by the anti CTLA-4 antibody ipilimumab who achieved a pathological complete response. Unfortunately, the patient died due to fatal gastrointestinal (GI) toxicity. Analysis of the BRAFV600E mutation in circulating tumoral DNA (ctDNA) from peripheral blood samples and serial tumor tissue biopsies throughout treatment demonstrated a good correlation with clinical evolution.