title: Fatal gastrointestinal toxicity with ipilimumab after BRAF/MEK inhibitor combination in a melanoma patient achieving pathological complete response.
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.
authors.affiliation: Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital-Quirónsalud Group, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Gonzalez-Cao
authors.affiliation: Dermatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors.forename: Aram
authors.initials: A
authors.lastname: Boada
authors.affiliation: Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital-Quirónsalud Group, Barcelona, Spain.|Pangaea Biotech, Laboratory of Oncology, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Teixidó
authors.affiliation: Pathology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Fernandez-Figueras
authors.affiliation: Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital-Quirónsalud Group, Barcelona, Spain.|Pangaea Biotech, Laboratory of Oncology, Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Mayo
authors.affiliation: Pathology Department, Dexeus University Hospital-Quirónsalud Group, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Tresserra
authors.affiliation: Albert Einstein Medical Center, Philadelphia, PA, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Bustamante
authors.affiliation: Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital-Quirónsalud Group, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Viteri
authors.affiliation: Radiotherapy Department, Hospital Quirónsalud, Barcelona, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Puertas
authors.affiliation: Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, Italy.
authors.forename: Mariacarmela
authors.initials: M
authors.lastname: Santarpia
authors.affiliation: Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital-Quirónsalud Group, Barcelona, Spain.
authors.forename: Aldo
authors.initials: A
authors.lastname: Riso
authors.affiliation: Medical Oncology Unit, Insituto Nacional de Cancerología, México.
authors.forename: Feliciano
authors.initials: F
authors.lastname: Barron
authors.affiliation: Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital-Quirónsalud Group, Barcelona, Spain.
authors.forename: Niki
authors.initials: N
authors.lastname: Karachaliou
authors.affiliation: Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital-Quirónsalud Group, Barcelona, Spain.|Catalan Institute of Oncology, Cancer Biology & Precision Medicine Programme, Germans Trias i Pujol Hospital and Health Sciences Institute, Badalona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
mesh_terms: D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001706:Biopsy; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D004273:DNA, Neoplasm / Q000097:blood; D017809:Fatal Outcome; D041981:Gastrointestinal Tract / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects*; D000074324:Ipilimumab / Q000009:adverse effects*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009360:Neoplastic Cells, Circulating / Q000378:metabolism; D010091:Oximes / Q000008:administration & dosage / Q000009:adverse effects*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000074322:Antineoplastic Agents, Immunological; D004273:DNA, Neoplasm; D007093:Imidazoles; D000074324:Ipilimumab; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; C561627:dabrafenib
keywords: BRAF mutation; ipilimumab; melanoma; sequential treatment; toxicity