James Larkin1, Michele Del Vecchio2, Paolo A Ascierto3, Ivana Krajsova4, Jacob Schachter5, Bart Neyns6, Enrique Espinosa7, Claus Garbe8, Vanna Chiarion Sileni9, Helen Gogas10, Wilson H Miller11, Mario Mandalà12, Geke A P Hospers13, Ana Arance14, Paola Queirolo15, Axel Hauschild16, Michael P Brown17, Lada Mitchell18, Luisa Veronese18, Christian U Blank19. 1. Royal Marsden Hospital NHS Foundation Trust, London, UK. Electronic address: james.larkin@rmh.nhs.uk. 2. Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy. 3. Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. 4. Dermatooncology Department, General University Hospital, Prague, Czech Republic. 5. Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel. 6. Universitair Ziekenhuis Brussel, Brussels, Belgium. 7. Service of Oncology-Hospital La Paz, Madrid, Spain. 8. Universität Tübingen-Hautklinik, Tübingen, Germany. 9. Melanoma Oncology Unit, Veneto Oncology Institute, Gattamelata, Padova, Italy. 10. Medical Oncology, University of Athens, Greece. 11. Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada. 12. Papa Giovanni XXIII Hospital, Bergamo, Italy. 13. Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands. 14. Department of Medical Oncology, Hospital Clínic, Barcelona, Spain. 15. IRCCS San Martino Hospital-IST, Genoa, Italy. 16. University Hospital Schleswig-Holstein, Department of Dermatology, Kiel, Germany. 17. Cancer Clinical Trials Unit, Royal Adelaide Hospital, and Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia. 18. F Hoffmann-La Roche, Basel, Switzerland. 19. Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands. Electronic address: c.blank@nki.nl.
Abstract
BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAF(V600) mutations who had few treatment options. METHODS: In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAF(V600) mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397. FINDINGS: Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53-65] and ten [4%, 2-7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42-45] and 82 [3%, 2-3], respectively). INTERPRETATION: Vemurafenib safety in this diverse population of patients with BRAF(V600) mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug. FUNDING: F Hoffmann-La Roche.
BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAF(V600) mutations who had few treatment options. METHODS: In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAF(V600) mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397. FINDINGS: Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53-65] and ten [4%, 2-7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42-45] and 82 [3%, 2-3], respectively). INTERPRETATION:Vemurafenib safety in this diverse population of patients with BRAF(V600) mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug. FUNDING: F Hoffmann-La Roche.
Authors: Daniel N Cohen; Steven K Lawson; Aaron C Shaver; Liping Du; Harrison P Nguyen; Qin He; Douglas B Johnson; Wilfred A Lumbang; Brent R Moody; James L Prescott; Pranil K Chandra; Alan S Boyd; Jeffrey P Zwerner; Jason B Robbins; Stephen K Tyring; Peter L Rady; James D Chappell; Yu Shyr; Jeffrey R Infante; Jeffrey A Sosman Journal: Clin Cancer Res Date: 2015-02-27 Impact factor: 12.531
Authors: A Boada; C Carrera; S Segura; H Collgros; P Pasquali; D Bodet; S Puig; J Malvehy Journal: Clin Transl Oncol Date: 2018-05-24 Impact factor: 3.405