Christian U Blank1, James Larkin2, Ana M Arance3, Axel Hauschild4, Paola Queirolo5, Michele Del Vecchio6, Paolo A Ascierto7, Ivana Krajsova8, Jacob Schachter9, Bart Neyns10, Claus Garbe11, Vanna Chiarion Sileni12, Mario Mandalà13, Helen Gogas14, Enrique Espinosa15, Geke A P Hospers16, Wilson H Miller17, Susan Robson18, Martina Makrutzki19, Vladan Antic20, Michael P Brown21. 1. The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066CX, The Netherlands. Electronic address: c.blank@nki.nl. 2. The Royal Marsden NHS Foundation Trust, London, UK. Electronic address: James.Larkin@rmh.nhs.uk. 3. Department of Medical Oncology, Hospital Clínic Barcelona, Barcelona, Spain. Electronic address: AMARANCE@clinic.ub.es. 4. Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany. Electronic address: ahauschild@dermatology.uni-kiel.de. 5. IRCCS San Martino-IST, Genova, Italy. Electronic address: paola.queirolo@hsanmartino.it. 6. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: Michele.delvecchio@istitutotumori.mi.it. 7. Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. 8. General University Hospital, Dermatooncology U, Prague, Czech Republic. Electronic address: Ivana.Krajsova@vfn.cz. 9. Chaim Sheba Medical Centre, Oncology Institute, Ramat-Gan, Israel. Electronic address: Jacob.schachter@sheba.health.gov.il. 10. Afdelingshoofd, Medische Oncologie, Brussels, Belgium. Electronic address: bart.neyns@uzbrussel.be. 11. Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany. Electronic address: claus.garbe@med.uni-tuebingen.de. 12. Oncology Institute of Veneto-IRCCS, Padova, Italy. Electronic address: vanna.chiarion@ioveneto.it. 13. Papa Giovanni XIII Hospital, Bergamo, Italy. Electronic address: mariomandala@tin.it. 14. University of Athens, Athens, Greece. Electronic address: hgogas@hol.gr. 15. Hospital La Paz, Madrid, Spain. Electronic address: eespinosa00@hotmail.com. 16. University Medical Centre Groningen, Groningen, The Netherlands. Electronic address: g.a.p.hospers@umcg.nl. 17. McGill University, Segal Cancer Centre, Montreal, Quebec, Canada. Electronic address: wilsonmiller@gmail.com. 18. F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: susan.robson@roche.com. 19. F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: martina.makrutzki@roche.com. 20. F. Hoffmann-La Roche Ltd, Basel, Switzerland. Electronic address: vladan.antic@roche.com. 21. Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia; Discipline of Medicine, University of Adelaide, Adelaide, Australia. Electronic address: MichaelP.brown@sa.gov.au.
Abstract
BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAFV600 mutations. We assessed the safety of vemurafenib in a large population of patients with few alternative treatment options; we report updated 2-year safety. METHODS: This was an open-label, multicentre study of vemurafenib (960 mg bid) in patients with previously treated or untreated BRAF mutation-positive metastatic melanoma (cobas® 4800 BRAF V600 Mutation Test). The primary end-point was safety; efficacy end-points were secondary. An exploratory analysis was performed to assess safety outcomes in patients with long duration of response (DOR) (≥12 or ≥24 months). RESULTS: After a median follow-up of 32.2 months (95% CI, 31.1-33.2 months), 3079/3219 patients (96%) had discontinued treatment. Adverse events (AEs) were largely consistent with previous reports; the most common all-grade treatment-related AEs were arthralgia (37%), alopecia (25%) and hyperkeratosis (23%); the most common grade 3/4 treatment-related AEs were squamous cell carcinoma of the skin (8%) and keratoacanthoma (8%). In the exploratory analysis, patients with DOR ≥12 months (n = 287) or ≥24 months (n = 133) were more likely to experience grade 3/4 AEs than the overall population. No new specific safety signals were observed with longer vemurafenib exposure. CONCLUSIONS: After 2 years' follow-up, safety was maintained in this large group of patients with BRAFV600 mutation-positive metastatic melanoma who are more representative of routine clinical practice than typical clinical trial populations. These data suggest that long-term vemurafenib treatment is effective and tolerable without the development of new safety signals.
BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAFV600 mutations. We assessed the safety of vemurafenib in a large population of patients with few alternative treatment options; we report updated 2-year safety. METHODS: This was an open-label, multicentre study of vemurafenib (960 mg bid) in patients with previously treated or untreated BRAF mutation-positive metastatic melanoma (cobas® 4800 BRAF V600 Mutation Test). The primary end-point was safety; efficacy end-points were secondary. An exploratory analysis was performed to assess safety outcomes in patients with long duration of response (DOR) (≥12 or ≥24 months). RESULTS: After a median follow-up of 32.2 months (95% CI, 31.1-33.2 months), 3079/3219 patients (96%) had discontinued treatment. Adverse events (AEs) were largely consistent with previous reports; the most common all-grade treatment-related AEs were arthralgia (37%), alopecia (25%) and hyperkeratosis (23%); the most common grade 3/4 treatment-related AEs were squamous cell carcinoma of the skin (8%) and keratoacanthoma (8%). In the exploratory analysis, patients with DOR ≥12 months (n = 287) or ≥24 months (n = 133) were more likely to experience grade 3/4 AEs than the overall population. No new specific safety signals were observed with longer vemurafenib exposure. CONCLUSIONS: After 2 years' follow-up, safety was maintained in this large group of patients with BRAFV600 mutation-positive metastatic melanoma who are more representative of routine clinical practice than typical clinical trial populations. These data suggest that long-term vemurafenib treatment is effective and tolerable without the development of new safety signals.
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