title: Prognostic markers and tumour growth kinetics in melanoma patients progressing on vemurafenib.
abstract: The BRAF inhibitor vemurafenib is an effective drug in patients with BRAF mutant metastatic melanoma, but resistance occurs after a median of 6 months. The anti-CTLA4-antibody, ipilimumab, is a standard first-line and second-line treatment option in Europe, with a median time to response of 2-3 months, but some patients show rapid clinical deterioration before that. The aim of this analysis was to identify prognostic markers for survival after failure of vemurafenib treatment to identify patients who have a sufficient life expectancy to respond to new immunotherapy treatments. We retrospectively analysed 101 consecutive unselected patients treated with vemurafenib for metastatic melanoma at a single institution. The association between clinical parameters and death within 3 months after cessation of vemurafenib (n=69) was assessed by binary logistic and Cox regression. Of the patients, 45% died within 3 months of progression on vemurafenib. Elevated baseline serum lactate dehydrogenase, absence of normalization of serum lactate dehydrogenase on vemurafenib therapy, performance status of at least 2 at progression and time from primary tumour to metastatic disease less than 5 years were identified as poor prognostic markers. In an exploratory tumour growth kinetics analysis (n=16), we found that following cessation of vemurafenib, approximately a third each showed a stable, decelerated or accelerated rate of tumour growth. Patients with these poor prognostic markers are unlikely to have sufficient life expectancy to complete ipilimumab treatment after failure with vemurafenib. Consideration needs to be given to the elective use of immunotherapy before patients become resistant to vemurafenib. This requires prospective randomized evaluation. Our tumour growth kinetics analysis requires confirmation; however, it may suggest that intermittent vemurafenib treatment should be investigated in clinical trials.
authors.affiliation: aDepartment of Medical Oncology, Royal Marsden NHS Trust, London bDepartment of Statistics, Royal Marsden NHS Trust, Surrey, UK.
authors.forename: Heike
authors.initials: H
authors.lastname: Seifert
authors.forename: Rosalie
authors.initials: R
authors.lastname: Fisher
authors.forename: Juan
authors.initials: J
authors.lastname: Martin-Liberal
authors.forename: Kim
authors.initials: K
authors.lastname: Edmonds
authors.forename: Peta
authors.initials: P
authors.lastname: Hughes
authors.forename: Komel
authors.initials: K
authors.lastname: Khabra
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
authors.forename: James
authors.initials: J
authors.lastname: Larkin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000188:drug therapy*; D013449:Sulfonamides / Q000627:therapeutic use*; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib