title: Long-term outcome in BRAF(V600E) melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression.
abstract: BACKGROUND
  Vemurafenib induces tumour regression in most patients with BRAF(V600E)-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAF(V600E) melanoma treated in the phase 1 vemurafenib trial is reported.
  
  
  METHODS
  Patients received vemurafenib 240-1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by Response Evaluation Criteria In Solid Tumors (RECIST). Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded.
  
  
  RESULTS
  Forty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (⩾ 240 mg twice daily). Forty-four patients had PD by the time of this analysis and four remained progression free (follow-up time, 1.2-56.1 months). Median OS was 14 months (range, 1.2-56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7-56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1-26.6). In the extension cohort, six and five patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy.
  
  
  CONCLUSIONS
  Some patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition.
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Avenue #777, Nashville, TN 37232, USA. Electronic address: igor.puzanov@vanderbilt.edu.
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.affiliation: Abramson Cancer Center and the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. Electronic address: Ravi.Amaravadi@uphs.upenn.edu.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.affiliation: Peter MacCallum Cancer Centre, 2 St Andrews Place, East Melbourne, Vic 3002, Australia. Electronic address: grant.mcarthur@petermac.org.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, USA. Electronic address: kflaherty@partners.org.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address: chapmanp@mskcc.org.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Avenue #777, Nashville, TN 37232, USA. Electronic address: jeff.sosman@vanderbilt.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Jonsson Comprehensive Cancer Center, University of California, Los Angeles, 11-934 Factor Bldg., 10833 Le Conte Ave., Los Angeles, CA 90095-1782, USA. Electronic address: aribas@mednet.ucla.edu.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Peter MacCallum Cancer Centre, 2 St Andrews Place, East Melbourne, Vic 3002, Australia. Electronic address: Mark.Shackleton@petermac.org.
authors.forename: Mark
authors.initials: M
authors.lastname: Shackleton
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: phwu@mdanderson.org.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.affiliation: Jonsson Comprehensive Cancer Center, University of California, Los Angeles, 11-934 Factor Bldg., 10833 Le Conte Ave., Los Angeles, CA 90095-1782, USA. Electronic address: BChmielowski@mednet.ucla.edu.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA. Electronic address: easybreathe@msn.com.
authors.forename: Keith B
authors.initials: KB
authors.lastname: Nolop
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA. Electronic address: plin@plexxikon.com.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Lin
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: KimKB@sutterhealth.org.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use*; D015996:Survival Rate; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF inhibitor; Metastatic melanoma; Vemurafenib