BACKGROUND: Approximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS: We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS: A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS: Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).
BACKGROUND: Approximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS: We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS: A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS:Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).
Authors: F Stephen Hodi; Steven J O'Day; David F McDermott; Robert W Weber; Jeffrey A Sosman; John B Haanen; Rene Gonzalez; Caroline Robert; Dirk Schadendorf; Jessica C Hassel; Wallace Akerley; Alfons J M van den Eertwegh; Jose Lutzky; Paul Lorigan; Julia M Vaubel; Gerald P Linette; David Hogg; Christian H Ottensmeier; Celeste Lebbé; Christian Peschel; Ian Quirt; Joseph I Clark; Jedd D Wolchok; Jeffrey S Weber; Jason Tian; Michael J Yellin; Geoffrey M Nichol; Axel Hoos; Walter J Urba Journal: N Engl J Med Date: 2010-06-05 Impact factor: 91.245
Authors: Keith T Flaherty; Igor Puzanov; Kevin B Kim; Antoni Ribas; Grant A McArthur; Jeffrey A Sosman; Peter J O'Dwyer; Richard J Lee; Joseph F Grippo; Keith Nolop; Paul B Chapman Journal: N Engl J Med Date: 2010-08-26 Impact factor: 91.245
Authors: Jessie Villanueva; Adina Vultur; John T Lee; Rajasekharan Somasundaram; Mizuho Fukunaga-Kalabis; Angela K Cipolla; Bradley Wubbenhorst; Xiaowei Xu; Phyllis A Gimotty; Damien Kee; Ademi E Santiago-Walker; Richard Letrero; Kurt D'Andrea; Anitha Pushparajan; James E Hayden; Kimberly Dahlman Brown; Sylvie Laquerre; Grant A McArthur; Jeffrey A Sosman; Katherine L Nathanson; Meenhard Herlyn Journal: Cancer Cell Date: 2010-12-14 Impact factor: 31.743
Authors: Hong Yang; Brian Higgins; Kenneth Kolinsky; Kathryn Packman; Zenaida Go; Raman Iyer; Stanley Kolis; Sylvia Zhao; Richard Lee; Joseph F Grippo; Kathleen Schostack; Mary Ellen Simcox; David Heimbrook; Gideon Bollag; Fei Su Journal: Cancer Res Date: 2010-06-15 Impact factor: 12.701
Authors: Georgia Hatzivassiliou; Kyung Song; Ivana Yen; Barbara J Brandhuber; Daniel J Anderson; Ryan Alvarado; Mary J C Ludlam; David Stokoe; Susan L Gloor; Guy Vigers; Tony Morales; Ignacio Aliagas; Bonnie Liu; Steve Sideris; Klaus P Hoeflich; Bijay S Jaiswal; Somasekar Seshagiri; Hartmut Koeppen; Marcia Belvin; Lori S Friedman; Shiva Malek Journal: Nature Date: 2010-02-03 Impact factor: 49.962
Authors: Eric W Joseph; Christine A Pratilas; Poulikos I Poulikakos; Madhavi Tadi; Weiqing Wang; Barry S Taylor; Ensar Halilovic; Yogindra Persaud; Feng Xing; Agnes Viale; James Tsai; Paul B Chapman; Gideon Bollag; David B Solit; Neal Rosen Journal: Proc Natl Acad Sci U S A Date: 2010-07-28 Impact factor: 11.205
Authors: Jonas N Søndergaard; Ramin Nazarian; Qi Wang; Deliang Guo; Teli Hsueh; Stephen Mok; Hooman Sazegar; Laura E MacConaill; Jordi G Barretina; Sarah M Kehoe; Narsis Attar; Erika von Euw; Jonathan E Zuckerman; Bartosz Chmielowski; Begoña Comin-Anduix; Richard C Koya; Paul S Mischel; Roger S Lo; Antoni Ribas Journal: J Transl Med Date: 2010-04-20 Impact factor: 5.531
Authors: Gideon Bollag; Peter Hirth; James Tsai; Jiazhong Zhang; Prabha N Ibrahim; Hanna Cho; Wayne Spevak; Chao Zhang; Ying Zhang; Gaston Habets; Elizabeth A Burton; Bernice Wong; Garson Tsang; Brian L West; Ben Powell; Rafe Shellooe; Adhirai Marimuthu; Hoa Nguyen; Kam Y J Zhang; Dean R Artis; Joseph Schlessinger; Fei Su; Brian Higgins; Raman Iyer; Kurt D'Andrea; Astrid Koehler; Michael Stumm; Paul S Lin; Richard J Lee; Joseph Grippo; Igor Puzanov; Kevin B Kim; Antoni Ribas; Grant A McArthur; Jeffrey A Sosman; Paul B Chapman; Keith T Flaherty; Xiaowei Xu; Katherine L Nathanson; Keith Nolop Journal: Nature Date: 2010-09-30 Impact factor: 49.962
Authors: Cory M Johannessen; Jesse S Boehm; So Young Kim; Sapana R Thomas; Leslie Wardwell; Laura A Johnson; Caroline M Emery; Nicolas Stransky; Alexandria P Cogdill; Jordi Barretina; Giordano Caponigro; Haley Hieronymus; Ryan R Murray; Kourosh Salehi-Ashtiani; David E Hill; Marc Vidal; Jean J Zhao; Xiaoping Yang; Ozan Alkan; Sungjoon Kim; Jennifer L Harris; Christopher J Wilson; Vic E Myer; Peter M Finan; David E Root; Thomas M Roberts; Todd Golub; Keith T Flaherty; Reinhard Dummer; Barbara L Weber; William R Sellers; Robert Schlegel; Jennifer A Wargo; William C Hahn; Levi A Garraway Journal: Nature Date: 2010-11-24 Impact factor: 49.962
Authors: K M Joyce; N M McInerney; C W Joyce; D M Jones; A J Hussey; P Donnellan; M J Kerin; J L Kelly; P J Regan Journal: Ir J Med Sci Date: 2014-11-01 Impact factor: 1.568
Authors: Anna E Vilgelm; Jeff S Pawlikowski; Yan Liu; Oriana E Hawkins; Tyler A Davis; Jessica Smith; Kevin P Weller; Linda W Horton; Colt M McClain; Gregory D Ayers; David C Turner; David C Essaka; Clinton F Stewart; Jeffrey A Sosman; Mark C Kelley; Jeffrey A Ecsedy; Jeffrey N Johnston; Ann Richmond Journal: Cancer Res Date: 2014-11-14 Impact factor: 12.701
Authors: M Dietel; A Enk; A Lehmann; J Bauer; C Garbe; U Kellner; T Kirchner; A Jung; H Kreipe; S Merkelbach-Bruse; R Büttner; J Rüschoff; W Schlake; P Schirmacher; R Penzel; R Stadler Journal: Pathologe Date: 2012-07 Impact factor: 1.011
Authors: Douglas B Johnson; Vita Saranga-Perry; Patrick J M Lavin; W Bryan Burnette; Stephen W Clark; David R Uskavitch; Deborah E Wallace; Mark A Dickson; Ragini R Kudchadkar; Jeffrey A Sosman Journal: J Clin Oncol Date: 2014-04-28 Impact factor: 44.544