title: Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer.
abstract: OBJECTIVE
  BRAF V600E mutation is seen in 5% to 8% of patients with metastatic colorectal cancer (CRC) and is associated with poor prognosis. Vemurafenib, an oral BRAF V600 inhibitor, has pronounced activity in patients with metastatic melanoma, but its activity in patients with BRAF V600E-positive metastatic CRC was unknown.
  
  
  METHODS
  In this multi-institutional, open-label study, patients with metastatic CRC with BRAF V600 mutations were recruited to an expansion cohort at the previously determined maximum-tolerated dose of 960 mg orally twice a day.
  
  
  RESULTS
  Twenty-one patients were enrolled, of whom 20 had received at least one prior metastatic chemotherapy regimen. Grade 3 toxicities included keratoacanthomas, rash, fatigue, and arthralgia. Of the 21 patients treated, one patient had a confirmed partial response (5%; 95% CI, 1% to 24%) and seven other patients had stable disease by RECIST criteria. Median progression-free survival was 2.1 months. Patterns of concurrent mutations, microsatellite instability status, CpG island methylation status, PTEN loss, EGFR expression, and copy number alterations were not associated with clinical benefit. In contrast to prior expectations, concurrent KRAS and NRAS mutations were detected at low allele frequency in a subset of the patients' tumors (median, 0.21% allele frequency) and were apparent mechanisms of acquired resistance in vemurafenib-sensitive patient-derived xenograft models.
  
  
  CONCLUSIONS
  In marked contrast to the results seen in patients with BRAF V600E-mutant melanoma, single-agent vemurafenib did not show meaningful clinical activity in patients with BRAF V600E mutant CRC. Combination strategies are now under development and may be informed by the presence of intratumor heterogeneity of KRAS and NRAS mutations.
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia. skopetz@mdanderson.org.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Jayesh
authors.initials: J
authors.lastname: Desai
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Joel Randolph
authors.initials: JR
authors.lastname: Hecht
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Dipen
authors.initials: D
authors.lastname: Maru
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Van
authors.initials: V
authors.lastname: Morris
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Arvind
authors.initials: A
authors.lastname: Dasari
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Woonbook
authors.initials: W
authors.lastname: Chung
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbs
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: James
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Keith B
authors.initials: KB
authors.lastname: Nolop
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Suman
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Scott Kopetz, Dipen Maru, Van Morris, Filip Janku, and Arvind Dasari, The University of Texas MD Anderson Cancer Center, Houston, TX; Emily Chan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Joel Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Brian James and Garth Powis, Sanford Burnham Institute, La Jolla; Keith B. Nolop, Plexxikon, Berkeley; Suman Bhattacharya, Genentech, South San Francisco, CA; Peter J. O'Dwyer, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA; Woonbook Chung and Jean-Pierre J. Issa, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA; Leonard Saltz, Memorial Sloan-Kettering Cancer Center, New York, NY; and Jayesh Desai and Peter Gibbs, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Leonard
authors.initials: L
authors.lastname: Saltz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D010865:Pilot Projects; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015996:Survival Rate; D014018:Tissue Distribution; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf