Format

Send to

Choose Destination
J Clin Oncol. 2015 Dec 1;33(34):4032-8. doi: 10.1200/JCO.2015.63.2497. Epub 2015 Oct 12.

Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer.

Author information

1
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.
2
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.

Abstract

PURPOSE:

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.

PATIENTS AND 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.

CONCLUSION:

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00405587.

PMID:
26460303
PMCID:
PMC4669589
DOI:
10.1200/JCO.2015.63.2497
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center