In a phase II pilot study reported in the Journal of Clinical Oncology, Scott Kopetz, MD, PhD, of The University of Texas MD Anderson Cancer Center, and colleagues found little clinical activity of vemurafenib (Zelboraf) in patients with metastatic BRAF-mutated colorectal cancer.1 The BRAF V600E mutation is found in approximately 5% to 8% of patients with metastatic colorectal cancer and is associated with poor prognosis.
Low Response Rate
In the study, 21 patients with BRAF V600E-positive metastatic colorectal cancer received oral vemurafenib at 960 mg twice daily. Twenty patients had received at least one prior chemotherapy regimen for metastatic disease.
Partial response was observed in one patient (5%, 95% confidence interval [CI] = 1%–24%), and stable disease was observed in seven (33%). Median progression-free survival was 2.1 months. There was no association of clinical benefit with patterns of concurrent mutations, microsatellite instability status, CpG island methylation status, PTEN loss, EGFR expression, or copy number alterations.
Low-Frequency Mutations
Low-frequency KRAS or NRAS mutations were found in 9 (56%) of 16 evaluable tumors, with a median allele frequency of 0.21%. These mutations appeared to be mechanisms of acquired resistance in vemurafenib-sensitive patient-derived xenografts.
The investigators concluded: “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 colorectal cancer. Combination strategies are now under development and may be informed by the presence of intratumor heterogeneity of KRAS and NRAS mutations.” ■
Disclosure: The study was supported by Plexxikon and Roche and by the National Institutes of Health and National Cancer Institute. For full disclosures of the study authors, visit jco.ascopubs.org.
Reference
1. Kopetz S, et al: J Clin Oncol 33:4032-4038, 2015.
