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2016/02/17

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

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

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Purpose

BRAF V600 Emutationisseenin 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.

Results

Twenty-one patients were enrolled, of whom 20 had received at least one prior metastatic chemotherapyregimen. Grade 3 toxicities included keratoacanthomas, rash, fatigue, and arthralgia. Ofthe 21 patients treated, one patient had a confirmed partial response (5%; 95% CI, 1% to 24%) and seven therpatients had stable disease by RECIST criteria. Medianprogression-freesurvival 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.

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J Clin Oncol © 2015 by American Society of Clinical Oncology.

Creative Commons Attribution Non-Commercial No Derivatives 3.0 License: https://creativecommons.org/licenses/by-nc-nd/3.0/us/

 

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