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

By S. Kopetz, J. Desai, E. Chan, J. Hecht, P. O'dwyer, D. Maru, V. Morris, F. Janku, A. Dasari, Woo-Baek Chung and 7 more. Journal of Clinical Oncology, 2015

634 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/97dff06f16e79b4a1b2c965791b41f7328993942

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. A. Bardelli

In Molecular Biology

1. J. Baselga
2. R. Salazar
3. Nikolaus Schultz
4. A. Bardelli
5. Jan H. M. Schellens
6. Marc Ladanyi
7. Barry S. Taylor
8. Gregory Riely

In Oncology

1. J. Baselga
2. Nikolaus Schultz
3. Gregory Riely
4. Fortunato Ciardiello
5. M. Hellmann
6. M. Callahan
7. M. Postow

Citations in the corpus

• Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. (2019, background): “Alanine aminotransferase 51 (23) 4 (2) 36 (17) 0 50 (26) 5 (3)”
• OncoKB: A Precision Oncology Knowledge Base (2017, background): “…inhibitor vemurafenib is a standard treatment option for patients with BRAF V600E mutant melanoma or NSCLC, robust clinical reports from multiple independent centers demonstrate that patients with BRAF V600E mutant colorectal cancer do not respond to RAF-inhibitors, at least as monotherapy 25,68 .”
• ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. (2016, background): “Also, BRAF V600E-mutated melanomas are sensitive to the BRAF-mutant inhibitor vemurafenib [69], but BRAF-mutated CRCs are not as sensitive [70, 71].”