BRAF is a serine/threonine-protein kinase in the RAS/RAF/MEK/ERK pathway, which plays an important role in cell proliferation and survival [
[1]
]. Mutations in the BRAF gene occur in about 10% of colorectal cancer patients. Most mutations are activating BRAF V600E mutations. These mutations are associated with poor overall survival and low
chemosensitivity, while non-V600E BRAF mutations tend to be associated with more favourable
outcomes [
2
,
3
,
4
]. To therapeutically address BRAF V600E mutations, the combination of cetuximab and encorafenib was established as
the standard of care for pre-treated BRAF V600Emut mCRC based on the phase III BEACON CRC trial [
[5]
]. Encorafenib is an inhibitor of BRAF, which downregulates the over-activated MAPK-pathway.
However, response rates to encorafenib monotherapy have been disappointing, with one
phase III trial showing an ORR of 1% [
[6]
]. One reason for this low response rate is the fact that BRAF inhibition leads to
a powerful feedback activation of EGFR in BRAF V600E mutant CRC [
[7]
]. This effect can be overcome by the addition of cetuximab to encorafenib. Together,
these targeted agents lead to a sustained downregulation of MAPK-signalling, which
translates to a significant survival benefit in pre-treated BRAF V600E mCRC [
[8]
].To read this article in full you will need to make a payment
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References
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- (Non-V600) BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer.J Clin Oncol. 2017; 35: 2624-2630
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- FOLFOXIRI plus panitumumab as first-line treatment of RAS wild-type metastatic colorectal cancer: the randomized, open-label, phase II VOLFI study (AIO KRK0109).J Clin Oncol. 2019; 37: 3401-3411
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- Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.J Clin Oncol. 2010; 28: 4697-4705
- Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer.J Clin Oncol. 2010; 28: 4706-4713
- Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology.J Natl Compr Cancer Netw. 2021; 19: 329-359
- Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients.Clin Cancer Res. 2015; 21: 1313-1320
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Article info
Publication history
Published online: August 12, 2022
Accepted:
July 8,
2022
Received:
July 6,
2022
Identification
Copyright
© 2022 Elsevier Ltd. All rights reserved.
