Panitumumab can safely and effectively be substituted for cetuximab in the treatment of BRAF V600Emut metastatic colorectal cancer (mCRC) – A case series

Abstract

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] Davies H. Bignell G.R. Cox C. et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417: 949-954 Crossref PubMed Scopus (8213) Google Scholar ]. 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 Jones J.C. Renfro L.A. Al-Shamsi H.O. et al. (Non-V600) BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J Clin Oncol. 2017; 35: 2624-2630 Crossref PubMed Scopus (185) Google Scholar , 3 Morris V. Overman M.J. Jiang Z.Q. et al. Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. Clin Colorectal Cancer. 2014; 13: 164-171 Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar , 4 Clarke C.N. Kopetz E.S. BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies. J Gastrointest Oncol. 2015; 6: 660-667 PubMed Google Scholar ]. 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] Tabernero J. Grothey A. Van Cutsem E. et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup Analyses from the BEACON study. J Clin Oncol. 2021; 39: 273-284 Crossref PubMed Scopus (90) Google Scholar ]. 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] Grothey A. Van Cutsem E. Sobrero A. et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013; 381: 303-312 Abstract Full Text Full Text PDF PubMed Scopus (1901) Google Scholar ]. 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] Prahallad A. Sun C. Huang S. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012; 483: 100-103 Crossref PubMed Scopus (1459) Google Scholar ]. 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] Tabernero J. Geel Rv Guren T.K. et al. Phase 2 results: encorafenib (ENCO) and cetuximab (CETUX) with or without alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC). J Clin Oncol. 2016; 34 (3544-3544) Crossref Google Scholar ].