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

Published:August 12, 2022DOI:https://doi.org/10.1016/j.ejca.2022.07.013
      BRAF is a serine/threonine-protein kinase in the RAS/RAF/MEK/ERK pathway, which plays an important role in cell proliferation and survival [
      • Davies H.
      • Bignell G.R.
      • Cox C.
      • et al.
      Mutations of the BRAF gene in human cancer.
      ]. 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 [
      • 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.
      ,
      • 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.
      ,
      • 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.
      ]. 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 [
      • 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.
      ]. 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% [
      • 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.
      ]. 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 [
      • Prahallad A.
      • Sun C.
      • Huang S.
      • et al.
      Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.
      ]. 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 [
      • 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).
      ].
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