Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

168 Applying Pharmacogenomics in Therapeutics
CETUXIMAB AND PANITUMUMAB
Cetuximab is a recombinant, human/mouse chimeric monoclonal antibody that binds
specifically to the extracellular domain of the human (EGFR) and competitively inhibits
the binding of EGF and other ligands, such as transforming growth factor-α. 8
Panitumumab is a recombinant, human IgG2 kappa monoclonal antibody that
also binds specifically to the human EGFR. Similarly, panitumumab (Vectibix ® )
also binds to the extracellular portion of the EGFR, which prevents ligandinduced
EGFR receptor tyrosine kinase activation, resulting in inhibition of cell
growth. 8 Binding of cetuximab and panitumumab to the EGFR on tumor cells
has been shown to block receptor phosphorylation and activation of receptorassociated
kinases, resulting in inhibition of cell growth, induction of apoptosis,
and decreased activity of matrix metalloproteinase and production of vascular
endothelial growth factor. 8
Both cetuximab and panitumumab are indicated for the treatment of metastatic
CRC in combination with FOLFOX or FOLFIRI regimen in patients who are K-RAS
wild-type status. In the Crystal trial, FOLFIRI + cetuximab was compared with
FOLFIRI alone, with the former having higher OS and PFS. In the PRIME study
comparing FOLFOX + panitumumab vs. FOLFOX, the regimen FOLFOX + panitumumab
yields higher OS and PFS, similar to cetuximab. 90,91
Similar to other EGFR inhibitors, both cetuximab and panitumumab also share
similar acneiform rash. Controversially, the rash might be a form of survival predictive
markers. There are currently no prospective trials to confirm this, but the general
consensus is to continue therapy and treat the side effects of the acneiform rash
with both pharmacological and nonpharmacological measures.
Gefitinib (Iressa ® ) is another TKI that targets EGFR. It is indicated for patients
with locally advanced or metastatic NSCLC after failure of platinum-based and
docetaxel therapies. 92 Gefitinib is the first selective EGFR inhibitor that targets
HER1 or ErbB-1. Clinically, when gefitinib was compared to carboplatin and paclitaxel,
the PFS was higher with gefitinib in patients with EGFR mutation positive. 93
Afatinib is an irreversible TKI and is indicated for the first-line treatment of
patients with metastatic NSCLC. Afatinib covalently binds to the kinase domains
of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4), and irreversibly inhibits
tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling.
Afatinib is indicated for the first-line treatment of patients with metastatic NSCLC
whose tumors have EGFR exon 19 deletions or exon 21 mutation (L858R), and a
secondary T790M mutation in some cases. In addition, afatinib inhibits in vitro proliferation
of cell lines overexpressing HER2. Now afatinib can be added to a list of
therapy options for patients with NSCLC. 94,95
Erlotinib reversibly inhibits the kinase activity of EGFR, with higher binding
affinity for EGFR exon 19 deletion or exon 21 mutation (L858R) than its affinity
for the wild-type receptor. It is indicated as the first-line treatment for patients with
metastatic NSCLC whose tumors have EGFR exon 19 deletion or exon 21 mutation
(L858R) as detected by an FDA-approved test. Advanced NSCLC will be highly
sensitive to EGFR-TKI, and TKIs are the first-line treatment for NSCLC with EGFR
mutations. 96