Anti-EGFR Therapies Overview

1. Mechanism of Action:

EGFR (Epidermal Growth Factor Receptor) is a receptor tyrosine kinase involved in cell proliferation, survival, and differentiation.
Anti-EGFR therapies block EGFR signaling by:
- Monoclonal antibodies (mAbs): Bind the extracellular domain of EGFR, preventing ligand binding and receptor activation.
  - Examples: Cetuximab, Panitumumab
- Tyrosine kinase inhibitors (TKIs): Small molecules that inhibit the intracellular tyrosine kinase domain of EGFR, preventing downstream signaling.
  - Examples: Erlotinib, Gefitinib, Osimertinib

Therapy Type	Drug	Common Indications
mAb	Cetuximab	Metastatic colorectal cancer (KRAS/NRAS wild-type), head & neck SCC
mAb	Panitumumab	Metastatic colorectal cancer (KRAS/NRAS wild-type)
TKI	Erlotinib	EGFR-mutated NSCLC
TKI	Gefitinib	EGFR-mutated NSCLC
TKI	Osimertinib	EGFR T790M mutation-positive NSCLC, first-line EGFR-mutated NSCLC

Primary resistance:
- KRAS, NRAS, or BRAF mutations → patients do not respond to anti-EGFR mAbs in colorectal cancer.
- EGFR exon 20 insertions → resistant to first/second-generation TKIs.
Acquired resistance:
- EGFR T790M mutation → resistance to first-generation TKIs; third-generation TKIs like osimertinib overcome this.
- MET amplification, HER2 amplification, or histologic transformation.

mAbs: Only effective in KRAS/NRAS wild-type tumors.
TKIs: Effective in EGFR-activating mutations (exon 19 deletions, L858R mutation).

Drug Class	Key Adverse Effects	Notes
mAb	Acneiform rash, hypomagnesemia, infusion reactions	Rash often correlates with response
TKI	Rash, diarrhea, interstitial lung disease, hepatotoxicity	Monitor LFTs and pulmonary symptoms

Anti-EGFR mAbs do not work in EGFR-mutant NSCLC; they are primarily used in colorectal cancer and head & neck cancers.
Immunotherapy (IO) tends to work poorly in EGFR-mutant tumors, partly due to low tumor mutational burden and immune-cold microenvironment.
Combination therapy strategies (e.g., anti-EGFR + chemotherapy) are sometimes used in resistant cases.

Feature	Anti-EGFR (Monoclonal Antibodies)	EGFR Inhibitors (TKIs / Small Molecules)
Type	Large proteins (antibodies)	Small molecules (tyrosine kinase inhibitors)
Target Site	Extracellular domain of EGFR receptor (prevents ligand binding)	Intracellular tyrosine kinase domain of EGFR receptor (blocks phosphorylation)
Examples	Cetuximab, Panitumumab	Erlotinib, Gefitinib, Osimertinib
Administration	IV infusion	Oral pills
Tumor Indications	Colorectal cancer (KRAS/NRAS wild-type), head & neck SCC	NSCLC with EGFR-activating mutations, some pancreatic cancers
Mechanism	Blocks EGFR signaling at receptor level, can induce antibody-dependent cytotoxicity (ADCC)	Blocks downstream EGFR signaling pathways (RAS-RAF-MEK, PI3K-AKT)
Resistance Mechanisms	KRAS/NRAS mutations, EGFR extracellular mutations	T790M mutation, MET amplification, secondary EGFR mutations
Side Effects	Rash, hypomagnesemia, infusion reactions	Rash, diarrhea, interstitial lung disease, hepatotoxicity

Anti-EGFR antibodies: used mostly in solid tumors without EGFR mutations but require wild-type KRAS/NRAS for colorectal cancer.
EGFR TKIs: used mostly in EGFR-mutated tumors (like NSCLC).
They cannot be used interchangeably; the tumor type and mutation status dictate the choice.