After a rocky start, drugs that inhibit the epidermal growth factor receptor (EGFR) pathway have evolved into a new treatment paradigm for patients with non–small cell lung cancer (NSCLC) whose tumors harbor EGFR
mutations. Three generations of drugs are now available, with new agents helping to overcome the significant challenge of resistance. Yet despite this tremendous progress, lung cancer is still the leader in cancer-related mortality. Many questions remain to be answered in order to achieve the best outcomes for all EGFR mutation-carrying patients.
Starting on a Bumpy Road
EGFR belongs to a family of four membrane receptor proteins (EGFR/ ERBB1/HER1; HER2/ERBB2; HER3/ERBB3; and HER4/ERBB4). These receptors exist as single units, but binding of their ligands prompts them to partner up with either another protein of the same type (homodimerization) or a different member of the family (heterodimerization
This binding causes the receptor to become activated by autophosphorylation at specific tyrosine residues. In their active state, they initiate a multistep phosphorylation cascade of signaling proteins that culminates in the transcription of a distinct set of genes in the nucleus that are involved in cancer hallmark processes.
Several strategies have been developed for blocking EGFR
signaling with drugs—monoclonal antibodies that bind to the extracellular domain of the receptor and block ligand binding, and small molecule inhibitors that interfere with tyrosine kinase activity. Both have been tested in patients with lung cancer and, while EGFR antibodies have had limited clinical success to date, EGFR tyrosine kinase inhibitors (TKIs) have proved to be very effective in patients with NSCLC. Initially, EGFR inhibitors were tested in all patients with NSCLC. The first-generation drugs gefitinib (Iressa) and erlotinib (Tarceva), both reversible inhibitors, received FDA approval in quick succession in 2003 and 2004, respectively, for use in patients who had progressed on first-line chemotherapy.
EGFR Signaling in NSCLC1
1. Wu K, House L, Liu W, Cho WC. Personalized targeted therapy for lung cancer. Int J Mol Sci. 2012;13(9):11471-11496. doi:10.3390/ijms130911471.
2. My Cancer Genome. www.mycancergenome.org
Unfortunately, in the case of gefitinib, subsequent phase III confirmatory trials failed to verify the survival benefit observed in the pivotal trials upon which its accelerated approval was based. The makers of this drug voluntarily withdrew it from market in the United States in 2005. In light of the modest efficacy observed in the broad NSCLC population and the significant cost of these drugs, opinion began to sour on the entire class.
Reversal of Fortune
Erlotinib and Gefitinib
In 2004, two research groups simultaneously identified the presence of mutations in the EGFR
gene in NSCLC tumors. Dubbed activating mutations, they are most found in the form of exon 19 deletions and L858R point mutations in exon 21 of the EGFR
gene, and result in the constitutive activation of the protein, leading to uncontrolled EGFR
signaling. These types of EGFR
mutations, located around the catalytic kinase domain of the receptor, are unique to lung cancer.
Prior to the discovery of EGFR
mutations, a picture of typical response to an EGFR TKI had already begun to emerge. Researchers had noted a responsive phenotype: patients who responded best tended to be East Asian, nonsmokers, female, and those with adenocarcinoma NSCLC histology. As it became clear that EGFR
mutations were present in around 10% of all patients with NSCLC, retrospective analyses of EGFR TKI clinical trials also presented a responsive genotype.
Confirming the observations from these retrospective analyses, numerous prospective, randomized trials have now demonstrated that, for patients with EGFR mutations, an EGFR TKI is superior to standard chemotherapy, with improved overall response rates (ORRs), disease control, symptom control, progression-free survival (PFS) and quality of life. No overall survival (OS) benefit was observed with either gefinitib or erlotinib, but this is believed to result from the extensive crossover in clinical trials.
Although the genotype and phenotype of EGFR TKI responders overlap to a large extent, it has become more apparent as researchers have tested these drugs in specific patient populations that the presence of activating EGFR
mutations (genotype), rather than phenotype, should guide treatment decisions.