Is There a Role for the Irreversible Epidermal Growth Factor Receptor Inhibitor EKB-569 in the Treatment of Cancer? A Mutation-Driven Question
Authors: Jose Baselga
Journal: Journal of Clinical Oncology (2006)

In this issue of the Journal of Clinical Oncology, the results of the phase I study of EKB-569 in patients with solid tumors are presented. EKB-569 is a potent and irreversible inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. In this study, EKB569 was safe, exposure was dose proportional, and it had a prolonged mean terminal half-life, which allows for a daily administration schedule. The dose-limiting toxicity was grade 3 diarrhea, which is similar to other EGFR inhibitors. As with other anti-EGFR inhibitors, skin rash and asthenia were also observed. The maximum-tolerated dose was found to be 75 mg/d, both in the intermittent and in the continuous administration schedule, and a lower dose of 50 mg/d has been chosen for phase II studies because it is associated with fewer drug-related severe toxicities and there is a strong suggestion that this dose level results in biologically relevant concentrations in plasma and inhibits EGFR function in patients. On the basis of the results of this trial, EKB-569 clearly meets the early requirements for further clinical development; it is well tolerated, it has shown predictable pharmacokinetics, an optimal dose has been identified, it has the expected toxicities, and there is evidence of in vivo inhibition of the receptor. As usual with this class of agents, hints of clinical benefit were also observed. The critical question ahead for this and other anti-EGFR agents in early clinical development is whether they will be superior or complementary to the currently available anti-EGFR agents. The field of EGFR inhibitors is becoming increasingly crowded with the following two classes of agents: monoclonal antibodies against the extracellular domain of the receptor and low molecular weight tyrosine kinase inhibitors (for review, see Baselga and Arteaga). These two classes of agents have partially different mechanisms of action and nonoverlapping clinical indications. Anti-EGFR monoclonal antibodies are approved in the treatment of colon cancer and may be soon approved in other indications such as head and neck tumors. In the class of low molecular weight EGFR tyrosine kinase inhibitors, gefitinib and erlotinib are approved for the treatment of non–small-cell lung cancer (NSCLC), and erlotinib recently obtained approval for the treatment of advanced pancreas carcinoma. Do we have any suggestion that EKB-569 may be superior or complementary to gefitinib and erlotinib? Superiority may be achieved by different means, such as broader or greater efficacy, enhanced safety, or a more convenient administration schedule. None of these means seem to apply to EKB-569. Although a potential advantage of an irreversible EGFR inhibitor would be an easier dosing schedule, both gefitinib and erlotinib are already administered on a convenient daily basis. In terms of additional diseasebased indications, a phase II study of EKB-569 is underway in patients with advanced colorectal cancer (CRC). Although we need to wait for the outcome of this trial, one is tempted to speculate that EKB-569 will be inactive as a single agent in CRC based on the minimal activity of other EGFR tyrosine kinase inhibitors in CRC. It would also seem fair to wait for the results of currently ongoing studies of EKB-569 and chemotherapy in patients with pancreatic cancer and CRC. It seems more likely that the potential advantages of EKB-569 and other irreversible EGFR inhibitors in the treatment of cancer may be linked to the biology of EGFR itself. The EGFR is a transmembrane receptor tyrosine kinase of the ErbB family that is abnormally activated in many epithelial tumors. Ligand binding results in homoor heterodimerization and activation of the highly conserved intracellular tyrosine kinase domain, resulting in phosphorylation of specific tyrosine residues that serve as docking sites of proteins whose recruitment activates a multitude of downstream signaling pathways, which, in turn, engage mitogenic signaling and other tumor-promoting activities. Clinical responses to gefitinib and erlotinib are highly dependent on the presence of EGFR somatic mutations that affect critical amino acids in the adenosine triphosphate– binding cleft of the tyrosine kinase domain of the receptor. Responses have also been reported in patients with EGFR gene amplification. EGFR mutations arise in the following four exons of the gene: substitutions for G719 in the nucleotide binding loop of exon 18, in-frame deletions within exon 19, in-frame insertions within exon 20, and substitution for L858 or L861 in the activation loop in exon 21. Interestingly, not all EGFR mutations result in enhanced sensitivity to gefitinib and erlotinib. Patients who initially respond to gefitinib or erlotinib may acquire secondary EGFR mutations that render them resistant to these agents, specifically the T790M mutation. T790M primary mutations may also occur in previously untreated patients. Primary transforming mutations may also be resistant to gefitinib and erlotinib; this has been recently shown by the identification of an exon 20 insertion mutant that is completely resistant to these inhibitors. In addition, the T790M mutation is JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 15 MAY 2