Understanding Resistance to EGFR Inhibitors—Impact on Future Treatment Strategies

Deric L. Wheeler; Emily F. Dunn; Paul M. Harari

In This Article

EGFR Inhibitors—From Bench to Clinic

EGFR has been linked to the growth of many human epithelial malignancies, including NSCLC, metastatic CRC, HNSCC, and pancreatic cancer. Systematic laboratory and clinical research have facilitated the translation of EGFR inhibitors into common use in clinical oncology. Table 3 provides details of selected clinical trials that have promoted these efforts. For each EGFR inhibitor, a complex series of preclinical and clinical milestones predate FDA approval. A common theme in some examples of EGFR drug development is the beneficial impact of information gained from basic, translational and clinical research studies over time. In each anatomic area described, there have been key elements of the progress that were derived from applying laboratory findings to the clinical arena, and clinical findings that have helped advances in the laboratory setting. Indeed, this is the essence of translational cancer research, and is beautifully reflected by the emerging story of EGFR drug development.

Gefitinib and Erlotinib in Clinical Trials

Phase II trials showed a promising response and symptom improvement rate with gefitinib as monotherapy in patients with advanced stage NSCLC, thereby contributing to FDA approval of this agent in 2003 as second-line or third-line treatment.[67,68] However, subsequent phase III trials, INTACT 1 and INTACT 2, which tested gefitinib in the first-line setting with concurrent doublet chemotherapy, did not identify improvement in overall survival or time to progression (TTP).[24,69] The FDA recommended, therefore, to limit the indications for gefitinib to patients currently or previously being treated or enrolled on approved clinical trials. Erlotinib also faced challenges in clinical advancement for NSCLC with two major phase III clinical trials, TALENT and TRIBUTE (similar design to the INTACT trials), which showed no improvement in overall survival or TTP.[70,71] It was not until the BR.21 trial, which compared erlotinib with placebo in the second-line or third-line setting for advanced NSCLC patients, that erlotinib established a survival benefit prompting FDA approval.[72] The mixed results of these clinical trials initiated further investigations aimed at identifying population subsets that may be more likely to benefit from EGFR TKIs. Analyses of biospecimens from clinical trials identified a unique subpopulation of patients (Asian, female, never-smokers, adenocarcinoma histology) who were most likely to respond to EGFR TKIs.[25,72,73] The landmark identification of a subset of lung cancers harboring mutations in the EGFR tyrosine kinase domain stimulated tremendous research activity and improved understanding of methods to enrich the selection of patients for lung cancer trials who are most likely to derive benefit from EGFR TKI therapy approaches.[74–76] This work also stimulated the discovery of an EGFR resistance mutation (T790M) in lung cancer patients receiving chronic gefitinib treatment.[77–79]

A series of clinical trials have specifically selected individuals with documented EGFR mutations to enrich the population of patients who are most likely to benefit from first-line treatment with EGFR TKI therapy.[80–86] These studies have uniformly demonstrated impressive response rates in the range of 50–70%, with excellent progression-free survival (PFS) and overall survival rates. These trials also exhibit notably improved treatment tolerance compared with conventional platinum-based doublet chemotherapy regimens, despite the inclusion in some studies of elderly patients with poor performance status. Indeed, gefitinib gained approval in Europe in 2009 for adults with locally advanced or metastatic NSCLC with EGFR mutations in all lines of therapy.

Cetuximab in Clinical Trials

Cetuximab has also undergone active clinical evaluation in advanced NSCLC. A series of phase II trials suggested activity of cetuximab in combination with platinum doublets in the first-line treatment setting.[87–91] Two phase III trials have been reported, including the FLEX and BMS099 trials.[92,93] The FLEX trial demonstrated an improvement in overall survival with the addition of cetuximab to first-line cisplatin and vinorelbine. The BMS099 trial evaluated the addition of cetuximab to carboplatin/taxane in the first-line setting and identified an improvement of overall response rate, but not a statistically significant improvement in PFS (the primary end point of the study).

A phase I trial of HNSCC in 1997–1998, where 16 patients with locoregionally advanced tumors were enrolled, provided the first clinical signal that adding cetuximab to radiation may improve tumor response and disease control.[94] Despite the absence of true phase II data, a phase III trial that enrolled 424 patients was carried out between 1999–2002 that confirmed a 10% overall survival advantage for patients receiving cetuximab in combination with curative radiation for advanced HNSCC compared with radiotherapy alone.[23] The influence of radiation and EGFR inhibition on proliferation, apoptosis, cell repopulation, angiogenesis, and DNA damage repair needs to be clarified. Interestingly, this result was in contrast to the trials in NSCLC where concurrent administration of EGFR inhibitors with cytotoxic chemotherapy did not prove advantageous. This finding may reflect the different tumor types (HNSCC versus NSCLC), different classes of EGFR inhibitors (monoclonal antibodies versus TKIs), or the distinction between radiation and chemotherapy as the cytotoxic treatment modality.

EGFR Inhibitors in CRC

The advancement of EGFR inhibitors in CRC also reveals a complex story with continuing stepwise improvements in our understanding of tumor biology and patient selection. The emergence of KRAS mutation status as a valuable predictor of response to cetuximab therapy for patients with metastatic CRC is a reminder that examination of molecular signatures for each individual tumor can provide powerful information to guide optimal therapy selection.[56,95–102] Panitumumab affords another valuable approach for metastatic CRC patients with chemorefractory disease.[66] Despite promising preclinical and early clinical data that suggested the potential value of combining EGFR inhibitors with VEGF inhibitors in CRC, clinical trial data did not demonstrate improved efficacy and showed increased toxicity in this setting.[103]