Management of acquired resistance to epidermal growth factor receptor kinase inhibitors in patients with advanced non-small cell lung cancer

Abstract

The widespread adoption of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for the first-line treatment of patients with advanced EGFR-mutated non-small cell lung cancer has resulted in acquired tyrosine kinase inhibitor resistance becoming a ubiquitous clinical problem. The identification of specific mechanisms of acquired resistance has allowed a better understanding of the biology and natural history of resistant disease, but is only now starting to impact treatment decisions. Strategies for managing acquired resistance in patients with advanced non-small cell lung cancer are complex and must be adapted to the individual characteristics of each patient's cancer. Although combination chemotherapy is the presumed standard of care for most patients, prospective trial data are lacking, highlighting the importance of offering patients participation in clinical trials in this setting. Emerging data from trials of third-generation mutant-specific EGFR kinase inhibitors suggests particular promise with this class of agents.

Keywords: acquired resistance; epidermal growth factor receptor (EGFR); non-small cell lung cancer; targeted therapy.

Figure 1

Different clinical presentations of acquired resistance in EGFR mutant NSCLC can be due to different resistance mechanisms. TOP – isolated CNS progression can occur due to poor TKI penetration into the CNS secondary to the blood-brain barrier. MIDDLE – the emergence of a T790M clone can cause indolent progression on EGFR TKI, but re-growth of sensitive clones can occur upon TKI cessation. BOTTOM – the emergence of an alternative resistance mutation can produce rapidly growing clones and rapid progression.

Figure 2

Approach to the management of EGFR mutant NSCLC with progression on first-line EGFR TKI. Here we propose a step-wise approach that considers progression characteristics and clinical trial availability before initiating second-line chemotherapy. RT: Radiation therapy

Figure 3

Relative potency of different EGFR kinase inhibitors against different EGFR genotypes in vitro. The Y-axis represents the relative IC50 normalized to the IC50 against EGFR sensitizing mutations (L858R or exon 19 deletion).^,, Second-generation EGFR TKIs like afatinib are more potent against T790M than gefitinib, but dosing in the clinic is limited by wildtype inhibition (and toxicity) at a relatively lower dose. Third-generation EGFR TKIs like CO-1686 and AZD9291 selectively inhibit EGFR T790M well below the dose at which wildtype EGFR is inhibited and have the potential to yield reduced toxicity as a result.