Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

Jonathan R Thompson,Smitha P Menon,Grace K Dy

doi:10.5599/admet.4.3.337

Abstract

<p class="ADMETkeywordsheading">Discovery of the epidermal growth receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) rearrangements has expanded the therapeutic landscape in non-small cell lung cancer (NSCLC). Survival outcomes for patients with these mutations have improved dramatically with EGFR and ALK tyrosine kinase inhibitors (TKIs). Multiple generations of EGFR and ALK TKIs have been rapidly developed, and patients and clinicians now have several options for first- and second-line treatments. While these small molecule TKIs have some similarities in therapeutic and pharmacologic profiles, the differences can be clinically substantial, allowing tailored treatment for each unique patient. This review details the clinical efficacy, pharmacology, safety profiles, CNS penetration, and mechanisms of resistance of the four EGFR TKIs and three ALK TKIs that are currently approved by the United States Food and Drug Administration (US FDA).</p>

Highlights

Lung cancer is the leading cause of cancer mortality worldwide, leading to 1.6 million deaths annually [1]
Case reports of two patients T790M-mutated epidermal growth factor receptor (EGFR) and untreated brain metastases showed that osimertinib 80 mg daily induced sustained partial responses to both Central nervous system (CNS) and systemic disease [96]
As the tumor environment is typically hypoxic, it is hypothesized that greater intra-tumoral tyrosine kinase inhibitors (TKIs) exposure and a greater therapeutic index will be achieved with this drug, and EGFR TKI resistance has been overcome with TH-4000 in animal models

Summary

Introduction

Lung cancer is the leading cause of cancer mortality worldwide, leading to 1.6 million deaths annually [1]. EGFR activating mutations and ALK gene rearrangements create constitutively active protein kinases for which there are multiple highly active tyrosine kinase inhibitors (TKIs) available for treatment. The first-generation EGFR TKIs, gefitinib and erlotinib, reversibly inhibit the intracellular catalytic domain of the EGFR tyrosine kinase. Prior to the widespread knowledge of EGFR activating mutations as predictive biomarker of treatment sensitivity to EGFR TKIs, erlotinib gained FDA approval in November 2004 for treatment of advanced NSCLC, regardless of tumor mutation status, after failure of first- or second-line chemotherapy.

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