Systemic treatment in EGFR-ALK NSCLC patients: second line therapy and beyond

Abstract

Over a short period of time, translational research has described a new clinically relevant molecular subset of non-small-cell lung cancer (NSCLC) that is defined by EGFR mutations or EML4-ALK fusions. Today, patients with metastatic disease can achieve survival rates at least double that of patients with wild-type tumors. Through the rational dissection of the mechanisms of drug sensitivity and resistance, promising strategies have been defined to further improve the outcomes of patients with NCSLC. This review adds to a growing body of knowledge into mechanisms of resistance that can be interrogated in NSCLC patients with EGFR mutations or EML4-ALK fusions, as well as strategies to overcome resistance to TKIs.

Keywords::

• EGFR
• EML4–ALK
• lung cancer
• TKI resistance
• tyrosine kinase inhibitors

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Translational research has described a new clinically relevant molecular subset of nonsmall-cell lung cancer that is defined by EGFR (EGF receptor) mutations or echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase (ALK) fusions.

• On the basis of the EURTAC study, the US FDA approved erlotinib for use in patients with lung cancers, harboring EGFR exon 19 deletions and EGFR L858R substitutions.

• Resistance mechanisms to EGFR inhibitors can be grouped into four categories: mutation of EGFR to a drug-resistant state (T790M); activation of a bypass signaling pathway; impairment of a pathway essential for apoptosis or autophagy and histological transformation to small cell lung cancer or an epithelial–mesenchymal transition.

• Crizotinib has become the gold standard for treating patients with ALK rearrangements.

• Resistance to crizotinib may frequently occur due to secondary mutations within the ALK kinase domain.

• Other ‘ALK-independent’ mechanisms, such as the activation of compensatory signaling pathways, may also confer resistance to targeted ALK agents.

Notes