Anaplastic lymphoma kinase inhibitors in phase I and phase II clinical trials for non-small cell lung cancer

ABSTRACT

Introduction: Crizotinib is a first-in-class ALK tyrosine kinase inhibitor (TKI), which has proven its superiority over standard platinum-based chemotherapy for the first-line therapy of ALK-rearranged non-small cell lung cancer (NSCLC) patients. The development of acquired resistance to crizotinib represents an ongoing challenge with the central nervous system being one of the most common sites of relapse. Ceritinib and alectinib are approved second-generation ALK TKIs. Several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib, are currently in development.

Areas covered: This review will focus on new ALK inhibitors, currently in phase 1 or 2 clinical studies. We will also comment on the mechanisms of resistance to ALK inhibition and the strategies to delay or overcome resistance.

Expert opinion: The therapeutic management of ALK-rearranged NSCLC has been greatly improved. Next-generation ALK inhibitors have shown differential potency against ALK rearrangements and ALK resistance mutations. The molecular profile of the tumor at the time of disease progression to crizotinib is crucial for the sequencing of novel ALK TKIs. Ongoing clinical studies will address key issues, including the optimal therapeutic algorithm and whether combinational approaches are more effective than single ALK inhibition for the outcome of ALK-rearranged NSCLC patients.

KEYWORDS:

• Anaplastic lymphoma kinase (ALK) gene
• non-small cell lung cancer (NSCLC)
• ALK tyrosine kinase inhibitors
• crizotinib

Article highlights

• The discovery of ALK rearrangements and development of ALK tyrosine kinase inhibitors represent key breakthroughs in personalized treatment for NSCLC

• Crizotinib, a first-in-class ALK inhibitor, is currently approved as first-line therapy of ALK-rearranged NSCLC patients because of demonstration of superior efficacy over standard platinum-based chemotherapy

• Despite initial remarkable responses to crizotinib, patients inevitably progress due to development of acquired resistance, with the central nervous system (CNS) being one of the most common sites of relapse

• Molecular mechanisms underlying crizotinib resistance include on-target genetic alterations, such as secondary ALK TK mutations, and off-target mechanisms, such as activation of bypass tracks and epithelial-mesenchymal transition (EMT)

• Ceritinib and alectinib are next-generation ALK TKIs approved for treatment of ALK-positive NSCLC patients previously treated with crizotinib

• Several novel, potent ALK inhibitors, with differential spectrum of activity against ALK resistance mutations and activity against other related oncoproteins are currently in phase 1 and 2 of clinical development

• Preliminary results have shown promising activity of these compounds in ALK-rearranged NSCLC patients, including those with CNS metastases

• Molecular profile of the tumor at the time of disease progression to ALK TKI therapy is crucial to better characterize resistance mechanisms and to help correctly sequence the multiple available ALK-directed therapies

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Declaration of interest

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.

Additional information

Funding

This work was funded by La Caixa Foundation and Red Tematica de Investigacion Cooperativa en Cancer (RTICC; grant RD12/0036/0072).