Pharmacotherapeutic advances with anaplastic lymphoma kinase inhibitors for the treatment of non-small cell lung cancer

ABSTRACT

Introduction

Anaplastic lymphoma kinase (ALK) inhibitors are potent oral anti-cancer agents acting as tyrosine kinase inhibitors (TKIs), which are approved for the treatment of ALK+ non-small cell lung cancer (NSCLC). Over the last years, several new molecules have been developed and are currently under clinical investigation.

Areas covered

In this paper, the authors review the most relevant clinical findings of ALK inhibitors in the treatment of ALK+ NSCLC. The authors discuss differences in the efficacy and treatment-related adverse events (AEs) incidence of distinct ALK inhibitors, molecular mechanisms of acquired resistance, and ongoing clinical studies assessing the use of ALK inhibitors in innovative settings and novel combinations.

Expert commentary

ALK inhibitors have dramatically improved the prognosis of patients with ALK+ NSCLC and revolutionized therapy options. Nowadays, several molecules are approved for the treatment of ALK+ NSCLC, either in first or further lines of systemic treatment. Several clinical trials are currently ongoing in order to define a potential role of ALK inhibitors in combination with novel anti-cancer agents, as well as monotherapy in neo- and adjuvant settings.

KEYWORDS:

• Non-small cell lung cancer
• crizotinib
• ceritinib
• alectinib
• brigatinib
• lorlatinib
• ensartinib

Article Highlights

• Anaplastic lymphoma kinase (ALK) inhibitors are oral multi-target tyrosine kinase inhibitors (TKIs) that display anti-tumor activity towards ALK-rearranged non-small cell lung cancer (NSCLC).

• The first-generation ALK inhibitor crizotinib was the first molecule to be developed, followed by the second- and third-generation drugs ceritinib, alectinib, brigatinib, lorlatinib, and ensartinib.

• Results of phase III clinical trials showed that ALK inhibitors are related to improved progression-free survival (PFS) compared with cytotoxic chemotherapy. Second and third generations of ALK inhibitors have shown important intracranial response and are therefore the preferred therapeutic regimens for patients with brain metastases.

• Lorlatinib, a third-generation ALK inhibitor, showed activity both in treatment-naive patients affected by ALK-positive NSCLC, and in those who had experienced progression on crizotinib, second-generation ALK TKIs, or after up to three previous ALK TKIs.

• Clinical trials are currently exploring combinations of ALK inhibitors in several settings and in combination with other molecules, in order to improve survival and overcome resistance mechanisms.

This box summarizes the key points contained in the article.

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.

Reviewer Disclosures

One reviewer declares that they have served as an advisor for Pfizer Inc, Roche and Takeda. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript has not been funded.