An update on Alectinib: a first line treatment for ALK-positive advanced lung cancer

ABSTRACT

Introduction

Alectinib is a second-generation, anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) for the treatment of ALK+ non-small cell lung cancer (NSCLC) and is able to induce significant and durable CNS responses. However, long-term use of alectinib has been clinically reported to cause some serious and even life-threatening adverse events. There are currently no effective interventions for its adverse events, and this undoubtedly leads to delays in patient treatment and limits its long-term clinical use.

Areas covered

Based on the clinical trials conducted so far, we summarize the efficacy and adverse events that occurred, especially those related to cardiovascular disorders, gastrointestinal disorders, hepatobiliary disorders, musculoskeletal and connective tissue disorders, skin and subcutaneous tissue disorders, and respiratory disorders. The factors that may influence alectinib selection are also described. Findings are based on a PubMed literature search of clinical and basic science research papers spanning 1998–2023.

Expert opinion

The significant prolongation of patient survival compared with first-generation ALK inhibitor suggests its potential as a first-line treatment for the NSCLC, but the severe adverse events of alectinib limit its long-term clinical use. Future research should focus on the exact mechanisms of these toxicities, how to alleviate the adverse events caused by alectinib clinically, and the development of next-generation drugs with reduced toxicities.

KEYWORDS:

• Alectinib
• NSCLC
• safety
• ALK inhibitors
• management strategies

Article highlights

• Some adverse events associated with alectinib may limit the application and long-term use of alectinib in clinic.

• Skin lesions, gastrointestinal toxicity and other general disorders such as anemia, myalgia and hyperbilirubinemia caused by alectinib are mild and recover on their own without medical intervention. Most of the above-mentioned grade 3/4 adverse events caused by alectinib are managed by dose adjustment or treatment interruption.

• Although severe hepatic toxicity, skeletal myopathy and respiratory disorders are uncommon in patients treated with alectinib, they can be life-threatening, especially in patients with high-risk factors. There is a need for early prevention and regular monitoring of patients.

• The exact mechanism of adverse events associated with alectinib remains unclear.

• Research into the molecular mechanisms of adverse events associated with alectinib is urgent in order to address intolerance in patients on long-term alectinib use.

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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by National Natural Science Foundation of China [No. 82173893]