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New generation anaplastic lymphoma kinase inhibitors
Angelo Delmonte1, Marco Angelo Burgio1, Alberto Verlicchi1
1Thoracic Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy.
Abstract:
Anaplastic lymphoma kinase (ALK) gene translocations are pro-tumoral driver alterations that encompass 3-7% of non-squamous non-small cell lung cancer (NSCLC) with specific, clinic and histologic features. The therapeutic strategy depends on anti-ALK tyrosine kinase inhibitors (TKIs) of which crizotinib was the first approved for clinical use. Despite its use improved significantly progression-free survival, overall response rate and duration of response of this illness, after a median period of 10.9 months all patients progress due to the development of acquired resistance mutations in the ALK tyrosine kinase domain in approximately one third of patients. Moreover, 60-90% of patients treated with crizotinib has a progression in the central nervous system (CNS) in absence of extracranial worsening of the disease. This is primarily attributed to poor CNS penetration by crizotinib as many pre-clinical and clinical models suggest. For instance, in order to overtake acquired resistance to crizotinib, prolong the control of the disease and manage CNS localizations, several II and III generation TKIs have been developed. Some of them were approved after the failure of crizotinib (ceritinib, alectinib, brigatinib and lorlatinib) and in first line setting (ceritinib, alectinib and brigatinib) while others are still under evaluation for TKI-naive patients such as lorlatinib, ensartinib and entrectinib. In this review we will discuss the most recent results of new TKIs in order to describe a fast growing therapeutic landscape in this setting.
Insights
Anaplastic lymphoma kinase (ALK) gene translocations drive non-small cell lung cancer. New tyrosine kinase inhibitors (TKIs) offer improved outcomes, overcoming resistance and central nervous system progression seen with crizotinib.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Anaplastic lymphoma kinase (ALK) gene translocations are key drivers in 3-7% of non-small cell lung cancer (NSCLC).
- Crizotinib, the first ALK tyrosine kinase inhibitor (TKI), improved survival but acquired resistance and central nervous system (CNS) progression limit its long-term efficacy.
- Poor CNS penetration of crizotinib contributes to CNS disease progression in 60-90% of patients.
Purpose of the Study:
- To review the latest clinical results of novel ALK TKIs.
- To describe the evolving therapeutic landscape for ALK-positive NSCLC.
- To highlight strategies for overcoming resistance and managing CNS metastases.
Main Methods:
- Review of recent clinical trial data for second and third-generation ALK TKIs.
- Analysis of efficacy in both crizotinib-resistant and TKI-naive patient populations.
- Evaluation of CNS penetration and activity of emerging ALK-targeted therapies.
Main Results:
- Second and third-generation ALK TKIs demonstrate significant activity post-crizotinib failure.
- Several novel TKIs are approved for first-line treatment of ALK-positive NSCLC.
- Ongoing trials are evaluating TKIs like lorlatinib, ensartinib, and entrectinib in TKI-naive patients, showing promising results for CNS control.
Conclusions:
- A new generation of ALK TKIs offers improved efficacy and CNS penetration for NSCLC patients.
- These agents represent a rapidly advancing field with potential to overcome resistance and CNS progression.
- The therapeutic landscape for ALK-positive NSCLC is rapidly evolving, providing new options for patients.
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