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Lorlatinib for the treatment of patients with non-small cell lung cancer

T Akamine1, G Toyokawa2, T Tagawa1

  • 1Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Drugs of Today (Barcelona, Spain : 1998)
|March 1, 2019
PubMed

Insights

Lorlatinib, a third-generation tyrosine kinase inhibitor (TKI), effectively targets anaplastic lymphoma kinase (ALK) and ROS1, overcoming resistance mutations and improving central nervous system efficacy in non-small cell lung cancer.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Conventional anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinase inhibitors (TKIs) face limitations including acquired resistance mutations (e.g., ALK G1202R, ROS1 G2032R) and poor blood-brain barrier (BBB) penetration, hindering efficacy against central nervous system (CNS) metastases.
  • Lorlatinib represents a significant advancement as a third-generation TKI designed to overcome these challenges.

Purpose of the Study:

  • To introduce lorlatinib, a novel TKI targeting ALK and ROS1.
  • To highlight lorlatinib's design to overcome resistance mechanisms and improve CNS penetration compared to earlier TKIs.
  • To discuss its regulatory milestones and clinical trial promise.

Main Methods:

  • Development of a potent and selective TKI.
  • Assessment of blood-brain barrier (BBB) permeability.
  • Evaluation of efficacy against resistance mutations and CNS metastases in preclinical and clinical settings.

Main Results:

  • Lorlatinib demonstrates enhanced potency and selectivity for ALK and ROS1.
  • Improved BBB permeability compared to previous-generation TKIs.
  • Received breakthrough therapy designation (FDA, April 2017) and regulatory approvals in Japan (September 2018) and the USA (November 2018).

Conclusions:

  • Lorlatinib is a promising therapeutic option for ALK-rearranged non-small cell lung cancer (NSCLC), particularly for patients with resistance mutations and CNS involvement.
  • Its improved pharmacokinetic profile and efficacy suggest a growing role in NSCLC treatment.
  • Clinical trial data indicate significant potential for lorlatinib in improving patient outcomes.
Keywords:
ALK inhibitorsCancer therapyLorlatinibNon-small cell lung cancerROS1 inhibitors

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