On April 29, lorlatinib (formerly known as lorlatinib) was approved by the State Food and Drug Administration for the use of one or more anaplastic lymphomas in the past. Kinase (ALK) tyrosine kinase inhibitor (TKI)-treated patients with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). Since then, the targeted drugs for lung cancer ALK gene mutation have truly achieved “three generations in the same family” in China, namely: first-generation crizotinib, second-generation alectinib, ceritinib, brigatinib, and ensartib. Nicholas, third-generation lorlatinib. Like targeted drugs for EGFR mutations, ALK inhibitors also have generation-by-generation properties.
The benefits of lorlatinib include:
1. The efficacy is significantly better than that of first-generation crizotinib
For different types of ALK+ patients, the first-line use of lorlatinib has an effective rate of up to 90%. In the CROWN clinical trial, the 3-year progression-free survival rates of patients in the lorlatinib group and crizotinib group were 64% vs 19%, respectively. The median progression-free survival in the crizotinib group was 9.3 months, while it had not been reached in the lorlatinib group, which is now more than 36.7 months. Compared with crizotinib, lorlatinib reduced the risk of disease progression or death by 72% in patients with ALK-positive advanced non-small cell lung cancer. It was approved by the FDA in March 2021 for the first-line treatment of ALK-positive non-small cell lung cancer.
2. Advantages for brain metastases from lung cancer
Brain metastases are a common site of disease progression in ALK-positive NSCLC, with up to 40% of patients with ALK-positive metastatic NSCLC developing brain metastases within 2 years of initial diagnosis or diagnosis. Lorlatinib has a strong ability to enter the brain and can act through the blood-brain barrier. In the CROWN study, the intracranial objective response rate was 82% with lorlatinib and 23% with crizotinib. Intracranial responses lasting 1 year were reported in 79% of patients in the lorlatinib group and 0% in the crizotinib group (0).
3. Can reverse first- and second-generation drug resistance
Lorlatinib is a life-saving drug after the resistance of the first and second-generation ALK-positive lung cancer targeted drugs, and it can inhibit 9 mutations of crizotinib resistance. For patients who are resistant to crizotinib, continuing to use lorlatinib has an effective rate of 69%; for patients with resistance to both first- and second-generation ALK inhibitors, lorlatinib is also effective, with an effective rate of up to 39% .
4. Also effective for ROS1 mutation
Lorlatinib is a dual-target inhibitor of ROS1 and ALK. In October 2019, The Lancet published the results of a phase 1/2 study of lorlatinib in the treatment of ROS1-positive NSCLC, with an ORR of 41% in the total population. The NCCN recommends lorlatinib for sequential therapy in patients with ROS1-positive advanced or metastatic non-small cell lung cancer that has progressed after first-line therapy.
With the widespread application of targeted therapy drugs, long-term survival of lung cancer patients is no longer an extravagant hope. ALK-positive non-small cell lung cancer ( The 5-year survival rate of patients with NSCLC is even more than 60%, and ALK inhibitors have become the cornerstone of the current treatment of advanced ALK-positive NSCLC.
The overall safety of lorlatinib is good, and the adverse reactions are mainly grade 1-2, but two adverse reactions need attention:
1. The most common side effects of lorlatinib are hypercholesterolemia and hypertriglyceridemia, with an incidence of more than 90%, which requires oral lipid-lowering drugs to control.
2. About a quarter of patients treated with lorlatinib experienced neurocognitive side effects, including difficulty with multitasking, slow speech, and memory loss. In addition, 15% of patients showed emotional instability. Neurocognitive and emotional side effects can be ameliorated or reversed by drug dose reduction or interruption.