- Lorlatinib (informal transliteration of the Chinese name) is a third-generation ALK/ROS1 inhibitor with potent, highly selective and brain-permeable properties that shows extraordinary efficacy potential in patients with ALK or ROS1-positive NSCLC that has progressed after treatment.
Small molecule tyrosine kinase inhibitors (TKI) are a class of targeted agents with better efficacy and more established applications. The EGFR-TKI or ALK-TKI class of targeted therapies can be very effective in the treatment of lung cancer, especially non-small cell lung cancer (NSCLC), in the presence of EGFR mutations or ALK rearrangement variants.
ALK and ROS1 rearrangements are unique molecular subtypes of lung cancer, and crizotinib, a first-generation ALK/ROS1 inhibitor, is the first-line agent for eligible patients. However, resistance occurs in most patients after a period of dosing, and the efficacy is more very limited in patients who develop central nerve metastases.
Ceretinib, erlotinib, and bucatinib, as second-generation ALK/ROS1 drugs, are effective in 40% to 50% of patients with crizotinib resistance, but are not effective in ALK G1202R point mutations. Therefore, the industry has been looking forward to the emergence of other alternative new drugs.
Laurelatinib is coming on strong
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Lorlatinib (informal transliteration) is a third-generation ALK/ROS1 inhibitor with potent, highly selective, and brain-permeable properties that has shown efficacy in patients with ALK or ROS1-positive NSCLC that has progressed after treatment, with low-dose effects in patients with point mutations such as ALK G1202R and ROS1 G2032A. The results of this study are summarized below.
In April 2017, loratinib was granted “breakthrough drug status” by the FDA for ALK-positive NSCLC that has progressed after prior treatment with one or more ALK inhibitors. The drug was also accepted for New Drug Application in the European Union and Japan.
These applications are largely based on data from previous studies. In biochemical and cellular assays, loratinib was more effective than the previous ALK inhibitors. The clinical phase I trial of loratinib enrolled 54 patients. The results showed that in these advanced NSCLC patients who were ALK or ROS1 positive, most had CNS metastases, and had failed no less than 2 previous TKI therapies, loratinib showed both systemic and intracranial efficacy, and therefore may be an effective treatment for ALK-positive NSCLC patients who are resistant to existing targeted therapies.
Lauratinib hits first line
In October 2017, complete data from the phase II study of loratinib were published. The trial enrolled 275 patients with NSCLC, with crizotinib as a control. The trial data showed:
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1. in untreated ALK-positive patients, the overall remission rate (ORR) for loratinib was 90%, with an intracranial overall remission rate (IC-ORR) of 75% in patients with brain metastases;
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2. In ALK-positive patients previously treated with crizotinib, with or without prior chemotherapy, the overall remission rate was 69% with lauratinib and 68% with brain metastases;
3. For ALK-positive patients previously treated with other ALK inhibitors, with or without chemotherapy, the overall remission rate was 33%; the overall intracranial remission rate for patients with brain metastases was 48%.
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4. Among patients who progressed after prior treatment with 2 to 3 ALK inhibitors, with or without chemotherapy, the objective remission rate was 39%, with an overall intracranial remission rate of 48% in patients with brain metastases.
5. The overall remission rate in ROS1-positive patients, with or without prior therapy, was 36%. The overall intracranial remission rate for patients with brain metastases was 56%.
The study also showed that loratinib was well tolerated, with the most common adverse reactions being hypercholesterolemia, hypertriglyceridemia, edema, peripheral neuropathy, and weight gain. Most adverse reactions were controlled by dose reduction, delayed dosing, or standard drug therapy, and there were no treatment-related deaths, with only 3% of patients discontinuing treatment due to drug-related adverse reactions.
Currently, another phase III clinical trial, CROWN (NCT03052608), comparing crizotinib with loratinib in the first line treatment of NSCLC, has begun enrolling patients. It is expected to provide strong evidence for the entry of loratinib into the first-line treatment of patients with lung cancer, particularly brain metastases from NSCLC.
Summary and outlook
Patients with ALK-positive metastatic NSCLC who have been previously treated with one or more ALK inhibitors are now virtually drug-free, with very low five-year survival rates. Based on current findings, there is extraordinary potential for loratinib in ALK-positive NSCLC patients who have progressed after treatment, particularly with brain metastases.