In 2007, Japanese professors firstly discovered ALK rearrangement and identified the fusion of ALK and EML4 in non-small cell lung cancer specimens. EML4 can promote the activation of ALK kinase domain, thereby promoting cell proliferation and ultimately leading to the occurrence and development of tumors. ALK tyrosine kinase inhibitors (TKI) inhibit signal transduction by inhibiting autophosphorylation, thus producing antitumor effects. At present, ALK-positive targeted drugs are being studied in the fourth generation, bringing hope to a large number of patients. ALK overexpression and point mutations have also been found in neuroblastoma, ovarian cancer, breast cancer, and other cancers.
First-generation ALK-TKI
As the first oral small molecule ATP-competitive ALK-TKI approved by the Food and Drug Administration (FDA), crizotinib is initially used as a MET-TKI and rapidly enters the ALK field after the discovery of the role ALK fusion plays in lung cancer. Studies have shown that its efficacy is better than that of first-line chemotherapy. The median progression-free survival (mPFS) (10.9 months VS. 7 months) and objective response rate (ORR) (74% VS 45%) are both increased. However, the central nervous system (CNS) permeability of crizotinib is poor, which makes patients taking crizotinib often develop disease progression due to brain metastasis within 1-2 years.
Second-generation ALK-TKI
The second-generation ALK-TKI solves the problem that it is difficult for first-generation ALK-TKI to enter the blood-brain barrier and is effective in patients with crizotinib resistance. The second-generation ALK-TKI includes ceritinib, alectinib, brigatinib, and ensartinib.
In 2013, Novartis reported the discovery of compound 3 (ceritinib), which resulted from structural optimization of compound 2 to improve kinase selectivity and prevent the formation of reactive metabolites. Ceritinib has obvious curative effect on most drug resistance mutations except G1202R and F1174C. The FDA approved it in 2014 for patients intolerant or resistant to crizotinib and approved it as a first-line treatment in 2017.
Alectinib is the second-generation ALK-TKI, which is specially designed for the ALK pathway. It was discovered by high-throughput screening in the compound library, and further optimized by remodeling the 3D structure to improve the binding force and selectivity of ALK kinase domain and enhance the inhibition of the target. Compared to the first-generation crizotinib, its IC50 is greatly reduced to 1.9nM with the specificity and efficacy of the drug improved.
Preclinical studies have confirmed the inhibitory effect of brigatinib on 17 types of ALK resistance mutations, including the G1202R mutation. The ALTA-1L research is a head-to-head first-line study of brigatinib and crizotinib, which demonstrates the obvious advantages of the former.
An analysis including brigatinib, alectinib, and crizotinib shows that alectinib has the highest efficacy among all ALK-positive patients, while brigatinib has the highest efficacy among ALK-positive patients with CNS metastasis. Therefore, the FDA approved brigatinib for patients intolerant to crizotinib or resistant to crizotinib in 2017 and approved it as a first-line treatment in 2020.
Third-generation ALK-TKI
As a third-generation ALK-TKI, lorlatinib can overcome a variety of ALK resistance mutations, including G1202R, and is an effective choice after the resistance to first- and second-generation ALK-TKI occurs.
Fourth-generation ALK-TKI
Preclinical studies have revealed that TPX-0131 is effective against resistance mutations of approved ALK-TKI, especially G1202R, L1196M, and compound mutations (e.g., G1202R/L1196M and G1202R/L1198F). It is similar to lorlatinib in inhibiting EML4-ALK phosphorylation while the inhibitory effect against G1202R and compound mutations is significantly higher than that of lorlatinib.
Other ALK-TKI
As ALK, TRKA-C, and ROS1-TKI, entrectinib does not seem to have advantages compared with other TKIs.
Rebastinib can overcome the resistance caused by acquired mutations in ALK, TRKA-C, and ROS1. At present, the clinical activity of rebastinib needs to be further verified.
CT-707 can be used in patients with initial treatment or crizotinib resistance. A preliminary study has proved that CT-707 is effective in ALK-positive Chinese patients, and the study is still in progress.
PLB1003 is a highly efficient second-generation ALK-TKI developed based on the enhanced drug resistance of EML4-ALK fusion gene. Preclinical data suggest that PLB1003 is safe and effective, with potential clinical benefit in patients with crizotinib resistance.
Conclusion
As the survival time of ALK-positive patients is gradually prolonged, it is very important to optimize the choice of medication. The PFS of second-generation ALK-TKI is significantly better than first-generation ALK-TKI for first-line treatment. Alectinib is the preferred first-line treatment based on multiple factors such as drug efficacy, drug accessibility, guideline recommendation, and economics. For patients already on first-line ALK-TKI, second-generation ALK-TKI can be used after drug resistance; for patients with second-generation ALK-TKI resistance, third-generation ALK-TKI can be used, and patients are recommended to undergo genetic testing again; for patients with third-generation ALK-TKI resistance, fourth-generation ALK-TKI can be tried in the future.
Related Tags:
| Name | Description |
| ALK | Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ALK gene. |
| MET | c-Met, also called tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR), is a protein that in humans is encoded by the MET gene. |
Related Products:
| Tag | Name | CAS | Synonyms | Description |
| MET | Crizotinib | 877399-52-5 | PF-02341066 | Crizotinib is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor. |
| ALK | Ceritinib | 1032900-25-6 | LDK 378; Zykadia; NVP-LDK378-NX | An anaplastic lymphoma kinase (ALK)-positive inhibitor used for the treatment of non-small cell lung cancer (NSCLC). |
| ALK | Alectinib | 1256580-46-7 | CH-5424802; AF-802; RG-7853; RO5424802 | Alectinib is an oral drug that blocks the activity of anaplastic lymphoma kinase (ALK) and is used to treat non-small-cell lung cancer (NSCLC). |
| ALK | Brigatinib | 1197953-54-0 | AP-26113 | Brigatinib is an orally bioavailable inhibitor of anaplastic lymphoma kinase (ALK; IC50 < 100 nM in Ba/F3 cells). |
| ALK | Ensartinib dihydrochloride | 2137030-98-7 | X-396 dihydrochloride | Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. |
| ALK | Lorlatinib | 1454846-35-5 | PF-06463922 | Lorlatinib is an ATP-competitive ROS1/ALK inhibitor with potential antitumor activity. |
| ALK | Entrectinib | 1108743-60-7 | RXDX-101; NMS-E628 | Entrectinib is an orally bioavailable pan-TrkA/B/C, ROS1 and ALK inhibitor with IC50 ranging between 0.1 and 1.7 nM. |
| ALK | Rebastinib | 1020172-07-9 | DCC-2036 | Rebastinib is an orally bioactive inhibitor of Bcr-Abl that binds to and inhibits Bcr-Abl fusion oncoprotein. |