At present, small molecular compounds used in tumor therapy mainly include tyrosine kinase inhibitors (TKI) and small molecular compounds acting on other targets. Tyrosine kinase inhibitors include receptor and non-receptor tyrosine kinase inhibitors. However, small molecular compounds targeting other targets include histone deacetylase inhibitors, sirolimus target protein inhibitors and apoptosis inducers.
Kzotinib
EML4-ALK is a potential therapeutic target for non-small cell lung cancer. At present, only crizotinib (PF-0234 1066), which is also an inhibitor of methionine /HGF receptor tyrosine kinase, has entered the clinical experimental research stage and was developed by Pfizer. It is a selective ATP competitive small molecule inhibitor that inhibits c-Met/ hepatocyte growth factor receptor (HGFR), ALK tyrosine kinase and its carcinogenic variants (such as c-Met/HGFR mutant or ALK fusion protein).
The objective remission rate of crizotinib in the treatment of ALK positive non-small cell lung cancer is 60%, and the progression-free survival time is 8- 10 months, which significantly improves and prolongs the overall survival time. It should be noted that the administration strategy of crizotinib is different from other targeted drugs. It takes four months to give eight months in the first year, and four months in the second year to get a lifetime gift. It costs hundreds of thousands in total, and the price is relatively high, so it must be clear that it is ALK mutation before use.
drug resistance
In any case, one disadvantage of targeted drugs is drug resistance. Patients who use crizotinib often develop resistance to crizotinib within 1-2 years, and the recurrence and progress of the central nervous system are more common.
? ALK secondary drug-resistant mutation
Principle of drug resistance: It accounts for about 37% of the drug resistance of ALK-positive non-small cell lung cancer, which is divided into ALK kinase region mutation (28%) and ALK fusion gene copy number amplification (9%). Coping strategy: ALK resistance is dominant, and ALK signaling pathway is often reserved, which can be controlled by more effective second-generation or third-generation ALK targeted inhibitors. Such as celetinib and Ai Le tinib. Patients with L 1 198F can use crizotinib again.
Promote gene transformation
Principle of drug resistance: Tumors activate other signal pathways through other mechanisms to replace the dependence on ALK and downstream signals. Such as EGFR mutation or phosphorylation, KRAS mutation and c-KIT amplification.
Coping strategy: according to the genes activated by bypass, consider using combined targeted drugs.
Tumor heterogeneity
Principle of drug resistance: Tumor cells have different driving genes in different time and space. Due to sampling bias, the results based on single gene detection can not understand the whole picture of tumor gene mutation. Coping strategies: multiple tests, using second-generation sequencing to increase the sequencing depth, and try to fully understand the gene mutation information of tumors.
Other drugs
After crizotinib resistance, there are second and third generation ALK inhibitors. Recently, it was found that the third generation ALK inhibitor, Loratinib (3922), was resistant. If the patient has drug resistance caused by L 1 198F, crizotinib can be used again. The following briefly introduces several second-generation and third-generation ALK targeted drugs:
The efficacy of 1 and ai-aletinib (code CH5424802) is 0/0 times that of Bizot tinib, which can resist most ALK kinase mutations and control brain lesions well. A clinical study in Japan used a dose of 300mg twice a day, and 43 of 46 patients achieved objective remission (the objective remission rate was 93.5%). Japan has approved the use of this drug, and the US FDA has also approved this drug for patients who are resistant to crizotinib treatment. A study was reported at the ASCO meeting on 20 16. In the first-line treatment of ALK positive non-small cell lung cancer, Ai Le tinib is obviously superior to crizotinib. The median PFS of crizotinib was 10.2 months, while that of Ai Le tinib was over 20.3 months. Compared with crizotinib, Ai Le tinib significantly reduced the risk of disease progression or death by 66%.
2.Ceritinib (LDK378) has a good activity on C 1 156Y. The maximum tolerated dose of this drug is 750mg per day, which may not be so high in Asia, that is, 600mg. The ORR of 79 patients with ALK positive non-small cell lung cancer who were resistant to crizotinib was 57%. A clinical study involving 1 14 patients showed that the median PFS of sertinib was 8.6 months. The most common side effects are nausea, diarrhea, vomiting and fatigue. Some patients have reported that the side effects of sertinib are very great and few people tolerate it, but if it survives, it may benefit for a long time.
3. A new dual inhibitor of ALK and EGFR, BRITINIB (AP26 1 13), can effectively inhibit ALK l 1 196m mutation and EGFR T790M mutation. According to a research result released at the ASCO meeting in 2065438+06, patients were randomly divided into two groups: patients in group A took 90mg of britinib orally every day, patients in group B took 90mg of britinib orally every day for the first 7 days, and then increased to 180mg. The effective rates of the two groups were 46%/54 respectively. There were 1 cases in group A and 5 cases in group B. The median PFS was 8.8 months/1.1month, respectively. It is proved that this medicine has a good curative effect.
4.Lorlatinib (PF06463922) should be regarded as the third generation ALK inhibitor, which can inhibit nine mutations of crizotinib resistance, and has strong blood-brain barrier permeability and strong brain entry effect, especially suitable for patients with advanced non-small cell lung cancer resistant to other ALK. 20 16 On June 5th, Pfizer announced the phase I/II clinical research data of this drug at ASCO meeting. Among the 54 registered patients, 4 1 was ALK positive and 12 was ROS positive, among which 39 patients had brain metastasis. The final dosage regimen of this clinical trial is 1 time 100mg per day, the total effective rate of patients is 46%, 3 patients achieve complete remission, 16 patients achieve partial remission, and the median PFS is 1 1.4 months. In addition, it also showed the effect of reducing the volume of metastatic brain tumors.
References:
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doi:？ 10.3779/ISSN . 1009-34 19.20 13 . 02 . 07
/p/2 1769033
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