The latest data of Lolatinib with an innovative structure is popular, and the new chapter of ALK first -line treatment

*For medical professionals for reading reference

Big Coffee authorized the latest results of CROWN research, and comment on the advantages of Loladinib.

After the first-generation and second-generation intercordnic lymphomin kinase (ALK) -Dyline lymphosate kinase inhibitors (TKI) came out, the adverse prognosis of patients with ALK mutant non-small cell lung cancer (NSCLC) in the past, making ALK mutations truly become "diamond mutations "But the targeted therapy of ALK mutation still has clinical needs that have not yet been met.

Recently, the three generations of Alk-TKI Lolatinib was approved by the State Drug Administration, and single drugs were used for the treatment of ALK's positive local advanced or metastatic NSCLC patients. Lolatini has achieved a significant improvement of anti -tumor activity through its unique structural advantages, and is expected to rewrite the pattern of ALK mutation NSCLC first and second -line therapy. The "medical community" invites Professor Liu Tao of Sun Yat -sen University to analyze the characteristics of ALK -positive NSCLC treatment of drugs from the perspective of pharmacy, and look forward to the advantages of Lolatini in Alk's positive NSCLC.

Iteration update-Alk-TKI's "Yangtze River Boat of the Yangtze River Push forward"

In the context of China's lung cancer treatment as a whole, the progress of ALK integration is very rapid. ALK-TKI has presented the scene of "three generations of the same hall". Professor Liu Tao explained from the perspective of drug research and development. The "survival of the fittest" during the update process. From the perspective of the mechanism of action, the first, second, and third-generation ALK-TKIs that have been approved for listing are all triple adenosine (ATP) competitive inhibitors [1]. , Inhibit ALK activity, block the activation of downstream signal pathways, and play an anti -tumor role. There are differences in the binding sites of these TKI and ALK ostease domain, so the effects are also different.

With the iterative update of ALK-TKI, the molecular structure of TKI drugs is also experiencing optimization and upgrading: the first generation of TKI Cizibinib, the second-generation TKI Alantinib, and Serentinib, all of which are non-loop-free , Long -chain -shaped compounds; and the three generations of Lolatinini are optimized based on the problem of first and second -generation TKIs, and adopted a completely different small molecular large -cycleamide structure [2].

The structure is better -interpreting the highlight of the unique large ring structure of Lolatini

From the perspective of the mechanism of drug action, Professor Liu Tao said that compared with the non -loop compounds, there are the following two structure advantages: the large ring structure:

The structure is more compact

Compared with non -loop -free compounds, the large ring structure is more compact, increasing the burial area, and can almost enter the pocket center of the ATP binding site. Improving the anti -drug resistance ability of Lolatinib; in addition, the structure of Lolatinib is still flexible, and the binding site is more comprehensive. These characteristics have enhanced Loladinib's anti -tumor activity [2]. The other TKI cannot completely enter the pocket due to a long chain.

Small molecular weight

Lolatinib adopts a large-cycle amide structure, making its drug molecular weight smaller, and improving molecular lipophilic [2], which is conducive to reducing the outer effect of P-glucocrin (P-GP) and enhancing Loladinib through The ability of the blood brain barrier [3], which effectively targets the brain metastases of patients with ALK mutations, and plays a dual role in treating brain metastases and brain protection. The molecular weight of the second -generation TKI drugs is relatively large, so it is more likely to be affected by the mutation of the front area of ​​the solvent. For example, the G1202R mutation is one of the main mutations that lead to the second -generation TKI resistance [4]; while Lolatinib's large -cycleamide structure, the structure, Avoid such situations.

The efficacy is better -Loladinib brings survival benefits to patients

Structural optimization can bring a strong mechanism, and the unique drug design of Lolatini is also transformed into excellent performance in clinical research. Professor Liu Tao pointed out that in 2022, the American Cancer Research Society (AACR) conference announced the latest follow -up data of the phase III CROWN research [5]. The study was included in 296 patients with previous unrepidedly treatment. Randomly divided into the Lolatinini group (n = 149) and the clipidininib group (n = 147).

As of September 20, 2021, the follow -up of the Loladininib and the Cizyininini group lasted 36.7 months and 29.3 months, respectively. Although the mid -level no progressive survival (PFS) of the Loladinib group has not yet reached, it is significantly better than the Kizotinib group. In 9.3 months of VS, the 3 -year PFS rate of the two groups was 63.5% VS 18.9%, respectively. Lolatinib has an overwhelming advantage. Compared with the Kazotinib group, the risk of disease progress or death in patients in the Lolatinib group decreased significantly by 73%, and the risk ratio (HR) was only 0.27. Optimum in treatment.

FIG

At the same time, research has confirmed that Lolatinib can strongly suppress intracranial lesions and prevent the progress of intracranial diseases. For the Loladinib group, the 3 -year intracranial progress rate of patients with a central nervous system (CNS) metastasis of the baseline exceeds 70%, and the proportion of intracranial progress without CNS metastasis patients with the baseline is as high as 99.1% Ni has a protective effect on the brain of ALK -positive NSCLC patients. Among the patients who can measure the brain metastases, Lolatininib and Klitininib groups have an objective relief rate (ORR) evaluated by BICR, respectively 83.3% VS 23.3%, respectively. 72.2% VS 7.7%, which reflects the large -cycleamide structure of Lolatinib significantly improved its ability to penetrate the blood brain barrier. Based on the excellent data of CROWN, the National Comprehensive Cancer Network (NCCN) released the 3rd edition of the 3rd edition of the NSCLC Clinical Practice in 2022, the first choice for the first choice for the first -line ALK -positive NSCLC treatment [6]. In addition to the field of first-line therapy, Lolatinib is also the first and second-generation Alk-TKI drug-resistant drugs, which is the last hole card that such patients depend on survival. The first and second -generation ALK inhibitors are not sensitive to Drug resistance of G202R, while Lolatinib has good anti -tumor activity for multiple ALK -resistant mutations including G1202R drug resistance [4].

Summarize

The advantages of Lolatinib's large -ring structure have greatly improved the activity of anti -tumor, and at the same time overcome the two major problems of CNS penetration and anti -resistance. CROWN's latest long -term data confirmed that Loladinib first -line therapy for ALK -positive NSCLC patients is better than Cizyinib. It is believed that with the approved listing in China in China, more ALK -positive late NSCLC patients will receive greater clinical benefits and further change the front -line pattern of Alk -positive NSCLC targeted therapy.

Expert Introduction

Professor Liu Tao

Director of Pharmacy, Director of the Pharmacy of Sun Yat -sen University, Director Pharmacist, Master Student at the School of Pharmacy of Sun Yat -sen University

American Pharmacist Association-Guangdong Pharmaceutical Society Drug Therapy Management (MTM) Training Pharmacist and Teachers

The Guangdong Pharmaceutical Society's anti -tumor drug prescription review and training teachers

Hosted and participated in the National Natural Science Foundation of China, Guangdong Provincial Department of Science and Technology, Guangdong Provincial Traditional Chinese Medicine Administration, and Guangdong Pharmaceutical Society research research

Research direction: Reasonable use of anti -tumor and related therapeutic drugs

Academic

Deputy Chairman of the China Pharmaceutical Education Association Clinical Drug Dependence Prevention and Evaluation Branch

Chairman of the Youth Committee of the Senior Pharmacy Committee of the Guangdong Pharmaceutical Society

Executive Deputy Chairman of the Guangdong Pharmaceutical Society of Tumor Medicine Expert Committee

Member of the 2nd Anti -tumor Drug Professional Committee of the Chinese Pharmaceutical Society

Executive Member of the China Anti -Cancer Association Cancer Clinical Pharmacy Commission

Reference materials:

[1] song x, et al. MedComm (2020). 2021; 2 (3): 341-350.

[2] Johnson Tw, et al. J Med Chem. 2014; 57 (11): 4720-4744.

[3] Angeli e, et al. Pharmaceutics. 2021; 13 (9): 1446.

[4] Pan Y, et al. FRONT Oncol. 2021; 11: 713530.

[5] solomen bj, et al. ACR 2022, abstract #ct223.

[6] 2022 NCCN NON-Small Cell LUNG CANCER Guidelines Version 3.

*This article is only used to provide scientific information to medical people, and does not represent the viewpoint of this platform

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