Professor Cheng Ying: Lolatini has set a new record of first -line treatment in the ALK field. The lower HR value may change clinical practice

*For medical professionals for reading reference

Alk positive NSCLC ushered in a new breakthrough in front -line treatment.

On April 29, 2022, the three-generation intercordnic lymphoma kinase (ALK)-The TKI Loladinib was approved by the National Drug Administration (NMPA), which was approved by the National Drug Administration (NMPA). Treatment of patients with advanced or metastatic non -small cell lung cancer (NSCLC). Lolatini has a strong blood -brain barrier through ability. It also shows amazing clinical efficacy in the Crown research of ALK -positive NSCLC in the first line. Essence It is believed that with the approval of the innovative products in China, it will bring opportunities for patients to gain longer survival benefits while enriching clinical treatment choices.

As an expert in the field of lung cancer treatment in Jilin Cancer Hospital, Professor Cheng Ying has a very rich clinical experience in the diagnosis and treatment of ALK -positive NSCLC. The "medical community" invites Professor Cheng Ying to comment on the clinical significance of the HR value of PFS in CROWN research, and the impact of Crown research on the nSCLC front -line treatment pattern.

Medical community

Throughout the PFS data published by Alk-TKI, what do you think of the lower PFS risk ratio (HR = 0.27) of Lollantinib vs. Cizibinib in Crown research?

Professor Cheng Ying: ALK mutation is recognized as a "diamond mutation", accounting for about 5%-7%of NSCLC. From the generation of Alk-TKI Kizinini, it is confirmed to bring significant survival benefits to patients with ALK positive NSCLC. The second-generation Alk-TKIS Siridinib, Alantinib, Bogntinib and domestic drug Endinib also continued to refresh the survival of ALK-positive NSCLC patients. Judging from the benefits of PFS, the PFS HR of the first-generation TKI Cizinib is 0.45, and the mid-bit PFS is 13.6 months; the PFS HR value of the second-generation TKIS is between 0.37-0.55, which further expands the survival of Alk-TKIS. Benefits.

Since then, the three generations of Alk-TKIS Lolatinib once again surprised us. In the III study of the first -line treatment of Klitininini -in the CROWN research, when the 3 -year follow -up (36.7 months), the Blind Independence Evaluation Committee (BICR ) The evaluation PFS is NR and 9.3 months, and HR reaches the lowest value of 0.27 (95%CI 0.184-0.388), which means that Lolatini can reduce the progress or death of the disease by 73%; the researchers evaluated PFS is NR and 9.1 months, and the HR value has been reduced to 0.19, creating the best PFS benefit record of Alk-TKIS so far. Lolatinib has also become Alk-TKIS, which has a PFS rate of more than 60%in the first three-year PFS rate, and 63.5%of the 3-year PFS rate of Bitkitininib has more than 3 times. In addition, the mid -PFS of Lolatinib has not been reached at 36.7 months of follow -up, reminding the PFS of the medicine to further increase, and Loladinib's excellent data has also given clinicians and patients clinical drug selection. Big confidence.

Medical community

Based on CROWN's dazzling data at the AACR conference in 2022, how do you think that Lolatini will have an impact on the first -line treatment pattern of ALK -positive NSCLC?

Professor Cheng Ying: The first interim analysis of CROWN research was published in Nejm in 2020. At the 2022 American Cancer Research Society (AACR) meeting, the data was announced again. The median PFS of the Latinini group has not yet reached. The median PFS of the Kizininib group is 9.3 months, the two -year PFS rates of the two groups are 68.2%and 21.5%, respectively. (HR = 0.27); the objective relief rate (ORR) of BICR assessment is 77.2%and 58.5%, respectively; patients with brain metastases with brain metastases in the baseline are NR and 7.2 months, respectively. In patients, the two groups were NR and 11.0 months, respectively, and HR = 0.29.

At the ASCO conference in 2022, the curative effect of sequential treatment after the Crorantininib or Krateininib was discontinued in the Crown research. The proportion of patients with the treatment of anti-tumor therapy for the treatment of anti-tumor therapy for the treatment of anti-tumor therapy for the treatment of anti-tumor therapy, respectively, and ALK-TKI as the first sequential treatment plan. The ORR of the patients with Guanzhi therapy was 24.2%and 15.5%, respectively, and the duration of median sequence therapy was 9.6 months and 13.3 months, respectively. The median PFS2 was NR and 39.6 months, and the HR value was 0.45 (95%CI: 0.2988888 -0.672), the 3 -year PFS2 rate of the Lolatinini group was as high as 74.0%(the control group was only 18.9%), suggesting that of the patients who progressed after the treatment of the first -line treatment of Lolatini, the relief rate was higher. Preface treatment can bring further survival benefits to patients.

In view of the excellent clinical research data obtained in CROWN in CROWN, in March 2021, the US Food and Drug Administration (FDA) approved its indications for ALK -positive NSCLC first -line therapy. The National Comprehensive Cancer Network (NCCN ) The guide also incorporated it into the first -line treatment and recommended as a preferred recommendation. In China, since 2021, the Chinese Clinical Oncology Society (CSCO) non -small cell lung cancer diagnosis and treatment guidelines are also based on CROWN research results for the first time as a III -level recommendation for treatment. In April 2022, Lolatini was approved to be listed in China for the treatment of the first -line treatment of ALK -positive NSCLC, becoming the first third -generation ALK inhibitor in China. The availability of the drug provides a more choice of survival advantages for the first -line therapy of the late NSCLC in China ALK mutation. It truly opened the era of "3+X" treatment. It will also cause new thinking such as how the front-line ALK-TKIS chooses, the superior population, and the treatment of treatment after drug resistance.

Medical community

Based on the dazzling data updated by Lollantinib AACR, which patients should you recommend or choose Lollantinib?

Professor Cheng Ying: At present, ALK-TKIS has entered the era of three generations. Unlike the first/second generation Alk-TKIS, the chemical structure of the three generations of Lolatinib is very different. The first/second-generation ALK-TKIS is long-chain, and Lolatinib is a compact large-cycleamide structure. The binding site with ATP pocket is deeper and stronger. The structure flexible can be folded. More comprehensive points can enhance the activity of anti-tumor and anti-drug resistance; large-cycle amide groups can optimize lipophilic, not affected by the external discharge of P-GP and BCRP, and smaller molecular weight (first/second generation> 450, Lolatinib 406) can increase the penetration of the central nervous system (CNS). Therefore, Lolatini can play a dual role in the treatment and prevention of intracranial metastases.

In the data released by AACR in 2022, in addition to the lowest value of HR history of 0.27 in PFS benefits, Loladinib also made people's eyes shine.

ALK -positive patients who are not metastasized by the baseline, Lolatinib acts as the role of "brain protection":

First of all, Lolatini is the only ALK-TKI, which has decreased more than 70%of the disease progress or death risk in the whole population. The HR of the ITT crowd is 0.27 and the HR is 0.21 among the patients who have brain metastasis. The risk of death is reduced by 79%; among the patients with no brain metastases, HR 0.29, the risk of progress or death is reduced by 21%. Secondly, the risk of intracranial progress by 92%of Lolatinininibininib (NR VS 16.6 months, HR 0.08). For patients with a brain -without migration, Lolatini has a thirteen -year intracranial progress rate of 99.1%(only 1 of 112 patients with intracranial progress), which is significantly higher than the 49.8%(HR 0.02) of the Kazininib group. It is also the only ALK-TKIS that reduces the risk of intracranial progress of patients by more than 90%, which has achieved comprehensive and in-depth brain protection of ALK-positive NSCLC patients.

For Alk -positive patients with the baseline with brain metastases, Lolatinib has a significant benefit:

Cranial progress is an ALK-positive NSCLC patient who needs to face the treatment challenge. Because the generation of Alk-TKI cannot effectively pass the blood and brain barrier, it causes the clinical effect of patients with brain metastases, making CNS a "refuge" for tumor growth. The total incidence of CNS metastasis after the treatment of first-line CNS can be increased to about 50%-60%. In the CROWN study, Lolatini has a very prominent effect on the baseline with brain metastases. Compared with clipininib, it can reduce the risk of intracranial progress by 90%, and the 3 -year intracranial progress rate is 72.8%; Lolatini The intracranial ORR reaches 83.3%, and the intracranial relief (CR) rate reaches 72.2%, which is the only ALK-TKI that can completely disappear the intracranial lesions of more than 70%of patients. In terms of systemic disease control of patients with brain metastases, Lolatinib reduced the risk of disease progress or death risk of up to 79%, and for the first time, the patient's three -year PFS rate exceeded 50%(50.3%). Lolatinib showed a strong curative effect in patients with brain metastases.

Therefore, no matter whether the patient is accompanied by brain metastases, Lolatinib is an ideal first -line therapy drug, which can be safely and effectively extended the PFS of ALK -positive NSCLC patients for more than three years. The incidence is only 7%), which is convenient for medication, which is conducive to patients' long -term medication.

However, it should be noted that the CROWN research design does not allow it to cross after progress. Can PFS extension finally transform into OS benefits? Objectively speaking, there is no sufficient evidence that the treatment effect of the first line using Lolatinib is definitely better than the role played by Lollantinib in back -line therapy. More data is required for support. In addition, in terms of toxicity and side effects, in addition to hyperlipidemia, the impact of Lolatinib on the function of the nervous system cannot be ignored. In the CROWN study, the proportion of patients with cognitive problems and emotional adverse reactions reached 21%and 16%, key attention should be given in clinical use; in the end, all drugs will inevitably occur after application of drugs, and Alk-TKIS is no exception. The resistance that overcomes the first -line application of Lolatinib is also a problem that needs to be explored in the future. Medical community

For the approval of Lolatinib, can you ask you to say a message?

Professor Cheng Ying: I am very happy to see ALK -positive NSCLC ushered in a new breakthrough in front -line treatment. Lolatini's front -line therapy has caused ALK -positive NSCLC PFS for more than three years, which has effectively promoted the management of slow diseases of lung cancer.

With the approval of Lolatinib in our country, it will save the life of more ALK -positive NSCLC patients and bring new hope to more families. Looking forward to entering medical insurance as soon as possible, benefiting more NSCLC patients, bringing high -quality and excellent treatment options.

Expert Introduction

Professor Cheng Ying

First -level professor, the leader

Doctoral tutor, postdoctoral workstation mentor

Enjoy the special allowance of the State Council, the Ministry of Health contributes to young and middle -aged experts

Secretary of the Party Committee of Jilin Cancer Hospital

Director of the Cancer Center of Jilin Province

Director of integrated diagnosis and treatment center of malignant tumor clinical research in Jilin Cancer Hospital

Director of Jilin Cancer Diagnosis and Treatment Center

Vice Chairman of the China Clinical Oncology Society (CSCO)

CSCO small cell lung cancer professional committee chairman

CSCO Clinical Research Expert Committee Council Chairman

The chairman of the Chinese Anti -Cancer Association's Lung Cancer Professional Committee

CSCO non -small cell lung cancer professional committee deputy chairman

CSCO Oncology Big Data Expert Committee Deputy Chairman

Deputy Chairman of the Cancer Cancer Specialist Committee of the Chinese Medical Association

Deputy Chairman of the Cancer Multi -disciplinary Diagnosis and Treatment Committee of the Chinese Physician Association

Deputy Chairman of the Professional Committee of Ling Cancer Training Professional Committee of the Chinese Medical Doctors Association

Members of the National Health and Family Planning Commission's common tumor standardized diagnosis and treatment expert group

Chairman of the Tumor Branch of the Jilin Provincial Physician Association

Chairman of the Jilin Provincial Medical Association Cancer Professional Committee

references

[1].NakagawaK,etal.Finalprogression-freesurvivalresultsfromtheJ-ALEXstudyofalectinibversuscrizotinibinALK-positivenon-small-celllungcancer.LungCancer.2020;139:195-199.[2].HornL,WangZ,WuG,etal.Phase3RandomizedStudyofEnsartinibvsCrizotinibinAnaplasticLymphomaKinase(ALK)–PositiveNSCLCPatients:eXalt3 .2020WCLCPRESIDENTIALSYMPOSIUM.

[3].CamidgeDR,etal.BrigatinibVersusCrizotinibinAdvancedALKInhibitor-NaiveALK-PositiveNon-SmallCellLungCancer:SecondInterimAnalysisofthePhaseIIIALTA-1LTrial.JClinOncol.2020;38(31):3592-3603.

[4].Benjamin J. Solomon, et al. Updated Efficacy and Safety From the Phase 3 CROWN Study of First-Line Lorlatinib vs Crizotinib in Advanced Anaplastic Lymphoma Kinase (ALK)–Positive Non-Small Cell Lung Cancer (NSCLC). AACR2022 , Abstract #ct223.

[5] .peters, et al. Alectinib versus crizotinib in Untreated Alk-POSITIVE NON-CELL LUNG CANCER. N English J med 2017 [6] .Camidge et al.

[7] .zou Z, Xing P, hao x, et al. IntracrArAnial Effical of Alectinib in Alk-positive nsclc Patients with cns metastases-a multicenter Retrospective study (22222222222222222222222222222222. 2022222222222222222.

*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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