Professor Song Yong: ALK-positive advanced NSCLC, you need to understand these developments!

*Only for medical professionals to refer to the current status and prospects of treatment of ALK-positive advanced NSCLC
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From July 15th to 18th, 2021, the "16th CSCO Changbai Tumor Summit Forum" was held in Changchun City
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The conference is oriented to clinical practice and application, focusing on cutting-edge precision medicine information, and discussing the innovative development of cancer diagnosis and treatment with cancer colleagues across the country
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Professor Song Yong from the Department of Respiratory Diseases of Nanjing University Jinling Hospital and the Institute of Respiratory Diseases of Nanjing University introduced the current status and prospects of ALK-positive advanced non-small cell lung cancer (NSCLC) treatment in detail at the meeting
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"Medical Cancer Channel" specially compiled this report for readers
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1.
Review of the course of targeted therapy for ALK-positive NSCLC.
Based on current clinical research, ALK-positive NSCLC tends to be a group of diseases, because ALK gene mutations can be mainly divided into fusion mutations, point mutations, and amplifications from the driving mechanism.
Mutations, their response to treatment is different
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Professor Song Yong first reviewed the characteristics and clinical research of ALK-TKI's third-generation drugs in detail
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The first-generation crizotinib has ALK-binding activity; the second-generation promotes exposure to the central nervous system, increases penetration into the brain, and is effective against the first-generation mutation; the third-generation loratinib has not yet been marketed in China , It is effective against the resistance of the first and second generation mutations
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The first-generation TKI crizotinib is the first targeted therapy for ALK-positive patients.
From PROFILE 1014 to PROFILE 1029, crizotinib and chemotherapy have achieved a good objective response rate (ORR) and no progress.
Lifetime (PFS)
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The results of the first-line clinical study of the second-generation TKI brigatinib ALTA-1L showed that the PFS was 24 months and the control group was only 11 months; the PFS in the first-line clinical study of ALEX was 34.
8 months
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The third-generation TKI loratinib.
Phase II clinical trials have proved that the ORR of loratinib is 90% for newly-treated patients, and the ORR for patients previously treated with crizotinib is 69.
5%, and for ALK-non-crizotinib in the past.
The ORR of patients treated with TKI was 32.
1%, and the ORR of patients treated with more than two ALK inhibitors was 38.
7%.
It is expected that they will benefit in overall survival (OS)
.

2.
Current status and progress of targeted therapy for ALK-positive NSCLC.
Strictly speaking, there has not been much progress in targeted therapy for ALK-positive NSCLC in the past one or two years.
Professor Song Yong briefly summarized the current situation as "successful" and expanded Describes a series of clinical trials
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①The second-generation TKI Ensatinib independently developed by China has achieved good results in the first-line clinical study of eXalt-3, with a PFS of 31.
3 months
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②The final OS analysis results of the Phase III J-ALEX study announced at the annual meeting of the American Society of Clinical Oncology (ASCO) this year showed that whether the first-line use of aletinib or crizotinib, the final OS results are almost the same, which is worth thinking about Why is the obvious difference in PFS not in exchange for OS benefit? Professor Song Yong further analyzed that part of the possible reason is that the follow-up treatment is not balanced
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In the crizotinib group, 91.
3% of patients received the first follow-up anti-tumor treatment, compared with only 46.
6% of the aletinib group; at the same time, 78.
8% of the crizotinib group received aletin However, only 10.
7% of patients in the aletinib group received crizotinib; the global ALEX study OS data is still immature, and new data is needed for further analysis
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③The third-generation TKI loratinib, the control group in the CROWN study was crizotinib
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The 12-month PFS rate was 78% in the loratinib group and 39% in the control group.
The HR was very low, 0.
28.
It can be seen that according to the current data, the advantages of the third-generation drugs compared to the first-generation drugs are very obvious
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Clinical trials have also found that the efficacy of loratinib is not affected by the mutation status of TP53
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Compared with the crizotinib group, regardless of the TP53 mutation status, the loratinib group had higher ORR, longer duration of remission (DOR) and PFS
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More importantly, compared with crizotinib, the risk of central nervous system (CNS) progression in the loratinib group was reduced by 93%
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The relationship between the efficacy of loratinib in the treatment of ALK-positive NSCLC and the type of EML4-ALK mutation: 20 ALK mutations and 1 ALK deletion were detected in 12 patients during the screening period (5 from the loratinib group, 7 from criazole Although the number of ALK mutations is very small, patients with or without ALK mutations treated with loratinib have higher ORR, longer DOR and PFS than crizotinib
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3.
Challenges and prospects of targeted therapy for ALK-positive NSCLC.
In view of the challenges and prospects of ALK-TKI therapy for ALK-positive NSCLC, Professor Song Yong summarized the following five points: ①Resistant third-generation targeted drugs may eventually not escape The fate of drug resistance is lost, but now that ALK-positive NSCLC mainly changes in the ALK-dependent pathway, the non-ALK-dependent changes are relatively small, which provides new possibilities for the development of a new generation of drugs or for drug use.
Sex
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Professor Song Yong gave two examples of ALK-TKI drug replacement.
After aletinib was resistant, brigatinib showed good activity in these patients [ORR reached 55.
6%, and disease control rate (DCR) was 89.
%], and it is well tolerated, providing a new option for the full-process management of first-line aletinib resistance
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At the same time, according to a domestic phase II registered clinical study, after crizotinib is resistant, enzatinib still has an effective rate of more than 70%
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To sum up, ALK is resistant, and there are more opportunities for alternative treatments between drugs, but the replacement is not random and must be accurately tested
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The third-generation ALK-TKI is effective against almost all ALK resistance mutations currently known, but the emergence of double mutations makes its resistance mechanism more complicated
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The in vitro study of the fourth-generation ALK-TKI drug has brought new hope.
TPX-0131 cell level IC50 is very low.
NUV-655 can not only overcome the G1202R+ compound mutation, but also has a strong ability to break through the blood-brain barrier
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For the emergence of other mutations, the strategy of combination therapy is particularly critical.
For example, MET mutations are more common in second-generation ALK-TKI resistance, and loratinib combined with crizotinib can overcome MET amplification resistance
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Professor Song Yong condensed that "the continuous advancement of drugs is the only way to overcome and delay drug resistance, and combined therapy can also be effective in some mechanisms
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" ②The status of immunotherapy in patients with ALK-positive NSCLC is more frequent in patients with ALK-positive and PD-L1 high expression.
However, the efficacy of immunotherapy is poor, and analysis suggests that it may be related to immune escape.
However, immunotherapy after ALK TKI resistance is still worth exploring
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③CNS metastasis is an important unmet clinical need.
Nearly 40% of ALK-positive NSCLC patients have brain metastases at first treatment.
After first-generation and some second-generation patients are resistant, the earliest metastasis site is also brain metastasis
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Comparing the three generations of drugs together, the outcome of treatment of NSCLC brain metastasis: the third generation is better than the second generation, and the second generation is better than the first generation
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④The value of ALK-TKI in patients with operable NSCLC is still to be studied.
There are currently studies exploring the neoadjuvant combined treatment of ALK-TKI.
Professor Song Yong concluded that "the first clues are visible, and the evidence is awaiting
.
"
⑤The whole diagnosis and treatment process IV.
Summary Professor Song Yong elaborated on the development of ALK-TKI in this meeting, and looked forward to the combination of ALK-TKI and immunotherapy and the candidate drugs of the fourth generation of ALK-TKI, and summarized the current ALK The challenges and prospects of targeted therapy for positive NSCLC
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It also emphasizes that for ALK-positive NSCLC, more efficient drugs should be considered for first-line treatment; more precise choices are needed to overcome drug resistance; and full-course management requires a more scientific combination
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 Prof.
Song Yong, Director of the Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing University School of Medicine, Director, Institute of Respiratory Medicine, Nanjing University, Nanjing University, Southern Medical University, Nanjing Medical University, Southeast University, PhD supervisor, Jiangsu Medical Association Respiratory Diseases National Committee of the Respiratory Branch of the Chinese Medical Association (Member of the Respiratory Branch of the Chinese Medical Association) Chairman of the Respiratory Branch of the Nanjing Medical Association Translational Lung Cancer Research (SCI included) Editor-in-chief of the "CSCO Changbai Tumor Summit Forum" is organized by China Society of Clinical Oncology (CSCO), CSCO Small Cell Lung Cancer Professional Committee, Jilin Province Anti-Cancer Association, Jilin Province Anti-Cancer Association Tumor Precision Medicine and Drug Therapy Professional Committee, Jilin Province Physician Association Tumor Professional Committee, Jilin Province Medical Association Tumor Professional Committee, The "Sixteenth CSCO Changbai Tumor Summit Forum" jointly sponsored by the Radiation Oncology Therapeutics Branch of the Jilin Medical Association and the Jilin Cancer Center and undertaken by the Jilin Provincial Tumor Hospital will arrive in the beautiful summer time as scheduled, and will be July 2021 From the 15th to the 18th, it was held in Changchun City as an offline conference to discuss the innovative development of cancer diagnosis and treatment with cancer colleagues across the country
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