The combination of precise detection and full-process management further optimizes the treatment of ALK-mutated lung cancer

*Only for medical professionals to read for reference.
How to optimize ALK targeted therapy and improve patient prognosis? Listen to what the big coffee guys say
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ALK mutation is a "diamond mutation" in non-small cell lung cancer (NSCLC), and tyrosine kinase inhibitor (TKI) targeted drug therapy has achieved remarkable results, especially the first represented by Alectinib.
The second-generation ALK-TKI drugs can effectively control the progression of the disease for a long time and prolong the overall survival (OS) of patients.
It has become the preferred treatment for advanced ALK mutation-positive patients
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 So in clinical work, how should we ensure the accuracy and reliability of ALK mutation detection, and strive for more patients to use TKI-type targeted drugs for treatment opportunities, and what issues should be paid attention to in the overall management of patients? "Medical Oncology Channel" invited Professor Zhou Jianying, Professor Teng Xiaodong, Professor Wang Yuehong, and Professor Bao Zhang from the First Affiliated Hospital of Zhejiang University School of Medicine, Professor Zhang Shirong, Hangzhou First People's Hospital Affiliated to Zhejiang University School of Medicine, and Lou Guangyuan, Affiliated Cancer Hospital of the University of Chinese Academy of Sciences Professor Ge Ting from Li Huili Hospital of Ningbo Medical Center gave comprehensive and detailed answers to related questions
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 Medical community: What are the methods for detecting ALK fusion mutations in NSCLC patients? What are the advantages and disadvantages of each? Professor Zhang Shirong: The main detection methods recommended by domestic and foreign guidelines include fluorescence in situ hybridization (FISH), immunohistochemical staining (IHC), amplification hindered mutation system (ARMS) and next-generation sequencing (NGS), among which FISH is the earliest application The Ventana IHC method is the most frequently used ALK detection method in China due to its high sensitivity and specificity.
The results are basically the same as the FISH method, but because different ALK fusion variants target TKIs The drug response is heterogeneous, and NGS may need to be used to subdivide the fusion type.
In the future, the detection sensitivity can be further improved through technologies such as molecular barcoding (UMI)
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 Professor Lou Guangyuan: In order not to miss ALK fusion-positive NSCLC patients as much as possible, it can be combined with RNA-based NGS detection (RNA-NGS) on the basis of IHC and other original detection methods.
It has unique advantages in detecting fusion mutations, but clinical There is little experience in use, and it needs to take into account the economic conditions of the patient
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 Professor Teng Xiaodong: From the perspective of pathology, most ALK fusion lung cancers have unique histological and morphological features.
Patients can be recommended to choose appropriate testing methods based on relevant features.
For example, small testing panels containing ALK genes are preferred to reduce the risk of patients receiving testing.
Economic burden
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 Medical community: For patients with ALK fusion and other driver gene-positive NSCLC, what role can NGS play in the overall management? Professor Zhang Shirong: Studies have shown that ALK fusion patients with positive NGS test and negative FISH test can benefit from ALK-TKI treatment
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In addition, NGS testing can also find new forms of ALK fusion mutations, and the frequency of testing will inevitably increase in the future, and RNA-NGS may be better than DNA-NGS in detecting fusion mutations
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 Professor Wang Yuehong: NGS has important value in clinical medication guidance, drug resistance management, prognostic judgment, discovery of new mutations/fusion types, etc.
for NSCLC patients with positive driver genes.
For example, the BFAST study has shown that blood-based NGS testing can guide Alatin The efficacy data is consistent with the overall ALEX study
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NGS testing can also further subdivide the mutation subtypes of the driver genes, suggesting that the selection of more appropriate drugs, such as patients with the L858R mutation in exon 21 in EGFR mutations, may be more suitable for EGFR-TKI-based combination therapy strategies
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NGS testing can also help discover possible drug resistance mechanisms in patients and guide the fine adjustment of treatment strategies.
Patients who have targeted drugs available for drug resistance sites can choose corresponding drugs accordingly
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NGS's distinction between EGFR, ALK and other mutation subtypes is also an important indicator for judging the effect of targeted therapy and patient prognosis.
For example, there are differences in the efficacy of crizotinib in the treatment of V1-V3 subtypes in the EML4-ALK fusion
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NGS can detect multiple sites at the same time, and it can also find co-mutations that affect the prognosis of patients.
For example, patients with EGFR and ALK fusion mutations with TP53 mutations have a relatively poor prognosis
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 Professor Ge Ting: Precise treatment and detection are the first priority.
The information provided by NGS detection is the basis of targeted therapy.
Some patients can even detect targetable sites multiple times, so that targeted drugs can be constantly replaced to control the progression of the disease and achieve long-term survival.

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 Medical community: What is the significance of NGS dynamic monitoring for the management of NSCLC patients with positive driver genes? Professor Wang Yuehong: In addition to discovering a new type of ALK fusion in NSCLC patients, pan-tumor NGS testing can also detect ALK fusion in other cancers and guide ALK-TKI treatment.
There have been cases of small cell lung cancer using ALK-TKI treatment.
More NGS testing will also help discover rarer NSCLC targeted therapy sites and guide future drug development
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Therefore, in the whole management of NSCLC patients, lifelong dynamic monitoring of NGS should be carried out if conditions permit
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Professor Bao Zhang: NGS dynamic monitoring is of great significance to the treatment of drug-resistant patients with gene-positive NSCLC targeted therapy.
It can guide treatment strategies and accumulate data for future related explorations and guide the direction
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 Professor Lou Guangyuan: The significance of NGS dynamic monitoring is also affected by the development of drugs.
In recent years, with the significant improvement in the availability of ALK-TKI targeted drugs in China, the value of information provided by NGS in guiding clinical medication has also increased
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 Professor Zhang Shirong: NGS dynamic monitoring can find concurrent point mutations or bypass resistance, which is an advantage that other testing methods do not have.
However, there is still a lack of consensus on dynamic monitoring frequency, monitoring timing, and testing samples, and further details are still needed.
Chemical analysis
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 Medical community: What is the current status of first-line targeted therapy for ALK fusion patients? Professor Lou Guangyuan: As the second-generation ALK-TKI such as aletinib has succeeded in the first-line treatment head-to-head study with crizotinib, and has achieved a complete victory in efficacy, the targeted therapy of ALK fusion has entered the "2+" X" era
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When selecting second-generation drugs, the efficacy indicators such as PFS and ORR should be comprehensively considered, such as the efficacy of brain metastases, and the safety of treatment.
At present, aletinib is consistent with the three guidelines of NCCN in the United States, ESMO in Europe, and CSCO in China.
Recommended preferred option
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In the two clinical phase III studies of ALEX and J-ALEX and the Japanese real-world study (WJOG 9516L), the median PFS of first-line treatment with aletinib can reach 34-40 months, and the ORR in the real-world study for the treatment of Chinese patients It can reach 75%-90% (both first-line and second-line treatment), which is relatively higher than the ORR in clinical studies, and further reflects the excellent efficacy.
Moreover, the published OS data of the ALEX study shows that the 5-year period of the aletinib group The survival rate reaches 62.
5%, which means that more than half of the patients can survive for more than 5 years, which has a significant benefit compared with crizotinib, while the OS data of other second-generation drugs are not mature
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 At present, it is known that aletinib, brigatinib and the third-generation TKI loratinib have better brain-entry ability, which is significantly improved compared with the first-generation TKI crizotinib
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For example, aletinib has a good effect on brain metastases in the ALEX study, and it can also significantly reduce the incidence of central nervous system progression.
These characteristics are also reflected in real-world studies
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In addition, the incidence of grade ≥3 adverse events (AEs) in the clinical study of aletinib is relatively low, and the interaction with other drugs is also less, and the combination medication is less affected.
It is not required when used in combination with drugs that affect the metabolism of CYP3A.
Adjust the dose
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 Professor Bao Zhang: All indications of aletinib have been included in the medical insurance.
The 5-year OS rate and other efficacy data are relatively best at present, and there are few drug interactions, which will not affect patients' treatment of comorbidities and chronic diseases
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Therefore, it is a priority recommended program, but it should also be noted whether the patient can tolerate side effects such as elevated bilirubin
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 Professor Ge Ting: The good efficacy of second-generation ALK-TKI such as aletinib is expected to enable the management of ALK fusion-positive patients to enter the "chronic disease" era.
Clinical work has also observed a large number of patients after receiving aletinib treatment Significant benefits
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 The medical profession: In order to achieve the full management of ALK fusion-positive patients, what aspects should be paid attention to in the rear-line treatment deployment? Professor Lou Guangyuan: After ALK targeted therapy has entered the "2+X" era, patients who are first-line resistant to aletinib should choose possible back-line treatment options based on the potential resistance mechanisms suggested by the test results, such as for Aletinib After letinib treatment, patients with ALK-dependent resistance, other second-generation ALK inhibitors such as brigatinib and ensatinib, and third-generation ALK inhibitor loratinib, may have a certain effect on resistance-related point mutations
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In addition, traditional chemotherapy, immune monotherapy or combination therapy are also options
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 Professor Zhou Jianying pointed out in the conference summary that with the increase in the detection rate of ALK mutations and the gradual popularity of targeted therapy, "difficult patients" who need to be treated in clinical work, such as treatments that have not reached the expected efficacy, primary or secondary The number of patients suffering from sexual resistance is also increasing
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With the help of NGS detection and pathological examination, clinicians can accurately identify the cause.
Starting from the first-line selection of powerful drugs such as aletinib, optimize the formation of targeted drugs and truly realize ALK-mutated lung cancer as a chronic disease.
To manage the goals
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 Expert profileProfessor Zhou Jianying Director of the Department of Respiratory Medicine, The First Affiliated Hospital of Zhejiang University School of Medicine, Director of the Lung Disease Diagnosis and Treatment Center Committee Member, Zhejiang Anti-Cancer Association, Lung Cancer Professional Group, Deputy Chairman, Chinese Medical Doctor Association, Respiratory Physician Branch, Standing Committee, Zhejiang University Respiratory Disease Institute, Deputy Director, Zhejiang University, Zhejiang University, Professor Teng Xiaodong, Zhejiang University School of Medicine, Zhejiang University First Affiliated Hospital, Chinese Medical Association, Standing Committee of CSCO Cancer Pathology Expert Committee Standing Committee Member, Wu Jieping Medical Foundation, Deputy Chairman of the Department of Pathology, Chairman of the Pathology Branch of the Zhejiang Medical Association Chairman of the Pathologists Branch of the Zhejiang Medical Association Chairman of the Zhejiang Provincial Anticancer Association Tumor Targeting and Cell Therapy Special Committee Deputy Chairman of the Health Commission Pathology Member of the Quality Control Expert Committee Professor Wang Yuehong, Deputy Director of the Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Zhejiang University School of Medicine, MD Anderson Cancer Center, United States Visiting Scholar, Chinese Medical Association Respiratory Medicine Branch Lung Cancer Group Member, Chinese Medical Doctor Association Respiratory Medicine Branch Lung Cancer Working Group Member, Vice Chairman, Lung Cancer Immunotherapy Committee, China Association for Lung Cancer Prevention Member Professor Bao Zhang, Deputy Chief Physician, Department of Respiratory Medicine, The First Affiliated Hospital of Zhejiang University School of Medicine, Visiting Scholar, Stanford University Medical Center, Member of Respiratory Therapeutics Group, Chinese Medical Association Respiratory Medicine Branch, Member of Molecular Oncology and Immunotherapy Professional Committee of Chinese Research Hospital Association Zhejiang Province Member of the Respiratory Precision Diagnosis and Treatment Group of the Respiratory Diseases Branch of the Medical Association Secretary and Member of the Endoscopy Alliance of the Respiratory Diseases Branch of the Zhejiang Medical Association.
Paper QVA149 (Indacaterol/ glycopyrrolate), Archer1050, Impress, Aura 3,MK033 and many other international multi-center clinical research Sub-I Professor Zhang Shirong, Ph.
D.
, associate researcher, master's supervisor, deputy director of the Molecular Pathology Center, Hangzhou First Hospital, Zhejiang University School of Medicine, deputy director of Zhejiang Provincial Key Laboratory of Clinical Oncology Pharmacology and Toxicology Director, Chinese Anti-Cancer Association Anti-Cancer Drug Professional Committee Member, CSCO China Cancer Driver Gene Analysis Alliance Executive Committee Standing Committee Member, CSCO China Genome Sequencing Technology Collaboration Professional Committee Member, Zhejiang Targeted Therapy Guidance Center Deputy Director, Zhejiang Anti-Cancer Association Youth Director, Zhejiang Mathematics and Science Member of the Standing Committee of the Precision Diagnosis and Treatment Committee of the Association, Member of the Molecular Targeting and Cell Therapy Branch of the Zhejiang Anti-Cancer Association Zhejiang Cancer Hospital) Chief Physician, Department of Thoracic Oncology, Member of China Medical Education Association Tumor Metastasis Committee, Youth Member, Lung Tumor Committee, China Medical Education Association, Zhejiang Anti-Cancer Association Tumor Targeting and Cell Therapy Committee Member, Zhejiang Anticancer Member of the Rehabilitation and Palliative Care Committee of the Cancer Society Professor Ge Ting, Chief Physician, Department of Respiratory Medicine, Li Huili Hospital, Ningbo Medical Center, Member of the Interventional Pulmonary Group, Respiratory Branch of Zhejiang Medical Association Member of the Allergic Physician Branch of the Provincial Medical Association Member of the Youth Expert Committee of Lung Cancer Medicine of the Beijing Medical Award Foundation Member of the Youth Committee of the Respiratory Branch of the Ningbo Medical Association Member of the Lung Cancer and Intervention Group of the Respiratory Branch of the Ningbo Medical Association *This article is only for medical professionals Scientific information does not represent the views of this platformProfessor, Chief Physician, Department of Respiratory Medicine, Li Huili Hospital, Ningbo Medical Center, Member of Pulmonary Intervention Group, Respiratory Branch of Zhejiang Medical Association, Member of Pulmonary Interstitial Disease Group, Respiratory Physician Branch of Zhejiang Medical Association, Member of Allergy Physician Branch of Zhejiang Medical Association, Member of Beijing Medical Award Fund Member of the Youth Expert Committee of Lung Cancer Medicine, Youth Member of the Respiratory Branch of Ningbo Medical Association Member of the Lung Cancer and Intervention Group of the Respiratory Branch of Ningbo Medical Association* This article is only used to provide scientific information to medical professionals and does not represent the views of this platformProfessor, Chief Physician, Department of Respiratory Medicine, Li Huili Hospital, Ningbo Medical Center, Member of Pulmonary Intervention Group, Respiratory Branch of Zhejiang Medical Association, Member of Pulmonary Interstitial Disease Group, Respiratory Physician Branch of Zhejiang Medical Association, Member of Allergy Physician Branch of Zhejiang Medical Association, Member of Beijing Medical Award Fund Member of the Youth Expert Committee of Lung Cancer Medicine, Youth Member of the Respiratory Branch of Ningbo Medical Association Member of the Lung Cancer and Intervention Group of the Respiratory Branch of Ningbo Medical Association* This article is only used to provide scientific information to medical professionals and does not represent the views of this platform