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    Home > Active Ingredient News > Digestive System Information > CheckMate-649 study data update, how do you think about "all patients benefit"?

    CheckMate-649 study data update, how do you think about "all patients benefit"?

    • Last Update: 2022-06-07
    • Source: Internet
    • Author: User
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    *For medical professionals to read and reference, it is a "lazy" to use the combined chemotherapy and immunity program when you see advanced gastric cancer!
    Gastric cancer is one of the most common digestive tract tumors in China.
    In 2020, there will be about 480,000 new cases of gastric cancer in China, accounting for 43.
    9% of the global total; the number of deaths will be about 370,000, accounting for 48.
    5% globally [1]

    .

    For more than ten years, there has been no progress in the first-line drug treatment of HER-2-negative advanced gastric cancer.
    Chemotherapy has always dominated the treatment of advanced gastric cancer, and the median overall survival (OS) of patients is difficult to exceed 1 year [2]

    .

    With the advent of the era of immunotherapy, this deadlock was gradually broken
    .

    Recently, the internationally renowned journal Natrue reported the long-term follow-up data of the CheckMate-649 study [3], mainly reporting the long-term follow-up results of nivolumab combined with chemotherapy and chemotherapy alone
    .

    The Medical Tumor Channel specially invited Professor Zhang Xiaotian from Peking University Cancer Hospital to interpret and analyze the latest research data released by the CheckMate-649 study
    .

    The clinical characteristics of gastric cancer patients in China and the West are quite different.
    Q: What is the current status of the diagnosis and treatment of gastric or esophageal adenocarcinoma in my country?
    What is the future of immunotherapy in the treatment of gastric or esophageal adenocarcinoma? Professor Zhang Xiaotian: China has a huge population base, and the number of gastric cancer patients accounts for more than 40% of the world's total.
    Most gastric cancer patients are in the advanced stage when they go to the clinic, and early gastric cancer patients account for less than 10% [4]

    .

    At the same time, gastric cancer and esophageal cancer have high heterogeneity, and the biological characteristics and clinical characteristics of domestic patients and Western patients are quite different
    .

    Therefore, there is a strong and unmet clinical need for gastric cancer drug therapy in China, so more research data on domestic gastric cancer patients is needed
    .

    With the continuous progress of gastric cancer drug treatment and the promotion of whole-process management of gastric cancer patients, the 5-year survival rate of gastric cancer patients in China has increased from less than 30% to 35.
    9%

    .

    Based on the CheckMate-649 study, the U.
    S.
    Food and Drug Administration (FDA) and the National Medical Products Administration (NMPA) have successively approved nivolumab injection combined with fluorouracil and platinum-based chemotherapy drugs for first-line treatment of advanced or metastatic gastric cancer , gastroesophageal junction cancer and esophageal adenocarcinoma patients, providing a new treatment option for patients with advanced gastric cancer

    .

    At the same time, according to the subgroup data of Chinese patients, it can be predicted that this treatment plan will bring greater benefits to the clinical treatment of gastric adenocarcinoma patients in China in the future
    .

    The CheckMate-649 study conquers the medical community by its strength.
    Guide Q: As a study that has been listed in Nature, what are the novelties and highlights of this study?
    Prof.
    Xiaotian Zhang: The CheckMate-649 study is the largest randomized, global phase III study on first-line immunotherapy for advanced gastric cancer so far, involving 2031 patients from many countries and regions around the world

    .

    Patients were randomly assigned to 3 treatment arms to receive nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone
    .

    The primary endpoint of the study was dual endpoints, PFS and OS in the PD-L1 CPS ≥5 patient population
    .

    The alpha split values ​​were 0.
    02 and 0.
    03, respectively, which made the primary endpoint data of the study need to meet higher statistical assumptions before they could be considered as positive clinical endpoints

    .

    This is also one of the reasons why official institutions, societies and societies in many countries have approved relevant adaptations and rewritten guidelines based on this research
    .

    At the same time, the CheckMate-649 study also brings some inspiration for the design of future clinical researches on gastric cancer
    .

    As we all know, gastric cancer is a highly heterogeneous disease, which brings certain difficulties to clinical research
    .

    For example, in the CheckMate-649 study, the benefit degree of patients in the Chinese subgroup will be significantly higher.
    It can be seen that patients in different countries and regions have different degrees of benefit.
    Therefore, in the future, stratified analysis needs to be more Influencing factors should be considered more

    .

    The CheckMate-649 study may become a "catfish" that promotes domestic drug research and development.
    Q: Could you please introduce the findings of this study?
    What are the implications of the results of this study for the clinical practice of diagnosis and treatment of gastric or esophageal adenocarcinoma in my country? Professor Zhang Xiaotian: The latest report of the CheckMate-649 study mainly reports the long-term follow-up results of nivolumab combined with chemotherapy and chemotherapy alone

    .

    Results The data showed that after at least 24 months of follow-up, in the patient population with PD-L1 CPS ≥ 5, the median OS of patients in the nivolumab plus chemotherapy group was still better than that in the chemotherapy alone group [14.
    4 months (95].
    %CI 13.
    1-16.
    2) vs.
    11.
    1 months (95%CI 10.
    0-12.
    1)]; similar results were observed across all patients [13.
    8 months (95%CI 12.
    4-14.
    5) vs.
    11.
    6 months (95 %CI 10.
    9-12.
    5)]

    .

    In the PD-L1 CPS ≥ 5 and overall patient population, the combination of nivolumab and chemotherapy was associated with a 30% (HR 0.
    70; 95% CI 0.
    61-0.
    81) and 21% reduction in the risk of death compared with chemotherapy, respectively.
    (HR 0.
    79; 95%CI 0.
    71-0.
    88)

    .

    Based on this study, the following changes and thoughts have been brought to the clinical diagnosis and treatment of patients with advanced gastric cancer in China: First, as mentioned before, based on this study, NMPA approved the relevant indications, which will help patients with HER-2 negative advanced gastric adenocarcinoma in China.
    New treatment options are coming

    .

    The "Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Gastric Cancer 2021" gave a class I recommendation for nivolumab combined with chemotherapy in the first-line treatment of patients with advanced gastric cancer with PD-L1 CPS ≥ 5
    .

    In addition, for patients with PD-L1 CPS <5, the first-line treatment regimen of chemoimmune combination can also be used depending on the patient's tumor burden and other conditions
    .

    In the future, the PD-L1 CPS score of patients may become one of the key considerations in the clinical diagnosis and treatment of advanced gastric cancer
    .

    Second, the results of the CheckMate-649 study will have a positive impact on the clinical application research of domestically developed immunotherapy drugs
    .

    At present, some studies have brought positive signals.
    The ORIENT-16 study [5] confirmed the clinical value of sintilimab combined with chemotherapy in the first-line treatment of advanced gastric cancer

    .

    In addition, there are also studies [6] showing that camrelizumab combined with chemotherapy followed by camrelizumab combined with apatinib as first-line therapy can improve the treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma.
    Considerable curative effect

    .

    Third, with the combination of chemoimmune therapy being increasingly applied to the first-line treatment of patients with advanced gastric cancer, there is still much controversy about how to further develop a second-line treatment plan when patients fail to receive treatment
    .

    Clinicians may choose to use chemotherapy alone or chemotherapy combined with antiangiogenic drugs, or continue to use chemoimmunotherapy by switching chemotherapy or immunotherapy drugs
    .

    How to provide more standardized clinical treatment for such patients in the future needs further research
    .

    In addition, whether the chemotherapy-immune combined treatment plan can further advance the front line and apply it to the perioperative treatment of patients with early gastric cancer also requires corresponding thinking and exploration by oncology clinicians
    .

    Is the chemoimmunotherapy regimen really suitable for all patients? Q: In the process of clinical practice, how to judge whether patients with PD-L1 CPS <5 are suitable for chemotherapy and immune combination therapy? Prof.
    Xiaotian Zhang: If only based on the results of the CheckMate-649 study, it would be a "lazy" behavior to use chemo-immunotherapy for all advanced gastric cancer patients.

    .

    For patients with PD-L1 CPS ≥5, the evidence for the use of chemoimmune combination therapy is relatively strong
    .

    However, whether patients with PD-L1 CPS <5 are suitable for chemotherapy-immune combination therapy needs to be further actively explored to find relevant biomarkers
    .

    For example, tumor mutational burden (TMB), copy number variation (CNA) burden, and neutrophil-to-lymphocyte ratio (NLR), among others
    .

    Recently, the researchers of CheckMate-649 announced the relevant biomarker analysis results at the 2022 American Association for Cancer Research (AACR) annual meeting [7].
    The researchers analyzed the baseline tumor mutation burden (TMB) and gene expression characteristics ( GES) for an exploratory efficacy analysis

    .

    The results showed that for patients with TMB-H (at least 199 mutations per exome) and low expression of epithelial-mesenchymal transition (EMT) and angiogenesis (Angio) genes, nivolumab in combination with chemotherapy was more successful.
    The benefit is greater

    .

    The PD-L1 CPS score is affected by a variety of factors.
    Therefore, assessing whether patients with PD-L1 CPS < 5 can benefit from chemoimmunotherapy is not a simple "YES or NO", but a very complicated and things to consider

    .

    Based on my personal clinical experience, when the patient does not have better treatment options, and the patient does not have negative factors related to immunotherapy, immunotherapy can be considered for patients with PD-L1 CPS <5
    .

    Based on the results of the CheckMate-649 study, all patients should not be treated with a chemoimmune combination regimen, but a more precise treatment regimen should be provided for patients
    .

    In the "post-649 era", clinical research on advanced gastric cancer will face higher requirements.
    Q: What can be further optimized for this research?
    What other questions need further exploration? Prof.
    Zhang Xiaotian: The CheckMate-649 study has been followed up with exploratory analysis in various aspects, including a very thorough analysis of biomarkers and patients' quality of life

    .

    In the future, there may be more explorations in pharmacoeconomics and translational medicine research
    .

    Today, tumor treatment has entered the era of immunotherapy.
    Based on the CheckMate-649 study, the clinical treatment of advanced gastric cancer has made a breakthrough from chemotherapy alone to combined chemoimmunotherapy

    .

    In the future, when conducting relevant exploratory research, it is necessary to compare with the combined chemotherapy and immunity regimen.
    If it is still compared with traditional chemotherapy alone, even if a positive result is obtained, it will be controversial.
    bigger challenge

    .

    As for whether patients with advanced gastric cancer can be exempted from chemotherapy, a number of studies are being actively explored, and it is hoped that more clinical diagnosis and treatment options can be brought to patients in the future
    .

    In addition, in the future, in addition to the expression of HER-2, the PD-L1 CPS score and various other biomarkers may become factors for treatment stratification in patients with gastric cancer, thereby providing patients with more precise treatment
    .

    Expert Profile Professor Zhang Xiaotian, MD, Department of Gastrointestinal Oncology, Peking University Cancer Hospital, Chief Physician, Professor, Doctoral Supervisor Deputy Director of International Cooperation and Exchange Department of Peking University Cancer Hospital, Deputy Director of Internal Medicine Teaching and Research Section Vice-chairman of the Cancer Support Committee of the Cancer Society, member of the Standing Committee of the Gastric Cancer Professional Committee of the China Anti-Cancer Association, Vice-chairman of the Precision Medicine and Oncology MDT Professional Committee of the Chinese Research Hospital Society https://gco.
    iarc.
    fr/today/data/factsheets/populations/160-china-fact-sheets.
    pdf[2] Yelena Y Janjigian, Kohei Shitara, Markus Moehler ,et al.
    First-line nivolumab plus chemotherapy versus chemotherapy chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate-649): a randomised, open-label, phase 3 trial[J].
    Lancet.
    2021 Jul 3;398(10294):27-40.
    [ 3] Shitara K, Ajani JA, Moehler M, et al.
    Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer.
    Nature.
    2022 Mar;603(7903):942-948.
    [4] Huang Changming, Lin Juli, Lin Guang Yong, et al.
    Comprehensive treatment strategy for locally advanced gastric cancer[J].
    Chinese Journal of Digestive Surgery, 2022, 21(3): 342-347.
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    cn115610-20220214-00079.
    [5] J.
    Xu, H.
    Jiang, Y.
    Pan, et al.
    Sintilimab plus chemotherapy (chemo) versus chemo as first-line treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ORIENT-16): First results of a randomized, double-blind, phase III study.
    2021ESMO, LBA53.
    [6] Peng Z, Wei J, Wang F, et al.
    Camrelizumab Combined with Chemotherapy Followed by Camrelizumab plus Apatinib as First-line Therapy for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma.
    Clin Cancer Res.
    2021 Jun 1;27 (11):3069-3078.
    [7] Ming Lei, Yelena Y.
    Janjigian, Jaffer A.
    Ajani, et al.
    Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer /gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate-649 biomarker analyses.
    2022AACR CT023Sintilimab plus chemotherapy (chemo) versus chemo as first-line treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ORIENT-16): First results of a randomized, double-blind, phase III study.
    2021ESMO, LBA53.
    [ 6] Peng Z, Wei J, Wang F, et al.
    Camrelizumab Combined with Chemotherapy Followed by Camrelizumab plus Apatinib as First-line Therapy for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma.
    Clin Cancer Res.
    2021 Jun 1;27(11):3069 -3078.
    [7] Ming Lei, Yelena Y.
    Janjigian, Jaffer A.
    Ajani, et al.
    Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/ esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate-649 biomarker analyses.
    2022AACR CT023Sintilimab plus chemotherapy (chemo) versus chemo as first-line treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ORIENT-16): First results of a randomized, double-blind, phase III study.
    2021ESMO, LBA53.
    [ 6] Peng Z, Wei J, Wang F, et al.
    Camrelizumab Combined with Chemotherapy Followed by Camrelizumab plus Apatinib as First-line Therapy for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma.
    Clin Cancer Res.
    2021 Jun 1;27(11):3069 -3078.
    [7] Ming Lei, Yelena Y.
    Janjigian, Jaffer A.
    Ajani, et al.
    Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/ esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate-649 biomarker analyses.
    2022AACR CT0232022AACR CT0232022AACR CT023Camrelizumab Combined with Chemotherapy Followed by Camrelizumab plus Apatinib as First-line Therapy for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma.
    Clin Cancer Res.
    2021 Jun 1;27(11):3069-3078.
    [7] Ming Lei, Yelena Y.
    Janjigian, Jaffer A.
    Ajani, et al.
    Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate-649 analyses.
    2022AACR CT023Camrelizumab Combined with Chemotherapy Followed by Camrelizumab plus Apatinib as First-line Therapy for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma.
    Clin Cancer Res.
    2021 Jun 1;27(11):3069-3078.
    [7] Ming Lei, Yelena Y.
    Janjigian, Jaffer A.
    Ajani, et al.
    Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate-649 analyses.
    2022AACR CT023Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate-649 biomarker analyses.
    2022AACR CT023Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate-649 biomarker analyses.
    2022AACR CT023
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