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    Home > Active Ingredient News > Digestive System Information > Professor Deng Yanhong: Facing the challenge, real cases of MSI-H/dMMR colorectal cancer show new strategies for immunotherapy!

    Professor Deng Yanhong: Facing the challenge, real cases of MSI-H/dMMR colorectal cancer show new strategies for immunotherapy!

    • Last Update: 2021-10-01
    • Source: Internet
    • Author: User
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    *Only for medical professionals to read the reference article to understand the current status of MSI-H/dMMR colorectal cancer treatment! Colorectal cancer (CRC) is the third most common malignancy in the world and the second most common cause of death
    .

    In China, CRC is one of the cancers with the highest incidence.
    Data show that in 2018, there were 521,500 new colorectal cancer patients in China, ranking second in the number of new cancers in China that year; 247,600 new CRC deaths, ranking The fifth place in the number of new cancer deaths
    .

    The incidence of CRC is obviously more urban than rural.
    In domestic urban areas, CRC has become the second most common malignant tumor
    .

    At the same time, the incidence of CRC has been increasing year by year in the past 20 years, becoming a huge social health burden
    .

    Despite the continuous emergence of treatment methods and drugs, the median 5-year survival rate of mCRC patients is only about 12.
    5%, and the efficacy is urgently needed to be improved
    .

    In recent years, immunotherapy has developed rapidly.
    Immunotherapy has significantly improved the effective rate of tumor treatment, and the patient's survival period has been significantly prolonged.
    Once immunotherapy is effective, the effect will be long-lasting.
    At present, many tumor types, especially lung cancer, lymphoma, and malignant melanoma Very good results have been achieved in the treatment
    .

    In contrast, the efficacy of immunotherapy in gastrointestinal tumors is still not ideal, but patients with highly unstable microsatellite/mismatch repair gene defect (MSI-H/dMMR) CRC are very effective for immunotherapy
    .

    In view of this, the Medical Oncology Channel invited Professor Deng Yanhong from the Sixth Affiliated Hospital of Sun Yat-sen University to share the application of immunotherapy in the field of colorectal cancer
    .

    Opportunities and challenges coexist.
    MSI-H colorectal cancer patients have a considerable prognosis.
    Compared with melanoma, kidney cancer, lung cancer and other tumors, the disease progresses relatively slowly, and some of the CRC patients with MSI-H/dMMR are the dominant population of immunotherapy.

    .

    Such patients are more sensitive to immunotherapy and have relatively good curative effects
    .

    Professor Deng Yanhong mentioned: “We can see that some patients with MSI-H can be cured by immunotherapy even though they are at an advanced stage
    .

    Although there are not many data now, we can observe MSI-H CRC patients for 3 years.
    The survival rate of MSI-H can be close to 70%.
    When the survival time of this part of patients exceeds 5 years, the tumor is likely to be cured, which is significantly improved compared to the 12.
    5% ​​survival rate
    .

    Although MSI-H patients are more sensitive to immunotherapy, but 50% of patients may develop primary drug resistance.
    How to overcome the problem of drug resistance is a key direction of future research
    .

    "In addition, more than 90% of CRC patients are of microsatellite stable (MSS) type, which is suitable for immunotherapy.
    The sensitivity is low and belongs to "cold tumor" 
    .

    How to transform this type of tumor into a "hot tumor" similar to MSI-H CRC that is sensitive to immunotherapy is the current research hotspot of immunotherapy.
    Among them, immunotherapy combined with other treatments is an important research direction: dual immune combination therapy, immune combination Anti-angiogenesis targeted therapy, immune combined chemotherapy and immune combined radiotherapy are currently being explored.
    Therefore, the progress of immunotherapy for MSS CRC is relatively slow.
    How to screen out biomarkers that can predict the treatment response of CRC patients is still current Difficulty
    .

    Precision treatment has become a trend.
    The guidelines recommend that MSI-H patients preferentially use immunotherapy.
    The reason why MSI-H/dMMR colorectal cancer is highly immune may be that patients have a higher tumor mutational burden (TMB)
    .

    Professor Yanhong Deng’s team has also explored this aspect.
    The results of the study presented in this year’s AACR poster suggest that the whole exome sequencing of 112 cases of advanced colorectal cancer is consistent with previous studies.
    MSI has a higher TMB than MSS.
    , And almost all the significantly differently mutated genes have a higher mutation frequency in the MSI group, which suggests that there are a large number of lymphocyte infiltration in the tumor microenvironment of MSI-H patients, which is the reason why they are more sensitive to immunotherapy
    .

    Referring to the current guidelines recommendations, Professor Deng Yanhong said: “MSI-H/dMMR patients are more sensitive to immunotherapy represented by PD-1 inhibitors, but for precise treatment, testing is required first, based on MSI-H/dMMR For the benefit of patients receiving immunotherapy, relevant guidelines have recommended that all CRC patients should undergo MSI status testing
    .

    Once a CRC patient that meets MSI-H/dMMR is detected, immunotherapy is recommended for the first-line treatment
    .

    If the second-line treatment meets MSI- H/dMMR, second-line immunotherapy is also recommended in time
    .

    The efficacy of immunotherapy in the perioperative period is also worth looking forward to
    .

    The NICHE study in the Netherlands has made a very successful exploration, and the study enrolled 40 patients with stage I to III colorectal cancer.
    , 21 cases were dMMR type, 20 cases were mismatch repair function normal (pMMR) (1 patient had both dMMR and pMMR), two doses of nivolumab and one dose of ipilimumab were given before surgery Anti-, the objective response rate (ORR) of 20 MSI-H cases was 100%, of which 60% (12/20) achieved pathological complete remission (pCR).
    Whether immune neoadjuvant therapy can replace traditional surgical treatment is worth exploring
    .

    Although there is still a lack of evidence-based medicine for perioperative patients, it can be seen that the sooner immunotherapy is used, the better the effect for patients with lower tumor burden, which may also become the future of rectal cancer.
    One of the development directions of immunotherapy
    .

    "Professor Deng Yanhong mentioned: "The current guidelines recommend different protocols for neoadjuvant treatment of colon cancer and rectal cancer.
    In the neoadjuvant treatment of rectal cancer, the current standard treatment is concurrent radiotherapy and chemotherapy.
    The anatomical location of rectal cancer is special and it is located in the pelvic cavity.
    However, some patients are also very sensitive to chemotherapy alone.
    Therefore, chemotherapy alone is the direction of future development.
    At present, our team is also carrying out this aspect.
    Among patients with rectal cancer, a small number of patients with MSI-H receive immunotherapy alone.
    The proportion of remission exceeds 50%, and the efficacy is significantly better than concurrent radiotherapy and chemotherapy; for patients with colon cancer, the guidelines mainly recommend neoadjuvant treatment of T4b population with chemotherapy alone
    .

    Similar to rectal cancer, immune neoadjuvant therapy is also very effective in patients with MSI-H.
    Therefore, although there is still a lack of sufficient evidence-based medical evidence to change clinical practice, for patients with MSI-H, immune neoadjuvant therapy may be Will be a consistent choice
    .

    "Filling the domestic gap, the Phase II clinical data of Envolizumab showed amazing efficacy.
    Starting in 2015, the KEYNOTE-016 study was the first to discover that the PD-1 drug Pembrolizumab can bring significant clinical benefits to MSI-H/dMMR mCRC At the beginning, the immunotherapy of CRC opened a new chapter.
    A horizontal comparison of the data of the three studies of KEYNOTE-177, KEYNOTE-164 and CheckMate-142 showed that for patients with MSI-H/dMMR mCRC, immunotherapy is better than chemotherapy ± target Xiang treatment can obtain better clinical benefits, and at the same time, dual-immune combined therapy has better efficacy than single-immune therapy, and some patients even get a chance to be cured
    .

    Professor Deng Yanhong pointed out: “The domestic clinical phase II of envolimab with detailed data released recently Data from the registration study showed that the ORR of Envolimab as a single agent (150 mg QW administration) for the second-line treatment of 103 patients with MSI-H/dMMR was 42.
    7%, including 65 patients with CRC, and the ORR reached 43.
    1%
    .

    The median progression-free survival (PFS) was 11.
    1 months, and the 1-year overall survival rate was 74.
    6%.
    The efficacy is basically equivalent to that of approved PD-1 inhibitors, reflecting the good therapeutic value of envolimab
    .

    In the registration study of envolimab monotherapy, the efficacy of treating MSI-H/MMR patients is significant, and the ORR of the treatment exceeds 40%, which is comparable to the clinical research data of foreign PD-1 inhibitors.
    The anti-structure innovation is a camel-derived nano antibody.
    It can be administered by subcutaneous injection.
    The patient can easily complete the drug.
    This makes the treatment more convenient, fast and safe, and helps improve patient compliance
    .

    Therefore, Envolimab can be said to fill the gap of domestic PD-L1 in the treatment of MSI-H colorectal cancer patients, as well as the gap of subcutaneous injections
    .

    "Real cases of MSI-H, immunotherapy brings hope of cure for rectal cancer patients.
    Professor Deng Yanhong mentioned a pair of rectal cancer mothers and sons that impressed her very deeply.
    She shared: "First, the patient’s son was diagnosed with MSI-H rectal cancer.
    Because the patient was relatively young, he refused radiotherapy and chemotherapy.
    After receiving 6 courses of immunotherapy, he was operated on.
    By then, the tumor had completely disappeared
    .

    A few months later, the mother was also diagnosed with rectal cancer, but the location was lower, at the anal orifice.
    Due to economic reasons, the mother first chose chemotherapy.
    After 6 cycles of high-intensity chemotherapy, the tumor did not shrink
    .

    Then she received immunotherapy, and after the immunotherapy, the tumor near the mother's anus disappeared completely
    .

    Due to the low location of the tumor, the patient refused the operation.
    We took biopsies from different parts of the tissue.
    The results showed that the patient’s efficacy was evaluated as complete remission (CR)
    .

    In addition, our hospital also admitted a patient with rectal cancer.
    The patient was a young woman.
    The imaging examination showed that the lower rectal cancer had metastasis to the lymph nodes adjacent to the mesangial and superior rectal arteries
    .

    The intestinal wall of the middle and lower rectum is thickened, the longitudinal diameter is about 48mm, and it surrounds the entire circumference of the intestine, and the distal end is 45mm from the anal margin.
    The clinical stage is cT3N2bM0.
    After MDT discussion, it is recommended to use the FOLFOXIRI regimen for neoadjuvant chemotherapy and neoadjuvant induction chemotherapy combined with preoperative Radiotherapy and chemotherapy (CRT)
    .

    After the patient refused neoadjuvant treatment, he underwent laparoscopic radical resection of rectal cancer (Dixon) + double-chamber ileum ostomy on November 2, 2017.
    The patient did not receive adjuvant chemotherapy after surgery, and was followed up regularly
    .

    At this time, the PCR-MSI detection prompt is MSI-H
    .

    Figure 1.
    Baseline enhanced CT of the patient’s chest, abdomen and pelvis.
    Figure 2.
    Baseline enhanced MR of the patient’s pelvic cavity.
    In March 2018, the patient’s CT and MR results showed liver metastasis.
    Four courses of FOLFIRI were performed from March to May 2018, and the efficacy was evaluated.
    The disease is stable (SD)
    .
    From
    June to July, continue to use FOLFIRI for 3 courses, and the results of the re-examination show that the lesion is larger than before
    .
    The
    patient took Chinese medicine on his own from August to November, and the curative effect evaluation showed the lesion on November 29 Significantly larger than before
    .

    Figure 3.
    Enhanced CT of the patient’s chest, abdomen and pelvis on March 8, 2018 Figure 4.
    Enhanced MR image of the patient’s upper abdomen on March 15, 2018 5.
    4 FOLFIRI posterior chest, abdomen and pelvic enhanced CT on December 03, 2018 The patient signed to participate in " A multi-center phase II clinical study on the clinical efficacy and safety of Envolimab as a single agent in the treatment of dMMR/MSI-H advanced colorectal cancer and other advanced solid tumors.
    " Envolimab began on December 27, 2018 Anti-therapeutic, subcutaneous injection, 150mg/0.
    75ml each time, once a week
    .
    After
    8 weeks, tumor efficacy evaluation, efficacy evaluation partial remission (PR), duration of remission (DoR) and PFS are more than 2 years, and PR is still ongoing , The depth of tumor response (DpR) was 76%
    .
    The
    adverse reactions were mild, all of grade 1-2, the grade 2 adverse reactions were keratitis, and there was no ≥ grade 3 adverse reactions
    .

    Figure 6.
    Enhanced CT of the patient's chest, abdomen and pelvis on December 20, 2018.
    Figure 7.
    Enhanced CT of the patient's chest, abdomen and pelvis on April 22, 2019.
    Sex
    .

    Envolimab is used as a PD-L1 immune preparation for gastrointestinal tumors, and it can be injected subcutaneously, which greatly improves the compliance of treatment.
    It is hoped that more clinical studies will be launched and more patients will benefit from treatment
    .

    Expert profile Deng Yanhong Professor Assistant to the Dean of the Sixth Affiliated Hospital of Sun Yat-Sen University, Director of the Cancer Center, Chief Physician, Doctoral Supervisor, Postdoctoral Cooperative Supervisor, National Drug Clinical Trial Data Verification Expert, Director of Clinical Research Center and Drug Clinical Trial Institution (GCP)
    .

    Studying in Seattle, United States, Fred Hutchinson/University of Washington Cancer Research Center
    .

    The FOWARC research conducted by him has obtained ASCO oral reports twice, and has published more than 60 papers in high-level academic journals such as JClin Oncol, JAMA, LancetOncology, and more than 30 of them are the first author or corresponding author
    .

    Presided over a number of key national research and development program (sub-project), the National Natural Science Foundation of China, the Guangdong Provincial Natural Science Foundation
    .

    Won the National "Ten Thousand Talents Program" Young Top Talents, Guangdong Special Support Program Young Top Talents, Guangdong Province Medical Outstanding Young Talents, 2016 National Science and Technology Progress Second Prize (Fifth), 2018 Guangdong Province Science and Technology Progress First Prize ( Fourth), the 6th Wuzhou Women's Science and Technology Award of the Chinese Women's Physician Association
    .

    Main academic appointments: Member of the expert group of Chinese Colorectal Cancer Diagnosis and Treatment Standards (National Health Commission) Vice President of Oncology Branch of Chinese Geriatrics Association Member of Standing Committee of Integrated Oncology Branch of Chinese Anticancer Association Member of Standing Committee of Chinese Anticancer Association Precision Therapy Professional Committee of Chinese Society of Clinical Oncology Member of the Standing Committee of the Youth Expert Committee, Vice Chairman of the Youth Committee of the Colorectal Cancer Professional Committee of the Chinese Anti-Cancer Association *This article is only used to provide scientific information to medical professionals, and does not represent the views of this platform
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