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    Home > Active Ingredient News > Antitumor Therapy > Professor Ma Fei commented on the PHILA study: Pyrrolidinib started the battle to break the first-line treatment of her2-positive breast cancer in the advanced stage!

    Professor Ma Fei commented on the PHILA study: Pyrrolidinib started the battle to break the first-line treatment of her2-positive breast cancer in the advanced stage!

    • Last Update: 2022-09-21
    • Source: Internet
    • Author: User
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    In recent years, the state's investment in innovative drugs has been increasing, and scientific research achievements in the field of breast cancer have been



    Pyrrolidinib is a small molecule, irreversible, pan-ErbB receptor tyrosine kinase inhibitor



    Professor Ma Fei of the Cancer Hospital of the Chinese Academy of Medical Sciences is invited to analyze the eye-catching performance


    Expert Profiles

    Professor Fei Ma

    • Cancer Hospital, Chinese Academy of Medical Sciences

    • Chief Physician and Director of the Internal Medicine Treatment Center of the Cancer Hospital of the Chinese Academy of Medical Sciences, and Doctoral Supervisor Changjiang Scholar Distinguished Professor

    • Secretary-General of the China Breast Cancer Screening and Early Diagnosis and Early Treatment Standardization Committee

    • Vice Chairman of the Breast Cancer Expert Committee of the National Center for Quality Control of Cancer

    • Secretary-General of the National Expert Committee for Clinical Application Monitoring of Antineoplastic Drugs

    • Vice Chairman of the Committee of Multiple Primary and Unknown Primary Tumors of the Chinese Anti-Cancer Association

    • Vice Chairman of the Integrated Tumor Cardiology Branch of the Chinese Anti-Cancer Association

    • Secretary-General of the Clinical Research Committee on Oncology Drugs of the Chinese Anti-Cancer Association

    • Vice Chairman of the Oncology Pharmacist Branch of the Chinese Pharmacist Association

    • Vice Chairman of the National Female Ovarian Protection and Anti-Aging Promotion Project Committee

    • Director General of the Geriatric Oncology Branch of the Chinese Society of Gerontology and Geriatrics

    • Dean of Chinese College of Cancer Health Management, Chinese Medical Association

    • Vice President of Health Communication Branch of China Health Management Association



    The following is a transcript of the interview:

    Medical Pulse: Hello Director Ma, it is a great honor to be able to interview you


    Professor Ma Fei: HER2-positive breast cancer is a difficult point and focus in breast cancer treatment, and it is also a hot spot



    However, we are also soberly aware that the current clinical needs are still not met: for example, for HER2-positive early-stage breast cancer, even if adjuvant therapy is standardized, or even if the adjuvant therapy strategy is strengthened, 20%-30% of patients will still progress to advanced breast cancer



    From the perspective of mechanism of action, trastuzumab and paltozumab are both macromolecular monoclonal antibodies against HER2, and the dual antibody combination chemotherapy strategy helps to overcome the drug resistance problem generated during the binding process of antibodies and receptors, and the two drugs are combined with different regions of HER2, and at the same time inhibit the formation of homologous dimers and heterodimers, which have complementary effects; Moreover, both drugs have antibody-dependent cell-mediated cytotoxic effects (ADCC), and ADCC effects are superimposed at the same time to enhance the efficacy of synergistic effects



    The PHILA study is a large-scale national multicenter, randomized, double-blind, parallel-controlled, phase III clinical study initiated by China to evaluate the efficacy and safety



    • More and more patients today use trastuzumab during the adjuvant therapy phase
      .

      However, in the CLEOPATRA study, only about 10% of patients had previously received neo-auxiliary or adjuvant therapy for trastuzumab, while a larger proportion of trastuzumab treated patients
      were included in the PHILA study.

      That's number one
      .

    • Second, the PHILA study is currently the world's largest data targeting Chinese population in the first-line treatment of advanced HER2-positive breast cancer, which is the most important advance
      in PHILA research.

    Pulse: The first-line protocol of pyrrolidinib as a HER2-positive late stage in the PHILA study showed frequent bright spots, bringing great benefits
    to patients.

    Can you interpret and comprehensively evaluate the efficacy data of pyrrolidinib?

    Professor Fei Ma: The PHILA study was selected for this year's ESMO Annual Conference Oral Presentation, presenting its results
    to the world.

    From the efficacy evaluated by the researchers, a substantial increase in mPFS was achieved from 10 months in the control group (trastuzumab + docetaxel) to 24 months in the experimental group (pirolotinib + trastuzumab + docetaxel); The mPFS evaluated by the Independent Committee was longer, reaching 33 months
    .

    For this result, the control group of the PHILA study was indirectly compared with the control group of the CLEOPATRA study, with single targets at 10 and 12 months, respectively, and the PHILA study had lower single target mPFS because a larger proportion of trastuzumab-treated patients were included; An indirect comparison of the data from the two study groups, namely the new dual-target strategy of small molecules combining macromolecules (pyrrolidinib + trastuzumab) compared with the previous dual antibody strategy (paltuzumab + trastuzumab), is that mPFS has been extended from 18 months to 24 months, that is, a significant increase
    of one and a half to two years.

    Another key issue is security
    .

    The PHILA study showed that the new dual-target combination chemotherapy did not add additional adverse effects, and common diarrhea was also within the clinical control range
    .

    Therefore, the PHILA study confirmed that the combination of three drugs (pyrrolidinib + trastuzumab + docetaxel) has good efficacy, clinical accessibility and safety
    .

    It is expected that the median total survival (mOS) will also improve significantly as the future follow-up period extends
    .

    The results of the 8-year follow-up of the previous CLEOPATRA study showed the benefit of long-term survival, and the HR value of the PHILA study was smaller than that of CLEOPATRA (HR=0.
    41 vs.
    HR=0.
    62), and it is believed that the benefits of PFS in future PHILA studies will eventually be converted into OS benefits
    .

    Medical Pulse: Can you talk about why the small molecule tyrosine kinase inhibitor pirroltinib combined with the macromolecular monoclonal antibody drug trastuzumab has achieved such a stunning therapeutic effect?

    Professor Ma Fei: Since the end of the last century, when trastuzumab was on the market, on the one hand, we were amazed at the clinical treatment effect it brought, but on the other hand, as clinical medical scientists, we also observed that some patients would have the problem
    of trastuzumab resistance.

    To solve the problem of drug resistance, we need to use pharmacological knowledge to explore
    from the perspective of molecular biological mechanisms.

    Antibody drug resistance mechanisms are complex, including the absence of her2 extracellular ligand binding region (extracellular ligand binding domain), downregulation of extracellular region expression, the combined effect of free extracellular region, or mutations in the intracellular kinase active region (intracellular tyrosine kinase domain) resulting in non-dependent activation of ligands
    .

    In the more than ten years that trastuzumab dominated the clinic, the benefits of cross-line treatment such as changing chemotherapy drugs to allow trastuzumab to continue to exert the ADCC effect were very small
    .

    Since then, the dual antibody regimen has been introduced, and further enhancing the ADCC effect still cannot meet the clinical needs
    .

    In addition to regulating the role of the PI3K/AKT/mTOR pathway (PAM pathway), another strategy to fundamentally solve most of the resistance mechanisms is the use
    of small molecule tyrosine kinase inhibitors (TKIs).

    Small molecule TKI is not affected by antigen modulation in the extracellular region or antigen deletion and shedding, and can directly act on the intracellular kinase active region, which can overcome the resistance
    caused by abnormal activation of the intracellular kinase active region.

    Trastuzumab and pirrolinib are not completely cross-resistant, and the combination of the two drugs can achieve synergistic effects from different mechanisms
    .

    The excellent performance of small molecule TKI has been observed in late second-line studies, and it is also believed that after combining with trastuzumab, it can complement each other's advantages and achieve the effect
    of "1+1>2".

    It is based on this theoretical basis that the combination of the two drugs has also shown excellent clinical efficacy improvement, which is a result
    of our PHILA study.

    Medical Pulse: Recently published the original text
    of Pyrrolidinib's late first-line Pooled Analyses in the journal Cancer Innovation, of which you are the editor-in-chief.

    This meta-analysis included patients in the advanced first-line trials of pyrrolidinib phase II, PHENIX, and PHOEBE studies, from which we can see that the single-target regimen of pyrrolidinib combined with capecitabine has also shown very good efficacy
    .

    What do you think pirratinib means for first-line anti-HER2 therapy?

    Professor Ma Fei: Previous data such as THE PHOEBE study confirm that pyrrolidinib is the first choice for advanced second-line, and its efficacy is beyond doubt
    .

    However, for this subset of primaryly resistant patients who develop disease progression within 6 months of trastuzumab use in the advanced stage of HER2-positive breast cancer, the single-target plus chemotherapy regimen of pyrrolidinib combined with capecitabine actually shows the potential and possibility
    of first-line therapy.

    The previous Pooled Analyses have given us great confidence, and it is hoped that through the "1+ 1>2" effect of biological mechanisms, pyrrolidinib combined with trastuzumab will be pushed from the posterior line to the second and first lines, and it is also possible to further improve the clinical diagnosis and treatment effect
    by using new combination strategies in neoadjuvant therapy and adjuvant therapy in the future.

    You are a participant in all the important studies of pyrrolidinib from Phase I-III, and you also have your own basic research on pyrrolidinib, and a series of research results of pirolotinib are also internationally recognized, how do you think of the achievements of Chinese experts in clinical research?

    Professor Ma Fei: China's drug research and development road has undergone a long history of changes, and since 2008, China's national strategy requires the research and development of new drugs from the past imitation, tracking to focus on China's original research and innovation
    .

    Pyrrolidinib is a Class 1.
    1 innovative drug independently developed in China, and is a typical and outstanding representative
    of the research and development of new anti-tumor drugs during the "13th Five-Year Plan" period in China.

    Previously, through the use of piroctinib in China to carry out a series of standardized clinical research and mechanism exploration, to achieve the effect of improving clinical diagnosis and treatment, this strategy not only solves the urgent clinical problems in China, but also provides a set of clinical solutions
    to the world.

    This means that China's clinical research has more and more historical missions and industry missions, and we will realize the transformation from follower to future leader – this is a mission call for
    our Chinese clinicians, clinical researchers, including our Chinese new drug developers.

    In the future, the national strategic deployment of "Healthy China 2030" will put forward a higher requirement for the diagnosis and treatment of tumors, so it is also necessary for all of us to go hand in hand, redouble our efforts, and work together to achieve such a grand strategic planning goal
    .

    Yimaitong: Do you think the results of the pyrrolidinib PHILA study can change the treatment pattern of HER2-positive breast cancer in China, and whether the THPy regimen can become the preferred treatment regimen for your clinical decisions?

    Professor Ma Fei: The research and development process and series of research results of pirolotinib represent the progress of China's innovative drug research to clinical research, as well as the breakthrough of translational research, and the three aspects go hand in hand to realize the process
    of our innovative research from quantitative change to qualitative change.

    In this process, we can see that through the breakthrough of innovative drug concepts and mechanisms, the clinical diagnosis and treatment effect has been greatly improved, and it has also brought new solutions to the problems that need to be solved in the clinic and the global public problems, so piroctinib has been widely recognized
    by international peers.

    For the clinic, our pursuit of efficacy for HER2-positive advanced breast cancer treatment is never-ending, our research data from the previous 12 months to 18 months to today's 24 months, I believe that today is an end point, but also a starting point, I hope that in the future through our further efforts, there can be 36 months, 52 months of improvement, and finally the survival of advanced patients to a great extent of prolongation, but also look forward to more in line with the drug resistance mechanism and clinical characteristics of the study landing, can achieve the desire to benefit more patients

    Edit: DKK

    Reviewer: CZJ

    Typography: Small garden

    Execution: Traveller


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