A Multi-center Phase II Study of Combining Cabozantinib and Atezolizumab as the 1st Line Therapy for PD-L1 Negative Advanced/Metastatic NSCLC (Cabatezo-1)

NSCLC patients with low expression level of PD-L1, esp. those with its level less than 1%, do not derive much benefit from anti-PD-1/L1 therapy (e.g. atezoilzumab). In this study, investigators hypothesize that the combination of cabozantinib (a multi-kinase inhibitor) and atezolizumab will result in better therapeutic value.

开始日期2024-12-01

申办/合作机构

Exelixis, Inc.

[+1]

NCT06341712 / Not yet recruiting临床2期

A Phase II, Randomized, Open-label Study to Assess the Efficacy, Safety, and Pharmacokinetics (PK) of Maintenance Cabozantinib (XL184) Plus Best Supportive Care (BSC) Versus BSC in Children, Adolescents and Young Adults (AYA) With Unresectable Residual Osteosarcoma Either at Diagnosis or at First Relapse After Standard Treatment

The participants of this study will be children, adolescents, and young adults with residual osteosarcoma, which cannot be removed completely through surgery.
Participants will have achieved a partial response or stable disease at the end of conventional chemotherapy. Osteosarcoma is cancer of the bone. The cancer cells make immature bone cells, known as osteoid.
Osteosarcoma is very rare, but it is the most common type of bone cancer in children and teens. It is most common in teens and young adults.
In this study, participants will receive either cabozantinib and best supportive care or the best supportive care alone. Best supportive care will be provided at the investigator's discretion and according to institutional guidelines.
It includes antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management (including radiotherapy), etc. but does not include tumor specific therapy.
Cabozantinib will be taken by mouth (orally), as a tablet, once a day. Cabozantinib will be provided to participants who tolerate it for as long as their disease does not progress. Participants in the study receiving best supportive care alone may switch to treatment with cabozantinib and best supportive care if their disease progresses and if other eligibility criteria are met.
Participants may withdraw consent to participate at any time.
The estimated duration of the study for participants is 24 months, however a participant could remain in the study longer if demonstrating treatment benefit.

开始日期2024-06-13

申办/合作机构

Ipsen SA

NCT06364631 / Recruiting临床3期IIT

First Line Randomised Study Platform to Optimize Treatment in Patients With Metastatic Renal Cell Carcinoma

Systemic therapy for renal cell carcinoma (RCC) relies on 2 classes of agents: anti-angiogenic targeted therapy (Vascular endothelial growth factor Tyrosine Kinase Inhibitor- VEGFR TKI) and immune checkpoint inhibitor (ICI), targeting either PD1/PDL1 axis or CTLA4. Combination therapy is SOC for clear cell RCC in all guidelines with either ICI-ICI or ICI-VEGFR TKI. However, no head-to-head comparison have been performed between the 2 approaches and patients are treated based on physician decision without clinical /biomarker factors to guide treatment selection. PDL1 staining is, to date, the biomarker that has demonstrated its ability to enrich for overall survival benefit favoring ICI-ICI strategy in PDL1(+) and ICI-VEGFR TKI in PDL1(-) patients.
Study design has been developed to demonstrate that ICI-ICI is superior to ICI-VEGFR TKI in prolonging Overall Survival (OS) for PDL1(+) patients and to demonstrate that ICI-VEGFR TKI is superior to ICI-ICI in prolonging Progression Free Survival (PFS) and OS for PDL1(-) patients.

开始日期2024-04-12

申办/合作机构

Gustave Roussy, Cancer Campus, Grand Paris

[+12]

100 项与苹果酸卡博替尼相关的临床结果

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100 项与苹果酸卡博替尼相关的转化医学

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100 项与苹果酸卡博替尼相关的专利（医药）

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1,521

项与苹果酸卡博替尼相关的文献（医药）

2024-06-01·Artificial intelligence chemistry

Machine learning models to predict ligand binding affinity for the orexin 1 receptor

Article

作者: O'Connor, Shayna L ; James, Morgan H ; Welsh, William J ; Zhang, Vanessa Y

The orexin 1 receptor (OX1R) is a G-protein coupled receptor that regulates a variety of physiological processes through interactions with the neuropeptides orexin A and B. Selective OX1R antagonists exhibit therapeutic effects in preclinical models of several behavioral disorders, including drug seeking and overeating. However, currently there are no selective OX1R antagonists approved for clinical use, fueling demand for novel compounds that act at this target. In this study, we meticulously curated a dataset comprising over 1300 OX1R ligands using a stringent filter and criteria cascade. Subsequently, we developed highly predictive quantitative structure-activity relationship (QSAR) models employing the optimized hyper-parameters for the random forest machine learning algorithm and twelve 2D molecular descriptors selected by recursive feature elimination with a 5-fold cross-validation process. The predictive capacity of the QSAR model was further assessed using an external test set and enrichment study, confirming its high predictivity. The practical applicability of our final QSAR model was demonstrated through virtual screening of the DrugBank database. This revealed two FDA-approved drugs (isavuconazole and cabozantinib) as potential OX1R ligands, confirmed by radiolabeled OX1R binding assays. To our best knowledge, this study represents the first report of highly predictive QSAR models on a large comprehensive dataset of diverse OX1R ligands, which should prove useful for the discovery and design of new compounds targeting this receptor.

2024-04-01·Clinical genitourinary cancer

Real-World Results of Cabozantinib Given as Alternative Schedule in Metastatic Renal Cell Carcinoma

Article

作者: Bruchbacher, Andreas ; Franke, Johannes ; Alimohammadi, Arman ; Schmidinger, Manuela ; Laukhtina, Ekaterina ; Fajkovic, Harun

BACKGROUND:

The multikinase-inhibitor Cabozantinib is a widely used treatment strategy in metastatic renal cell carcinoma (mRCC), either in combination with the programmed cell death protein-1 (PD-1) inhibitor nivolumab or as monotherapy. Cabozantinib is given continuously at a dose of 60 mg once daily when used as a single agent and at 40 mg when combined with nivolumab. Treatment-related adverse events (TRAE's) were shown to occur frequently.

OBJECTIVE:

We aimed to assess the safety and efficacy of cabozantinib in patients with mRCC. Patients were treated in various lines. Furthermore, we analyzed the impact of an alternative treatment schedule in patients not able to maintain continuous dosing.

PATIENTS:

This is a single center retrospective study from the Medical University of Vienna.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

Overall response rates (ORR), progression free survival (PFS) and overall survival (OS) were evaluated for the entire cohort, by treatment line and by treatment schedule.

RESULTS:

Between January 2014 until April 2021, 71 patients received cabozantinib. Sixty-seven patients were eligible for full evaluation. By IMDC criteria, 32.4%, 59.2%, and 8.5% were classified as favorable, intermediate and poor risk respectively. Cabozantinib was offered as a 2nd-line or 3rd-line treatment in 38.0% and 32.4% of patients, respectively. An alternative treatment schedule was offered in 39.1% of patients. Objective responses were found in 43.3% (CR 6%) of patients and the median PFS was 10.8 months (95% CI: 5.5-16.2). When compared to continuous dosing, an alternative treatment schedule was associated with longer PFS (12.2 months (95% CI: 0-25.5) vs. 6.1 months (95% CI: 0.37-11.8) (P = .014, HR 0.46 (95% CI: 0.24-0.86), respectively) and a lower frequency and severity of TRAE's.

CONCLUSIONS:

Safety and efficacy of cabozantinib in real world is comparable to what has been observed in the pivotal trials, irrespective of the treatment line. An alternative schedule may further improve efficacy and safety.

2024-04-01·Clinical genitourinary cancer

Prognostic Stratification by the Meet-URO Score in Real-World Older Patients With Metastatic Renal Cell Carcinoma (mRCC) Receiving Cabozantinib: A Subanalysis of the Prospective ZEBRA Study (Meet-URO 9)

Article

作者: Sorarù, Mariella ; Signori, Alessio ; Grillone, Francesco ; Catalano, Fabio ; Procopio, Giuseppe ; Cremante, Malvina ; Rescigno, Pasquale ; Damassi, Alessandra ; Dionese, Michele ; Fornarini, Giuseppe ; Buti, Sebastiano ; Giudice, Giulia Claire ; Banna, Giuseppe Luigi ; Murianni, Veronica ; Di Napoli, Marilena ; Anpalakhan, Shobana ; Rebuzzi, Sara Elena ; Fratino, Lucia ; Ballestrin, Melissa ; Maruzzo, Marco ; Nasso, Cecilia ; Santini, Daniele ; Basso, Umberto

BACKGROUND:

The addition of neutrophil to lymphocyte ratio (NLR) and bone metastases to the IMDC classification provided by the Meet-URO score, resulted in higher prognostic accuracy in metastatic renal cell carcinoma (mRCC) patients receiving ≥2nd line nivolumab or cabozantinib in 2 retrospective analyses and 1st line nivolumab-ipilimumab in an expanded access programme. Prognostic estimates for older mRCC patients might be key for clinical decision-making.

METHODS:

The outcome of real-world older (≥70 years) mRCC patients treated with any line cabozantinib within the multicenter observational prospective ZEBRA (Meet-URO 9) study was analyzed according to the baseline Meet-URO score. The primary endpoint was overall survival (OS). The discriminative ability by Harrell's c-index and calibration were assessed to compare the Meet-URO and IMDC scores.

RESULTS:

A total of 104 mRCC patients received cabozantinib as 1st (38%), 2nd (20%), or ≥3rd (41%) line. With a median follow-up of 11.2 months, the median OS (mOS) was of 18.4 months. According to the IMDC score, favorable (15%), intermediate (65%) and poor-risk (19%) patients had a mOS not reached, of 15.6 and 5.7 months respectively (p = .011). According to the Meet-URO score groups, mOS was not reached in both group 1 (10%) and group 2 (25%), while in group 3 (33%), group 4 (25%) and group 5 (8%) mOS was of 13.6, 12.5, and 3.7 months, respectively (p < .001). The discriminative ability of the Meet-URO score was maintained by merging groups 1 to 2 vs. 3 to 4 vs. 5 (p < .001). The Meet-URO score (with either the original 5-group stratification or the modified 3-group one) showed higher accuracy than the IMDC score (c-index of 0.686 and 0.676 vs. 0.622).

CONCLUSION:

This analysis confirmed the prognostic accuracy of the Meet-URO score in older mRCC patients treated with cabozantinib and its role as a convenient tool for informing the patient and clinical decisions.

418

项与苹果酸卡博替尼相关的新闻（医药）

2024-06-28

·BioSpace

City of Hope Study Suggests Changing the Gut Microbiome Improves Health Outcomes for People Newly Diagnosed With Metastatic Kidney Cancer

City of Hope developed a novel use of biotherapeutic product CBM588 in the treatment of cancer; new research suggests the agent adjusts people’s microbiome, possibly leading to enhanced effectiveness of Food and Drug Administration-approved cancer immunotherapies Scientists are in discussions to translate City of Hope’s promising phase 1 trial results into a global phase 2/3 trial sponsored by the SWOG Cancer Research Network LOS ANGELES--(BUSINESS WIRE)-- Physician scientists from City of Hope, one of the largest cancer research and treatment organizations in the United States, found that people with metastatic kidney cancer who orally took a live biotherapeutic product called CBM588 while in treatment with immunotherapy and enzymatic tyrosine kinase inhibitors experienced improved health outcomes. The phase 1 trial was published today in Nature Medicine. Microorganisms in the gut modulate the immune system. City of Hope researchers are now in discussions with the global SWOG Cancer Research Network to design a phase 2/3 trial to assess the City of Hope-identified novel use of CBM588 and microbiome modulation in people with advanced cancer. Sumanta Pal, M.D., professor and vice chair of academic affairs in City of Hope’s Department of Medical Oncology & Therapeutics Research, is slated to be co-leader of the potential phase 2/3 SWOG trial. “We at City of Hope are the first to demonstrate a live bacterial product’s ability to improve clinical outcomes for patients with kidney cancer treated with immunotherapy. CBM588 could be exciting in cancer treatment because of its potential to enhance the efficacy of immune checkpoint inhibitor-based treatment, improve patient outcomes and modulate the gut microbiota in beneficial ways,” said Pal, a City of Hope medical oncologist and corresponding author of the new study. “Ongoing and larger clinical trials are crucial to validate these benefits and address current challenges. If the positive results observed in this small trial and a previous trial with nivolumab and ipilimumab are confirmed, CBM588 could become a valuable supplement in the treatment of various cancers, particularly for patients treated with immune checkpoint inhibitors." An estimated 44% of U.S. patients with cancer in 2018 were eligible for checkpoint inhibitor drugs, according to a JAMA Network Open article that flags the increasing trend of this percentage. In the single-center, phase 1 trial, 30 people with metastatic kidney cancer were randomized to receive cabozantinib, an inhibitor of vascular endothelial growth factor receptor, and targeted immunotherapy nivolumab with or without CBM588 as first-line treatment. Participants’ gut microbiome were analyzed via stool samples in the beginning for a baseline and then 13 weeks into treatment. City of Hope has granted an exclusive worldwide license to Osel for intellectual property on the novel use of CBM588 to enhance the efficacy of checkpoint inhibitors used to treat cancer, including metastatic renal cell carcinoma. Scientists from Osel and Miyarisan Pharmaceutical Co. Ltd, the manufacturer of CBM588, collaborated on the study. To date, many studies on lung cancer, melanoma and metastatic kidney cancer, among other diseases, have shown that the composition of the gut microbiome could predict immunotherapy outcomes for patients with cancer. Current guidelines for metastatic renal cell carcinoma (kidney cancer) recommend that newly diagnosed patients receive either dual checkpoint inhibitor therapy or a combination of immunotherapy and tyrosine kinase inhibitor, but most patients eventually experience disease progression while on treatment. Positive patient outcomes usually do not last, and subsequent treatments are largely palliative rather than curative. So, physician scientists are looking to combine current strategies with new treatments that do not introduce toxic side effects, such as through microbiome modulation. In the trial, City of Hope researchers observed an increase in the abundance of unclassified Ruminococcaceae genera, which has been linked with improved clinical outcomes with immune checkpoint inhibitors in recent studies. Clostridium butyricum MIYAIRI 588, the bacterium in CBM588, produces butyric acid, which is critical for intestinal health and is a well-known immunomodulator. “While not yet part of standard cancer treatment protocols, microbiome modulation is a promising area of research with the potential to enhance the efficacy of cancer therapies, particularly immunotherapies. Current applications are primarily within clinical trials, but the growing body of evidence suggests that microbiome-based interventions may soon become a valuable component of cancer treatment strategies,” said Hedyeh Ebrahimi, M.D, M.P.H., City of Hope postdoctoral medical oncology fellow and first author of the study. City of Hope is accelerating its research on the direct link between a healthy gut and the effectiveness of immune therapies, such as CAR T cell therapy. Its enhanced microbiome program spans from basic to clinical research and includes studying the gut microbiome’s role in protecting transplant patients from complications experienced during their recovery. “This study demonstrates again that the microbiome has an important role in the efficacy and toxicity of cancer immunotherapy and can be targeted to improve outcome,” said Marcel van den Brink, M.D., Ph.D., president of City of Hope Los Angeles and City of Hope National Medical Center, and the Deana and Steve Campbell Chief Physician Executive Distinguished Chair. The Nature Medicine study entitled “Cabozantinib and nivolumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial” was supported by Exelixis Inc. (XL184-IST123). CBM588 was supplied by Miyarisan Pharmaceutical Co., Ltd. and Osel Inc. About City of Hope City of Hope's mission is to make hope a reality for all touched by cancer and diabetes. Founded in 1913, City of Hope has grown into one of the largest cancer research and treatment organizations in the U.S. and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center at its core, City of Hope brings a uniquely integrated model to patients spanning cancer care, research and development, academics and training, and innovation initiatives. City of Hope’s growing national system includes its Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and cancer treatment centers and outpatient facilities in the Atlanta, Chicago and Phoenix areas. City of Hope’s affiliated group of organizations includes Translational Genomics Research Institute and AccessHopeTM. For more information about City of Hope, follow us on Facebook, X, YouTube, Instagram and LinkedIn. View source version on businesswire.com: Contacts Zen Logsdon 626-409-9367 zlogsdon@coh.org Source: City of Hope View this news release online at:

临床1期免疫疗法引进/卖出临床结果

2024-06-27

·PRNewswire

American Cancer Society Projects Over 2 Million New Cases in 2024: Biotech Innovations Respond

USA News Group News Commentary Issued on behalf of Oncolytics Biotech Inc. VANCOUVER, BC, June 27, 2024 /PRNewswire/ -- USA News Group News Commentary – According to the American Cancer Society, 2024 will be the first year the USA expects to have more than 2 million new cancer cases. In order to respond to the rising rates of cancer, the National Cancer Institute is making calls for change in how cancer clinical research is performed "Because our patients can't wait." According to Spherical Insights, the Global Oncology Drugs Market is projected to grow by 11.5% CAGR through 2033 to US$564.5 billion, highlighting the need for more effective therapies and incentives for those who develop them. The biotech sector is actively addressing this need, with recent notable developments from several companies, including: O ncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC), GSK plc (NYSE: GSK), Guardant Health, Inc. (NASDAQ: GH), Exelixis, Inc. (NASDAQ: EXEL), and Gilead Sciences, Inc. (NASDAQ: GILD). The article continued: According to the World Health Organization, the global cancer burden is growing amidst a mounting need for services. As well, an alarming trend is emerging, where cancer cases in younger people are rising sharply. Oncolytics Biotech® Announces Productive FDA Type C Meeting on its Metastatic Breast Cancer Program Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC), a leading clinical-stage company specializing in immunotherapy for oncology, today announced that the Company received productive feedback from its Type C meeting with the U.S. Food and Drug Administration (FDA), supporting the planned potential registration-enabling trial for pelareorep in HR+/HER2- metastatic breast cancer (mBC). The FDA supports progression-free survival as the primary endpoint of the study, with overall survival as a key secondary endpoint. The Company's proposed study will enroll patients who have failed hormonal therapy and have received no more than one line of antibody-drug conjugate (ADC) therapy. "Aligning with the FDA on key design elements and objectives of our planned registrational trial for pelareorep marks a critical step towards bringing this innovative treatment to patients," said Thomas Heineman, M.D., Ph.D., Chief Medical Officer at Oncolytics. "Our de-risked program builds on compelling data and key learnings from two randomized studies, BRACELET-1 and IND-213, which demonstrated clinically meaningful benefit in patients receiving pelareorep and paclitaxel compared to paclitaxel alone. Additionally, translational data from the AWARE-1 study highlights pelareorep's immune-mediated mechanism of action in breast cancer patients. We are now well-positioned to deliver on our mission of making pelareorep available to breast cancer patients in need of better treatment options." Wayne Pisano, Interim CEO and Chair of the Board of Oncolytics, commented, "We are appreciative of the thoughtful dialog with the FDA and are pleased to have reached an important regulatory milestone that provides a clear path forward for pelareorep's advancement towards registration in HR+/HER2- mBC. Looking ahead, initiating a registration-enabling trial has become a major corporate objective, and in parallel, we remain on track to report survival data from the BRACELET-1 study in HR+/HER2- mBC in the second half of the year. We believe these data will further bolster our compelling data package and underscores the therapeutic potential of pelareorep. We remain committed to improving the standard of care and addressing the high unmet medical needs of these patients." CONTINUED… Read this and more news for Oncolytics Biotech at: In other industry developments and happenings in the market this week include: GSK plc (NYSE: GSK), a global biopharma company, recently released positive results from an interim analysis of the DREAMM-8 phase III head-to-head trial evaluating belantamab mafodotin, in combination with pomalidomide plus dexamethasone (PomDex), versus a standard of care, bortezomib plus PomDex, as a second line and later treatment for relapsed or refractory multiple myeloma. As per the release, the drug combination reduced the risk of disease progression or death by nearly 50% versus standard of care. "With the robust results from the DREAMM-8 phase III head-to-head trial, we now have consistent data from two phase III trials supporting the potential for belantamab mafodotin combinations to redefine the treatment of multiple myeloma at or after first relapse," said Hesham Abdullah, Senior Vice President, Global Head Oncology, R&D, of GSK. "This is exciting news given the high unmet need for new and efficacious combinations once patients relapse or stop responding to initial treatments. We continue to share data and discuss our path forward with regulators." Guardant Health, Inc. (NASDAQ: GH), a leading precision oncology company, recently announced the launch of a new version of its Guardant360 TissueNext test that expanded the number of genes it identifies in a tumor tissue sample to 498. In addition to the panel expansion, Guardant has improved the test's operational workflow for a faster turnaround time. "The launch of the new Guardant360 TissueNext test is another step forward in our mission to conquer cancer with data," said Helmy Eltouky, Chairman and co-CEO of Guardant Health. "In addition to identifying guideline-recommended biomarkers, the upgraded test now provides more comprehensive gene coverage, so oncologists can make better informed decisions about the optimal treatment strategy for their patients with advanced cancer and help improve their outcomes." Exelixis, Inc. (NASDAQ: EXEL), a globally ambitious oncology company innovating next-generation medicines and regimens at the forefront of cancer care, recently settled two patent litigations with Cipla Ltd. and Cipla USA, Inc. (collectively Cipla) in response to Cipla's Abbreviated New Drug Application (ANDA) seeking approval to market generic versions of CABOMETYX® (cabozantinib) tablets prior to the expiration of the applicable patents. Prior to the settlement earlier this year, Exelixis also announced detailed results of its Phase 3 CONTACT-02 pivotal trial evaluating the above-mentioned cabozantinib in combination with atezolizumab in metastatic castration-resistant prostate cancer at this year's ASCO GU 2024 event. As per the results, the combination reduced the risk of disease progression or death by 35%. "Given there are limited options after progression on novel hormonal therapy, we recognize the need for a regimen that can delay disease progression, that has an acceptable tolerability profile and that is widely available to patients who may not have the means or desire to travel to specialized centers for other therapies," said Amy Peterson, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis. "We look forward to discussing these important results with the U.S. Food and Drug Administration, and to learning more in the next analysis of overall survival, anticipated this year." Through its recently-acquired Kite subsidiary, Gilead Sciences, Inc. (NASDAQ: GILD) recently announced results from three new analyses for Yescarta (axicabtagene ciloleucel) in relapsed/refractory (R/R) large B-cell lymphoma (LBCL), including both new clinical research and real-world evidence highlighting manufacturing and product characteristics of Yescarta, and outpatient administration of both Yescarta and Tecartus® (brexucabtagene autoleucel) at the 2024 European Hematology Association (EHA) Annual Congress, June 13-16, Madrid. "We are committed to improving survival outcomes for people living with difficult-to-treat blood cancers," said Ibrahim Elhoussieny, Vice President, Medical Affairs, of Kite. "These new data support the potential benefit of utilizing Yescarta in earlier lines of treatment, both in terms of manufacturing success and product characteristics. Additional data support the safety and feasibility of administering CAR T-cell therapy in the outpatient setting. These data contribute to the body of evidence for efficient utilization and delivery of Yescarta and Tecartus and further support our ambition for patients." Source: CONTACT: USA NEWS GROUP [email protected] (604) 265-2873 DISCLAIMER: Nothing in this publication should be considered as personalized financial advice. We are not licensed under securities laws to address your particular financial situation. No communication by our employees to you should be deemed as personalized financial advice. Please consult a licensed financial advisor before making any investment decision. This is a paid advertisement and is neither an offer nor recommendation to buy or sell any security. We hold no investment licenses and are thus neither licensed nor qualified to provide investment advice. The content in this report or email is not provided to any individual with a view toward their individual circumstances. USA News Group is a wholly-owned subsidiary of Market IQ Media Group, Inc. ("MIQ"). MIQ has been paid a fee for Oncolytics Biotech Inc. advertising and digital media from the company directly. There may be 3rd parties who may have shares of Oncolytics Biotech Inc., and may liquidate their shares which could have a negative effect on the price of the stock. This compensation constitutes a conflict of interest as to our ability to remain objective in our communication regarding the profiled company. Because of this conflict, individuals are strongly encouraged to not use this publication as the basis for any investment decision. The owner/operator of MIQ own shares of Oncolytics Biotech Inc. which were purchased in the open market, and reserve the right to buy and sell, and will buy and sell shares of Oncolytics Biotech Inc. at any time without any further notice commencing immediately and ongoing. We also expect further compensation as an ongoing digital media effort to increase visibility for the company, no further notice will be given, but let this disclaimer serve as notice that all material, including this article, which is disseminated by MIQ has been approved by Oncolytics Biotech Inc.; this is a paid advertisement, we currently own shares of Oncolytics Biotech Inc. and will buy and sell shares of the company in the open market, or through private placements, and/or other investment vehicles. While all information is believed to be reliable, it is not guaranteed by us to be accurate. Individuals should assume that all information contained in our newsletter is not trustworthy unless verified by their own independent research. Also, because events and circumstances frequently do not occur as expected, there will likely be differences between the any predictions and actual results. Always consult a licensed investment professional before making any investment decision. Be extremely careful, investing in securities carries a high degree of risk; you may likely lose some or all of the investment. SOURCE USA News Group

临床3期临床结果免疫疗法

2024-06-27

·医药魔方

PD-(L)1的下一步怎么走？有人选择打出这张“明牌”

癌症，这个现代医学面临的最重大的课题，似乎已变得并非那么不可战胜。尤其是近十年来，以PD-(L)1为代表的免疫肿瘤药物横空出世，多次刷新各个肿瘤领域的治疗标准，在深刻改变了癌症治疗格局的同时也收获了巨大的商业成功，甚至成为化疗之后，又一肿瘤治疗的基石。正因如此，这一赛道从产品数量到获批适应症都已呈现极为拥挤的态势：一边是全球已有22款PD-(L)1单抗获批上市，其中17款已在中国上市、7款还在等待监管机构批准；另一边则是非小细胞肺癌、胃癌、食管癌等大癌种的单药/联合化疗方案几乎被探索殆尽。留给后来者的市场空间只会越来越小。另一方面，未被满足的临床需求始终存在，对更高疗效目标的追求也远未到尽头。而疗效的突破往往建立在前人探索的基础之上，正如同PD-(L)1的成功要很大程度上归功于在各种标准化疗方案上做“加法”，在PD-(L)1隐约已成为又一标准治疗的当下，探索“PD-(L)1+”治疗模式——与更多药物组成搭档，或开发PD-(L)1多靶点药物——已成为业界公认的重要突破口之一，各路玩家纷纷围绕不同的思路展开了探索。各花入各眼，PD-(L)1搭档怎么选？长期以来，抗血管生成药物是各家PD-(L)1产品除化疗外最常规的搭档，例如卡博替尼、仑伐替尼、阿帕替尼，以及大分子的贝伐珠单抗等。但这种组合疗法的适应症覆盖局限于肝细胞癌、肾细胞癌等几个特定癌种。此外还有一些依赖特定靶点的靶向药物（如抗HER2靶向药物），与PD-(L)1的联用更是仅局限于个别适应症。近年来，随着多款新型ADC展现出色的疗效数据后，PD-(L)1+ADC组合随即成为如今热点之一，首个PD-1+ADC的联用方案也已于去年4月获FDA批准上市。此外，其他新型方案，如各种新型免疫检查点抑制剂（TIGIT等）与PD-(L)1的联用，以及各种PD-(L)1双抗，如PD-(L)1/CTLA-4双抗、PD-(L)1/VEGF双抗的探索同样如火如荼。不过，前沿治疗模式的推广总是伴随着长时间的摸索、验证过程。就目前而言，上述新型“PD-(L)1+”模式的探索、应用都还处在起步阶段，其整体的获益-风险比还有待在更大规模的真实世界应用中进一步验证，治疗相关不良事件（TRAE）的管理经验也还需进一步累积。处在当下免疫单药/联合化疗的探索空间逐步缩小、而新型方案仍然“青黄不接”的阶段，面临尚未被满足的治疗需求，临床更亟需的可能是应用范围更广、且既能提升疗效，又具有更高确定性的“PD-(L)1+”方案。相对而言，在另一条“PD-(L)1+”的路线——双免领域，得益于更早的起步，现有选择已发展得更为成熟。例如，全球首个“PD-1+CTLA-4”双免疫联合方案“O+Y”组合（纳武利尤单抗+伊匹木单抗）至今已经过了近10年长期、广泛的验证，堪称现阶段“PD-(L)1+”方案中的“明牌”。一方面，“O+Y”的协同作用机制明确，且双免的特点使得其不受特定靶点限制，覆盖瘤种广泛，目前已在全球获批9项适应症，涵盖黑色素瘤、肾细胞癌、结直肠癌、非小细胞肺癌、肝癌、胸膜间皮瘤、食管鳞癌，是迄今为止除联合化疗外，获批适应症最多的PD-(L)1组合疗法。另一方面，“O+Y”经过了长时间、大规模人群的探索和应用，其开展的10余项III期研究中，多数的最低随访时间已超过4年，部分研究（CheckMate-214/067）最低随访甚至已达到了90个月，有效性明确，安全性可控。尽管BMS同样手握ADC等新型药物管线，但目前来看，“O+Y”这手“明牌”在阵中仍扮演着不可替代的角色。尤其是近期，可以看到“O+Y”在适应症拓展方面明显发力，仅最近半年，就相继取得了CheckMate-8HW与CheckMate-9DW两项重量级III期临床研究的成功。值得一提的是，这两项研究对应的癌种分别为结直肠癌和肝细胞癌，均属于消化肿瘤，这也延续了O药一直以来在中国市场深耕高发的消化道癌种、紧盯未满需求的传统：早在胃癌、食管癌等上消化道大适应症仍存未被覆盖的时代，O药就凭借CheckMate-649/648/577等经典研究，在所有PD-(L)1中率先完成了上消化道领域疾病部位和病理类型的全面覆盖，填补了大量临床空白。（关于O药在上消化道领域的布局，参见：PD-1江湖，还能如何演绎？）从CheckMate-8HW与CheckMate-9DW可以看出，O药在中国市场的扩张步伐仍在延续上述思路，从上消化道拓展到了更广泛的消化肿瘤领域——其实不停变化的不只是持续更迭的治疗方案，疾病负担也在变：根据最新数据[1]，肝癌和结直肠癌已超越胃癌，成为中国发病率最高的两类消化肿瘤。不仅如此，中国肝癌和结直肠癌患者也是更容易从免疫治疗获益的群体。因而，于中国患者而言，上述两项免疫治疗的突破显得尤为关键。但此时毕竟不同于2020年：目前，免疫治疗早已成为了这两大癌种的一线标准治疗。不过，这一背景恰恰也给了“PD-(L)1+”模式更大的施展舞台：通过发掘其中仍未被满足的临床需求，“O+Y”组合在两项研究中均成功突破了现有治疗方式的瓶颈，触达了更高的疗效目标。接下来，本文也将结合“O+Y”的机制及疗效特点，围绕具体研究试对上述思路做进一步阐释。优势互补、高效协同：双免组合的机制奥秘 “O+Y”不仅在既往多项III期研究中被证实获益显著，而且在后续随访中表现出长期、持续的应答。以今年的ASCO大会上，针对食管鳞癌一线治疗的III期CheckMate-648研究45个月随访结果为例，经过近4年随访，接受“O+Y”组合治疗的患者在长期生存率和缓解持续时间（DOR）上获益更为明显。这一疗效特点的背后，是“O+Y”明确的作用机制优势。 CheckMate-648研究45个月随访结果来源：ASCO 2024大会摘要[2] O药和Y药分别靶向的PD-1与CTLA-4均为免疫检查点分子，但两者的作用阶段、机制有所不同，分工明确： CTLA-4抑制剂——Y药主要作用于T细胞的活化阶段，可控制初始T细胞（包括记忆性T细胞）的活化，激活T细胞识别低亲合力抗原，增殖为效应T细胞，增加能够识别肿瘤的克隆数；而PD-1抑制剂——O药主要作用于T细胞的效应阶段，直接阻断肿瘤细胞上的程序性死亡配体1（PD-L1）和T细胞上PD-1结合，解除肿瘤细胞的免疫“刹车”作用，重新激活T细胞，增强了T细胞效应功能。除了上述经典机制解释外，近年来有一种观点认为[3]，Y药还可通过其抗体依赖细胞介导的细胞毒性作用（ADCC效应），清除肿瘤微环境内异常高表达CTLA-4的调节性T细胞（Treg）[4]，从而进一步解除免疫抑制、加强抗肿瘤效果，这一机制使得“O+Y”有别于现有的PD-1/CTLA-4双抗药物：PD-1/CTLA-4双抗的靶细胞也包括效应阶段的T细胞，因此在药物设计中必须去除其ADCC效应以防止活化的T细胞被吞噬[5]，而这也可能导致损失ADCC效应带来的这部分潜在疗效。总之，“O+Y”组合通过合理的机制互补与协同效应，可以充分调动人体内的免疫“大军”，并改善长期免疫监视，实现高效、持久的抗肿瘤效果。也正是通过将其机制、疗效优势与未满足的临床需求相结合，“O+Y”近期在CheckMate-8HW与CheckMate-9DW两项重磅研究中取得成功，进一步夯实了自身地位。 CheckMate-8HW研究： MSI-H/dMMR结直肠癌一线疗效创新高国家癌症中心最新数据显示[1]，结直肠癌（CRC）已取代胃癌，成为中国最高发的消化肿瘤，在所有癌症中位居第二，仅次于肺癌。CRC的治疗现状不容乐观，其一线治疗首选仍为化疗，但其中有一类人群较为特殊——微卫星高度不稳定/错配修复缺陷表型（MSI-H/dMMR）结直肠癌患者。这类患者对一般的靶向疗法应答不佳，但对免疫检查点抑制剂敏感。因此，这类患者也是免疫治疗的重点人群。目前，全球仅有一项PD-1单药适应症获批用于一线治疗MSI-H/dMMR CRC。相比于化疗，PD-1单药虽能将患者的疾病进展或死亡风险降低41%，但其在短期和长期获益上仍有提高的空间。短期方面，患者对PD-1单药的应答率较低，约30%的患者无法从中获益，用药后快速出现进展；长期来看，2年PFS率不足50%[6]。那么，在PD-1单药的基础上加入另一免疫治疗药物，是否会成为该类患者疗效进一步提升的突破口？年初举行的ASCO-GI大会上，CheckMate-8HW研究用震撼性的数据给出了回答：相比于化疗方案，“O+Y”组合可将患者的疾病进展风险降低79%，2年PFS率高达72%[7]。 CheckMate-8HW主要终点：PFS 以上数据为双免疗法在机制层面良好的协同效应提供了又一项有力例证，且这一效应在MSI-H/dMMR这一优势人群中可能被进一步放大，最终使得整体疗效在PD-1单药的高水准之上实现了又一次突破。不仅如此，“O+Y”的安全性一如既往得稳定可控，其3-4级TRAE发生率仅为化疗组一半（23% vs. 48%）。如果说CheckMate-8HW的PFS数据带给人的感受是“震撼”，那么本次ASCO大会上公布的PFS2结果[7]（即一线治疗进展+二线治疗进展/死亡的时间）则更深层次地体现了双免治疗强大而独特的“记忆”效应，可为后续免疫治疗的全过程提供获益：在对照组高达67%患者接受后续免疫治疗的情况下，“O+Y”仍可降低73%的二次进展或死亡风险。值得一提的是，这项研究还包括一个O药单药对照组（尚未披露结果）。从这一设计可以看出来，“O+Y”在追求更高的绝对疗效的同时，也并不回避和目前标准的PD-1单药进行比较，这在PD-(L)1药物逐渐坐稳肿瘤治疗“基石”地位的当下倒是颇有些未雨绸缪的意味。近期，NMPA已授予“O+Y”组合用于一线治疗MSI-H结直肠癌的新适应症上市申请优先审评资格，国内这类患者有望很快迎来全新的一线治疗方案。 CheckMate-9DW研究：免疫治疗用于肝癌一线首次优于仑伐替尼而在中国同样高发的肝癌领域，如今已不再缺乏治疗选择，但缺少疗效足够好的药物：一方面，现有的一线免疫治疗方案ORR多数不足30%，且应答短暂，长期生存获益局限；另一方面，翻阅这些免疫治疗方案III期研究的设计，会发现获批近20年之久的索拉非尼仍是对照组的“常驻嘉宾”——尽管早在2018年，REFLECT研究就证实仑伐替尼几乎全面优于索拉非尼，但截至CheckMate-9DW前，仍没有任何免疫疗法在III期研究中头对头打败仑伐替尼。在此背景下开展的CheckMate-9DW并不满足于拿到一个和同类研究相近的结果，从研究设计便足见其雄心勃勃：试验主角选择了“O+Y”组合的同时，挑战对象也从一位（索拉非尼）增加至两位（研究者选择的仑伐替尼或索拉非尼）。事后来看，CheckMate-9DW的对照组高达85%的患者选用了仑伐替尼，侧面反映出研究的设计不仅更贴合临床实践，以患者为中心，也意在挑战更高的疗效目标。今年ASCO，CheckMate-9DW研究作为肝胆肿瘤领域唯一的LBA入选大会。结果不负众望，“O+Y”组合成为了第一个在头对头研究中战胜仑伐替尼的肝癌一线治疗方案，将整体疗效提升到了一个新的高度——ORR首次达到36%，而且一旦有效，获益持久：中位获益时间超过30个月，近一半患者的OS可达到两年，使其得以在一众治疗方案中脱颖而出。 CheckMate-9DW：主要结果来源：ASCO 2024大会摘要[8] 不仅如此，以上数据都是中期分析的结论（中位随访35.2个月）。考虑到“O+Y”目前表现出的突出应答率、应答持续时间和既往研究中普遍观察到的“长尾效应”，随着随访时间延长，可以期待其长期生存优势还有进一步扩大的空间。 PD-(L)1成为基石后的下一步：变化的环境，与不变的应对在免疫治疗的竞争进入下半场，“PD-(L)1+”模式的竞争成为主旋律之一的当下，如何才能确保自身的竞争优势？“O+Y“双免组合提供了颇具价值的参考：在不断动态变化的外界环境中，我们仍能总结出一些不变的应对之道。首先，做好充分的前瞻性布局，才能在转变来临时手握具有确定性的“明牌”，稳健地谋得“先手”；其次，不止步于现有疗效，不断挑战更高标准：即便是在免疫治疗已成为标准的领域，疗效始终存在进一步提升的空间；最后，也是最关键的一点：始终将未被满足的临床需求作为突破口：创新药的竞争，归根结底还是洞悉临床需求、满足临床需求的竞争。 ### - 上下滑动查看参考资料 - [1] Cancer incidence and mortality in China, 2022. [2] Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): 45-month (mo) follow-up from CheckMate 648. [3] https://mp.weixin.qq.com/s/AJ9Xytw2FGEXYxPuYD7FZQ [4] Anti-CTLA-4 antibodies in cancer immunotherapy: selective depletion of intratumoral regulatory T cells or checkpoint blockade? [5] Cadonilimab, a tetravalent PD-1/CTLA-4 bispecific antibody with trans-binding and enhanced target binding avidity [6] Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. [7] Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Expanded efficacy analysis from CheckMate 8HW. [8] Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): First results from CheckMate 9DW. Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

免疫疗法上市批准抗体药物偶联物临床结果

100 项与苹果酸卡博替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10095	苹果酸卡博替尼	L01XE26	DB08875

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
甲状腺癌	美国	Exelixis, Inc.	2021-09-17
分化型甲状腺癌	韩国	Ipsen Ltd.	2017-09-26
肝细胞癌	欧盟	Ipsen Pharma SAS	2016-09-09
肝细胞癌	冰岛	Ipsen Pharma SAS	2016-09-09
肝细胞癌	列支敦士登	Ipsen Pharma SAS	2016-09-09
肝细胞癌	挪威	Ipsen Pharma SAS	2016-09-09
肾细胞癌	欧盟	Ipsen Pharma SAS	2016-09-09
肾细胞癌	冰岛	Ipsen Pharma SAS	2016-09-09
肾细胞癌	列支敦士登	Ipsen Pharma SAS	2016-09-09
肾细胞癌	挪威	Ipsen Pharma SAS	2016-09-09
晚期肾细胞癌	美国	Exelixis, Inc.	2016-04-25
转移性甲状腺髓样癌	欧盟	Ipsen Pharma SAS	2014-03-21
转移性甲状腺髓样癌	冰岛	Ipsen Pharma SAS	2014-03-21
转移性甲状腺髓样癌	列支敦士登	Ipsen Pharma SAS	2014-03-21
转移性甲状腺髓样癌	挪威	Ipsen Pharma SAS	2014-03-21
甲状腺髓样癌	美国	Exelixis, Inc.	2012-11-29

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
实体瘤	申请上市	中国	江苏豪森药业集团有限公司	2020-09-28
前列腺腺癌	临床3期	美国	Exelixis, Inc.	2020-06-30
前列腺腺癌	临床3期	日本	Exelixis, Inc.	2020-06-30
前列腺腺癌	临床3期	阿根廷	Exelixis, Inc.	2020-06-30
前列腺腺癌	临床3期	澳大利亚	Exelixis, Inc.	2020-06-30
前列腺腺癌	临床3期	奥地利	Exelixis, Inc.	2020-06-30
前列腺腺癌	临床3期	比利时	Exelixis, Inc.	2020-06-30
前列腺腺癌	临床3期	巴西	Exelixis, Inc.	2020-06-30
前列腺腺癌	临床3期	加拿大	Exelixis, Inc.	2020-06-30
前列腺腺癌	临床3期	智利	Exelixis, Inc.	2020-06-30

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03141177 (CM9ER, ASCO2024) 人工标引	临床3期	晚期肾细胞癌一线	651	Cabozantinib plus nivolumab (CN)	廠襯襯襯蓋製齋鹽艱憲(願醖構獵憲鑰齋憲積壓) = 觸觸鬱膚窪憲顧蓋構廠遞憲願憲鹹積選範憲糧 (鏇獵鬱網鑰憲顧憲壓憲 ) 更多	积极	2024-05-24
NCT03141177 (CM9ER, ASCO2024) 人工标引	临床3期	晚期肾细胞癌一线	651	Sunitinib (SUN)	廠襯襯襯蓋製齋鹽艱憲(願醖構獵憲鑰齋憲積壓) = 壓積觸築齋醖製獵壓鏇遞憲願憲鹹積選範憲糧 (鏇獵鬱網鑰憲顧憲壓憲 ) 更多	积极	2024-05-24
NCT03141177 (CheckMate 9ER, ASCO2024) 人工标引	临床3期	晚期肾细胞癌一线	651	Nivolumab + Cabozantinib	鬱夢壓淵顧獵觸簾糧夢(糧製觸淵鑰簾製鏇窪網) = 鬱齋蓋夢憲糧鹹糧膚範淵鏇範襯構網構衊鏇壓 (夢築齋遞網襯糧襯鑰廠 ) 更多	积极	2024-05-24
NCT03141177 (CheckMate 9ER, ASCO2024) 人工标引	临床3期	晚期肾细胞癌一线	651	Sunitinib	鬱夢壓淵顧獵觸簾糧夢(糧製觸淵鑰簾製鏇窪網) = 簾鹽壓積壓膚廠蓋鏇齋淵鏇範襯構網構衊鏇壓 (夢築齋遞網襯糧襯鑰廠 ) 更多	积极	2024-05-24
NCT05007613 (phase II trial, ASCO2024)	临床2期	晚期食管鳞状细胞癌	-	Anti-PD-L1 therapy	鏇艱夢蓋鹽築壓鬱網積(襯遞積齋積窪壓築壓繭) = 選鏇鹹鑰艱襯蓋壓艱艱蓋鹽淵醖鬱膚壓鬱構壓 (夢醖糧網獵餘遞廠艱餘 )	-	2024-05-24
NCT03370718 (Pubmed)	临床2期	肾上腺皮质癌	18	Cabozantinib 60 mg	選選蓋齋鏇鬱醖齋醖鑰(鏇願選積鹽窪範構遞廠) = Treatment-related adverse events of grade 3 or worse occurred in 11 (61%) of 18 patients 積鑰鹹廠夢鏇積窪獵憲 (鏇顧網網醖鏇觸製積構 )	积极	2024-04-09
NCT04588051 (Pubmed)	临床2期	肝细胞癌 immune checkpoint inhibitor (ICI)	47	Cabozantinib 60mg/day	願範範願繭願網範選願(壓醖遞壓積鏇範獵廠製) = 糧獵糧積獵鏇夢構憲醖窪選積蓋襯選廠鏇鹹醖 (遞齋鏇遞廠齋願製範餘 ) 更多	-	2024-03-26
NCT04868773 (Phase 1 Study of Cabozantinib and Trifluridine/Tipiracil in Metastatic Colorectal Adenocarcinoma, Pubmed)	临床1期	转移性结直肠癌	15	Cabozantinib 20 mg	齋鏇構鏇鬱構願鑰糧鹽(艱淵構艱獵憲艱蓋鏇構) = Most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%), and rash (25%) 選膚願膚衊製餘簾範網 (襯醖膚築構糧壓齋窪憲 )	积极	2024-03-01
NCT03685448 (UNICAB, ASCO_GU2024) 人工标引	临床2期	肾细胞癌	31	Cabozantinib	齋廠觸醖艱糧構顧襯壓(憲觸餘鑰糧糧鏇網簾齋) = 襯窪築鹽淵繭蓋壓積衊構艱膚網齋齋衊積鹹餘 (夢壓顧鏇築範襯糧獵積 ) 更多	积极	2024-01-25
NCT05122546 (ASCO_GU2024) 人工标引	临床1期	转移性肾细胞癌	30	cabozantinib +nivolumab	膚鬱膚壓觸獵窪壓願網(廠製築獵窪製廠鹹積糧) = 鬱網鹽窪醖築蓋齋製繭繭鏇願淵膚鏇願選廠襯 (齋鏇觸襯製艱蓋醖製獵 )	积极	2024-01-25
NCT05122546 (ASCO_GU2024) 人工标引	临床1期	转移性肾细胞癌	30	cabozantinib +nivolumab+CBM588	膚鬱膚壓觸獵窪壓願網(廠製築獵窪製廠鹹積糧) = 襯築淵鹽醖遞襯壓製憲繭鏇願淵膚鏇願選廠襯 (齋鏇觸襯製艱蓋醖製獵 )	积极	2024-01-25
NCT03534804 (PemCab, ASCO_GU2024) 人工标引	临床2期	尿路上皮癌一线	36	Pembrolizumab+Cabozantinib	衊衊製鹹願廠製壓網簾(網鬱製廠鹽夢鑰簾鑰糧) = 網積選廠膚觸製餘築醖艱鹹膚願鏇窪鏇蓋積齋 (齋衊鏇餘餘鏇鹹範願衊 ) 更多	积极	2024-01-25
NCT04400474 (CABATEN \| GETNE-T1914, ASCO_GU2024) 人工标引	临床2期	肾上腺皮质癌	24	Cabozantinib+atezolizumab	鬱鏇膚鹹衊選廠衊餘衊(夢築製鏇選鹹積窪衊範) = 艱鹽襯簾鬱餘膚網蓋鹹顧蓋蓋獵窪餘糧鏇築積 (顧鹽網艱築遞壓繭鏇廠, 1 ~ 27) 更多	积极	2024-01-25