PRISM: PRecIsion in SCLC Via a Multicohort Study: Randomized Phase II Studies Evaluating Maintenance Durvalumab With or Without Biomarker-Directed Therapy for Extensive Stage Small Cell Lung Cancer (ES-SCLC)

This phase II trial tests how well biomarker tests on patients tumor tissue works in selecting personalized treatments for patients with extensive stage small cell lung cancer (ES-SCLC). Biomarker tests look for certain features in cancer cells that may give doctors more information about what is driving cancer and how to treat it. Based on the biomarker test results, study doctors can determine the subtype of ES-SCLC that study treatments can target. This study also tests different types of maintenance treatment for ES-SCLC with drugs durvalumab, saruparib, ceralasertib or monalizumab. Maintenance treatment is given after initial treatment and is given to help keep the cancer under control and prevent it from getting worse. Immunotherapy with monoclonal antibodies, such as durvalumab and monalizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Saruparib is a PARP inhibitor. PARP is a protein that helps repair damaged deoxyribonucleic acid (DNA). Blocking PARP may prevent cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Ceralasertib may stop the growth of tumor cells and may kill them by blocking some of the enzymes needed for tumor cell growth. Giving biomarker selected personalized maintenance treatment with durvalumab, saruparib, ceralasertib or monalizumab may work better in treating patients with ES-SCLC.

开始日期2025-03-08

申办/合作机构

SWOG

[+1]

NCT06503614

/ Recruiting临床2期IIT

ENHANCE (Elevated NKG2A and HLA-E Amplify NK/CD8 Checkpoint Engagers): a Phase 2 Trial of Durvalumab (MEDI4736) Plus Monalizumab in Non-Muscle-Invasive Bladder Cancer

This is a phase 2 open-label two cohort study of durvalumab plus monalizumab in patients with BCG-unresponsive or exposed CIS NMIBC. Arm A will enroll 43 participants who have cancer in situ (CIS) with or without high grade papillary urothelial cancer. Arm B will enroll 17 participants who do not have cancer in situ (CIS) but do have high grade papillary urothelial cancer. Eligible patients will be enrolled to receive up to 13 cycles of monthly combination of monalizumab and durvalumab. Both monalizumab and durvalumab will be administered intravenously (IV) every 28 days.

开始日期2025-03-01

申办/合作机构

Hoosier Cancer Research Network

[+3]

NCT06152523

/ Not yet recruiting临床2期IIT

Monalizumab and MEDI5752 in Patients With MSI and/or dMMR Metastatic Cancer

MSI is a molecular indicator of defective DNA mismatch repair (dMMR). The MSI/dMMR status is observed in all tumor types, representing notably 5% of metastatic colorectal cancers (mCRC), 25% of advanced endometrial cancer and 8% of metastatic gastric cancer.
MSI/dMMR cancers are highly immunogenic. MSI/dMMR tumors are characterized by a high tumor mutational burden with highly immunogenic neoantigens. These tumors are associated with an upregulation of immune checkpoints (PD1, PDL1, CTLA4, etc.) that protects MSI cancer cells from their hostile immune micro-environment, characterized by a high infiltration of activated cytotoxic T CD8+ and NK lymphocytes. Consequently, MSI/dMMR cancers are highly sensitive to ICIs, whatever the tumor location. MSI/dMMR status is a predictive biomarker for the efficacy of immunotherapy, regardless of the tumor type. Then, by several phase II and III studies The efficacy of immunotherapy has been demonstrated as front-line treatment for patients with chemotherapy-naive MSI/dMMR mCRC and gastric cancer. The phase III KEYNOTE-177 trial evaluating first-line treatment of pembrolizumab in patients with MSI/dMMR mCRC demonstrated its superiority over first-line chemotherapy, with a significant improvement of health-related quality of life. At final analysis, the median follow-up was 44.5 months. Median PFS was 16.5 versus 8.2 months (HR = 0.59; 95%CI 0.45-0.79). The hazard ratio favored pembrolizumab versus chemotherapy with a trend toward reduction in the risk of death (HR 0.74; 95% CI, 0.53-1.03; P=0.0359), despite a 60% effective crossover rate. Pembrolizumab has been approved by the FDA and the EMA for patients with newly diagnosed MSI/dMMR mCRC and is now the standard of care for this population. Also, the phase III CHECKMATE-649 trial reveal that the Combination of immunotherapy and cytotoxic chemotherapy is the new standard of care for patients with newly diagnosed metastatic oesogastric cancer. Importantly, results of the CHECKMATE-649 are outstanding for the subgroup population of MSI/dMMR gastric cancer patients (N = 44). Indeed, the unstratified hazard ratio for OS with nivolumab plus chemotherapy versus chemotherapy alone was 0.33 (95% CI 0.12-0.87) for patients with MSI/dMMR tumors. All in all, ICIs are the standard of care in first-line setting for patients with mCRC or metastatic oesogastric cancer. Besides, several phase II studies suggest that ICI combinations might overcome primary resistance to anti-PD1 monotherapy These data justify the development of bispecific monoclonal antibodies targeting both PD1 and CTLA4 such as MEDI5752. MEDI5752 has been developed based on the observation that there is a higher expression of PD-1/CTLA-4 on tumor resident versus peripheral T cells. Preclinical data show MEDI5752 fully suppresses PD-1 and preferentially inhibits CTLA-4 in the tumor versus the periphery, which is meant to uncouple CTLA-4 dependant peripheral toxicity from antitumor activity Natural killer cells are integral to the functioning of the innate immune system and play an important role in innate antitumor immunity. There is a growing body of evidence for targeting the NKG2A/HLA-E axis in combination with other ICIs to sensitize tumors to ICI therapy. NKG2A recognizes the non-classical HLA class I molecule HLA-E. The NKG2A receptor is found on peripheral NK cells and subsets of T cells in cancer patients. It is also present in tumor-infiltrating NK and cytotoxic T cells. Importantly, NK cells and the NKG2A/HLA-E axis play a crucial role in MSI/dMMR tumors. Therefore, a combined blockade of non-redundant checkpoint pathways to unleash NK and T cells seems particularly promising for MSI/dMMR neoplasms. Monalizumab specifically binds and blocks the inhibitory receptor NKG2A. Monalizumab has been investigated in combination with ibrutinib (in chronic lymphoid leukemia), cetuximab +/- durvalumab (in squamous cell carcinoma of the head and neck, and in solid tumors), durvalumab +/- FOLFOX (in solid tumors). In the first-in-human dose escalation of monalizumab plus durvalumab, a manageable toxicity profile was shown.
Taken together, these data provide a strong rational to combine an inhibitor of the NKG2A/HLA-E axis with a bispecific monoclonal antibody targeting both PD1 and CTLA4 for patients with metastatic MSI/dMMR cancers.

开始日期2023-12-01

申办/合作机构

Assistance Publique des Hôpitaux de Paris SA

100 项与 Monalizumab 相关的临床结果

登录后查看更多信息

100 项与 Monalizumab 相关的转化医学

登录后查看更多信息

100 项与 Monalizumab 相关的专利（医药）

登录后查看更多信息

项与 Monalizumab 相关的文献（医药）

2024-09-13·Future Oncology

PACIFIC-9: Phase III trial of durvalumab + oleclumab or monalizumab in unresectable stage III non-small-cell lung cancer

Article

作者: Mann, Helen ; Yoh, Kiyotaka ; Bielecka, Zofia Felicja ; Gopinathan, Aarthi ; Barlesi, Fabrice ; Cho, Byoung Chul ; Aggarwal, Charu ; Newton, Michael ; Goldberg, Sarah B ; Zimmer Gelatti, Ana Caroline

Evidence from the Phase III PACIFIC trial established durvalumab, a monoclonal antibody (mAb) targeting PD-L1, following concurrent chemoradiotherapy (cCRT) as a global standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). There remains an unmet need to improve upon the outcomes achieved with the PACIFIC regimen. Combining durvalumab with other immunotherapies may improve outcomes further. Two such immunotherapies include oleclumab, an mAb targeting CD73, and monalizumab, an mAb targeting NKG2A. Both agents demonstrated antitumor activity in early-phase trials. PACIFIC-9 (NCT05221840) is an international, double-blind, randomized, placebo-controlled, Phase III trial comparing durvalumab plus either oleclumab or monalizumab with durvalumab plus placebo in patients with unresectable, stage III NSCLC and no disease progression following cCRT.Clinical Trial Registration: NCT05221840 (ClinicalTrials.gov).

2024-07-01·Journal for ImmunoTherapy of Cancer

IFNγ mediates the resistance of tumor cells to distinct NK cell subsets

Article

作者: Heigwer, Florian ; Garcés-Lázaro, Irene ; Boutros, Michael ; Ng, Siu Wang ; Hofman, Tomáš ; Cerwenka, Adelheid

Background:

Immune checkpoint blockade targeting the adaptive immune system has revolutionized the treatment of cancer. Despite impressive clinical benefits observed, patient subgroups remain non-responsive underscoring the necessity for combinational therapies harnessing additional immune cells. Natural killer (NK) cells are emerging tools for cancer therapy. However, only subpopulations of NK cells that are differentially controlled by inhibitory receptors exert reactivity against particular cancer types. How to leverage the complete anti-tumor potential of all NK cell subsets without favoring the emergence of NK cell-resistant tumor cells remains unresolved.

Methods:

We performed a genome-wide CRISPR/Cas9 knockout resistance screen in melanoma cells in co-cultures with human primary NK cells. We comprehensively evaluated factors regulating tumor resistance and susceptibility by focusing on NK cell subsets in an allogenic setting. Moreover, we tested therapeutic blocking antibodies currently used in clinical trials.

Results:

Melanoma cells deficient in antigen-presenting or the IFNγ-signaling pathways were depleted in remaining NK cell-co-cultured melanoma cells and displayed enhanced sensitivity to NK cells. Treatment with IFNγ induced potent resistance of melanoma cells to resting, IL-2-cultured and ADCC-activated NK cells that depended onB2Mrequired for the expression of both classical and non-classical MHC-I. IFNγ-induced expression of HLA-E mediated the resistance of melanoma cells to the NKG2A+KIR−and partially to the NKG2A+KIR+NK cell subset. The expression of classical MHC-I by itself was sufficient for the inhibition of the NKG2A−KIR+, but not the NKG2A+KIR+NK cell subset. Treatment of NK cells with monalizumab, an NKG2A blocking mAb, enhanced the reactivity of a corresponding subset of NK cells. The combination of monalizumab with lirilumab, blocking KIR2 receptors, together with DX9, blocking KIR3DL1, was required to restore cytotoxicity of all NK cell subsets against IFNγ-induced resistant tumor cells in melanoma and tumors of different origins.

Conclusion:

Our data reveal that in the context of NK cells, IFNγ induces the resistance of tumor cells by the upregulation of classical and non-classical MHC-I. Moreover, we reveal insights into NK cell subset reactivity and propose a therapeutic strategy involving combinational monalizumab/lirilumab/DX9 treatment to fully restore the antitumor response across NK cell subsets.

2024-05-01·Combinatorial chemistry & high throughput screening

A Novel Natural Killer Cell-related Gene Signature for Improving the Prediction of Prognosis and Immunotherapy Response in Bladder Cancer

Article

作者: Yang, Guanghua ; Li, Shuai ; Wei, Xifeng ; Liu, Ranlu ; Ma, Xudong

Background::

Bladder cancer (BLCA) is a commonly diagnosed cancer worldwide that exhibits high rates of recurrence and metastasis. Immunotherapy is increasingly being recognised in the clinical management of bladder cancer. In addition, the prospect of developing Natural Killer (NK) cell-related immunotherapy is promising in BLCA.

Methods::

We established and verified a prognostic signature based on NK cell-related gene expression. We then calculated the NKscore of BLCA samples and correlated it with the clinical outcomes, molecular subtypes of BLCA, tumour microenvironment (TME), and predicted efficacy of immune checkpoint inhibitors (ICI) and chemotherapy drugs to thoroughly explore the implications of the NKscore. Finally, the role of the NK signature gene HECTD1 in BLCA was verified by Quantitative Real-time PCR, Cell Counting Kit-8 Assay (CCK-8), Transwell Assay and Colony Formation Experiment.

Results::

We analysed NK cell-associated genes and identified six genes with significant prognostic relevance. A high NK score significantly represents a worse prognosis. NKscore was significantly correlated with seven types of classical molecular subtype classifications of BLCA. In addition, NKscore positively correlates with NK-related immune checkpoints, suggesting that emerging NK cell immune checkpoint inhibitors, such as monalizumab, may have potential therapeutic promise for patients with high NKscore. The results of the T cell inflamed score (TIS) and tumour immune dysfunction exclusion (TIDE) score confirmed the suitability of immunotherapy for patients with a high NK score. Likewise, patients with a high NK score may be more suitable for several significant chemotherapeutic drugs. Functional experiments showed that the knockdown of HECTD1 significantly attenuated the proliferation, migration, and invasion ability of tumour cells.

Conclusion::

To sum up, the capability of our signature to predict prognosis and immunotherapy response was robust. Hopefully, these results will provide new insights for BLCA research and patient immunotherapy.

114

项与 Monalizumab 相关的新闻（医药）

2025-01-27

·PipelineReview

Innate Pharma Announces First Patient Dosed in Phase 1 Study of Its Nectin-4 Targeting Antibody Drug Conjugate IPH4502 in Selected Advanced Solid Tumors

IPH4502 is a novel and differentiated topoisomerase I inhibitor ADC conjugated to exatecan targeting Nectin-4 MARSEILLE, France I January 27, 2025 I Innate Pharma SA (Euronext Paris: IPH; Nasdaq: IPHA) (“ Innate ” or the “ Company ”) today announced the first patient was dosed in its Phase 1 study ( NCT06781983 ), investigating the safety and tolerability of IPH4502, an innovative Antibody-Drug Conjugate (ADC), in patients with advanced solid tumors known to express Nectin-4. IPH4502 is a novel and differentiated topoisomerase I inhibitor ADC designed to precisely target Nectin-4, a cell adhesion molecule that is overexpressed in several types of solid tumors, including urothelial carcinoma (UC), breast cancer, non-small cell lung cancer or gastro-intestinal cancer. IPH4502 targets tumors with a wide range of Nectin-4 expression, supporting its development beyond UC. IPH4502 differentiated topoisomerase I inhibitor payload supports its potential in patients with tumors resistant to MMAE-ADC. The Phase 1, open-label, multi-center study, includes a Part 1 Dose Escalation and a Part 2 Dose Optimization, and will assess the safety, tolerability, and preliminary efficacy of IPH4502 as a single agent in advanced solid tumors known to express Nectin-4, including but not limited to urothelial carcinoma, non-small cell lung, breast, ovarian, gastric, esophageal, and colorectal cancers. The study plans to enroll approximately 105 patients. “We are thrilled to initiate the Phase 1 study with IPH4502, a promising therapy for patients with advanced solid tumors known to express Nectin-4,” said Dr Shiraj Sen, Medical Oncologist and Phase 1 Investigator, Director of Clinical Research, NEXT Oncology-Dallas. “IPH4502 is uniquely designed to target tumors with both high and low expression of Nectin-4, offering hope for improved outcomes in a population where effective treatment options are limited, and relapses occur frequently. This study represents an important step forward in advancing innovative care for these patients.” “The initiation of this Phase 1 trial represents a significant milestone for Innate Pharma as our clinical stage pipeline now includes targeted ADCs. We are optimistic about the potential of IPH4502 to address unmet needs in the treatment of advanced solid tumors, with a well differentiated Nectin-4 targeting and the promise of ADC technology to provide a new therapeutic option for patients ,”added Dr Sonia Quaratino, Chief Medical Officer at Innate Pharma. More information about the trial can be found on clinicaltrials.gov . About IPH4502 IPH4502 is a novel topoisomerase I inhibitor Antibody Drug Conjugate (ADC) conjugated to exatecan targeting Nectin-4. It is currently investigated in a Phase 1 trial in advanced solid tumors expressing Nectin-4. Nectin-4 is a cell membrane adhesion protein overexpressed in several solid tumors, including urothelial, breast, esophageal, lung, ovarian, and pancreatic cancers, with limited expression in normal tissues. In non-clinical models, IPH45 is well tolerated and shows anti-tumor activity in vitro and in vivo . About Innate Pharma Innate Pharma S.A. is a global, clinical-stage biotechnology company developing immunotherapies for cancer patients. Its innovative approach aims to harness the innate immune system through three therapeutic approaches: multi-specific NK Cell Engagers via its ANKET® (Antibody-based NK cell Engager Therapeutics) proprietary platform and Antibody Drug Conjugates (ADC) and monoclonal antibodies (mAbs). Innate’s portfolio includes several ANKET ® drug candidates to address multiple tumor types as well as IPH4502, a differentiated ADC in development in solid tumors. In addition, anti-KIR3DL2 mAb lacutamab is developed in advanced form of cutaneous T cell lymphomas and peripheral T cell lymphomas, and anti-NKG2A mAb monalizumab is developed with AstraZeneca in non-small cell lung cancer. Innate Pharma is a trusted partner to biopharmaceutical companies such as Sanofi and AstraZeneca, as well as leading research institutions, to accelerate innovation, research and development for the benefit of patients. Headquartered in Marseille, France with a US office in Rockville, MD, Innate Pharma is listed on Euronext Paris and Nasdaq in the US. Learn more about Innate Pharma at www.innate-pharma.com . Follow us on LinkedIn and X . SOURCE: Innate Pharma

免疫疗法临床1期抗体药物偶联物

2025-01-22

·医脉通

首次NSCLC围术期医保也报销，盘点免疫治疗年度“热搜榜单”：2024年，这些研究凭什么火到出圈？

普惠患者，围术期免疫治疗踏入医保时代温故方能知新，回望2024年，免疫治疗的每一次突破，既是对科学边界的不断拓展，也是对患者生命意义的深刻回应。2024年末，新版《国家基本医疗保险、工伤保险和生育保险药品目录（2024版）》（以下简称“医保目录”）公布，并于2025年1月1日起正式实施。特瑞普利单抗成为唯一一个*围术期免疫治疗适应症进入医保目录的药物，这也是医保目录中首次纳入围术期免疫治疗适应症1。这一事件使得围术期免疫治疗正式步入医保时代，患者的治疗负担必将得到显著缓解，助力围术期免疫治疗更加可及，为更多患者提供完成全疗程治疗的机会。借此机会，医脉通肿瘤科对2024年全年NSCLC围术期免疫治疗重要研究与事件进行系统梳理，以飨读者。 2024围术期大事记：重温全球大会学术盛宴 2024年，免疫治疗的研究热潮继续席卷全球，多项重磅研究和前沿数据在各大国际学术会议上相继发布。这些数据不仅丰富了免疫治疗的理论体系，也为临床实践提供了更坚实的科学依据，共同推动免疫治疗走向更精准、更规范的发展路径。以下，将聚焦这一年学术盛宴中的亮点，梳理全球会议上发布的重要研究成果。 2024 欧洲肿瘤内科学会虚拟全体大会（ESMO VP 2024） RATIONALE-315研究EFS数据发表：EFS风险显著降低 RAITONALE-315在2024年3月的ESMO虚拟全体大会上首次公布了EFS数据，数据显示，替雷利珠单抗组的中位EFS尚未达到，而对照组为16.6个月；风险比（HR）为0.56（95% CI: 0.40-0.79，P=0.0003），表现出显著统计学差异。此外替雷利珠单抗联合化疗治疗组的客观反应率（ORR）为71.2%（对照组55.1%）。另外在手术安全性方面，手术延期率略高（16.3% vs 12.7%），≥3级术后并发症率较低（11.1% vs 15.6%），90天术后死亡率接近（1.3% vs 1.8%）。这一结果表明该方案能显著延长生存期，同时在手术优化和安全性上保持良好平衡2。 2024欧洲肺癌大会（ELCC 2024） CheckMate 77T研究：全疗程新辅助治疗有效提高病理缓解率，但接受部分治疗亦有获益 CheckMate 77T的研究数据显示，完成完整4个周期新辅助治疗的患者在病理缓解方面展现出显著优势，强化了免疫联合化疗对肿瘤降解的治疗价值。完成4个周期新辅助治疗的患者，其病理完全缓解率（pCR）达到26.7%，主要病理缓解率（MPR）为38.2%；而新辅助治疗周期<4个周期的患者在pCR和MPR方面分别为18.4%和21.1%。但数据也同样提示，即使不能完成完整的4个周期新辅助治疗，同样在病理缓解率和无事件生存期（EFS）方面显著优于对照组：对照组的pCR和MPR均为0%，两组间EFS HR=0.513。美国癌症研究协会2024年会（AACR 2024） IMpower010研究亚裔亚组分析：验证辅助免疫治疗在亚裔人群中的一致性在亚裔亚组129名PD-L1 TC ≥1%的 II-IIIA期NSCLC患者中，阿替利珠单抗组的未分层总生存期（OS）风险比为0.73（95% CI：0.28, 1.88），显示出对阿替利珠单抗的生存获益趋势。在安全性方面，阿替利珠单抗组有95.1%的患者报告了任意级别不良事件（AE），对照组为72.0%；3/4级AE的发生率分别为24.6%和13.1%。这些结果表明，阿替利珠单抗在亚洲患者中的疗效和安全性与全球数据一致4。 AEGEAN研究探索性分析数据：提示ctDNA预测潜力 AEGEAN研究探索性分析显示，ctDNA的动态变化可有效预测围术期免疫治疗的疗效。基线ctDNA阳性的患者中，所有实现pCR的患者和超过90%的实现MPR的患者在第四治疗周期实现ctDNA清除，且自第二治疗周期起，度伐利尤单抗组实现缓解患者的变异等位基因频率（VAF）水平显著低于未缓解者。百分比残余变异频率（%RVT）的显著下降也早于安慰剂组，显示出ctDNA在疗效评估中的敏感性。上述结果表明，ctDNA具备成为围术期免疫治疗核心生物标志物的潜力5。美国临床肿瘤学会2024年会（ASCO 2024） CheckMate 77T研究III期患者探索性分析：III期患者获益倾向明显，N2患者尤其明显 CheckMate 77T研究的探索性分析显示，围术期纳武利尤单抗显著改善了可切除III期NSCLC患者的EFS。特别是在淋巴结分期为N2的患者中，1年EFS率为70%（对照组45%，HR=0.46），pCR率为22.0%（对照组5.6%）。在非N2患者中，1年EFS率为74%（对照组62%，HR 0.60），pCR率为25.5%（对照组5.3%）。术后淋巴结降期率在纳武利尤单抗组为52%（其中46%降至ypN0），安慰剂组为45%。以上数据均提示N2人群可能是围术期免疫治疗的的优势获益人群6。 AEGEAN研究N2亚组分析：N2分期患者获益倾向更明显无独有偶，AEGEAN研究同样在ASCO 2024大会上发表了其N2人群的亚组分析，同样提示N2人群可能是围术期免疫治疗的的优势获益人群。分析显示，围术期度伐利尤单抗联合新辅助化疗显著改善了基线N2状态III期NSCLC患者的EFS（EFS=HR 0.63）、pCR率（16.6% vs 4.9%）和MPR率（32.6% vs 15.1%）。其中单站N2患者的pCR受益尤为显著，pCR率相比对照组提升了13.9%7。 KEYNOTE-671研究生存质量数据发表：围术期免疫联合治疗不影响生活质量 KEYNOTE-671的健康相关生存质量（HRQoL）数据显示，围术期帕博利珠单抗治疗相比对照组在新辅助与辅助阶段均没有带来明显的HRQoL各项量表评分变化，提示围术期免疫联合治疗对患者生活质量没有负面影响8。 CheckMate 816研究4年随访数据更新：验证新辅助免疫治疗的长期优势 CheckMate 816研究四年随访数据显示，新辅助纳武利尤单抗联合化疗在可切除的IB-IIIA期NSCLC患者中，持续显著改善EFS和OS。对比对照组，4年的EFS率为49% vs 38%，OS率为71% vs 58%。此外，实现pCR的患者展现出更显著的生存优势，4年OS率分别为95%和63%9。 IMpower010研究5年随访数据更新：PD-L1表达阳性人群持续获益 IMpower010研究超过60个月的随访数据显示，在PD-L1 TC ≥1%和TC ≥50%的II-IIIA期NSCLC患者中，阿替利珠单抗组的无病生存期（DFS）和OS持续显示获益。在PD-L1 TC ≥1%的人群中，阿替利珠单抗治疗组与对照组的中位DFS分别为68.5和37.3个月（HR=0.70），相差31.2个月；阿替利珠单抗治疗组中位OS仍未达到，对照组为87.1个月（HR=0.77）。更新的随访数据中也没有发现新的安全性问题10。 TRAILBLAZER研究首次披露：新靶点双抗转化治疗崭露头角作为一项概念验证性II期研究，TRAILBLAZER研究评估了PD-L1/TGF-β双靶点抗体SHR-1701在不可切除III期NSCLC中的疗效。研究中，主要分析队列的患者接受SHR-1701联合化疗诱导治疗后， ORR为58%，18个月 EFS为56.6%。同时有25%的患者成功转为手术治疗，并全部实现R0切除，接受手术患者的18个月EFS为74.1%，而放疗患者为57.3%。安全性分析显示，≥3级治疗相关不良事件（TRAEs）以血液毒性为主，且未见新安全信号。这些结果表明，SHR-1701联合化疗在不可切除III期NSCLC中展现出良好的疗效和可接受的安全性，且部分患者能够通过该治疗方案成功实现转化，初步显示出其治疗潜力11。 2024世界肺癌大会（WCLC 2024） NeoCOAST-2研究结果首次发表：带来围术期免疫多药联合方案的潜在可能 NeoCOAST-2是一项II期多臂平台研究，评估度伐利尤单抗联合化疗及其它新型抗肿瘤药物在可切除NSCLC患者中的疗效和安全性。在保证各组间基线特征平衡的前提下，患者被随机分为三组： Arm 1：度伐利尤单抗+化疗+Oleclumab（抗CD73单抗）； Arm 2：度伐利尤单抗+化疗+Monalizumab（抗NKG2A单抗）； Arm 4：度伐利尤单抗+化疗+Dato-DXd（TROP2 ADC）。结果显示，手术完成率在各组相似（92.1%-95.8%）。pCR率方面，Arm 1为20.0%，Arm 2为26.7%，Arm 4为34.1%；mPR率方面，Arm 1为45.0%，Arm 2为53.3%，Arm 4为65.9%。在安全性方面，治疗相关不良事件（TRAEs）发生率分别为：Arm 1为95.9%，Arm 2为91.5%，Arm 4为96.3%；3级及以上TRAEs发生率以Arm 4最低（18.5%），显著低于Arm 1（33.8%）和Arm 2（38.0%）。研究表明，Dato-DXd联合方案（Arm 4）在提高病理缓解率和保持安全性方面优势显著，为新的围术期免疫联合治疗方案提供了潜在选择12。国产PD-1双抗初露峥嵘，双双发表II期围术期研究结果在WCLC 2024发表的一项II期研究结果中，一项纳入60例可切除NSCLC患者的II期研究显示，PD-1/VEGF双抗依沃西单抗单药和联合化疗（紫杉醇+铂类）均展现出良好疗效。单药组（20 mg/kg）MPR率为60%，pCR率为30%；联合化疗组MPR和pCR分别为71.8%和43.6%。其中鳞状细胞癌患者的疗效更显著，MPR和pCR高达83.3%和53.3%。EFS和OS数据尚未成熟，安全性良好，无严重手术相关不良事件13。另一项II期研究则展示了PD-1/CTLA-4双抗卡度尼利单抗的围术期治疗初步结果。结果显示，在8例接受新辅助卡度尼利单抗联合化疗的患者中，7例实现客观缓解，6例接受手术并完成R0切除，其中4名患者达到MPR率，2名患者达到pCR。治疗相关不良事件以1-2级为主，仅1例出现3级房室传导阻滞14。免疫+血管靶向新辅助治疗初步结果发表，潜力可期在WCLC 2024上发表的这项II期研究显示，29名接受2-3周期卡瑞利珠单抗+阿帕替尼+化疗新辅助治疗的IIIA期（N2）NSCLC患者中，19名患者完成R0切除，MPR率和pCR率均为36.8%，疾病控制率（DCR）达到86.2%，ORR为20.7%。65.5%的患者报告了3/4级非手术相关不良事件，主要为白细胞减少（31.0%）、血小板减少（17.2%）、皮疹（17.2%）和疲劳（13.8%）。血液学毒性较少，安全性可控15。 CheckMate 816 vs CheckMate 77T研究：验证辅助阶段免疫治疗必要性，寻找辅助治疗优势获益人群研究者通过将CheckMate 816和CheckMate 77T研究通过倾向评分加权法调整了基线人口学和疾病特征后，比较了新辅助纳武利尤单抗联合化疗与围术期纳武利尤单抗在可切除NSCLC患者中的疗效。分析结果显示，CheckMate 77T围术期治疗通过增加术后辅助免疫治疗，使EFS获益倾向进一步提升（HR=0.61），特别是PD-L1低表达的患者，似乎从辅助治疗中获益的倾向更加明显（HR=0.51）。安全性分析显示，尽管围术期治疗的严重不良事件（SAE）发生率略高于新辅助治疗（41% vs 16%），但总体安全性可控，治疗相关不良事件（TRAE）发生率相当16。 LCMC3研究最终OS数据与ctDNA探索性分析数据发表：验证辅助免疫治疗获益 LCMC3研究评估了围术期阿替利珠单抗治疗在可切除NSCLC患者中的疗效，并对ctDNA的预测能力进行了探索性分析。在137名接受新辅助阿替利珠单抗治疗患者中，MPR率为20%，4年DFS和OS分别为70%和82%。MPR患者的4年DFS率优于非MPR患者（86% vs 67%，P=0.047）。其中接受辅助阿替利珠单抗治疗的患者与未接受者相比，3年DFS显著改善（83% vs 64%，P=0.023）。此外，术后ctDNA阴性患者的DFS显著优于阳性患者（HR=0.29, P=0.006），而ctDNA动态清除的实现也与DFS（HR=0.25, P=0.010）和OS（HR=0.26, P=0.034）显著改善相关17。 NADIM & NADIM II研究汇总分析：探索围术期免疫治疗生物标志物 WCLC 2024大会上，NADIM研究发表了5年随访更新数据。数据显示，46例可切除IIIA期NSCLC患者接受新辅助化疗联合纳武利尤单抗及纳武利尤单抗辅助治疗1年后的5年PFS率为65.0%，5年OS率为69.3%；若仅考虑癌症相关事件，PFS和OS分别为75.8%和82.2%。同时达到pCR的患者5年PFS和OS显著提高至92.0%和95.8%。此外，研究者还将NADIM研究与NADIM II研究进行了合并分析，寻找潜在的疗效预测因子。分析结果显示，基线T细胞受体（TCR）谱系（聚集度、均匀性和TOP1%克隆空间）在预测围术期免疫治疗疗效方面具有重要意义。对两项研究合并后的71名患者的TCR数据分析表明，TCR指标与pCR、PFS和OS显著相关，ROC曲线AUC分别为0.79（p=0.0078）、0.86（p=0.0011）和0.95（p<0.0001），优于PD-L1（AUC=0.71，p=0.0037）和TMB（AUC=0.61，p=0.226），是有十分有潜力的生物标示物18。特瑞普利单抗联合化疗新辅助治疗探索性分析：寻找潜在新型生物标志物 WCLC 2024大会上发表的一项研究评估了特瑞普利单抗联合化疗在IIB至IIIB期NSCLC患者中的新辅助治疗效果。100名患者中，83名（83%）成功接受R0切除，MPR率为65.1%（54/83）。术后病理评估表明所有手术患者均实现R0切除。术后并发症发生率为25.3%，大多为轻度至中度。对生物标志物的探索性分析显示，MPR患者的甲基化片段比率（MFR）和染色体非整倍体特征片段（CAFF）评分显著下降（P < 0.001），并在治疗后保持低水平（P < 0.001）。非MPR组中，治疗第一周期时MFR有所下降（P < 0.05），但在手术前未见显著变化（P = 0.132），CAFF评分亦无显著降低（P = 0.111）。研究表明特瑞普利单抗联合化疗在新辅助治疗中疗效良好，MFR和CAFF评分可能作为有效的生物标志物，用于预测新辅助免疫联合治疗患者的反应19。 2024 欧洲肿瘤内科学会年会（ESMO 2024） POTENTIAL研究：I期高风险患者或可从新辅助免疫治疗中获益多中心II期POTENTIAL研究探索了纳武利尤单抗新辅助治疗在高复发风险I期非小细胞肺癌（NSCLC）患者中的安全性和有效性。入组I期患者的肿瘤为纯实性，且无磨玻璃影成分，实性成分在术前CT上测量为2-4 cm，并且排除了已知EGFR突变、ALK融合或ROS1融合的患者。纳武利尤单抗新辅助治疗3个周期之后进行肺叶切除和淋巴结清扫。研究结果显示，共有52名患者接受评估，所有患者均进行了手术切除。pCR率达到23.1%（12/52，95% CI 12.5-36.8%），主要病理缓解（MPR）率为46.2%（24/52，95% CI 32.2-60.5%）。研究未观察到新的安全信号或治疗相关死亡。中位随访时间为33.7个月，2年无复发生存率（RFS）为88.0%，2年OS为93.8%，为高复发风险的I期NSCLC患者接受新辅助免疫治疗的获益提供了新的证据和潜在选择20。 RATIONALE-315研究公布患者报告结局（PRO）结果 RATIONALE-315研究PRO分析结果显示，相比对照组，替雷利珠单抗联合铂类化疗作为围术期治疗在整体健康状况（GHS/QoL）、身体功能和疲劳等指标上未见显著差异，但替雷利珠单抗组在咳嗽症状上显示了明显改善，胸痛恶化风险也显著降低（HR=0.59），表明其在延缓症状恶化方面具有一定优势21。 KEYNOTE-671研究IA2亚组分析再证辅助治疗获益倾向 KEYNOTE-671研究者基于第二次期中分析结果（IA2）进行了辅助治疗阶段的获益分析。结果显示，在接受了帕博利珠单抗辅助治疗的患者中，从辅助治疗阶段开始计算的EFS和OS的HR分别为0.55和0.71，为围术期免疫治疗中辅助治疗的必要性再添力证22。 IMpower010研究ctDNA探索性分析 IMpower010研究的探索性分析显示，在600名可评估患者中，21%（112/534）的术后患者为ctDNA阳性。术后ctDNA阴性的II-IIIA期患者则显示了更长的DFS，中位DFS分别为未达到和60.62个月（HR=0.74），而ctDNA阳性患者的中位DFS仅为19.12个月和7.92个月（HR=0.64），表明ctDNA阳性是DFS的负面预后因素。但在PD-L1 TC ≥1%的患者中，无论ctDNA阳性与阴性，都能观察到阿替利珠单抗辅助治疗的获益倾向23。 2024年欧洲肿瘤内科学会免疫肿瘤学大会（ESMO I-O 2024） KEYNOTE-671 4年随访更新数据公布 KEYNOTE-671研究4年随访更新数据显示，围术期帕博利珠单抗联合化疗相比单纯新辅助化疗和手术在早期NSCLC患者中持续显著改善EFS和总生存期OS。围术期帕博利珠单抗组与对照组的中位EFS分别为57.1个月和18.4个月（HR=0.57）；OS方面，帕博利珠单抗组的48个月OS率为68.0%（对照组为56.7%），中位OS仍未达到，OS HR为0.73（95% CI, 0.58–0.92），48个月OS率分别为68.0%和56.7%24。站在2025的开头，寄语未来 2024年，围术期免疫治疗的突破式进展再一次验证了免疫治疗在非小细胞肺癌（NSCLC）领域中的核心地位。CheckMate 77T、KEYNOTE-671、AEGEAN等多项III期研究全面展示了围术期免疫治疗其在延长EFS、提高病理缓解率及改善患者远期生存方面的显著价值。同时展现了围术期免疫治疗的精准发展方向。通过生物标志物的深入探索，如ctDNA、MFR、TCR谱系特征等等，临床医生能够更精准地识别获益人群，并在疗效预测和动态监测方面取得了重大进展。这些标志物的应用不仅提升了治疗决策的科学性，还为进一步优化联合治疗方案提供了强有力的支持。在实际临床应用中，围术期免疫治疗策略也正从实验室走向更广泛的患者群体，从III期到II期、甚至高危I期，再到不可切除的III期患者，研究不断尝试为更多的患者群体带来新的治疗机会。在已经实施的新版国家医保目录中，特瑞普利单抗“新辅助+辅助”适应症的纳入，也必将助力围术期免疫治疗门槛的降低1，让围术期免疫治疗来到更多亟需的患者身旁。此外，结合免疫治疗与化疗、新型靶向药物或双抗等的多模态治疗也逐渐成为新的探索趋势，以追求疗效上的进一步突破，同时在手术安全性和并发症管理方面表现出更优的平衡。当前，围术期免疫治疗已成为NSCLC诊疗的重要组成部分25。展望2025年，未来的研究需要进一步加强全球合作与本地创新，推动治疗可及性和患者获益的最大化。期待2025年，围术期免疫治疗能够为更多患者带来突破性的生存改善和生活质量提升，持续为生命延续注入希望。科学的脚步未曾停歇，更美好的2025正在前方召唤，等待着我们以创新与努力去拥抱。 *：截至2025年1月22日参考文献 1.《国家基本医疗保险、工伤保险和生育保险药品目录（2024版）》. 2024. 2.Yue D, Wang W, Liu H, et al. VP1-2024: RATIONALE-315: event-free survival (EFS) and overall survival (OS) of neoadjuvant tislelizumab (TIS) plus chemotherapy (CT) with adjuvant TIS in resectable non-small cell lung cancer (NSCLC)[J]. Annals of Oncology, 2024, 35(3): P332-333. 3.Awad M, Cascone T, Spicer J, et al. LBA2 Clinical outcomes with perioperative nivolumab (NIVO) in patients (PTS) with resectable NSCLC from the phase III CheckMate 77T study[J]. ESMO Open, 2024, 9(Supplement 3): 102985. 4.Wang J, Fan Y, Fang J, et al. Abstract CT239: IMpower010: Updated overall survival and safety results from Asian patients in a Phase III study of adjuvant atezolizumab vs best supportive care in resected stage IB-IIIA NSCLC[J]. Cancer Research, 2024, 84(7_Supplement): CT239-CT239. 5.Gale D, Zhu Z, Lai Z, et al. Abstract CT238: Associations of ctDNA levels during neoadjuvant treatment with pathological response in patients with resectable NSCLC from the phase 3 AEGEAN trial[J]. Cancer Research, 2024, 84(7_Supplement): CT238-CT238. 6.Provencio M, Awad M M, Spicer J, et al. Clinical outcomes with perioperative nivolumab (NIVO) by nodal status among patients (pts) with stage III resectable NSCLC: Results from the phase 3 CheckMate 77T study[J]. Journal of Clinical Oncology, 2024, 42 (suppl 17): LBA8007. 7.Heymach J, Reck M, Mitsudomi T, et al. Outcomes with perioperative durvalumab (D) in pts with resectable NSCLC and baseline N2 lymph node involvement (N2 R-NSCLC): An exploratory subgroup analysis of AEGEAN[J]. Journal of Clinical Oncology, 2024, 42 (suppl 17): 8011. 8.Garassino M C, Wakelee H A, Spicer J, et al. Health-related quality of life (HRQoL) outcomes from the randomized, double-blind phase 3 KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC)[J]. Journal of Clinical Oncology, 2024, 42 (suppl 17): 8012. 9.Spicer J, Girard N, Provencio M, et al. Neoadjuvant nivolumab (NIVO)+ chemotherapy (chemo) vs chemo in patients (pts) with resectable NSCLC: 4-year update from CheckMate 816[J]. Journal of Clinical Oncology, 2024, 42 (suppl 17): LBA8010. 10.Wakelee H A, Altorki N K, Zhou C, et al. IMpower010: Final disease-free survival (DFS) and second overall survival (OS) interim results after≥ 5 years of follow up of a phase III study of adjuvant atezolizumab vs best supportive care in resected stage IB-IIIA non-small cell lung cancer (NSCLC)[J]. Journal of Clinical Oncology, 2024, 42 (suppl 17): LBA8035. 11.Wu Y L, Zhou Q, Pan Y, et al. Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III NSCLC (TRAILBLAZER): Efficacy, safety and feasibility of surgical conversion outcomes from a proof-of-concept, phase 2 trial[J]. Journal of Clinical Oncology, 2024, 42 (suppl 17): 8082. 12.Cascone T, Florian G, Bonanno L, et al. PL02. 07 Neocoast-2: Efficacy and Safety of Neoadjuvant Durvalumab (D)+ Novel Anticancer Agents+ CT and Adjuvant D±Novel Agents in Resectable NSCLC[J]. Journal of Thoracic Oncology, 2024, 19(10): S1-S2. 13.Wang C, Zhao X, Zhang L, et al. OA01. 06 A Phase II Study of Perioperative Ivonescimab Alone or Combined with Chemotherapy in Resectable Non-Small Cell Lung Cancer[J]. Journal of Thoracic Oncology, 2024, 19(10): S10. 14.Wang L, Su C. EP. 11D. 01 A Phase II Study of Cadonilimab Plus Chemotherapy as First-Line Treatment for PD-L1-Negative Advanced Non-Small Cell Lung Cancer: LungCadX[J]. Journal of Thoracic Oncology, 2024, 19(10): S614. 15.Zhao L, Chen W, Guo T, et al. MA01. 05 Efficacy and Safety of Neoadjuvant Camrelizumab and Apatinib Combined with Chemotherapy in Stage IIIA (N2) NSCLC: A Single Arm, Phase II Trial[J]. Journal of Thoracic Oncology, 2024, 19(10): S53. 16.Forde P M, Peters S, Donington J, et al. PL02. 08 perioperative vs neoadjuvant nivolumab for resectable NSCLC: patient-level data analysis of CheckMate 77T vs CheckMate 816[J]. Journal of Thoracic Oncology, 2024, 19(10): S2. 17.Owen D H, Chaft J E, Haura E B, et al. MA15. 09 LCMC3: Long-Term Disease-Free and Overall Survival and their Association with ctDNA after Neoadjuvant Atezolizumab for NSCLC[J]. Journal of Thoracic Oncology, 2024, 19(10): S119. 18.Martínez-Toledo C, Sierra B, Molina-Alejandre M, et al. P3. 08E. 04 TCR Metrics as Predictive Biomarkers of Response and Survival after Perioperative Chemoimmunotherapy. NADIM & NADIM II Trials[J]. Journal of Thoracic Oncology, 2024, 19(10): S337. 19.Liu B, Wu N, Yan S, et al. P1. 03D. 01 Efficacy and Biomarker Analysis of Neoadjuvant Toripalimab Plus Chemotherapy in Resectable Stage IIB-IIIB Non-Small Cell Lung Cancer (NSCLC)[J]. Journal of Thoracic Oncology, 2024, 19(10): S152. 20.Tsutani Y, Sakairi Y, Ikeda N, et al. 1207MO Neoadjuvant nivolumab monotherapy for high-risk clinical stage I non-small cell lung cancer: A phase II POTENTIAL study[J]. Annals of Oncology, 2024, 35: S776. 21.Cappuzzo F, Wang C, Wang W, et al. 1213P Neoadjuvant tislelizumab (TIS) plus chemotherapy (CT) with adjuvant TIS vs. neoadjuvant placebo (PBO) plus CT with adjuvant PBO in resectable non-small cell lung cancer (NSCLC): patient-reported outcomes (PRO) in the RATIONALE-315 trial[J]. Annals of Oncology, 2024, 35: S781-S782. 22.Garassino M C, Gao S, Liberman M, et al. 1210P Neoadjuvant pembrolizumab (pembro) or placebo (pbo) plus chemotherapy and adjuvant pembro or pbo for early stage NSCLC: Subgroup analyses of the phase III KEYNOTE-671 study[J]. Annals of Oncology, 2024, 35: S778-S779. 23.Wakelee H, Reck M, Felip E, et al. 1211P IMpower010: ctDNA status and 5y DFS follow up in patients (pts) with resected NSCLC who received adjuvant chemotherapy (chemo) followed by atezolizumab (atezo) or best supportive care (BSC)[J]. Annals of Oncology, 2024, 35: S779-S780. 24.Majem M, Garassino M C, Zhao G, et al. LBA3 Perioperative pembrolizumab (pembro) plus neoadjuvant chemotherapy (chemo) in early-stage non-small-cell lung cancer (NSCLC): A 4-year update of KEYNOTE-671[J]. Immuno-Oncology and Technology, 2024, 24. 25.中国临床肿瘤学会（CSCO）非小细胞肺癌诊疗指南[M]. 2024年4月第1版. 人民卫生出版社, 2024. END 医脉通是专业的在线医生平台，“感知世界医学脉搏，助力中国临床决策”是平台的使命。医脉通旗下拥有「临床指南」「用药参考」「医学文献王」「医知源」「e研通」「e脉播」等系列产品，全面满足医学工作者临床决策、获取新知及提升科研效率等方面的需求。

免疫疗法临床结果

2025-01-08

·求实药社

壮士断腕还是另辟蹊径？CD73单抗的价值迷雾

短短过了几个月，天境杭州与赛诺菲的BD就掀起了波澜。2024年九月，天境杭州以大约2.5亿人民币的首付款拿到了CD73单抗的尤莱利单抗（Uliledlimab）的大中华区开发及商业化权益，且该药的后续临床推进主要是由天境杭州负责。而昨晚海外的天境生物（I-MAB）却传来消息，公司宣布放弃CD73单抗的开发，转而将重点放在推进CLDN18.2/4-1BB双抗Givastomig（TJ-CD4B）的开发上，同时，I-MAB在美股股价迎来了大涨。一次对管线研发的放弃，得到的却是股价大涨的结果，背后的逻辑是什么？ 01 天境生物情况回顾先叙述本次天境生物的决策，需要先了解两个点：其一，天境生物此前完成了境内境外的拆分，境外的天境生物在纳斯达克名为I-MAB；其二，赛诺菲与天境生物的BD发生在分拆之后，也就是说与其交易的是国内的天境杭州，而本次宣布放弃开发的是境外的I-MAB。首先是天境生物的坎坷历程。天境生物原本是由三境生物和天视珍合并，2020年在美国纳斯达克上市，也就是现在的I-MAB。之后的故事并不美好，天境生物股价的峰值与中国biotech整体板块的估值巅峰可以对应，在2021年Q2-Q3左右，超过了60亿美元，之后便是一路下坡，如今市值已经不到一亿美元。其中比较知名的里程碑事件是去年天境生物的CD47单抗在以19亿美元巨额资金BD给艾伯维后被退货。之后便是“分家”。在国内资本市场的寒冬阶段，天境生物面临国内的杭州天境的一次巨额对赌压力：如果杭州天境在境内没有上市成功，天境生物就需要拿出2亿美金来回购股东们手里的股票。在天境生物自身市值都不到2亿美元的情况之下，这笔资金无疑是个巨额数字，于是拆分境内资产给杭州天境的股东，成了一个无奈之下的选择。而境外的天境生物则专注于在海外发展，让自己成为一家美国底色的biotech。它带走的管线包括一条CD73单抗和两条双抗。当然，三条临床阶段管线的权益都不包括大中华区，大中华区的权益属于境内的天境生物。（I-MAB管线）之后便是第二个点，境内的天境生物，它现在的名称为TJ biopharma，手上留有多条临床III期阶段接近商业化的资产，不过可以看到在权益上，即将商业化的资产天境的权益都限于中国或大中华区。（天境杭州管线）而赛诺菲和天境杭州就是在这样的背景之下达成BD的，这在当时被看成是境内天境生物的一次翻身仗：将大中华区的权益卖出了总付款19.5亿人民币的高价格。而如今境外的I-MAB选择终止研发CD73单抗，不免有些戏剧性，境外的I-MAB决策宣布，I-MAB获得了投资者认可，但在部分市场投资者的眼里：赛诺菲间接当了一回“接盘侠”。 02 CD73单抗本身在管线上，如何看待CD73单抗，为什么境外的I-MAB要选择放弃该管线的开发？先从机制开始叙述。CD73单抗同样是与PD-1单抗联用，来提高免疫细胞功能的。如图所示，CD73是一种酶，将单磷酸腺苷（AMP）水解成腺苷（途中的ADO），而腺苷在肿瘤微环境中一方面可以削弱免疫细胞如T细胞，NK细胞的杀伤效应，另一方面可以促进肿瘤的血管生成与肿瘤细胞的增殖。（图片来源：I-MAB官网）从这个角度出发，阻断AMP转化成腺苷，就可以增强免疫细胞的抗肿瘤作用，因此才会有从CD73这个腺苷转化酶上下手的思路。（图片来源：药闻窗）竞争格局如图所示，阿斯利康的Oleclumab遥遥领先，2022年开始三期临床，预计2026年5月读出顶线数据，主要适应症是NSCLC，这与天境生物的尤莱利单抗是一样的。这个靶点也主要是在2020-2022年极度热门。早期的数据来看，可以从阿斯利康的Oleclumab与Durvalumab（PD-1单抗）联用的情况来窥探一二。根据该临床II期试验，两者联用ORR达到了30%，高于Durvalumab单药治疗的ORR17.7%，PFS的HR达到了0.44，从HR上看有显著的差异性。不过，该II期临床还做了另一项联用试验：durvalumab与monalizumab（NKG2A抗体）联用，该联用试验的ORR要比Oleclumab的效果要好，达到了35.5%，PFS的HR达到了0.42。对于阿斯利康而言，二者两条管线是共同推进的，III期临床试验PACIFIC-9的设计上，也被设计成PD-1单抗单用，以及分别于两种药物联用的三个组。也就是说，对于阿斯利康而言，CD73单抗只是它之后免疫联用疗法中备选的一项，同一个临床III期试验共同推进，最后根据结果，看未来商业化主要推哪款单抗。就II期临床来看，CD73单抗疗效相比较而言略微占劣势。另一家推进该靶点的巨头是BMS，管线为BMS-986179，不过BMS-986179给人的感觉是推进速度并不快，换句话说，并没有那么受重视。其2016年就开展了临床I期试验，2021年才完成，自此之后，clinical.gov网站上便查不到它的任何临床试验。也就是说，从2021年之后，该药的研发推进便中断了。同样的趋势还发生在诺华的CD73单抗——NZV930上，其临床试验并不是结束，而是终止（terminated）。 MNC在国际市场上对该管线的态度是值得寻味的，它到底是不是一个好的靶点，或者说有一些问题国外无法解决，但是国内可以解决？事实上，国内一些知名的biotech对CD73单抗并没有放弃，典型例子是康方的AK119,它将与AK112联用，在多种实体瘤上发挥功效。从这个角度再去看MNC在靶点上的困境，会不会是该管线需要配合强力的双抗，才能打出漂亮疗效的战绩？而康方的双抗正好能够提供CD73单抗最前沿的双抗平台。但联用方面，I-MAB面临一个问题：单抗与双抗的适应症错配，无法将自身的管线进行联用（其CD73联用的是特瑞普利单抗）。CD73一般首先推的适应症是NSCLC，阿斯利康和天境生物都是如此。但是I-MAB又需要去重点推进其双抗Givastomig上，其主要靶点claudin18.2是众所周知的消化道靶点，其主要推的适应症也是胃癌，目前获得了FDA的孤儿药认定。这种情况下，对于一家持续亏损的biotech而言，总要做出取舍。是选择一条单药使用无法发挥很好效果，必须至少有PD-1联用的管线，还是一条走在前沿，FDA给了孤儿药认证的双抗管线？I-MAB选择了后者，并且该选择得到了投资者的认可。 03 I-MAB的双抗生力军Giva 如上文所述，I-MAB做出的优先推进Givastomig（以下简称Giva）的决定获得了投资者的认可，股价获得了大涨。该药两个靶点：claudin18.2和4-1BB，其中一个不用多介绍，胃癌，胰腺癌等消化道癌症的热门靶点，4-1BB也并不算冷门，是非常值得开发的免疫共刺激靶点，在双抗和三款的第二，第三靶点上，4-1BB都是一个较为热门的选择。（图片来源：I-MAB官网PPT）该双抗结构和作用机制如poster所示，在CLDN18.2高表达的肿瘤细胞中，它可以一边连接CD8＋T细胞，一边连接肿瘤细胞，达到类似TCE细胞的效果。（图片来源：I-MAB官网PPT）如图所示，临床前的联用模型中，联用的红色曲线，在加入Giva的情况下，达到了非常具有差异化抑制肿瘤生长效果。此外，在安全性方面，在食蟹猴研究中，Giva在重复剂量高达100 mg/kg/week时耐受性良好，且不会对肝功能产生不利影响，并且未观察到外周细胞因子释放或免疫激活。目前Giva已经在2024年ESMO上展现了其初步疗效和安全性。（图片来源：I-MAB官网PPT）临床试验设计如图所示，最后确定的剂量为12mg/kg，Q2W。疗效如下图所示，有待临床Ib/II期试验的进一步观测。安全性方面，34.9%患者报告了三级以上不良反应事件，一例患者发生了四级不良反应（血小板计数下降），没有五级不良反应。总体而言，疗效方面的有效性可以进一步期待。I-MAB既然做出了这样的选择，那么就应该有它自身的考量。目前有一种猜测是该药与BMS发生BD交易的可能性。主要的依据是Giva正在与O药联用临床试验，受到了该潜力的驱动引起了投资者的热情。结语：本次I-MAB境外的一通操作确实是壮士断腕，也在股价上取得了积极的反映，总体来说本次事件让人们重新把目光落回了CD73抗体上，这个靶点到底还有多大的潜力，要配合怎样的药物去打组合拳。国内康方还在推，国外MNC却大多已经放弃，这其实说明了很多问题，至少可以确定的是，CD73需要有很强的配套管线，一家家底不够殷实的biotech在它身上黑暗中摸索，或许得不到太过理想的收益。这或许就是本次放弃的底层逻辑。至于赛诺菲之后会选择如何做，也是非常有悬念的事情。联系我们 ABC 2025 展位火热预定中！扫码立即咨询电话：13816031174 （同微信）赞助形式包括但不仅限于演讲席位、会场展位、会刊彩页、晚宴赞助、会议用品宣传等。点击此处“阅读全文”咨询更多精彩！

临床3期引进/卖出

100 项与 Monalizumab 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
-	Monalizumab	-	DB12824

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
局部晚期非小细胞肺癌	临床3期	美国	AstraZeneca PLC	2022-02-07
局部晚期非小细胞肺癌	临床3期	中国	AstraZeneca PLC	2022-02-07
局部晚期非小细胞肺癌	临床3期	日本	AstraZeneca PLC	2022-02-07
局部晚期非小细胞肺癌	临床3期	澳大利亚	AstraZeneca PLC	2022-02-07
局部晚期非小细胞肺癌	临床3期	巴西	AstraZeneca PLC	2022-02-07
局部晚期非小细胞肺癌	临床3期	加拿大	AstraZeneca PLC	2022-02-07
局部晚期非小细胞肺癌	临床3期	哥伦比亚	AstraZeneca PLC	2022-02-07
局部晚期非小细胞肺癌	临床3期	法国	AstraZeneca PLC	2022-02-07
局部晚期非小细胞肺癌	临床3期	德国	AstraZeneca PLC	2022-02-07
局部晚期非小细胞肺癌	临床3期	意大利	AstraZeneca PLC	2022-02-07

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


WCLC2024	临床2期	广泛期小细胞肺癌一线 NKG2A/CD94 \| HLA-E	6	Platinum-based chemotherapy + Durvalumab + Monalizumab	醖觸製鑰遞膚淵繭淵網(鏇襯襯糧願襯襯壓製遞) = 築遞襯壓憲夢夢觸餘鏇糧鑰鏇夢廠網簾憲餘齋 (憲獵選鑰糧憲夢獵蓋築 )	积极	2024-09-08
NCT03822351 (COAST, ASCO2024) 人工标引	临床2期	不可切除的非小细胞肺癌	189	durvalumab	獵糧壓繭選觸顧衊淵衊(構遞齋糧醖鑰廠鬱築膚) = 窪觸鬱網鬱蓋窪選構淵獵壓蓋鹽餘鑰構憲壓簾 (艱構壓觸範糧鬱餘範餘, 14.3 ~ 35.9) 更多	积极	2024-05-24
				durvalumab+oleclumab	獵糧壓繭選觸顧衊淵衊(構遞齋糧醖鑰廠鬱築膚) = 鹹襯齋網窪窪積選鹽壓獵壓蓋鹽餘鑰構憲壓簾 (艱構壓觸範糧鬱餘範餘, 23.1 ~ 48.4) 更多
NCT03794544 (NeoCOAST, AACR2024) 人工标引	临床2期	可切除非小细胞肺癌新辅助	47	durvalumab	淵簾衊繭鹹壓獵選構廠(顧壓鬱願餘選壓顧繭窪) = Percent CD73+ TC and B cell abundance was higher in patients with MPR vs those without MPR in the durva + ole arm, but not in the durva monotherapy or durva + mona arms. Increased CD8 T cell and NK cell abundance was not associated with MPR in any arm. 襯製膚壓獵鬱選鹹鏇獵 (鑰範鏇齋顧遞衊鏇醖築 ) 更多	积极	2024-03-22
				durvalumab+oleclumab
NCT03088059 (EORTC-HNCG-1559, ESMO2023)	临床2期	复发性头颈部鳞状细胞癌 PD(L)1	66	Durvalumab + Monalizumab	鹽鹽窪鹹蓋積繭網襯壓(鬱鬱顧淵壓蓋窪鬱淵艱) = 窪鹹遞鏇獵觸膚蓋醖構餘鹹夢淵獵鑰夢製簾夢 (襯窪齋鹽醖製選鏇構築 ) 更多	不佳	2023-10-22
				monalizumab (Physician's choice)	鹽鹽窪鹹蓋積繭網襯壓(鬱鬱顧淵壓蓋窪鬱淵艱) = 願醖願遞餘齋糧廠觸壓餘鹹夢淵獵鑰夢製簾夢 (襯窪齋鹽醖製選鏇構築 ) 更多
NCT04590963 (INTERLINK-1, Corporate Publications) 人工标引	临床3期	复发性头颈部鳞状细胞癌	600	Cetuximab+Monalizumab	艱簾築構餘壓構膚憲淵(鑰選觸鏇淵衊糧襯衊製) = not reach 鹽觸窪觸構齋鑰鹹衊鑰 (鑰憲壓觸蓋築簾糧積選 )	不佳	2022-08-01
				Cetuximab+Placebo
NCT03794544 (AACR2022) 人工标引	临床2期	非小细胞肺癌新辅助	84	Durvalumab	齋獵選製積顧憲齋憲憲(鹽積製蓋糧範齋膚遞製) = 淵夢選齋齋衊選夢築襯糧齋憲簾觸夢蓋觸夢構 (選鬱鹹夢顧鏇窪蓋鏇製, 2.4 ~ 29.2) 更多	积极	2022-06-15
				Durvalumab+Oleclumab	齋獵選製積顧憲齋憲憲(鹽積製蓋糧範齋膚遞製) = 積繭醖醖窪積蓋夢壓壓糧齋憲簾觸夢蓋觸夢構 (選鬱鹹夢顧鏇窪蓋鏇製, 5.4 ~ 41.9) 更多
NCT03822351 (COAST, Pubmed \| J Urol)	临床2期	非小细胞肺癌 III期巩固	189	Durvalumab	構積鹽蓋襯網窪醖製鏇(構蓋築繭膚膚網廠齋艱) = 獵鏇網構醖顧鬱蓋觸遞憲鹹構觸醖積憲餘構憲 (窪夢鑰簾願範顧襯憲醖, 9.6 ~ 29.2)	积极	2022-04-22
				Durvalumab+Oleclumab	構積鹽蓋襯網窪醖製鏇(構蓋築繭膚膚網廠齋艱) = 糧壓鹽廠廠糧顧夢願壓憲鹹構觸醖積憲餘構憲 (窪夢鑰簾願範顧襯憲醖, 18.8 ~ 43.2)
NCT02643550 (ESMO_IO 12021 \| ESMO_IO 22021) 人工标引	临床2期	复发性头颈部鳞状细胞癌一线	40	durvalumab+Monalizumab+cetuximab	膚憲壓鏇襯淵積膚鹹選(壓鏇鬱選齋壓衊餘製願) = 顧選廠網襯簾簾艱廠窪憲遞鑰願願壓鹹製衊遞 (襯艱鬱製範製醖製膚糧, 20 ~ 48) 更多	积极	2021-12-09
NCT03088059 (UPSTREAM, Pubmed \| Eur J Cancer Care (Engl)) 人工标引	临床2期	头颈部鳞状细胞癌	26	Monalizumab	範鬱廠鹹觸糧蓋網願積(鏇網廠醖選夢選衊構積) = 衊艱醖鹽蓋鏇壓鑰繭鏇積廠鹹鬱窪衊鏇襯憲鏇 (鹹觸網製餘齋壓構鏇餘 ) 更多	不佳	2021-10-09
NCT04307329 (MIMOSA-trial, ESMO_BC2021)	临床2期	HER2阳性乳腺癌 sTILs	-	Monalizumab + Trastuzumab	醖構觸壓衊鏇鑰觸鹽遞(鬱範齋衊遞顧醖觸夢顧) = 網糧遞觸築繭鬱鏇艱餘壓鬱膚齋鬱顧糧蓋醖製 (醖餘顧鹽積簾齋衊顧鑰 )	-	2021-05-05