The goal of this interventional study is to determine pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) and Efti treatment. This is a prospective single arm interventional trial in patients with early-stage HR+/HER2 -ve breast cancer (Stage I-III) who are eligible for neoadjuvant chemotherapy (NAC). Enrolled patients will be treated with single agent efti for 3 weeks and then start NAC in combination with efti. There are 2 standard NAC usually used and will be determined by treating physician prior to starting on this trial.

开始日期2025-11-01

申办/合作机构

Immutep SAS

NCT06726265

/ Recruiting临床3期

TACTI-004, a Double-Blinded, Randomized Phase 3 Trial in Patients With Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC) Receiving Eftilagimod Alfa (MHC Class II Agonist) in Combination With Pembrolizumab (PD-1 Antagonist) and Chemotherapy.

The purpose of this study is to compare eftilagimod alfa (efti) in combination with pembrolizumab and chemotherapy versus placebo in combination with pembrolizumab and chemotherapy with respect to overall survival (OS) and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) among adults with metastatic non-small cell lung cancer (NSCLC).
Participants will receive either efti plus standard treatment (pembrolizumab and platinum doublet chemotherapy) or placebo plus standard treatment and will be treated for up to 2 years.

开始日期2025-03-21

申办/合作机构

Immutep SAS

[+1]

NCT06128863

/ Active, not recruiting临床2期IIT

Phase II, Single-arm Clinical Trial Evaluating Efficacy and Safety of Pembrolizumab in Combination with a Soluble LAG-3 Protein, Eftilagimod Alpha, and Radiotherapy in Neoadjuvant Treatment of Patients with Soft Tissue Sarcomas (EFTISARC-NEO)

This is a phase II single-arm single-stage study evaluating efficacy and safety of pembrolizumab in combination with a soluble LAG-3 protein, eftilagimod alpha (Efti) and radiotherapy in neoadjuvant treatment of patients with soft tissue sarcomas. This study will determine the pathologic response rate (defined as percentage of tumor hyalinization/fibrosis) to the combination treatment.

开始日期2023-07-17

申办/合作机构

Maria Sklodowska-Curie National Research Institute of Oncology

[+1]

100 项与重组人源淋巴细胞激活基因-3（hLAG-3）融合蛋白(Immutep) 相关的临床结果

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100 项与重组人源淋巴细胞激活基因-3（hLAG-3）融合蛋白(Immutep) 相关的转化医学

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100 项与重组人源淋巴细胞激活基因-3（hLAG-3）融合蛋白(Immutep) 相关的专利（医药）

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项与重组人源淋巴细胞激活基因-3（hLAG-3）融合蛋白(Immutep) 相关的文献（医药）

2024-11-01·JTO clinical and research reports

Eftilagimod Alpha (a Soluble LAG-3 Protein) Combined With Pembrolizumab in Second-Line Metastatic NSCLC Refractory to Anti–Programmed Cell Death Protein 1/Programmed Death-Ligand 1-Based Therapy: Final Results from a Phase 2 Study

Article

作者: Roxburgh, Patricia ; Krebs, Matthew G. ; Majem, Margarita ; Clay, Tim ; Mueller, Christian ; Andres, B. ; Doger, Bernard ; Triebel, F. ; Krebs, Matthew G ; Doger, B. ; Forster, Martin ; Majem, M. ; Triebel, Frédéric ; Forster, M. ; Iams, W. ; Clay, T. ; Bajaj, P. ; Iams, Wade ; Perera, Suvini ; Peguero, J. ; Mueller, C. ; Bajaj, Pawan ; Krebs, M.G. ; Barba, Andres ; Roxburgh, P. ; Perera, S. ; Peguero, Julio

Introduction:

Eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, triggers antigen-presenting cell and T-cell (CD4⁺ and CD8⁺) activation and helps overcome resistance to programmed cell death protein 1 or programmed cell death-ligand 1 (PD-(L)1) inhibitors. We assessed efti plus pembrolizumab in second-line anti-PD-(L)1-refractory metastatic patients with NSCLC.

Methods:

After confirmed progression on anti-PD-(L)1-based first-line therapy, patients received efti (30 mg subcutaneously every 2 weeks for eight 3-week cycles and then every 3 weeks for up to 54 weeks) plus pembrolizumab (200 mg intravenously every 3 weeks for up to 105 weeks). The primary endpoint was the objective response rate by modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapies. Secondary endpoints included disease control rate, progression-free survival, overall survival (OS), and tolerability. Exploratory endpoints included tumor growth kinetics and predefined subgroup analyses. Programmed cell death-ligand 1 tumor proportion score was assessed centrally.

Results:

Thirty-six patients were enrolled from April 2019 to August 2021 using Simon's two-stage design. Most patients (81.8%) had low or negative (<50%) PD-(L)1 tumor proportion score. First-line therapy was anti-PD-(L)1-based for all patients, combined with chemotherapy for 66.7%. The confirmed objective response and disease control rates were 8.3% and 33.3%. The median progression-free survival was 2.1 months and the median OS was 9.9 months. Patients exhibiting high PD-(L)1 expression or acquired resistance to PD-(L)1 inhibitors revealed superior response and survival outcomes, and OS was closely correlated with disease control. No treatment-emergent adverse event led to permanent discontinuation of study treatment.

Conclusions:

Efti plus pembrolizumab was well-tolerated and revealed signs of antitumor activity in patients with NSCLC resistant to PD-(L)1 inhibitors, warranting further investigation. Trial registration number: NCT03625323.

2024-09-03·CLINICAL CANCER RESEARCH

Eftilagimod Alpha (Soluble LAG3 Protein) Combined with Pembrolizumab as Second-Line Therapy for Patients with Metastatic Head and Neck Squamous Cell Carcinoma

Article

作者: Patel, Grisma ; Pousa, Antonio L. ; Roxburgh, Patricia ; Bajaj, Pawan ; Brignone, Chrystelle ; Mueller, Christian ; Krebs, Matthew ; Doger, Bernard ; Forster, Martin ; Triebel, Frederic ; Peguero, Julio ; Brana, Irene ; Carcereny, Enric

Abstract:

Purpose::

Eftilagimod alpha (efti), a soluble LAG3 protein, activates antigen-presenting cells (APC) and downstream T cells. TACTI-002 (part C) evaluated whether combining efti with pembrolizumab led to strong antitumor responses in patients with second-line recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) while demonstrating good tolerability.

Patients and Methods::

In this multinational phase II trial using Simon’s two-stage design, patients who were PD-L(1)-naïve with R/M HNSCC who had failed first-line platinum-based therapy, unselected for PD-L1, received intravenous pembrolizumab (200 mg, once every 2 weeks) combined with subcutaneous efti (30 mg once every 2 weeks for 24 weeks and once every 3 weeks thereafter). The primary endpoint was objective response rate per RECIST 1.1 modified for immune-based therapy by investigator assessment. Additional endpoints included duration of response, progression-free survival, overall survival, and tolerability. Pharmacodynamic effects (absolute lymphocyte count) and Th1 cytokine biomarkers (IFNγ/CXCL10)] were evaluated in liquid biopsies.

Results::

Between March 2019 and January 2021, 39 patients were enrolled; 37 were evaluated for response. All patients received prior chemotherapy, and 40.5% were pretreated with cetuximab; 53.1% of patients had PD-L1 combined positive score <20. With a median follow-up of 38.8 months, the objective response rate was 29.7%, including 13.5% complete responders. The median duration of response was not reached. Rapid and sustained absolute lymphocyte count increase was observed in patients who had an objective response. Th1 biomarkers increased sustainably after first treatment. No unexpected safety signals were observed.

Conclusions::

Efti plus pembrolizumab was safe and showed encouraging antitumor activity and pharmacodynamic effects in patients with second-line head and neck squamous cell carcinoma (HNSCC), thus supporting further evaluation of this combination in earlier treatment lines.

2024-02-01·Clinical cancer research : an official journal of the American Association for Cancer Research

Paclitaxel plus Eftilagimod Alpha, a Soluble LAG-3 Protein, in Metastatic, HR+ Breast Cancer: Results from AIPAC, a Randomized, Placebo Controlled Phase IIb Trial

Article

作者: Perjesi, Luca ; Dalenc, Florence ; Pápai, Zsuzsanna ; Duhoux, Francois P. ; Armstrong, Anne ; Brignone, Chrystelle ; Marme, Frederik ; Kuemmel, Sherko ; Jager, Agnes ; Dirix, Luc ; Cuypere, Eveline ; Triebel, Frederic ; Wildiers, Hans ; Schröder, Carolina P. ; Mueller, Christian ; Vuylsteke, Peter ; Menke-van der Houven van Oordt, Catharina Willemien ; Chan, Steve ; Huober, Jens ; Brain, Etienne

Abstract:

Purpose::

Eftilagimod alpha (efti), a soluble lymphocyte activation gene (LAG-3) protein and MHC class II agonist, enhances innate and adaptive immunity. Active Immunotherapy PAClitaxel (AIPAC) evaluated safety and efficacy of efti plus paclitaxel in patients with predominantly endocrine-resistant, hormone receptor–positive, HER2-negative metastatic breast cancer (ET-resistant HR+ HER2− MBC).

Patients and Methods::

Women with HR+ HER2– MBC were randomized 1:1 to weekly intravenous paclitaxel (80 mg/m2) and subcutaneous efti (30 mg) or placebo every 2 weeks for six 4-week cycles, then monthly subcutaneous efti (30 mg) or placebo maintenance. Primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints included overall survival (OS), safety/tolerability, pharmacokinetics/pharmacodynamics, and quality of life. Exploratory endpoints included cellular biomarkers.

Results::

114 patients received efti and 112 patients received placebo. Median age was 60 years (91.6% visceral disease, 84.1% ET-resistant, 44.2% with previous CDK4/6 inhibitor treatment). Median PFS at 7.3 months was similar for efti and placebo. Median OS was not significantly improved for efti (20.4 vs. 17.5 months; HR, 0.88; P = 0.197) but became significant for predefined exploratory subgroups. EORTC QLQC30-B23 global health status was sustained for efti but deteriorated for placebo. Efti increased absolute lymphocyte, monocyte and secondary target cell (CD4, CD8) counts, plasma IFNγ and CXCL10 levels.

Conclusions::

Although the primary endpoint, PFS, was not met, AIPAC confirmed expected pharmacodynamic effects and demonstrated excellent safety profile for efti. OS was not significantly improved globally (2.9-month difference), but was significantly improved in exploratory biomarker subgroups, warranting further studies to clarify efti's role in patients with ET-resistant HER2− MBC.

227

项与重组人源淋巴细胞激活基因-3（hLAG-3）融合蛋白(Immutep) 相关的新闻（医药）

2025-12-02

·GlobeNewswire-Health Care

Immutep to Present New Data from AIPAC-003 Phase II at the 2025 San Antonio Breast Cancer Symposium

Immunotherapy-chemotherapy combination of eftilagimod alfa (efti) and paclitaxel led to strong objective response rates and immune activation in heavily pretreated metastatic breast cancer patientsAIPAC-003 has resulted in successful completion of FDA’s Project Optimus requirements and selection of 30 mg as efti’s optimal biological dose SYDNEY, AUSTRALIA, Dec. 02, 2025 (GLOBE NEWSWIRE) -- Immutep Limited (ASX: IMM; NASDAQ: IMMP) (“Immutep” or “the Company”), a late-stage immunotherapy company targeting cancer and autoimmune diseases, today announces new data from the AIPAC-003 trial will be presented at the 2025 San Antonio Breast Cancer Symposium (SABCS) taking place in San Antonio, Texas, from December 9-12, 2025. The Phase II study randomised female participants (N=66) with HR+ and HER2-negative/HER2-low metastatic breast cancer (MBC) resistant to endocrine-based therapy (ET) including cyclin-dependent kinase 4/6 (CDK4/6) inhibitors or metastatic triple-negative breast cancer (mTNBC) not eligible for PD-(L)1-based therapy. Patients were randomised 1:1 to receive either 30 or 90 mg eftilagimod alfa (efti) in combination with paclitaxel to determine the optimal biological dose (OBD) consistent with the FDA’s Project Optimus initiative. Both efti dosing levels on top of weekly paclitaxel in heavily pretreated metastatic breast cancer patients, who received a median of three prior lines of systemic therapy, led to strong objective response rates (ORR) and disease control rates (DCR) of 41.9% and 87.1% (30 mg efti) and 48.5% and 78.8% (90 mg efti), respectively, in the evaluable population (N=64). Time to onset of response (TTR) was comparable at 2.0 months (30 mg) versus 1.9 months (90 mg). Additionally, both dosing levels elicited the desired pharmacodynamic (PD) response in line with efti’s mechanism of action with substantial increases in immune activation biomarkers including absolute-lymphocyte count (ALC) and interferon-gamma (IFN-γ). Data cut-off date for efficacy results was 15 September 2025. Dr. Nuhad Ibrahim, Professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center noted, “Evaluating two biologically active doses allowed us to integrate clinical response data with meaningful pharmacodynamic readouts. In keeping with Project Optimus principles, the study generated rigorous comparative data in heavily pretreated metastatic breast cancer patients showing consistent efficacy measures and immune-activation signals across both arms, reinforcing efti’s novel mechanism of action and the clinical potential of this immunotherapy-chemo combination.” Tolerability at 90 mg was suboptimal including dose-limiting toxicities (DLT) and a higher proportion of local injection site reactions (LISR). In line with FDA guidance/advice and as previously reported on 13 October 2025, 30 mg of efti administered subcutaneously has been defined as the OBD. Marc Voigt, CEO of Immutep said, “We are pleased to conclude this important phase of efti’s clinical development and are fully committed to advancing this novel immunotherapy to address the needs of cancer patients globally, especially in light of our ongoing Phase III in 1st line NSCLC. This study holds significant importance in satisfying FDA’s Project Optimus requirements and defining efti’s OBD across our entire oncology clinical pipeline and potential future combinations with new therapeutic agents such as ADCs and bispecifics as well as for a potential future Biological Licence Application.” The AIPAC-003 trial has resulted in the successful completion of the FDA’s Project Optimus requirements and agreement on 30 mg as efti’s OBD carries strategic importance in ongoing and future clinical programs in oncology. This includes the global TACTI-004 (KEYNOTE-F91) Phase III trial evaluating efti in combination with MSD’s (Merck & Co., Inc., Rahway, NJ, USA) anti-PD-1 therapy KEYTRUDA® (pembrolizumab), and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer (1L NSCLC), regardless of PD-L1 expression, which is now in the process of opening sites in the United States. Details on the SABCS 2025 presentation are as follows: Title: Optimal biological dose of eftilagimod alpha, a soluble LAG-3 protein, in metastatic breast cancer patients receiving weekly paclitaxel in AIPAC-003Presenter: Dr. Nuhad Ibrahim, Professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer CenterPresentation number: PS1-09-16Abstract number: 315Date and time: Wednesday, December 10th at 12:30-2:30 p.m. CST The poster presentation is available on the Posters & Publications section of Immutep’s website. About ImmutepImmutep is a late-stage biotechnology company developing novel immunotherapies for cancer and autoimmune disease. The Company is a pioneer in the understanding and advancement of therapeutics related to Lymphocyte Activation Gene-3 (LAG-3), and its diversified product portfolio harnesses LAG-3’s ability to stimulate or suppress the immune response. Immutep is dedicated to leveraging its expertise to bring innovative treatment options to patients in need and to maximise value for shareholders. For more information, please visit www.immutep.com. KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Australian Investors/Media:Eleanor Pearson, Sodali & Co.+61 2 9066 4071; eleanor.pearson@sodali.com U.S. Investors/Media:Chris Basta, VP, Investor Relations and Corporate Communications+1 (631) 318 4000; chris.basta@immutep.com

免疫疗法临床结果临床3期临床2期

2025-11-13

·GlobeNewswire-Health Care

Translational Data and Significant Pathologic Response Rates from EFTISARC-NEO Phase II Highlighted in Oral Presentation at CTOS 2025

Novel combination with neoadjuvant eftilagimod alfa (efti) achieves significant 51.5% tumour hyalinization/fibrosis across multiple soft tissue sarcoma subtypes including rare and highly aggressive tumours with poor prognosisEarly translational data show a strong immune system activation inline with efti’s mode of action with statistically-significant increases in multiple cytokines and chemokines High levels of key immune proteins in EFTISARC-NEO including interferon-gamma (IFN-γ) correlate with pathologic responses indicating a significant destruction/alteration of tumour tissue following treatment, which is generally associated with better outcomes for patients and potentially improved survival rates SYDNEY, AUSTRALIA, Nov. 13, 2025 (GLOBE NEWSWIRE) -- Immutep Limited (ASX: IMM; NASDAQ: IMMP) (“Immutep” or “the Company”), a late-stage immunotherapy company targeting cancer and autoimmune diseases, today announces positive data from the EFTISARC-NEO trial that were detailed in an oral presentation by Paweł Sobczuk, M.D., Ph.D., Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland, at the Connective Tissue Oncology Society (CTOS) 2025 Annual Meeting held in Boca Raton, Florida. The investigator-initiated Phase II study evaluating eftilagimod alfa (efti) with radiotherapy plus KEYTRUDA® (pembrolizumab) in the neoadjuvant setting for resectable soft tissue sarcoma (STS) significantly exceeded the study’s prespecified level of pathologic response rates. In the evaluable patient population (N=38), the novel combination with efti reached a median 51.5% tumour hyalinization/fibrosis (p<0.001), meeting the study’s primary endpoint.1 These promising results were achieved in patients with ten different STS subtypes including rare and/or highly aggressive tumours with poor prognosis such as myxofibrosarcoma (N=16), undifferentiated pleomorphic sarcoma (N=10) and malignant peripheral nerve sheath tumor (N=2). Early translational data from the initial twenty patients who underwent surgery in the trial show a strong immune system activation in line with efti’s mode of action, with statistically significant increases in the expression of key cytokines and chemokines in peripheral blood — specifically CXCL9, CXCL10, IL-23, and IFN-γ. Immune Response Biomarkers (fold change from week 1 through pre-surgery) Serum BiomarkerFold change (p-value)C-X-C motif chemokine ligand 9 (CXCL9)2.5x (p<0.01)C-X-C motif chemokine ligand 10 (CXCL10)1.8x (p<0.0001)Interleukin-23 (IL-23)2.2x (p<0.05)Interferon-gamma (IFN-γ)2.5x (p<0.05) The increase on treatment of immune response biomarkers like IFN-gamma correlated with pathologic responses in this study, meaning patients with a biomarker increase during treatment also had a higher probability of a good clinical response at surgery. The promising tumour hylanization/fibrosis rate achieved (over 3X greater than standard-of-care radiotherapy based on historical data)1 may hold significance in terms of future outcomes as it serves as an early surrogate endpoint correlated with enhanced overall survival and recurrence-free survival in STS patients.2,3 Disease-free survival and overall survival data are immature at this stage and will be presented in the future. Further correlative translational studies are also ongoing. Dr. Paweł Sobczuk, one of the trial’s principal investigators, stated: “We are excited to share these strong results in resectable soft tissue sarcoma, a challenging indication with a high unmet medical need. This level of efficacy, observed across ten different STS subtypes including rare, highly aggressive tumours with poor prognosis, further supports the hypothesis that efti’s distinctive activation of antigen-presenting cells—and consequent induction of both adaptive and innate immunity—plays a key role in driving a coordinated immune response to fight cancer. This novel combination with neoadjuvant efti warrants further investigation in registrational settings.” “Our team was delighted to have recently been awarded the distinguished Golden Scalpel Award (Złoty Skalpel)* for EFTISARC-NEO. This honour is reserved for projects that demonstrate exceptional innovation and impact in medical research and clinical practice,” added Dr. Sobczuk. Dr. Frédéric Triebel, CSO of Immutep, said: “We are pleased to see a confirmation of earlier promising data on now 38 patients in this difficult-to-treat cancer. The prolonged increase in serum immune response biomarkers, observed two weeks after efti subcutaneous injection, is indicative of a robust adaptive and innate immune response. This enhanced immune activity is crucial because it means the body’s own defences are being mobilised to target and destroy cancer cells more effectively, further supporting the positive impact of the observed pathologic responses. The recent results suggest that efti may have potential applications beyond advanced or metastatic cancer, extending into earlier-stage disease.” As neoadjuvant immunotherapy becomes more established in the treatment of early-stage cancers, the findings from EFTISARC-NEO highlight the possibility for efti to be used in patients who have a lower tumor burden at diagnosis. This could expand the range of patients who might benefit from efti, potentially increasing its role in the treatment landscape for cancers that are still localized and resectable. STS is an orphan disease with high unmet medical need and a poor prognosis for patients. The incidence of STS varies in different regions globally. In the United States, the number of new STS cases in 2025 is estimated to be ~13,520 with ~5,420 deaths, according to the American Cancer Society.4 For more information on EFTISARC-NEO, visit clinicaltrials.gov (NCT06128863). The CTOS 2025 oral presentation slides can be found on the Posters & Publications page of Immutep’s website. *About the Golden Scalpel Award in PolandThe Golden Scalpel Award in Poland is recognized as a benchmark of excellence within the medical community. It is presented by independent experts to initiatives that set new standards in advancing healthcare. This year, EFTISARC NEO was the only oncology project to receive this accolade, underscoring its leadership and breakthrough potential in cancer treatment. About Eftilagimod Alfa (Efti)Efti is a novel immunotherapy that directly activates antigen-presenting cells or APCs (e.g. dendritic cells, monocytes) via the MHC Class II pathway to fight cancer. As an MHC Class II agonist, its activation of APCs engages the adaptive and innate immune system to initiate a broad anti-cancer immune response. This includes priming and activating cytotoxic T cells as well as generating important co-stimulatory signals & cytokines that further boost the immune system’s ability to combat cancer. Efti is under evaluation for a variety of solid tumours including non-small cell lung cancer (NSCLC) in a pivotal Phase III trial called TACTI-004 (KEYNOTE-F91), as well as head and neck squamous cell carcinoma (HNSCC), soft tissue sarcoma, and breast cancer. Its favourable safety profile enables various combinations like with anti-PD-[L]1 immunotherapy, radiotherapy, and/or chemotherapy. Efti has received Fast Track designation in first line HNSCC and in first line NSCLC from the United States Food and Drug Administration (FDA). About ImmutepImmutep is a late-stage biotechnology company developing novel immunotherapies for cancer and autoimmune disease. The Company is a pioneer in the understanding and advancement of therapeutics related to Lymphocyte Activation Gene-3 (LAG-3), and its diversified product portfolio harnesses LAG-3’s ability to stimulate or suppress the immune response. Immutep is dedicated to leveraging its expertise to bring innovative treatment options to patients in need and to maximise value for shareholders. For more information, please visit www.immutep.com. 1. ESMO Congress 2025 Proffered Paper presentation, “EFTISARC-NEO: A phase II study of neoadjuvant eftilagimod alpha, pembrolizumab and radiotherapy in patients with resectable soft tissue sarcoma”. 2. Schaefer IM et al. Histologic Appearance After Preoperative Radiation Therapy for Soft Tissue Sarcoma: Assessment of the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group Response Score. Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):375-383. doi: 10.1016/j.ijrobp.2017.02.087. Epub 2017 Feb 24. PMID: 28463157.3. Rao SR et al. Extent of tumor fibrosis/hyalinization and infarction following neoadjuvant radiation therapy is associated with improved survival in patients with soft-tissue sarcoma. Cancer Med. 2022 Jan;11(1):194-206. doi: 10.1002/cam4.4428. Epub 2021 Nov 27. PMID: 34837341; PMCID: PMC8704179.4. American Cancer Society statistics: https://www.cancer.org/cancer/types/soft-tissue-sarcoma/about/key-statistics.html KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Australian Investors/Media:Eleanor Pearson, Sodali & Co.+61 2 9066 4071; eleanor.pearson@sodali.com U.S. Investors/Media:Chris Basta, VP, Investor Relations and Corporate Communications+1 (631) 318 4000; chris.basta@immutep.com

临床结果免疫疗法临床2期快速通道临床3期

2025-11-11

·Biotech前瞻

IBD二期失败，PD-1激动剂的“自免蓝海”之路并非坦途

点击蓝字关注我们本期看点以PD-1、CTLA-4抑制剂为代表的免疫抑制剂的问世，深刻改变了肿瘤治疗格局，进入到免疫治疗新时代。而肿瘤与自身免疫之间的界限，并不是完全隔绝的。恒瑞医药近期在PD-1激动剂抗体领域有了新的研发动向。目前，全球范围内针对PD-1激动剂的研发竞争激烈，恒瑞的加入值得关注。本期内容 01 PD-1激动剂 02 CTLA-4激动剂 03 LAG3激动剂 04 总结与展望【01 PD-1激动剂】 2025年11月11日，生物制药公司AnaptysBio宣布，其在研T细胞耗竭剂rosnilimab治疗中重度溃疡性结肠炎的II期研究未能达到主要终点及任何关键次要终点。数据显示，rosnilimab组与安慰剂组的临床缓解率无统计学显著差异。受此消息影响，公司股价当日大幅下跌14.3%。AnaptysBio已决定立即终止该药物在溃疡性结肠炎适应症的开发。此次失败凸显了新药研发的“适应症特异性”挑战。Rosnilimab作为一种PD-1激动剂，其通过耗竭致病性T细胞来抑制免疫反应。虽然该机制在今年六月公布的类风湿关节炎II期研究中显示出优异疗效，但未能转化到溃疡性结肠炎的治疗上，可能与疾病机理、患者群体及肠道局部免疫微环境差异有关。面对挫折，AnaptysBio迅速调整战略，计划将资源集中用于rosnilimab在类风湿关节炎和银屑病关节炎的后续研发上，相关数据预计于2026年第一季度公布。同时，公司此前提出的分拆计划——将稳定特许权收入与高风险研发资产分离——预计将继续推进，以期更清晰地展现公司价值并吸引不同类型的投资者。礼来丨PD-1激动剂丨Peresolimab 在PD-1激动剂赛道上，先行者是礼来，但也经历了初期效果惊艳，近日又被礼来从最新的研发管线中移除的结局，免疫检查点激动剂的研发，注定是坎坷的。 2023年5月18日，N Engl J Med 期刊上刊发了礼来PD-1激动剂Peresolimab治疗类风湿性关节炎的II期结果，在这项2a期双盲、随机、安慰剂对照试验中，研究者按照2:1:1的比例将患有中重度类风湿性关节炎的成年患者（这些患者对常规合成的抗风湿性疾病药物（DMARD）或生物或靶向合成的DMARD不应答、耐药或副作用不可耐受）分配给700 mg Peresolimab组，300mg Peresolimab组或安慰剂组，每4周静脉注射一次。Peresolimab在类风湿性关节炎患者的2a期试验中显示出疗效。这些结果证明对PD-1受体的刺激具有治疗类风湿性关节炎的潜在疗效。但遗憾的是，在礼来2024年三季度报中，礼来已经宣布将PD-1激动剂抗体Peresolimab移出研发管线，可见PD-1激动剂研发足够坎坷。近年来，肿瘤赛道内卷之下，不少企业也开始布局减肥、自免领域，自免领域市场潜力还是蛮大的，而且CTLA-4激动剂早已经获批上市。国内布局企业：国内方面，金赛药业的PD-1激动剂抗体GenSci120已率先推进到临床阶段，获批开展用于类风湿关节炎、系统性红斑狼疮、原发性干燥综合征及炎症性肠病等多个自身免疫病适应症的临床研究。恒瑞也于今年公布了其在研 PD-1 激动剂的专利。 02 CTLA-4激动剂 Abatacept(阿巴西普) 2005年，百时美施贵宝（BMS）生产的全球第一款CTLA-4融合蛋白Orencia®（Abatacept，阿巴西普）获FDA审批上市，用于治疗成人类风湿性关节炎。国内由先声药业引进，商品名为恩瑞舒®。具体作用机制总结如下：活化T细胞数量的增加与类风湿性关节炎的发病机制相关 T细胞激活需要来自抗原呈递细胞 (APCs)的两个信号通路同时激活：第一个信号是抗原特异性的，TCR识别APCs表面MHCⅡ提呈的同源抗原（CD28信号传导促进细胞因子IL-2 mRNA的产生和进入细胞周期、T细胞存活、T辅助细胞分化和免疫球蛋白同型转换）。第二个信号来自于APCs配体 (CD80/CD86)和T细胞表面的共刺激受体 (CD28)的结合，共刺激受体CD28与CD80/CD86的相互作用在T细胞活化共刺激信号中起重要作用。 CTLA-4的免疫刹车作用 CTLA-4与T细胞共刺激受体CD28同源，当与APCs表面的CD80/CD86结合时，起到“关闭”开关的作用，可以作为一种免疫检查点来下调免疫反应。 Abatacept作用机制 Abatacept（CTLA-4Ig） Abatacept（CTLA-4Ig）是一种可溶性重组人源化融合蛋白（CTLA-4Ig），由CTLA-4的胞外区和IgG1的Fc部分组成。Abatacept与APC上的共刺激分子CD80和CD86结合，从而阻断与T细胞上的CD28的相互作用。在人类机体中，Abatacept治疗对包括类风湿性关节炎在内的各种自身炎症性疾病患者有效。【03 LAG3激动剂】作为LAG-3（淋巴细胞激活基因-3）治疗领域的先锋，Immutep公司一直就LAG3靶点进行药物的研发和布局，目前，主要有2款产品，IMP761和IMP321。 IMP761 IMP761是一种首创的免疫抑制性LAG-3激动剂抗体，具有治疗多种自身免疫疾病的潜力。它通过特异性沉默积累在疾病部位的自身免疫记忆T细胞，恢复免疫系统的平衡。IMP761在临床前研究中显示出了积极的安全性和免疫抑制效果，包括在体外和体内抑制抗原特异性T细胞介导的免疫反应。此外，IMP761在1期人体临床试验中显示出良好的安全性，没有治疗相关的不良事件。IMP761的临床试验由荷兰莱顿的人类药物研究中心（CHDR）进行，旨在评估其安全性和免疫抑制效果。 IMP321（eftilagimod alpha） IMP321，也称为eftilagimod alpha或“efti”，是一种可溶性LAG-3融合蛋白（LAG-3Ig），属于首创的抗原呈递细胞（APC）激活剂。efti能够结合MHC II类分子，激活并促进CD8+细胞毒性T细胞、CD4+辅助T细胞、树突细胞、NK细胞和单核细胞的增殖。此外，efti还能上调关键生物分子的表达，如IFN-γ和CXCL10，进一步增强免疫系统对抗癌症的能力。 cited by：immutep官网 2024年12月10日，Immutep 在ClinicalTrials网站登记一项双盲、随机、III期研究（TACTI-004），研究Eftilagimod Alfa（Efti，LAG-3融合蛋白）联合标准治疗（帕博利珠单抗+铂类双药化疗）对比安慰剂联合标准治疗针对晚期一线非小细胞肺癌（NSCLC）患者的疗效。研究计划招募756名患者，预计2027年6月初步完成。研究的主要终点为OS和PFS。美国时间2024年7月12日，eftilagimod alfa（efti）联合帕博利珠单抗一线治疗PD-L1表达阴性的头颈鳞状细胞癌（HNSCC）患者取得突破性进展：在TACTI-003（KEYNOTE-PNC-34）IIb期临床试验的Cohort B中，eftilagimod alfa联合帕博利珠单抗，在31名可评估患者中达到了35.5%的ORR（根据RECIST 1.1标准评估）；这一数据在不含化疗的治疗手段中属于最高记录之一。特别值得一提的是，该联合疗法的完全反应率（CR）高达9.7%，意味着三名患者在接受治疗后肿瘤完全消失。基于既往展示出的良好安全性和疗效数据，efti已获得FDA授予的一线治疗HNSCC（无论PD-L1表达如何）的快速通道指定。2022年10月5日，FDA已授予eftilagimod alpha（efti，又名IMP321）快速通道资格，与帕博利珠单抗联用，一线治疗非小细胞肺癌（NSCLC）。 04 总结与展望 PD-1激动剂抗体通过激活PD-1通路，理论上可用于治疗自身免疫性疾病，通过抑制过度活跃的免疫反应来发挥作用，有望为PD-1靶点开辟一个全新的治疗赛道。当然，PD-1激动剂的研发也充满挑战，其科学机制复杂，如何精确调控免疫平衡是关键。恒瑞的PD-1激动剂目前仍处于早期专利阶段，后续仍需密切关注其临床研究进展和数据披露。 ★

100 项与重组人源淋巴细胞激活基因-3（hLAG-3）融合蛋白(Immutep) 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
-	重组人源淋巴细胞激活基因-3（hLAG-3）融合蛋白(Immutep)	-	DB16150

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
转移性非小细胞肺癌	临床3期	美国	Immutep SAS	2025-03-21
转移性非小细胞肺癌	临床3期	阿根廷	Immutep SAS	2025-03-21
转移性非小细胞肺癌	临床3期	澳大利亚	Immutep SAS	2025-03-21
转移性非小细胞肺癌	临床3期	奥地利	Immutep SAS	2025-03-21
转移性非小细胞肺癌	临床3期	比利时	Immutep SAS	2025-03-21
转移性非小细胞肺癌	临床3期	巴西	Immutep SAS	2025-03-21
转移性非小细胞肺癌	临床3期	保加利亚	Immutep SAS	2025-03-21
转移性非小细胞肺癌	临床3期	加拿大	Immutep SAS	2025-03-21
转移性非小细胞肺癌	临床3期	智利	Immutep SAS	2025-03-21
转移性非小细胞肺癌	临床3期	克罗地亚	Immutep SAS	2025-03-21

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临床结果

适应症

分期

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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


NCT06128863 (EFTISARC-NEO, ESMO2025)	临床2期	软组织肉瘤新辅助	40	pembrolizumabeftilagimod alpha + pembrolizumabeftilagimod alpha (radiotherapy)	構鬱鹹顧齋醖餘網築淵(構壓築壓構壓網鹽鬱願) = 鑰簾憲鏇淵衊襯遞繭觸獵鹽憲願遞鬱廠鏇壓廠 (艱構餘顧觸製顧網壓鹽 ) 更多	积极	2025-10-17
NCT06128863 (EFTISARC-NEO, GlobeNewswire) 人工标引	临床2期	软组织肉瘤新辅助	40	Eftilagimod alfa (Efti) with RadiotherapyEftilagimod alfa (Efti) with Radiotherapy plus KEYTRUDA® (pembrolizumab)KEYTRUDA® (pembrolizumab)	鬱願選艱鹹遞廠糧衊鏇(構壓製簾製窪築夢鹹簾) = 鑰繭蓋蓋鹹鏇衊繭廠鹽顧鬱觸獵廠獵醖製簾鏇 (糧鏇遞淵觸繭鹹夢鏇繭 ) 达到	积极	2025-05-27
NCT03252938 (INSIGHT-003, Company_Website) 人工标引	临床1期	非鳞状非小细胞肺癌一线	-	Eftilagimod alpha (Efti) + KEYTRUDA (Pembrolizumab) + Chemotherapy (PD-L1 TPS 0-100%)	鹹醖範衊獵網鑰鬱獵選(憲積繭蓋鹹網構築廠願) = 蓋糧糧鹹獵壓夢蓋觸築齋網構繭夢願廠醖廠餘 (簾築廠鬱製鏇繭鑰鹹顧 ) 更多	积极	2025-05-15
				Eftilagimod alpha (Efti) + KEYTRUDA (Pembrolizumab) + Chemotherapy (PD-L1 TPS <1%)	鹹醖範衊獵網鑰鬱獵選(憲積繭蓋鹹網構築廠願) = 鏇憲鏇鹽獵鬱窪鹽鹽鹹齋網構繭夢願廠醖廠餘 (簾築廠鬱製鏇繭鑰鹹顧 ) 更多
NCT04811027 (TACTI-003 \| KEYNOTE-PNC-34 \| TACTI-003 Cohort B, GlobeNewswire) 人工标引	临床2期	头颈部鳞状细胞癌 PD-L1 CPS <1	31	Eftilagimod alfa (Efti) + Pembrolizumab (PD-L1 CPS <1)	顧蓋憲醖繭顧鑰襯範膚(艱醖積遞壓觸選構齋觸) = 餘膚簾獵願鹹蓋醖襯蓋製醖構淵簾壓網觸範製 (選鬱鏇選築遞衊觸簾積 )	积极	2025-05-05
NCT03625323 (TACTI-002 \| INSIGHT-003, CTgov)	临床2期	转移性头颈部鳞状细胞癌 \| 头颈部鳞状细胞癌 \| 非小细胞肺癌 ... 更多	187	eftilagimod alpha+pembrolizumab (KEYTRUDA®) (1st Line NSCLC)	鹽鏇鑰衊遞遞鹽膚顧襯 = 鏇壓構構襯窪餘遞壓鏇衊願範衊簾鬱繭鏇鑰網 (夢願糧鹹齋製廠繭範鹹, 鹽製衊構範蓋夢淵顧築 ~ 範醖積願範衊蓋顧襯衊) 更多	-	2024-12-18
				eftilagimod alpha+pembrolizumab (KEYTRUDA®) (2nd Line NSCLC)	鹽鏇鑰衊遞遞鹽膚顧襯 = 獵願餘蓋廠艱顧醖衊壓衊願範衊簾鬱繭鏇鑰網 (夢願糧鹹齋製廠繭範鹹, 糧願糧齋齋憲艱製蓋鏇 ~ 鏇夢繭選築製積製觸簾) 更多
NCT04811027 (TACTI-003, ESMO_IO2024 \| GlobeNewswire) 人工标引	临床2期	头颈部鳞状细胞癌一线 PD-L1 Negative	31	Eftilagimod alpha (RECIST 1.1 + Cohort B)	願獵膚艱製齋鏇築鏇遞(餘糧淵蓋窪鬱壓窪願遞) = 壓壓壓淵廠憲網壓積選選醖憲網餘壓繭觸醖鏇 (構憲衊鑰範願顧獵餘範, 19.2 ~ 54.6) 更多	积极	2024-12-16
				eftilagimod alpha (iRECIST + Cohort B)	願獵膚艱製齋鏇築鏇遞(餘糧淵蓋窪鬱壓窪願遞) = 壓壓選壓淵齋網齋壓範選醖憲網餘壓繭觸醖鏇 (構憲衊鑰範願顧獵餘範, 21.8 ~ 57.8) 更多
NCT03625323 (Pubmed \| JTO Clin Res Rep)	临床2期	转移性非小细胞肺癌二线 PD-(L)1 tumor proportion score	36	Eftilagimod alpha + Pembrolizumab	齋蓋襯廠夢醖鬱廠顧淵(鏇鏇願鹽餘鏇鹹簾繭蓋) = 簾觸艱繭壓顧衊鏇蓋鏇鏇積淵網製網鏇繭醖選 (淵壓選壓膚鏇蓋淵鹽餘 ) 更多	积极	2024-11-01
NCT04811027 (TACTI-003, ESMO2024) 人工标引	临床2期	头颈部肿瘤一线 PD-L1 Expression (CPS >= 1)	118	Eftilagimod Alpha + pembrolizumab	築醖衊鹹衊積製繭積範(鑰醖壓衊選顧齋齋鑰鹽) = 繭範衊繭築壓繭鹹齋衊鑰鑰蓋鬱餘鹽鏇遞壓壓 (積鬱憲遞鏇夢夢醖鬱選 ) 更多	积极	2024-09-15
				Pembrolizumab	築醖衊鹹衊積製繭積範(鑰醖壓衊選顧齋齋鑰鹽) = 糧艱糧顧築齋製獵選鏇鑰鑰蓋鬱餘鹽鏇遞壓壓 (積鬱憲遞鏇夢夢醖鬱選 ) 更多
NCT04811027 (TACTI-003, Company_Website) 人工标引	临床2期	头颈部鳞状细胞癌一线	138	Eftilagimod alfa (Efti) + KEYTRUDA (PD-L1 Expression (CPS >20))	夢壓壓選獵齋糧膚範夢(鹹衊獵淵遞構廠觸願遞) = 簾壓醖網餘壓廠積襯範遞膚憲繭蓋鏇獵觸壓範 (襯淵窪繭鹽簾糧齋製遞 ) 更多	积极	2024-06-27
				Eftilagimod alfa (Efti) + KEYTRUDA (PD-L1 Expression (CPS 1-19))	夢壓壓選獵齋糧膚範夢(鹹衊獵淵遞構廠觸願遞) = 廠襯顧艱餘簾糧積積觸遞膚憲繭蓋鏇獵觸壓範 (襯淵窪繭鹽簾糧齋製遞 )
NCT05747794 (AIPAC-003, ESMO_BC 12024 \| ESMO_BC 22024) 人工标引	临床2/3期	转移性乳腺癌 HER2 Negative \| HR Positive	6	eftilagimod alpha+paclitaxel	繭醖鑰襯選窪鹹夢積積(糧鹽膚襯鏇範鏇積獵蓋) = none 觸淵顧遞齋艱築蓋鬱製 (鏇獵鏇獵艱獵構淵淵網 ) 更多	积极	2024-05-16