Lurbinectedin

SOUTH SAN FRANCISCO, Calif.--( BUSINESS WIRE )--Asher Biotherapeutics, a biotechnology company developing precisely-targeted immunotherapies for cancer and infectious diseases, today announced a clinical trial collaboration and supply agreement with Amgen (NASDAQ:AMGN) to evaluate etakafusp alfa (formerly known as AB248), Asher Bio’s investigational CD8+ T cell targeted interleukin-2 (IL-2) immunotherapy, in combination with IMDELLTRA ® (tarlatamab), Amgen’s DLL3-targeting Bispecific T-cell Engager (BiTE ® ) therapy, in patients with extensive-stage small cell lung cancer (ES-SCLC). “ This clinical trial collaboration and supply agreement with Amgen allows us to further expand on the Phase 1 results for etakafusp alfa in a new combination with IMDELLTRA ® in a global Phase 1b study in ES-SCLC,” said Don O’Sullivan, Ph.D., Chief Business Officer of Asher Bio. “ Based on emerging data to date, we believe etakafusp alfa has the potential to improve the efficacy of T cell engagers (TCEs) by selectively expanding the CD8+ T cell population, improving effector function, tumor infiltration and reversing TCE-induced T cell desensitization. We look forward to collaborating with Amgen to assess the potential for the novel combination to improve outcomes for patients with ES-SCLC.” As part of this collaboration agreement, Amgen will sponsor and operationalize a global Phase 1b study to evaluate the safety and early efficacy of etakafusp alfa in combination with IMDELLTRA ® in patients with ES-SCLC. Asher Bio will retain full ownership of etakafusp alfa and will supply Amgen with etakafusp alfa at no cost. About SCLC SCLC is one of the most aggressive and devastating solid tumor malignancies, with a median survival of approximately 12 months following initial therapy and a 3% five-year relative survival rate for ES-SCLC. 1,2,3 Current second-line treatments impart a short duration of response (median DoR: 3.3–5.3 months) and limited survival (median OS: 5.8-9.3 months), while current third-line treatments for SCLC, which consist primarily of chemotherapy, yield a short median DoR of 2.6 months and a median OS of 4.4-5.3 months. 4-8 SCLC comprises ~15% of the 2.4 million plus patients diagnosed with lung cancer worldwide each year. 9-11 Despite initial high response rates to first-line platinum-based chemotherapy, most patients quickly relapse within months and require subsequent treatment options. 13 About Etakafusp Alfa ( AB248) Etakafusp Alfa ( AB248 ) is a novel CD8+ T cell selective IL-2, generated by fusing a reduced potency IL-2 mutein to an anti-CD8β antibody. It was specifically engineered to selectively and potently activate CD8+ T-cells which are the immune cells that drive anti-tumor efficacy, while avoiding natural killer (NK) cells, which can act as a pharmacological sink and contribute to toxicity, and regulatory T (Treg) cells, which are immunosuppressive. Asher Bio is currently evaluating etakafusp alfa in a Phase 1a/1b clinical trial, AB248-101. The trial consists of a dose escalation and expansion phase to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of etakafusp alfa alone and in combination with pembrolizumab in subjects with locally advanced/metastatic solid tumors who failed prior therapies. Initial pharmacokinetic and pharmacodynamic data from the ongoing Phase 1a/1b clinical trial support etakafusp alfa’s proof of mechanism and activity with a highly differentiated clinical profile. Early data shows potent and selective CD8+ T cell activation without substantial changes to Treg and NK cell numbers and initial evidence of anti-tumor activity, including confirmed objective responses, with a generally well-tolerated safety profile. Please refer to www.clinicaltrials.gov (NCT05653882) for additional details related to this Phase 1a/1b clinical trial. About Asher Bio Asher Bio is a biotechnology company developing therapies to precisely engage specific immune cells to fight cancer and chronic viral infection. We utilize our proprietary cis-targeting platform to develop therapies engineered to overcome limitations of other immune-based treatments by selectively activating specific immune cell types with validated disease fighting functionality. Our candidates feature an antibody connected to a modified immunomodulatory protein, such as a cytokine. Our candidate design is intended to enable our candidates to selectively activate the desired immune cells and not other cells that contribute to toxicity or immune suppression. Our lead program etakafusp alfa (AB248), an IL-2 molecule specifically targeted to CD8+ effector T cells, is currently in Phase 1 trials for oncology. Our broader portfolio includes AB821, an IND-ready CD8-targeted IL-21 immunotherapy, and early-stage programs targeting CAR-T cells, myeloid cells and CD4+ T cells. Asher Bio was founded by Ivana Djuretic and Andy Yeung with support from Third Rock Ventures and is located in South San Francisco. For more information, please visit http://www.asherbio.com and follow us on X (formerly Twitter) @ AsherBio and on LinkedIn . 1 American Cancer Society. Lung Cancer Survival Rates. 2 Paz-Ares L, Chen Y, Reinmuth N, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open. 2022;7:100408. 3 Liu SV, Reck M, Mansfield AS, et al. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol. 2021;39:619-630. 4 Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645-654. 5 Von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999;17(2):658-67. 6 Von Pawel J, Jotte R, Spigel DR, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol. 2014;32(35):4012-9. 7 Coutinho AD, Shah M, Lunacsek OE, et al. Real-world treatment patterns and outcomes of patients with small cell lung cancer progression after 2 lines of therapy. Lung Cancer. 2019;127:53-58. 8 Borghaei H, Pundole X, Anderson E, et al. Treatment patterns and outcomes in recent US clinical practice for SCLC patients after two prior lines of therapy. Presentation at World Conference on Lung Cancer 2023. September 9-12, 2023; Singapore, SGP. Poster #EP13.07-03. 9 Oronsky B, Abrouk N, Caroen S, et al. A 2022 Update on Extensive Stage Small-Cell Lung Cancer (SCLC). J Cancer. 2022;13:2945-2953. 10 World Health Organization. Lung. 2020. 11 Sabari JK, Lok BH, Laird JH, et al. Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol. 2017;14:549-561.

本文研究结果表明，药物卢比替定疗法能上调SCLC患者临床样本中的MHC-I/II基因和CE8的表达，同时研究人员还提供了关于卢比替定对STING介导的多模态免疫激活影响效应的新见解。 卢比替定(lurbinectedin)是一种被批准用于治疗人类小细胞肺癌（SCLC）的二线治疗药物，目前研究人员正在进行卢比替定联合PD-L1阻滞的SCLC临床试验，然而，卢比替定在患者机体中的免疫调节效应，目前研究人员并不清楚。 近日，一篇发表在国际杂志Cell Reports Medicine上题为“Lurbinectedin sensitizes PD-L1 blockade therapy by activating STING-IFN signaling in small-cell lung cancer”的研究报告中，来自西奈山Icahn医学院等机构的科学家们通过研究识别出了人类小细胞肺癌疗法的作用机制，这类肺癌是一种极具侵袭性且难以治疗的癌症，相关研究结果表明，作为SCLC的二线治疗药物，卢比替定能激活STING-IFN信号通路从而增强机体抵御肿瘤的免疫反应。 小细胞肺癌是人类最具侵袭性的癌症之一，其在美国所有癌症患者病例中占到了10%至15%的比例，每年大约有3万至3.5万新发病例，当大多数患者被诊断出疾病时，癌症通常已经发生扩散，从而难以进行治疗。诸如化疗和免疫疗法等当前大多数疗法只能为患者提供暂时的疾病缓解，且患者5年的生存率不到10%。研究者Triparna Sen及其同事揭示了2020年FDA批准的药物卢比替定是如何激活称之为STING的关键免疫信号通路的。 全文的图形摘要 STING信号是一种先天性的免疫信号，其会导致IFN信号上调，而IFN的表达往往在STING信号的下游，这种激活就会增强干扰素和促炎性趋化因子的产生，并会促进主要组织相容性复合体I（MHC-I）蛋白的表达，MHC-I对于免疫细胞识别并攻击癌细胞非常重要。文章中没研究这发现，卢比替定的免疫调节效应或能明显增强PD-L1阻滞疗法的疗效，从而就为疗法选择有限的患者提供新的治疗希望。此外，研究人员还研究了顽固性肺癌亚型的生物学特性，旨在识别出靶向性新型疗法。 研究者Sen博士说道，我们的研究首次揭示了药物卢比替定的免疫增强特性，通过激活STING通路，这种药物就能促进一种强大的抗肿瘤免疫反应，并改善一线和维持疗法环境中患者的治疗结局，这一研究发现或能重新定义广泛期SCLC患者的治疗前景或蓝图。本文研究发现尤为及时，因为最近诸如IMforte III期研究等临床试验表明，当卢比替定与PD-L1抑制剂阿特朱单抗（atezolizumab）结合使用时或能改善SCLC患者的治疗结局。这些有希望的结果或许能进一步证实将卢比替定与免疫疗法结合从而增强与侵袭性疾病作斗争的患者的生存率和生活质量。 综上，本文研究结果表明，药物卢比替定疗法能上调SCLC患者临床样本中的MHC-I/II基因和CE8的表达，同时研究人员还提供了关于卢比替定对STING介导的多模态免疫激活影响效应的新见解，并阐明，卢比替定疗法或许能代表一种能潜在增强SCLC免疫疗法疗效的新型策略。（生物谷Bioon.com） 参考文献： Subhamoy Chakraborty,Utsav Sen,Kedwin Ventura, et al. Lurbinectedin sensitizes PD-L1 blockade therapy by activating STING-IFN signaling in small-cell lung cancer, Cell Reports Medicine (2024). DOI:10.1016/j.xcrm.2024.101852