Gemcitabine

Immunocore presents Phase 1 data of brenetafusp, an ImmTAC bispecific targeting PRAME, in patients with ovarian cancer Brenetafusp is clinically active as monotherapy and in combination with chemotherapy in heavily pre-treated, platinum-resistant ovarian cancer patients T cell fitness gene expression signature in blood is an important parameter of clinical activity for tebentafusp in uveal melanoma and for brenetafusp across different tumor types 14 September 2024 -- Immunocore Holdings plc (Nasdaq: IMCR) (“Immunocore” or the “Company”), a commercial-stage biotechnology company pioneering and delivering transformative immunomodulating medicines to radically improve outcomes for patients with cancer, infectious diseases and autoimmune diseases, today presented Phase 1 data with brenetafusp in patients with platinum resistant ovarian cancer at the 2024 European Society for Medical Oncology (ESMO) Congress. In a proffered session to be held on Monday, September 16, 2024, the Company will present translational Phase 1/2 data with KIMMTRAK® (tebentafusp-tebn) and brenetafusp demonstrating that T cell fitness gene expression signature in blood is an important parameter associated with clinical activity for both therapies in metastatic uveal melanoma. “Brenetafusp monotherapy is active in heavily pre-treated, platinum resistant ovarian cancer patients and can be combined safely with chemotherapy. We see the hallmarks of ImmTAC clinical activity in this Phase 1 data, such as disease control, ctDNA molecular response, and association with T cell fitness, which increases our confidence in the potential for brenetafusp in ovarian cancer,” said David Berman, Head of Research and Development. “While early, the promising efficacy data from chemotherapy plus brenetafusp led us to expand the combinations we are studying, including in earlier-line platinum sensitive disease.” Dr. Claire Friedman, Gynecologic Medical Oncologist & Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center, said: “While many solid tumors have benefited from the advances in immunotherapy, the treatment of recurrent ovarian cancer has remained an ongoing challenge. These data offer proof of concept that patients with advanced, platinum-resistant ovarian cancer can benefit from brenetafusp, alone or in combination with chemotherapy, and support further development of the drug in this patient population.” Thirty-seven patients with heavily pre-treated (median 5 prior lines) serous ovarian cancer were treated with brenetafusp monotherapy, including four patients previously presented in the efficacy data set at ESMO 2022. A majority of patients had received prior bevacizumab (81%) and PARP inhibitors (59%). Brenetafusp was well tolerated with no treatment-related discontinuation or death observed. The most frequent treatment-related adverse event was reversible and manageable cytokine release syndrome, observed in 57% of patients, with the majority being Grade 1. Thirty-one of the 37 monotherapy patients were evaluable for RECIST v1.1 tumor assessment, 58% of whom demonstrated disease control (partial response and stable disease), including two confirmed partial responses (6.5% RECIST response rate). Of patients who had tumor progression, 64% were treated beyond progression (median of 2 additional months). Across all 37 patients, the median progression-free survival (PFS) was 3.3 months, and the overall survival (OS), while still maturing, was 73% at 6 months. Of the 29 monotherapy patients evaluable for circulating tumor DNA (ctDNA) response, 31% (9/29) had a molecular response (≥0.5 log reduction by week 9). Twenty-eight monotherapy patients were evaluable for baseline blood T cell fitness (TCF) gene expression signature. There was greater activity in patients with a TCF signature above median versus those at or below the median, respectively, including: disease control (80% vs 38%), PFS (3.7 months vs 2.2 months) and six-month OS (93% vs 47%). As presented today at ESMO in a pre-clinical study poster (1021P), the combination of chemotherapy with brenetafusp has the potential to enhance clinical activity by increasing expression of the antigen presentation machinery in cancer cells. In the Phase 1 trial, 16 patients with platinum-resistant ovarian cancer were treated with brenetafusp and either gemcitabine, nab-paclitaxel or pegylated doxorubicin chemotherapy. These patients were heavily pre-treated (median of 4 prior treatment lines) including prior bevacizumab (75%) and PARP inhibitors (75%). The safety profile of brenetafusp in combination with chemotherapy was consistent with the expected profile of each individual agent. Thirteen of the 16 combination patients were evaluable for RECIST v1.1 tumor assessment. All 13 patients received prior platinum and taxane therapy, and 6 received prior gemcitabine. Sixty nine percent (9/13) of patients achieved disease control, including three partial responses (23% RECIST response rate). Historical chemotherapy efficacy data in this heavily pre-treated patient population is sparse but indicate response rates are less than 10%, with disease control rates typically ~40-50%1. Eleven of the 16 combination patients were evaluable for ctDNA response. The molecular response rate was 82% (9/11). As previously reported for brenetafusp in cutaneous melanoma (ASCO 2024), ctDNA molecular response in this trial was also associated with longer OS and PFS. At an oral proffered session on Monday, September 16, 2024, the Company will present translational data from previously treated, metastatic uveal melanoma (mUM) patients, including 132 patients treated with KIMMTRAK in a Phase 1/2 trial, and 22 patients treated with brenetafusp in a Phase 1 trial. In the KIMMTRAK cohort, patients with a TCF signature greater than or equal to the median had higher clinical activity compared to patients with a TCF signature below the median, respectively, including longer OS (28 months vs 11 months), PFS (5 months vs 2 months) and disease control (67% vs 36%). The association of TCF signature with longer OS was independent of known prognostic factors in uveal melanoma. In addition, the TCF signature was associated with greater tumor reduction and a higher rate of on-target, melanocyte-related adverse events; both are consistent with the mechanism of action, and suggest that the signature is not purely prognostic. This TCF signature, discovered for KIMMTRAK in mUM, was subsequently confirmed as an important parameter of clinical activity for brenetafusp in mUM (ESMO 2024), ovarian cancer (ESMO 2024), and cutaneous melanoma (ASCO 2024). The accumulating data suggests that ImmTAC therapies may deliver greater clinical activity in earlier line patients, where TCF is expected to be higher, leading the Company to investigate brenetafusp in these populations. Immunocore’s proprietary T cell receptor (TCR) technology generates a novel class of bispecific biologics called ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules that are designed to redirect the immune system to recognize and kill cancerous cells. ImmTAC molecules are soluble TCRs engineered to recognize intracellular cancer antigens with ultra-high affinity and selectively kill these cancer cells via an anti-CD3 immune-activating effector function. Based on the demonstrated mechanism of T cell infiltration into human tumors, the ImmTAC mechanism of action holds the potential to treat hematologic and solid tumors, regardless of mutational burden or immune infiltration, including immune “cold” low mutation rate tumors. IMC-F106C-101 is a first-in-human, Phase 1/2 dose escalation trial in patients with multiple solid tumor cancers including non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), endometrial, ovarian, cutaneous melanoma, and breast cancers. The Phase 1 dose escalation trial was designed to determine the maximum tolerated dose (MTD), as well as to evaluate the safety, preliminary anti-tumor activity and pharmacokinetics of IMC-F106C (brenetafusp), a bispecific protein built on Immunocore’s ImmTAC technology, and the Company’s first molecule to target the PRAME antigen. The Company is enrolling patients into three expansion arms in ovarian, NSCLC, and endometrial cancers. The IMC-F106C-101 trial is adaptive and includes the option for Phase 2 expansion, allowing for approximately 100 patients treated per tumor type in the Phase 1 and 2 expansion arms. Dose escalation continues in additional solid tumors as well as plans for combination arms with standards-of-care, including checkpoint inhibitors, chemotherapy, and tebentafusp. Most patients with ovarian cancer are diagnosed with advanced disease, giving it the highest mortality amongst gynecological malignancies in the US and Europe. The current standard of care is surgery followed by platinum-based chemotherapy, and although many patients initially respond, the disease often recurs and, over time, becomes resistant to further platinum therapy. There is significant unmet need for new therapies that improve clinical outcomes in both platinum-sensitive and platinum-resistant ovarian cancer patients. Uveal melanoma is a rare and aggressive form of melanoma affecting the eye. Although it is the most common primary intraocular malignancy in adults, the diagnosis is rare, and up to 50% of people with uveal melanoma will eventually develop metastatic disease. Unresectable or metastatic uveal melanoma typically has a poor prognosis and had no approved treatment until KIMMTRAK. KIMMTRAK is a novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. KIMMTRAK specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. This is the first molecule developed using Immunocore’s ImmTAC technology platform designed to redirect and activate T cells to recognize and kill tumor cells. KIMMTRAK has been approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma in the United States, European Union, Canada, Australia, and the United Kingdom. Immunocore is committed to helping patients who need KIMMTRAK obtain access via our KIMMTRAKConnect program. The program provides services with dedicated nurse case managers who provide personalized support, including educational resources, financial assistance, and site of care coordination. To learn more, visit KIMMTRAKConnect.com or call 844-775-2273. Immunocore is a commercial-stage biotechnology company pioneering the development of a novel class of TCR bispecific immunotherapies called ImmTAX – Immune mobilizing monoclonal TCRs Against X disease – designed to treat a broad range of diseases, including cancer, autoimmune diseases, and infectious diseases. Leveraging its proprietary, flexible, off-the-shelf ImmTAX platform, Immunocore is developing a deep pipeline in multiple therapeutic areas, including nine active clinical and pre-clinical programs​ in oncology, infectious diseases, and autoimmune diseases. The Company’s most advanced oncology TCR therapeutic, KIMMTRAK has been approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma in the United States, European Union, Canada, Australia, and the United Kingdom. The content above comes from the network. if any infringement, please contact us to modify.

正在西班牙巴塞罗那召开的2024年欧洲肿瘤内科学会（ESMO）大会上，上海交通大学医学院附属瑞金医院张伟滨教授研究团队的鲍其远教授在现场口头报告了一项VEGFR2抑制剂阿帕替尼（Apa）联合化疗用于骨肉瘤可切除肺转移的开放标签、单臂Ⅱ期临床试验（PROACH研究）的结果[1]。该研究首次验证了在标准化疗基础上加入抗血管生成药物阿帕替尼，对于可切除的转移性骨肉瘤患者而言，有望成为一种新的治疗策略。 2024 ESMO现场图：鲍其远教授进行口头报告 研究背景 骨肉瘤(Osteosarcoma)是起源于间叶细胞恶性增殖产生骨样基质所构成的骨肿瘤，是最常见的原发性骨恶性肿瘤，多发生于骨骼快速生长发育的青少年或者儿童。75%的患者发病年龄在10～20岁，年发病大约为2～3/100万，占人类恶性肿瘤的0.2%，占原发骨肿瘤的11.7%。同其他实体瘤类似，骨肉瘤恶性程度高、预后差、易出现远处转移，尤其短时间内容易出现肺转移，病死率较高[2]。 根据国际指南，手术对于骨肉瘤肺转移的治疗效果优于二线化疗药物，但以往研究多聚焦于二线药物改良，效果有限，仅短暂延长无进展生存期并易产生耐药。 血管内皮生长因子受体(VEGFR)靶向的酪氨酸激酶抑制剂在治疗复发性和不可切除骨肉瘤方面已展现出有潜力的治疗获益。56%～72%的骨肉瘤首次复发患者可切除[3]。然而，此类药物应用于可切除的转移性骨肉瘤时，其临床获益相对有限，提示现有治疗策略在这一特定患者群体中的局限性。在常规方案中添加VEGFR抑制剂能否改善可切除性和术后结局，迄今为止尚未探索。阿帕替尼是恒瑞医药研发的一种小分子、高选择性VEGFR抑制剂，具有快速的药代动力学，尤其有利于围手术期给药(血浆水平达峰时间=2h，消除半衰期=8.5~9h)[4] 。 上海交通大学医学院附属瑞金医院张伟滨教授研究团队设计了一套新方案(PROACH研究[5])：通过阿帕替尼联合二线药物的优化方案先期控制肺部病灶，随后积极手术切除，旨在提升患者的无瘤生存率和远期治愈率。2023年，该研究的初步结果入选了欧洲肿瘤内科学会亚洲年会(ESMO ASIA)壁报环节，初步结果显示，该方案在18个月时达到62%的无瘤生存率，展现出良好治疗潜力[6]。基于前期积极成果，团队本次对本研究的最终结果进行总结。 研究方法 本研究旨在探索VEGFR2抑制剂阿帕替尼(Apa)联合吉西他滨-多西他赛(Gem-tax)化疗方案对骨肉瘤可切除肺转移(PMs)患者的治疗效果。通过PROACH研究(NCT03742193)，本研究系统地评估了阿帕替尼联合Gem-tax新辅助治疗，后续以阿帕替尼单药维持治疗的策略在改善患者预后方面的潜力。入组患者在接受肺转移灶切除术前完成三个周期的阿帕替尼+Gem-tax治疗，术后辅助治疗四个周期后序贯使用阿帕替尼单药维持直至疾病进展(PD)或不可耐受毒性。若39例可评估疗效患者中有≥17例的患者达到达到无进展状态(历史对照为<30%)，则达到主要终点。 图1. 转移灶切除术策略图 研究结果 自2019年3月至2022年11月，本研究共纳入43例符合条件的可切除骨肉瘤肺转移(PM)患者。基线数据显示，28%的患者存在≥10个肺转移灶，而56%的患者有双侧肺转移。 采用新辅助阿帕替尼+Gem-Tax方案治疗后，91%(39/43)的患者成功完成了预定的转移瘤切除术，研究观察到18例(46.2%)可评价患者在12个月时仍处于无进展状态，满足了预设的主要终点标准。 本研究中位无进展生存期(mPFS)为12.8个月，中位生存期(mOS)达到42.1个月，术前71%的肿瘤出现不同程度缩小和降期。术后二年以上仍有约40%处于无瘤生存状态。 图2. mPFS和术前肿瘤大小变化 肿瘤反应率是目前评价骨肉瘤新辅助化疗(NAC)疗效的病理学金标准之一，决定是否有必要更改术后的化疗方案。肿瘤反应率的分级方法有很多报道，目前认为肿瘤反应率与患者的预后有明显相关性。 本研究中肺转移手术后肿瘤标本中位肿瘤非活细胞比率高达90%(范围：35%-100%)，这一数据显著优于仅Gem-Tax治疗的对照结果。 图3. 中位肿瘤非活细胞比率高达90% 研究结论 本研究首次验证了在标准化疗基础上加入抗血管生成药物阿帕替尼，对于可切除的转移性骨肉瘤患者而言，有望成为一种新的治疗策略。这一发现不仅可能丰富了骨肉瘤肺转移的临床治疗选择，也为未来相关研究指明了方向。研究中较高的术前肿瘤降期率、病理学肿瘤反应率及患者无瘤生存较高提示该联合方案具有潜在协同效应，尚待进一步转化和开展相关研究。 作为创新型国际化制药企业，恒瑞医药长期坚持“科技为本，为人类创造健康生活”的使命，针对肿瘤等严重威胁人类生命健康的疾病开展科研攻关，已上市的17款1类创新药中抗肿瘤创新药达9款。公司另有90多个自主创新产品正在临床开发，300余项临床试验在国内外开展。本次ESMO大会，公司携13款创新药的37项抗肿瘤领域研究登上国际学术舞台，奏响了抗肿瘤领域自主创新实力的强音，也是中国医药研发创新力量的展现。 未来，恒瑞医药将继续坚持“以患者为中心”的理念，重创新，强研发，力争研制出更多的新药、好药，服务“健康中国”，惠及全球患者。 参考文献： [1]Q. Bao, J. Wen, Z. Zhang, X. Yang, Y. Shen, W. Zhang.The final results of pulmonary resectable metastases of osteosarcoma with antiangiogenic and chemotherapy (PROACH): An open-label, single-arm phase II clinical trial. ESMO 2024.1724MO. [2]国家卫生健康委.儿童及青少年骨肉瘤诊疗规范(2019版)儿童及青少年骨肉瘤诊疗规范(2019版） [3]Harting MT, 2006; Leary, SES.2013;Liu Z, 2022 [4]阿帕替尼研究者手册 [5]Q. Bao, Y. Hu, Y. Shen, W. Zhang . Pulmonary resectable metastases of osteosarcoma with apatinib and chemotherapy (PROACH): A multi-center phase II randomized clinical trial.ESMO 2019.1734TiP. [6]Q. Bao, Z. Zhang, J. Wen, R. Wan, X. Yang, X. Chen, Y. Shen, W. Zhang. Pulmonary resectable metastases of osteosarcoma with apatinib and chemotherapy (PROACH): An open-label, single-arm phase II clinical trial. ESMO Asia 2023.615P. 声明： 1. 本新闻旨在分享研发前沿资讯，仅供医疗卫生专业人士基于学术目的参阅，非广告用途。 2. 恒瑞医药不推荐任何未被批准的药品、适应症的使用。 撰稿：中央医学事务部 排版：程梦真 责编：李玉莹 往期精选 |  研发创新  | 慢病创新里程碑！恒瑞首个自免创新药夫那奇珠单抗获批上市 恒瑞医药新突破！中国首个自研阿片类镇痛创新药富马酸泰吉利定获批上市 |  国际化  | 海外BD再传捷报！恒瑞医药GLP-1类创新药组合实现海外许可 恒瑞医药与默克达成合作，携手推进癌症创新疗法 |  重磅奖项  | 喜报！恒瑞医药荣获2023年度国家科技进步奖 恒瑞医药连续六年入选全球制药企业50强榜单！ |  社会公益  | “健康中国行·重走长征路”项目启动仪式圆满举行！恒瑞提供公益支持，助力健康中国 恒瑞医药集团向中国扶贫基金会捐赠3000万设立“健康帮扶基金”