Onatasertib

点击蓝字 关注我们近日，四川大学华西医院临床试验中心郑莉教授团队在Signal Transduction and Targeted Therapy发表文章“Multicenter phase 1/2 study of onatasertib, a dual TORC1/2 inhibitor, combined with the PD-1 antibody toripalimab in advanced solid tumors”。该论文首次揭示了mTORC1/2双重抑制剂Onatasertib联合特瑞普利单抗，在晚期实体瘤特别是宫颈癌中的安全性和初步疗效，为mTOR信号通路抑制剂联合检查点抑制剂治疗作为晚期实体瘤治疗的新策略提供了科学依据。尽管免疫检查点抑制剂（如PD-1/PD-L1抗体）在多种实体瘤治疗中取得了突破，但单药治疗患者的获益有限。PI3K-AKT-mTOR信号通路的异常激活在肿瘤细胞增殖和存活中起关键作用，因此mTOR抑制剂目前正被开发为多种肿瘤的潜在治疗药物。然而，第一代靶向mTORC1的抑制剂可能导致AKT的反馈激活，而对mTORC2耐药。第二代mTOR抑制剂能够同时抑制mTORC1和mTORC2。临床前研究提示，mTORC1/2抑制剂可调节免疫微环境，并与免疫治疗具有协同增效作用，但未被临床证实。该研究前瞻性地首次探索出双重mTORC1/2抑制剂onatasertib联合PD-1抗体特瑞普利单抗在晚期实体瘤中安全治疗方案，并发现了宫颈癌等优势适应症。该研究分为剂量探索和剂量拓展两个阶段。在剂量递增阶段，应用“3+3”设计探索15/20/30 mg onatasertib联合固定剂量特瑞普利的安全给药方案和初步疗效。在剂量拓展阶段对包括宫颈癌等优势瘤种进行了治疗方案进一步确认和临床疗效的初步验证（NCT04337463），每6周用RECIST 1.1标准评估肿瘤反应，对PD-L1表达（TPS≥1%为阳性）进行了分层分析。研究共纳入46例既往接受2线治疗的晚期实体瘤患者（其中45.7%宫颈癌），考察治疗方案的安全性、耐受性、客观缓解率（ORR）、疾病控制率（DCR）、无进展生存期（PFS）、药代动力学（PK）特征及PD-L1表达相关性。 流程图总体疗效：ORR为26.1%，DCR为73.9%，中位PFS为4.3个月，显示出联合疗法的初步抗肿瘤活性。宫颈癌亚组：ORR 52.4%（PD-L1⁺：66.7% vs PD-L1⁻：41.7%），中位PFS 5.8个月；特别是在PD-L1阴性宫颈癌患者中ORR达41.7%，突破免疫单药治疗局限。15 mg剂量组：中位PFS达7.8个月，治疗持续时间长达43.6周，显示出更优的生存获益与耐受性。onatasertib和特瑞普利联合治疗疗效分析a.46例患者按肿瘤类型分组的治疗持续时间、最佳总体反应及进展时间b.宫颈癌患者靶病灶的反应随时间的变化c.宫颈癌患者靶病灶的最佳反应onatasertib和特瑞普利联合治疗的生存分析（a,b）三个剂量组的PFS和OS（c,d）按PD-L1状态分层的PFS和OS分析该研究工作在晚期实体瘤患者中阐明了mTORC1/2双重抑制剂onatasertib联合特瑞普利单抗的安全性是可控的，并且在晚期实体瘤中显示出令人欣喜的临床活性，尤其是在宫颈癌患者中的疗效不受PD-L1表达的限制。这一重要发现为既往难以从免疫治疗中获益的宫颈癌患者提供了新的治疗选择，具有重要的临床意义。声明：本文由“肿瘤界”整理与汇编，欢迎分享转载，如需使用本文内容，请务必注明出处。来源：四川大学华西医院官网、华西医学时间官微编辑：lagertha审核：南星

ATG-037, an oral small molecule CD73 inhibitor, in combination with MSD's anti-PD-1 therapy, KEYTRUDA® (pembrolizumab), achieved an overall response rate (ORR) of 36.4% and disease control rate (DCR) of 100% in checkpoint inhibitor (CPI)-resistant melanoma patients in the ongoing STAMINA-01 trial, with one patient maintaining a partial response (PR) and remained on treatment for over 2 years without any safety concerns. In CPI-resistant non-small cell lung cancer (NSCLC), the combination of ATG-037 and pembrolizumab achieved an ORR of 22% and DCR of 67% in the same study. ATG-008, an oral dual mTORC1/2 inhibitor, in combination with toripalimab, achieved an ORR of 22.2% and DCR of 85.2% in CPI-resistant cervical cancer patients in the ongoing TORCH-2 trial. SHANGHAI and HONG KONG, May 22, 2025 /PRNewswire/ -- Antengene Corporation Limited (" Antengene", SEHK: 6996.HK), a leading innovative, commercial-stage global biopharmaceutical company dedicated to discovering, developing and commercializing first-in-class and/or best-in-class medicines for hematologic malignancies and solid tumors, today announced that it will present the latest clinical data of its CD73 oral small molecule inhibitor ATG-037 and oral dual mTORC1/2 inhibitor ATG-008 in Poster Presentations at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place from May 30th to June 3rd in Chicago, IL, the United States. Details of the Poster Presentations: ATG-037 (CD73 Small Molecule Inhibitor) Title: A First-In-Human Phase I/Ib study of ATG-037 Monotherapy and Combination Therapy with Pembrolizumab in Patients with Advanced Solid Tumors - STAMINA-01 Abstract: 3123 Session: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology Date: June 2, 2025 Time: 1:30 PM - 4:30 PM (Central Time) 2:30 AM - 5:30 AM, June 3, 2025 (Beijing Time) Robust clinical benefit observed in CPI-resistant patients: As of April 27, 2025, the study has already completed the dose escalation part in which 43 patients were enrolled and received monotherapy. Among them, 28 CPI-resistant patients also received the combination therapy. Among patients treated with the combination therapy, 6 patients (4 melanoma and 2 NSCLC patients) achieved a confirmed PR with an ORR of 21.4%, and 16 patients achieved stable disease (SD) with a DCR of 78.6%. The combination regimen delivered particularly encouraging efficacy in melanoma, with all 11 CPI-resistant patients achieving disease control (DCR 100%) and an ORR of 36.4% (4 PRs), including 1 patient having maintained PR and remained in the study for over 2 years without any safety concerns. In CPI-resistant NSCLC, the combination regimen achieved an ORR of 22% (PRs) and a DCR of 67%. These results highlight the potential of ATG-037 to deliver meaningful clinical benefit across multiple tumor types, reinforcing its promise as a novel treatment option in CPI-resistant cancers. Manageable safety profile: Treatment-related adverse events were reported in 56% (24/43) of patients receiving monotherapy and 61% (17/28) of patients receiving the combination therapy. The majority of these TRAEs were grade 1-2. Only one serious TRAE (grade 3 immune mediated hepatitis) was observed in the study. Two key differentiators: ATG-037 is an oral small molecule CD73 inhibitor offering greater convenience over intravenous (IV) injectable agents and is uniquely designed to overcome the 'hook effect' commonly seen in anti-CD73 antibodies, enabling complete and more effective CD73 inhibition. The STAMINA-01 trial: STAMINA-01 is a Phase I/Ib study jointly conducted by Antengene and MSD (Merck & Co., Inc., Rahway, NJ, USA). The study was designed to evaluate the safety, pharmacokinetics, and optimal dosing of ATG-037 as a monotherapy and in combination with MSD's anti-PD-1 therapy, KEYTRUDA® (pembrolizumab), in patients with refractory/relapsed solid tumors. At present, dose optimization and dose expansion parts of the study are being carried out as planned in China and Australia. KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. ATG-008 (mTORC1/2 Small Molecule Inhibitor) Title: A TORC1/2 inhibitor onatasertib combined with toripalimab in patients with advanced cervical cancers with prior anti-PD-(L)1 therapy Abstract: 5540 Session: Gynecologic Cancer Date: June 1, 2025 Time: 9:00 AM - 12:00 PM (Central Time) 10:00 PM, June 1, 2025 - 1:00 AM, June 2, 2025 (Beijing Time) The TORCH-2 trial: ATG-008 is an oral dual mTOR1/2 inhibitor. The TORCH-2 trial is a Phase I/II dose escalation and dose expansion study of ATG-008 in combination with the anti-PD-1 monoclonal antibody toripalimab in patients with advanced solid tumors. This abstract reports data from patients with advanced cervical cancer who had previously received at least prior 1 line of anti-PD-(L)1 therapy and 1 line of platinum chemotherapy, regardless of the PD-L1 expression. As of November 25, 2024, 30 qualified patients were enrolled and received ATG-008 15 mg orally once a day (QD) in combination with toripalimab 240 mg, once every 21 days (Q3W). Among them, 14 and 16 patients had received 1 and at least 2 prior lines of systemic therapy, respectively. The median time since initial diagnosis was 37 months. Encouraging efficacy in patients with CPI-resistant cervical cancer: Among 27 efficacy-evaluable patients, the combination regimen achieved an ORR of 22.2% and a DCR of 85.2%. The ORRs of PD-L1 positive and PD-L1 negative populations were 30% (3/10) and 33.3% (2/6), respectively. The median time to response was 1.7 months (1.4, 4.2) and the median duration of response (DOR) was 5.7 months (95% CI: 2.7, NE). The median progression-free survival (PFS) was 4.2 months (95% CI: 3.3, 5.8) and the median overall survival (OS) was 21.4 months (95% CI: 15.5, NE). These results underscore the potential of ATG-008 in combination with toripalimab in providing meaningful clinical benefit for CPI-resistant cervical cancer patients, reinforcing its promise as a novel treatment option for this difficult-to-treat patient population. Manageable safety profile: All 30 patients experienced at least one TEAE, and 22 patients (73.3%) reported grade ≥3 TRAEs. The most common all-grade TRAEs were hyperglycaemia (56.7%), rash (43.3%) and white blood cell decreased (43.3%). Most TRAEs were grade 1-2, and no TEAE led to death. About Antengene Antengene Corporation Limited ( "Antengene", SEHK: 6996.HK) is a leading commercial-stage R&D-driven global biopharmaceutical company focused on the discovery, development, manufacturing and commercialization of innovative first-in-class/best-in-class therapeutics for the treatment of hematologic malignancies and solid tumors, in realizing its vision of "Treating Patients Beyond Borders". Antengene has built a pipeline of 9 oncology assets at various stages going from clinical to commercial, including 6 with global rights, and 3 with rights for the APAC region. To date, Antengene has obtained 31 investigational new drug (IND) approvals in the U.S. and Asia, and submitted new drug applications (NDAs) in 11 Asia Pacific markets, with the NDA for XPOVIO® (selinexor) already approved in Mainland of China, Taiwan China, Hong Kong China, Macau China, South Korea, Singapore, Malaysia, Thailand, Indonesia and Australia. Forward-looking statements The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, we undertake no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development. For a further discussion of these and other factors that could cause future results to differ materially from any forward-looking statement, please see the other risks and uncertainties described in the Company's Annual Report for the year ended December 31, 2024, and the documents subsequently submitted to the Hong Kong Stock Exchange. For more information, please contact: Investor Contacts: Donald Lung E-mail: [email protected] Mobile: +86 18420672158 PR Contacts: Peter Qian E-mail: [email protected] Mobile: +86 13062747000 SOURCE Antengene Corporation Limited WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED