Toripalimab

- Randomized Phase 2 study initiated evaluating the combination of casdozokitug, toripalimab and bevacizumab in patients with liver cancer - REDWOOD CITY, Calif., Dec. 18, 2024 (GLOBE NEWSWIRE) -- Coherus BioSciences, Inc. (“Coherus,” NASDAQ: CHRS) today announced that an abstract highlighting final clinical and biomarker data from its Phase 2 clinical trial evaluating casdozokitug (casdozo), a selective and potent IL-27-antagonistic antibody, in combination with atezolizumab (atezo) and bevacizumab (bev) in treatment naïve patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC), has been selected for a poster presentation at the upcoming 2025 ASCO GI Annual Meeting, being held January 23-25, 2025, in San Fransisco, CA. “Casdozo is a first-in-class antibody, and in oncology, is the first IL-27 cytokine antagonist to demonstrate monotherapy responses and immune activation with a safety profile that lends itself to combination,” said Rosh Dias, M.D., Coherus’ Chief Medical Officer. “We look forward to sharing the final data from this Phase 2 combination study of casdozo with standard of care with the medical community at the upcoming 2025 ASCO-GI annual meeting. We now have data across several tumor types for casdozo demonstrating clinical activity. We are particularly excited about HCC given the strong preclinical package for targeting IL-27 in liver cancer and now translation to the clinic.” Coherus has initiated a new randomized Phase 2 study (NCT06679985) evaluating casdozo, in combination with bevacizumab and toripalimab, Coherus’ next-generation anti-PD-1 monoclonal antibody, in participants with first-line HCC. This randomized, parallel, open-label Phase 2 study is designed to evaluate the safety, efficacy, and Project Optimus1 dosing of the triplet combination. The study is expected to enroll up to 72 patients, who will be randomized to receive one of two biologically active doses of casdozo with toripalimab plus bevacizumab or toripalimab plus bevacizumab without casdozo. “Advancing casdozo development in first-line HCC with a randomized Phase 2 combination study marks a significant milestone in our strategic path to progress our clinical pipeline, which is focused on overcoming immune suppression in the tumor microenvironment to extend survival and improve outcomes for patients and pursuing new indications for toripalimab in the U.S.,” continued Dr. Dias. “Casdozo has shown encouraging responses in the first line setting when added to the existing standard of care, atezolizumab and bevacizumab, and we’re excited to build upon these data with this new Phase 2 study evaluating casdozo in combination with toripalimab and bevacizumab.” In the Phase 3 HEPATORCH study, conducted by Junshi Biosciences, patients with advanced HCC treated with toripalimab combined with bevacizumab as a first-line therapy showed significantly better clinical efficacy than sorafenib monotherapy.2 HEPATORCH patients showed an objective response rate of 25.3% versus 6.1% in the sorafenib group, a median progression-free survival of 5.8 months, and a median overall survival of 20 months, compared to 4 and 14.5 months, respectively, for the sorafenib group.3 Toripalimab in combination with bevacizumab was well tolerated, with a toxicity profile consistent with the known toxicity profile of each monotherapy, with no new safety signals identified.3 The results of the HEPATORCH study support the clinical study of toripalimab in combination with bevacizumab as a new first-line treatment option for advanced HCC which, along with the results from the Phase 2 casdozo study reported to date, support pursuing a triple combination of casdozo with toripalimab plus bevacizumab in patients with advanced or metastatic HCC. ASCO-GI 2025 Presentation Details Title: Results from a phase 2 study of triplet blockade of the IL-27, PD-(L)1, and VEGF pathways with casdozokitug (casdozo, CHS-388) in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (uHCC) Lead Author: Daneng Li, City of Hope National Comprehensive Cancer CenterAbstract #: 605Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary TractDate and Time: Friday, January 24, 2025; 11:30 a.m. – 1:00 p.m. PT Hepatobiliary cancers include a spectrum of invasive carcinomas arising in the liver (hepatocellular carcinoma; HCC), gall bladder, and bile ducts (collectively called biliary tract cancers). The most common type of primary liver cancer in adults is HCC (accounting for ~90%), which is the third leading cause of cancer-related deaths worldwide. According to the NCI Surveillance, Epidemiology and End Results Program (SEER), there will be an estimated 41,630 new cases and 29,840 deaths from liver and intrahepatic bile duct cancer in the US in 2024.4 The U.S. 5-year relative survival rate for liver and intrahepatic bile duct cancer is 21.7%.4 The liver cancer treatment pattern has changed in recent years with the emergence of immunotherapy combinations and will continue to evolve as more treatment options become available for these highly lethal cancers. About Coherus BioSciences Coherus is a commercial-stage biopharmaceutical company focused on the research, development and commercialization of innovative immunotherapies to treat cancer. Coherus is developing an innovative immuno-oncology pipeline that is expected to be synergistic with toripalimab and its proven commercial capabilities in oncology. Coherus’ immuno-oncology pipeline includes multiple antibody immunotherapy candidates focused on enhancing the innate and adaptive immune responses to enable a robust antitumor immunologic response and enhance outcomes for patients with cancer, particularly patients underserved by current immunotherapy treatments. Casdozokitug is a novel IL-27 antagonistic antibody being evaluated in two ongoing clinical studies: a Phase 1/2 study in advanced solid tumors and a Phase 2 study in hepatocellular carcinoma. CHS-114 is a highly selective, competitively positioned, cytolytic anti-CCR8 antibody currently in a Phase 1 study in patients with advanced solid tumors, including HNSCC. CHS-1000 is a novel humanized Fc-modified IgG1 monoclonal antibody specifically targeting ILT4 (LILRB2). An IND for CHS-1000 was allowed to proceed by the FDA in the second quarter of 2024 and proceeding to the first-in-human clinical study is subject to further evaluation in our portfolio prioritization process. Coherus markets LOQTORZI® (toripalimab-tpzi), a novel next-generation PD-1 inhibitor, and UDENYCA® (pegfilgrastim-cbqv), a biosimilar of Neulasta. In December 2024, Coherus announced that it entered into an agreement for the divestiture of the UDENYCA franchise. The proposed transaction is expected to close by the end of the first quarter of 2025. Neulasta® is a registered trademark of Amgen, Inc. Forward-Looking Statements Except for the historical information contained herein, the matters set forth in this press release are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding Coherus’ expectations about identifying synergies between its I-O pipeline and its commercial operations and its I-O pipeline and toripalimab; future enrollment estimates for Coherus’ clinical studies; Coherus’ expectations that it will be able to demonstrate that its clinical pipeline candidates can extend patient survival; and the ability to satisfy the closing conditions to consummate the proposed transaction for the divestiture of the UDENYCA franchise at all or in the estimated time. Such forward-looking statements involve substantial risks and uncertainties that could cause Coherus’ actual results, performance or achievements to differ significantly from any future results, performance or achievements expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the risks and uncertainties inherent in the clinical drug development process; risks related to Coherus’ existing and potential collaboration partners; risks of Coherus’ reliance on third-parties; the risks and uncertainties related to manufacturing and supply of Coherus’ products, the risks and uncertainties of the regulatory approval process, including the speed of regulatory review and the timing of Coherus’ regulatory filings; uncertainties as to the timing for completion of the proposed transaction; uncertainties as to the Company’s ability to obtain the approval of its shareholders required to consummate the proposed transaction for the divestiture of UDENYCA; the possibility that competing offers will be made by third parties; the occurrence of any event, change or other circumstance that may give rise to a right of one or both parties to terminate the agreement to divest UDENYCA; the possibility that the proposed transaction for the divestiture of UDENYCA may not be completed in the time frame expected by the Company or at all, including due to the possibility that a governmental entity may prohibit, delay, or refuse to grant approval, if required, for the consummation of the proposed transaction to divest UDENYCA (or only grant approval subject to adverse conditions or limitations). All forward-looking statements contained in this press release speak only as of the date of this press release. Unless required by law, the Company is not under any duty and undertakes no obligation to publicly update or revise any forward-looking statement to reflect changes in underlying assumptions or factors, of new information, data or methods, future events or other changes. For a further description of the significant risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to Coherus’ business in general, see Coherus’ Quarterly Report on Form 10-Q for the fiscal quarter ended September 30, 2024 filed with the Securities and Exchange Commission on November 6, 2024, including the section therein captioned “Risk Factors” and in other documents Coherus files with the Securities and Exchange Commission including, when available, the proxy statement of the Company relating to the proposed transaction for the divestiture of UDENYCA. UDENYCA® and LOQTORZI®, whether or not appearing in large print or with the trademark symbol, are trademarks of Coherus, its affiliates, related companies or its licensors or joint venture partners unless otherwise noted. Trademarks and trade names of other companies appearing in this press release are, to the knowledge of Coherus, the property of their respective owners. Coherus Contact Information:For Investors:Jodi SieversVP, Investor Relations & Corporate CommunicationsIR@coherus.com For Media:Argot Partners(212) 600-1902coherus@argotpartners.com 1Project Optimus: Reforming the dose optimization and dose selection paradigm in oncology 2Shanghai Junshi Biosciences Co., Ltd (2024, June 11) Junshi Biosciences Announces Phase 3 Study of Toripalimab Combined with Bevacizumab for the First-line Treatment of Advanced Hepatocellular Carcinoma Meets Primary Endpoint 3FAN, J. (2024) HEPATORCH: A randomized, open-label, multicenter, phase III clinical study of the safety and efficacy of toripalimab combined with bevacizumab versus sorafenib as first-line treatment for advanced hepatocellular carcinoma presented at the 2024 Annual Meeting of Chinese Society of Clinical Oncology 4National Cancer Institute Cancer Stat Facts: Liver and Intrahepatic Bile Duct Cancer; retrieved December 17, 2024, from https://seer.cancer.gov/statfacts/html/livibd.html

胃癌（GC）在全球范围内属于第五大常见癌症类型。伴随分子靶向治疗的兴起，针对HER2靶点的曲妥珠单抗，已然成为HER2阳性胃癌的一线治疗用药。另外，针对血管内皮生长因子受体2的单克隆抗体雷莫芦单抗与紫杉醇联合运用，在二线治疗过程中也展现出了对患者生存状况的改善作用。而用于PD-1的纳武单抗（Nivolumab）则获批应用于三线或后续治疗阶段。不过，对于那些不可切除或者已处于转移性晚期的胃癌患者而言，其预后状况依旧难以令人满意。所以，积极开发新型治疗策略已然成为当下极为紧迫的任务。 除了上面提到的靶点和药物外，一个暴露于胃和胃食管结合部腺癌（GEJ）表面，极具治疗潜力的靶点——CLDN18.2，也是胃癌患者务必知晓的。特别是随着全球首款 CLDN18.2 靶向药佐贝妥昔单抗（Zolbetuximab）震撼上市之后，更是使得CLDN18.2这一明星靶点再度引起广泛关注。 一、胃癌患者必须知道的明星靶点——CLDN18.2 CLDN是体内上皮细胞粘附所必需的，对屏障功能至关重要，它是一个至少包含27种跨膜蛋白的家族，在信号转导和肿瘤发生中发挥作用，如肿瘤细胞的生长和存活、肿瘤增殖、转移和肿瘤组织中的癌症干细胞等。其中，1998年发现的CLDN18.2蛋白是在正常和恶性胃粘膜上皮细胞中，表达的紧密连接蛋白中的一种分子。 在正常胃黏膜上皮中，CLDN18.2（Claudin18.2）表达严格局限于除胃干细胞区以外的胃黏膜分化上皮细胞。但在胃癌、胃食管结合部腺癌（GEJ）、食管癌、结肠癌、胰腺癌、乳腺癌、肝癌、卵巢癌、非小细胞肺癌等某些恶性肿瘤中，它也普遍表达。 值得注意的是，在正常组织中，组织粘附复合物内的CLDN18.2表位完全无法接近；然而，在恶性转化时，细胞粘附被破坏，CLDN18.2表位暴露在胃和GEJ（G/GEJ）腺癌细胞表面，使其成为一个有希望的靶点，尤其在消化系统肿瘤中（如胃癌、胃食管结合部癌、食管癌和胰腺癌）异常过表达，比如，在胃癌或胃食管结合部癌中，在高达70%-80%的胃癌或胃食管结合部癌患者，以及60%的胰腺癌患者可检测到Claudin 18.2的高度表达。因此确诊胃癌、食管癌、胰腺癌等消化道肿瘤后，除了检测HER2、PD-L、MET等靶点外，还要再检测下是否存在Claudin 18.2。 ▼晚期胃癌CLDN18.2靶向治疗的发展 ▲图源“MDPI”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 二、针对CLDN18.2靶点的抗癌新药及新技术 截至 2023 年 8 月，Clinical Trials.gov (NCT) 网站上，共有 43 项正在进行的针对CLDN18.2的临床试验，包括CAR-T疗法、ADC（抗体-药物偶联物）药物、双特异性抗体 (BsAbs)等。 （一）全球首款CLDN18.2靶向疗法-佐贝妥昔单抗震撼上市，显著延长生存期！ 2024年3月26日，佐贝妥昔单抗（Zolbetuximab，VYLOY，代号IMAB362）获日本厚生劳动省(MHLW)批准上市，用于CLDN18.2阳性、不可切除、晚期或复发性胃癌的治疗，它是首个同时也是目前唯一获得世界监管机构批准的CLDN18.2靶向疗法。 全球知名期刊《自然医学》报道了“ 佐贝妥昔单抗的Ⅲ期GLOW临床研究（NCT03653507） ”的惊艳数据，本次共入组507例既往未接受过治疗的CLDN18.2阳性、HER2阴性的局部晚期或转移性胃癌或胃食管交界癌患者，将其分为两组，即佐贝妥昔单抗组（接受佐贝妥昔单抗+CAPOX治疗）、安慰剂组（接受安慰剂+CAPOX治疗）。结果显示如下： 1、 中位无进展生存期（PFS） ： 接受佐贝妥昔单抗治疗的患者，PFS显著延长 ，中位PFS分别为 8.21个月 （佐贝妥昔单抗组） vs 6.80个月 （安慰剂组）（详见下图）。12个月PFS率分别为 35% （佐贝妥昔单抗组） vs 19% （安慰剂组）；24个月PFS率分别为 14% （佐贝妥昔单抗组） vs 7% （安慰剂组）。 ▲图源“nature”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 2、 中位总生存期（OS） ： 佐贝妥昔单抗组患者的OS在统计学上显著延长 ，中位OS分别为 14.39个月 （佐贝妥昔单抗组） vs 12.16个月 （安慰剂组）（详见下图）。12个月的OS率分别为 58% （佐贝妥昔单抗组） vs 51% （安慰剂组）；24个月的OS率分别为 29% （佐贝妥昔单抗组） vs 17% （安慰剂组）。 ▲图源“nature”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 （二）北肿公布CT041第1阶段试验最终结果：疾病控制率高达96.1% CT041（satri-cel）是一款靶向Claudin18.2（CLDN18.2）的自体CAR-T细胞（嵌合抗原受体T细胞）。近日，北肿研发团队公布了关于“ CT041-CG4006的1期临床试验（NCT03874897）的最终结果 ”。 本次共入组98例CLDN18.2阳性晚期胃肠道肿瘤患者，入组接受不同剂量的CT041（即CAR-T细胞）回输治疗，治疗剂量分别为2.5×108（89例患者）、3.75×108（6例患者）、5.0×108（3例患者），中位随访时间为32.4个月。 结果显示：在全部98例患者中，91.8%（90例）基线有靶病灶，治疗后70例患者出现不同程度的肿瘤缩小， 总缓解率为38.8% ， 疾病控制率（DCR）高达91.8% ， 中位总生存期（OS）长达8.8个月 （95% CI：7.1,10.2）， 中位无进展生存期（PFS）为4.4个月 （95% CI：3.7,6.6）。 ▼CT041治疗后疗效的泳道图 ▲图源“nature medicine”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 三、更多在研的Claudin18.2的新药/新技术 除了上面提到的佐贝妥昔单抗、CT041（CAR-T）外，目前国内外还有多款在研的针对Claudin18.2的新药获新疗法，包括但不限于以下几类： 1、TQB2103 TQB2103是中国生物制药自主研发的针对CLDN18.2的ADC药物。TQB2103与表面表达CLDN18.2的肿瘤细胞结合后，被内化并运输到溶酶体，在溶酶体中释放细胞毒性有效载荷，从而通过脱氧核糖核酸（DNA）损伤选择性杀死肿瘤细胞。通过旁观者效应，它可以杀死相邻的阴性肿瘤细胞。目前正在进行一项I期临床试验，评估TQB2103注射液对晚期癌症患者的耐受性、安全性和有效性（NCT05867563）。 2、ASKB589 ASKB589是一种人源化抗CLDN18.2IgG1mAb，具有高亲和力和增强的ADCC。已公布ASKB589对晚期实体瘤患者的I/II期剂量递增和扩展研究的初步结果（NCT04632108）。本研究评估了ASKB589单药治疗（A部分）和与化疗联合治疗（B部分）的最大耐受剂量（MTD）、安全性和耐受性、PK、PD和疗效。在A部分9名可评估患者（≥10mg/kgASKB589）中，5名患者（45%）的肿瘤缩小，而2名患者获得部分缓解（PR）。此外，6名患者病情稳定（SD），疾病控制率（DCR）高达89%。在B部分12名可评估患者（≥6mg/kgASKB589）中，所有患者的肿瘤均缩小，9名患者获得PR，客观缓解率（ORR）高达75%，DCR疾病控制率（DCR）更是达到100%。综上，ASKB589显示出高达20mg/kg剂量的可控安全性和良好的抗肿瘤活性。 3、IMC002 IMC002是一种基于抗CLDN18.2VHH抗体的自体CAR-T细胞疗法，具有高特异性，与CLDN18.2无交叉反应。一项1期、开放标签、多中心、剂量递增研究旨在评估IMC002对CLDN18.2阳性胃肠道肿瘤患者的安全性、可行性和初步疗效，包括但不限于晚期胃癌、食管胃交界处腺癌和晚期胰腺癌（NCT05946226）。约9-18名CLDN18.2阳性晚期胃肠道肿瘤患者将依次纳入三个剂量递增队列，以评估自体IMC002治疗的安全性和可行性。患者入组后将接受白细胞分离术和IMC002产品制备。如果病情迅速进展，患者可按照研究者的决定接受桥接疗法。在接受环磷酰胺、氟达拉滨和白蛋白紫杉醇淋巴细胞清除治疗后，患者将被分配到三个剂量递增组接受CAR-T细胞治疗。 4、SYSA1801 SYSA1801是一种靶向CLDN18.2的ADC，可递送微管抑制剂MMAE。临床前研究表明，SYSA1801在表达CLDN18.2的胃癌、胰腺癌和肺癌的多种细胞系和PDX中表现出显著的体内和体外抗肿瘤活性。I期试验纳入的33名耐药复发性实体瘤患者中，26名（78.8%）患有胃癌。在第I部分中，患者接受了高达3mg/kg的SYSA1801。在17名可评估的胃癌患者中，ORR为47.1%（8名患者为PR），DCR为64.7%（3名患者为SD）。SYSA1801的最佳剂量正在探索中（NCT05009966）。 5、LM-302 LM-302（TPX-4589）是一种针对CLDN18.2而开发的新型ADC，由重组人源化抗CLDN18.2IgG1mAb（LM-102）与细胞毒性有效载荷MMAE偶联而成。根据临床前数据，在高表达和低表达的胃和胰腺CLDN18.2肿瘤模型中，LM-302体外有效抑制肿瘤细胞增殖，体内减少肿瘤生长。此外，在GC肿瘤模型中，与佐贝妥昔单抗相比，LM-302表现出更好的内化和疗效。目前，针对CLDN18.2阳性晚期实体瘤患者的LM-302的I期研究正在评估中（NCT05001516）。此外，目前正在进行一项I/II期、开放标签、多中心研究，旨在评估LM-302联合特瑞普利单抗（抗PD-1抗体）对晚期实体瘤患者的安全性和耐受性（NCT05188664）。 四、小编寄语 CLDN18.2作为胃癌治疗领域的新兴靶点，为胃癌患者带来了新的希望。随着研究的不断深入和临床实践的逐步积累，基于CLDN18.2的治疗药物和方案将不断优化和完善。未来，我们有望看到更多高效、低毒的CLDN18.2靶向治疗药物问世，并且在联合治疗模式的探索上取得更大突破，从而显著提高胃癌患者的治疗效果，改善患者的生存质量和预后，为胃癌的攻克迈出坚实的一步。胃癌患者及其家属应该与医生积极沟通，了解CLDN18.2靶点相关知识以及其在治疗方案中的应用可能性，共同参与到胃癌的精准治疗决策过程中，以争取更好的治疗效果和生存机会。 五、参考资料 [1]Inamoto R,et al.Claudin18. 2 in advanced gastric cancer[J]. Cancers, 2023, 15(24): 5742. https://www.mdpi.com/2072-6694/15/24/5742 [2]Shah M A,et al.Zolbetuximab plus CAPOX in CLDN18. 2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial[J]. Nature medicine, 2023, 29(8): 2133-2141. https://www.nature.com/articles/s41591-023-02465-7 [3]Qi C,et al.Claudin18. 2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results[J].Nature Medicine, 2024:1-11. https://www.nature.com/articles/s41591-024-03037-z 本文为全球肿瘤医生网原创，未经授权严禁转载