Head and Neck Neoplasms

SHANGHAI, China, April 07, 2024 (GLOBE NEWSWIRE) -- Shanghai Junshi Biosciences Co., Ltd (“Junshi Biosciences”, HKEX: 1877; SSE: 688180), a leading innovation-driven biopharmaceutical company dedicated to the discovery, development, and commercialization of novel therapies, announced that the National Medical Products Administration (“NMPA”) has approved the supplemental new drug application (“sNDA”) for toripalimab (product code: JS001) in combination with axitinib for the first-line treatment of patients with medium to high risk unresectable or metastatic renal cell carcinoma (“RCC”). This is the first approved immunotherapy for renal carcinoma in China. Renal carcinoma is the third most common malignancy of the urinary system globally, and RCC accounts for 80%~90% of all cases of renal carcinoma. There were approximately 77,000 new cases of and 46,000 deaths due to renal carcinoma in China in 2022. Distant metastasis occurred in about one-third of renal carcinoma patients at initial diagnosis, and in 20%-50% of localized patients after nephrectomy. According to the risk classification of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), the median overall survival (“OS”) of patients with low, medium and high risk metastatic RCC receiving anti-vascular targeted treatment were 35.3, 16.6 and 5.4 months, respectively. Therefore, compared to low-risk patients, the clinical needs for new treatment options are more urgent for patients with medium and high risk advanced RCC. The approval of the sNDA is mainly based on data from the RENOTORCH study (NCT04394975), a multi-center, randomized, open-label, active-controlled Phase 3 clinical study led by principal investigators Professor Jun GUO from Peking University Cancer Hospital and Professor Yiran HUANG from Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The study was conducted across 47 medical centers, and represents the first pivotal Phase 3 clinical study of immunotherapy for patients with advanced RCC in China. A total of 421 randomized patients with medium to high risk unresectable or metastatic RCC were enrolled in the study and randomly assigned in a 1:1 ratio to receive toripalimab in combination with axitinib (n=210) or sunitinib alone (n=211). The primary endpoint is progression free survival (“PFS”) as assessed by the Independent Review Committee (“IRC”), and secondary endpoints include PFS as assessed by investigators, objective response rate (“ORR”) as assessed by IRC or investigators, duration of response (“DoR”), disease control rate (DCR), OS, safety profile, etc. Previously, the study results of RENOTORCH made its debut at the Proffered Paper Session of the European Society for Medical Oncology (ESMO) congress 2023. The full text was simultaneously published in Annals of Oncology, the official journal of ESMO. The study data showed that, based on the assessment results of IRC, compared with sunitinib monotherapy, toripalimab in combination with axitinib for the treatment significantly prolonged the PFS of patients by nearly twofold (median PFS: 18.0 vs. 9.8 months, P=0.0028), and the risk of disease progression or death was reduced by 35% (hazard ratio [HR]=0.65; 95% CI: 0.49, 0.86). In addition, the ORR was higher (56.7% vs. 30.8%, P<0.0001) and the DoR was longer (median DoR: not reached vs 16.7 months; HR=0.61) in the toripalimab group. The OS of the toripalimab group also showed a clear trend of benefit (median OS: not reached vs 26.8 months), and the risk of death was reduced by 39% (HR=0.61; 95%CI: 0.40, 0.92). In terms of safety, toripalimab in combination with axitinib demonstrated a favorable safety and tolerability profile, and no new safety signals were observed. “From a global perspective, targeted therapy in combination with immunotherapy has become the standard treatment approach for advanced RCC,” said Professor Jun GUO from Peking University Cancer Hospital. “However, no such treatments have been approved in China. The approval of toripalimab’s new indications opens a new chapter in combined targeted therapy and immunotherapy in China, and it will transform current clinical practices for advanced RCC and introduce new treatment options for medium to high-risk patients!” “The treatment methods for advanced RCC are limited, especially for medium to high risk patients, who often face suboptimal prognoses,” said Professor Yiran HUANG from Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. “The approval of toripalimab combined with axitinib addresses the gap in first-line immunotherapy for renal cancer in China. Compared to targeted monotherapy, toripalimab combined with targeted therapy will significantly improve patients’ PFS, offering promising prospects for many advanced RCC patients in China.” “Thank you to all medical professionals, patients, and R&D personnel involved in the RENOTORCH study for their contributions,” said Dr. Jianjun ZOU, Global Research and Development President of Junshi Biosciences. “Their dedication has led to a pioneering breakthrough in renal cancer, first of its kind in China! Junshi Biosciences will remain committed to addressing domestic clinical needs and continue investing in research and development to help patients live longer and better!” About Toripalimab Toripalimab is an anti-PD-1 monoclonal antibody developed for its ability to block PD-1 interactions with its ligands, PD-L1 and PD-L2, and for enhanced receptor internalization (endocytosis function). Blocking PD-1 interactions with PD-L1 and PD-L2 promotes the immune system’s ability to attack and kill tumor cells. More than forty company-sponsored toripalimab clinical studies covering more than fifteen indications have been conducted globally by Junshi Biosciences, including in China, the United States, Southeast Asia, and Europe. Ongoing or completed pivotal clinical trials evaluating the safety and efficacy of toripalimab cover a broad range of tumor types, including cancers of the lung, nasopharynx, esophagus, stomach, bladder, breast, liver, kidney, and skin. In China, toripalimab was the first domestic anti-PD-1 monoclonal antibody approved for marketing (approved in China as TUOYI®). Currently, there are eight approved indications for toripalimab in China: unresectable or metastatic melanoma after failure of standard systemic therapy;recurrent or metastatic nasopharyngeal carcinoma (“NPC”) after failure of at least two lines of prior systemic therapy;locally advanced or metastatic urothelial carcinoma that failed platinum-containing chemotherapy or progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy;in combination with cisplatin and gemcitabine as the first-line treatment for patients with locally recurrent or metastatic NPC;in combination with paclitaxel and cisplatin in first-line treatment of patients with unresectable locally advanced/recurrent or distant metastatic esophageal squamous cell carcinoma (“ESCC”);in combination with pemetrexed and platinum as the first-line treatment in EGFR mutation-negative and ALK mutation-negative, unresectable, locally advanced or metastatic non-squamous non-small cell lung cancer (“NSCLC”);in combination with chemotherapy as perioperative treatment and subsequently with monotherapy as adjuvant therapy for the treatment of adult patients with resectable stage IIIA-IIIB NSCLC;in combination with axitinib for the first- line treatment of patients with medium to high risk unresectable or metastatic RCC. The first six indications have been included in the National Reimbursement Drug List (NRDL) (2023 Edition). Toripalimab is the only anti-PD-1 monoclonal antibody included in the NRDL for the treatment of melanoma. In the United States, the U.S. FDA has approved the Biologics License Application for toripalimab in combination with cisplatin and gemcitabine for the first-line treatment of adults with metastatic or recurrent locally advanced NPC, and for toripalimab, as a single agent, for the treatment of adults with recurrent, unresectable, or metastatic NPC with disease progression on or after platinum-containing chemotherapy in October 2023. The FDA has granted toripalimab 2 Breakthrough Therapy designations for the treatment of NPC, 1 Fast Track designation for the treatment of mucosal melanoma, and 5 Orphan Drug designations for the treatment of esophageal cancer, NPC, mucosal melanoma, soft tissue sarcoma, and small cell lung cancer (SCLC). In Europe, marketing authorization applications (MAA) were accepted by the European Medicines Agency (EMA) and the MHRA for 1) toripalimab combined with cisplatin and gemcitabine for the first-line treatment of patients with locally recurrent or metastatic NPC and 2) toripalimab combined with paclitaxel and cisplatin for the first-line treatment of patients with unresectable locally advanced/recurrent or metastatic ESCC, in December 2022 and February 2023. In Australia, the new chemical entity (NCE) application was accepted by the Australia Therapeutic Goods Administration (“TGA”) in November 2023. The TGA has also granted toripalimab an Orphan Drug designation for the treatment of NPC. In Singapore, the NDA application was accepted by the Singapore Health Sciences Authority (“HSA”) in January 2024. The HSA has also granted priority review designation for the NDA. About Junshi Biosciences Founded in December 2012, Junshi Biosciences (HKEX: 1877; SSE: 688180) is an innovation-driven biopharmaceutical company dedicated to the discovery, development and commercialization of innovative therapeutics. The company has established a diversified R&D pipeline comprising over 50 drug candidates, with five therapeutic focus areas covering cancer, autoimmune, metabolic, neurological, and infectious diseases. Four of the company’s innovations have already reached the Chinese or international markets, one of which is toripalimab, China’s first domestically produced and independently developed anti-PD-1 monoclonal antibody, approved in China and the US. Additionally, more than 30 drugs are currently in clinical development. During the COVID-19 pandemic, Junshi Biosciences actively shouldered the social responsibilities of a Chinese pharmaceutical company through its involvement in developing etesevimab, MINDEWEI®, and other novel therapies for the prevention and treatment of COVID-19. With a mission of “providing patients with world-class, trustworthy, affordable, and innovative drugs”, Junshi Biosciences is “In China, For Global.” At present, the company boasts approximately 3,000 employees in the United States (San Francisco and Maryland) and China (Shanghai, Suzhou, Beijing, Guangzhou, etc.). For more information, please visit: http://junshipharma.com. Junshi Biosciences Contact InformationIR Team:Junshi Biosciencesinfo@junshipharma.com+ 86 021-6105 8800 PR Team:Junshi BiosciencesZhi Lizhi_li@junshipharma.com+ 86 021-6105 8800

本文为转化医学网原创，转载请注明出处 作者：Sophia 导读： 在可切除的食管鳞状细胞癌 （ESCC） 中，卡瑞利珠单抗联合化疗和阿帕替尼随后微创食管切除术的疗效尚不清楚。我们的目标是填补这一知识空白。 2024年4月5日，浙江大学医学院吴明联合Hong Shen共同在《EClinicalMedicine》（IF：15.1）上发表题为“Camrelizumab, chemotherapy and apatinib in the neoadjuvant treatment of resectable oesophageal squamous cell carcinoma: a single-arm phase 2 trial”的研究论文， 研究结果为卡瑞利珠单抗、化疗和阿帕替尼在局部晚期胚胎细胞癌新辅助治疗中的应用提供了临床证据，具有良好的抗肿瘤活性和可接受的安全性。 https://www-thelancet-com.libproxy1.nus.edu.sg/journals/eclinm/article/PIIS2589-5370(24)00158-5/fulltext#%20 研究背景 01 食管癌（EC）是全球第七大常见癌症，也是全球癌症相关死亡的第六大原因。我国是EC高发国家，主要病理类型为食管鳞状细胞癌（ESCC）。中国ESCC的发病率和死亡率均约占全球年发病率的50%。尽管过去几十年来已经使用了手术、放疗、化疗和其他治疗等多模式治疗，但 ESCC 患者的生存率仍然相对较低。 由于早期ESCC的临床症状不明显，大多数ESCC患者被诊断为晚期，这导致这些患者的生存率低。 对于诊断为可切除 ESCC 的患者，手术是主要的治疗方法。然而，直接手术通常对局部晚期 ESCC 患者无效。当单独进行手术时，外科医生很难实现 R0 切除，这会导致术后肿瘤早期复发，随后生存率低。因此，有效的围手术期新辅助治疗对于降低术后复发风险、提高术后生存率是必要的。 理想的围手术期新辅助治疗不应增加术后并发症，严重不良事件很少。 免疫疗法已证明对晚期食管鳞状细胞癌 （ESCC） 具有抗肿瘤活性的疗效。免疫治疗联合化疗和抗血管生成在晚期 ESCC 中具有潜在的协同作用。卡瑞利珠单抗联合化疗和阿帕替尼作为一线治疗，在晚期胚胎细胞癌患者中具有良好的抗肿瘤活性和可控的安全性。对于诊断为可切除 ESCC 的患者，手术是主要的治疗方法。然而， 卡瑞利珠单抗联合化疗和阿帕替尼随后微创食管切除术对这些患者的疗效证据仍然有限。 研究结果 02 2020 年 11 月 23 日至 2022 年 12 月 31 日期间入组了 42 名患者。疾 病控制率为100.0%（95%CI，91.6-100%），客观缓解率为83.3%（95%CI，68.6-93.0%）。 6 例（14.3%）患者发生 3 级不良事件。最常见的是白细胞计数减少（31.0%）、脱发（81.0%）、虚弱（38.1%）和反应性皮肤毛细血管内皮增生（35.7%）。41例患者接受微创食管切除术;所有 41 例患者均实现了 R0 切除，18 例 （43.9%，95% CI，28.5–60.3%） 患者实现了 PCR。 中位随访时间为23个月，2年生存率为85.9%。PCR组和NPCR组的T细胞亚群对新辅助治疗的反应一致。 相比之下，一些自然杀伤 （NK） 细胞 （NK-C03、NK-C11）、B 细胞 （B-C06） 和单核细胞 （M-C05） 在新辅助治疗前表现出 PCR 组和 NPCR 组之间的显著差异。新辅助治疗后，PCR组和NPCR组M-C06差异有统计学意义。NK-C12和B-C15在新辅助治疗前后均有显著差异。 在这项单臂研究中， 卡瑞利珠单抗、化疗和阿帕替尼在局部晚期 ESCC 新辅助治疗中的应用显示出良好的抗肿瘤活性和可接受的安全性。在新辅助治疗中，NK细胞、B细胞和单核细胞亚群对免疫治疗反应性的预测能力高于T细胞亚群。 需要更长的随访时间以评估生存结果，并需要进行 3 期随机试验以进一步评估拟议的治疗方法。 参考资料： https://www-thelancet-com.libproxy1.nus.edu.sg/journals/eclinm/article/PIIS2589-5370(24)00158-5/fulltext#%20 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情

正文共2141字 共3图预计阅读时间：7分钟ADC领域会不断刷新你的认知，这是必然的。高达430亿美元的并购，还有上周刚刚刷屏的第四家被收购的中国biotech，当你以为ADC领域的热度总该已经到达巅峰时，层出不穷的新消息却总会给你新的惊喜。那如何避开繁杂的理论知识去认识ADC呢？DS-8201或许能提供点儿帮助。DS-8201：最畅销的ADC2023年，Enhertu（DS-8201，德曲妥珠单抗）以高达25亿美元的年销售额成功击败Kadcyla（T-DM1，恩美曲妥珠单抗）成为年度最畅销的ADC药物。作为拥有者之一，2023年阿斯利康通过Enhertu获得超过12亿美元的收入。阿斯利康与DS-8201的缘分开始于五年前的一场交易。2019年4月，面临收入下滑风险的阿斯利康罕见出手，以总计69亿美元（13.5亿美元首付款+后续的研发注册和商业里程金）的高价，与第一三共针对抗体偶联药物DS-8201签订全球开发和商业化合作协议，协议指出双方将共同负责DS-8201在全球（日本除外）的开发和商业化。彼时的DS-8201虽未上市，但已初显潜力。对于ADC的结构，相信大部分人都已经很熟悉了，即抗体（antibody）+连接子（linker）+有效载荷（payload）。DS-8201的抗体部分采用了曲妥珠单抗（靶向HER2的单克隆抗体），有效载荷部分为一种强效的细胞毒素——拓扑异构酶I抑制剂Dxd（deruxtecan），连接子则是一种可裂解的四肽。值得注意的一点是，Dxd不仅能按常规程序消灭直接结合的癌细胞，还能透过细胞间隙作用于附近HER2阴性但侵袭性强的肿瘤细胞，产生“旁观者效应”，消除低表达HER2但仍具威胁的癌细胞。同时，DS-8201拥有较高的载药比（药物与抗体比约为8:1），这也进一步保证了其后续表现出的好疗效。被阿斯利康看中时，DS-8201用于治疗HER2阳性乳腺癌/肺癌以及HER2低表达乳腺癌的临床试验正在进行中。且当时已有数据可证明DS-8201对HER2低表达，甚至只有微微阳性的患者的有效性。这意味着，DS-8201将有机会覆盖更大的乳腺癌人群，可从20%拓展到了70-80%甚至更大。DS-8201也早就获得了FDA的初步认可。2017年FDA授予DS-8201突破性药物资格，用于已经接受HER 2 单抗治疗且在接受T-DM1（Kadcyla）治疗后病情出现进展的HER2阳性、局部晚期/转移性乳腺癌患者。上文提到的T-DM1来自罗氏，于2013年被FDA批准上市，用于治疗HER2阳性转移性乳腺癌。T-DM1是全球第一款靶向HER2的ADC药物，属于第二代ADC药物（第一代ADC药物中比较有代表性的是辉瑞的Mylotarg），曾长期占据最畅销ADC的位子。可以说，DS-8201一开始瞄准的就是最强ADC的位子。再说回2023年销售额的赶超，似乎也并不值得意外。同时，由于受到DS-8201影响，Kadcyla2023年销售额下跌到19.66亿美元，根据现在正在进行的临床试验来看，未来上升空间有限。DS-8201：新增长点来了就在昨天，阿斯利康/第一三共宣布了一个震惊肿瘤领域的消息，：DS-8201新适应症获加速批准，以后只要是HER2阳性的实体瘤患者，无论什么癌种，都能用DS-8201了。新闻稿原文的表述是：DS-8201已获FDA加速批准，用于治疗既往接受过全身治疗且没有令人满意的替代治疗方案的不可切除或转移性HER2阳性（IHC 3+）实体瘤成人患者。图片来源：阿斯利康官网这是ADC领域的一个大突破，首款不限癌种的ADC诞生了。新适应症的获批将为DS-8201销售额再创新高提供动能，这对于现如今的DS-8201很重要。2019年12月，DS-8201被FDA批准上市，随后相继在日本、欧盟等30多个地区的准入成功。2023年2月，DS-8201又被NMPA批准上市，用于治疗HER2阳性乳腺癌。随着准入地区和适应症的不断扩大，DS8201的销售额也一直稳步增长。但是，根据阿斯利康2023年报，DS-8201在美国地区销售额的增长幅度依然放缓，同比114%的销售增幅主要由欧洲和其他地区贡献。要强调的是，在DS-8201全球市场中，美国地区的销售额占比超过一半。再者欧洲和其他地区能在2023年有明显增幅，依靠的是准入初期放量或新适应症扩展，难以保证后续还能继续保持同样的增长幅度。图片来源：阿斯利康及第一三共官网所以，此次新适应的开辟可谓是雪中送炭，正解燃眉之急（略微夸张得讲）。根据此次发布的新闻稿可知，此次批准基于DESTINY-PanTumor02、DESTINY-Lung01和DESTINY-CRC02三项研究的积极结果，完全批准取决于验证性试验中临床获益的验证和描述。在此之前，DS8201共获批6个适应症，覆盖了HER2阳性/HER2低表达的乳腺癌、晚期胃癌、非小细胞肺癌等。图片来源：第一三共官网新适应症获批后，DS-8201覆盖的癌种将扩大到胆道癌、膀胱癌、宫颈癌、子宫内膜癌、卵巢癌、胰腺癌等（简单举例，并不是所有）。这将ADC药物的应用范围拉到了一个新高度，也让人不仅发问是不是只要靶点本身够强，再用ADC进行加持，就能有无限可能。这里有必要简单介绍一下HER2——ADC领域最热门的靶点。HER2，英文全称为Human Epidermal Growth Factor Receptor 2，即人表皮生长因子受体2，是一种位于细胞膜上的酪氨酸激酶受体蛋白，属于ErbB/HER家族成员之一，其他成员包括HER1（EGFR/erbB1）、HER3（erbB3）和HER4（erbB4）。HER2一般在正常情况下表达低或不表达，但在多种恶性肿瘤中高表达。有文献报道，HER2高表达在乳腺癌检出率约11-25%，胃癌检出率约7-34%，食管和胃食管结合部癌检出率约12-14%，胆管癌检出率约12.8%，结直肠癌检出率约1.6-5%。同样在多种肿瘤中高表达的还有Claudin18.2（CLDN18.2）。最初，CLDN18.2 蛋白仅被发现高表达于多种胃癌组织。但随后有研究表明，CLDN18.2 也能在乳腺癌、结肠癌、肝癌、头颈癌，以及肺癌等多种原发恶性肿瘤中异常激活和过度表达。目前，信达生物、康诺亚/阿斯利康的CLDN18.2 ADC均已进入III期临床阶段。按逻辑进行不成熟推测，是不是一众在研的Claudin18.2 ADC将来也有机会复刻类似DS-8201今日的成功。小结DS-8201的喜，对于竞争对手来讲就是无尽的忧。同为HER2 ADC，除了经常被拉出来比较的罗氏TDM-1，荣昌生物的维迪西妥单抗也早在2021年就获NMPA批准上市。除此之外，恒瑞医药、复星医药及石药集团等一众国内企业研发的HER2 ADC也已经在路上。如今DS-8201展现出的后劲或许已影响到不少还在研HER2 ADC药物的未来。参考资料1.各公司官网2.Min Yan , Maria Schwaederle, David Arguello,et al. HER2 expression status in diverse cancers: review of results from 37,992 patients[J]. Cancer Metastasis Rev,2015 Mar;34(1):157-64.3.其他公开资料封面图来源：PIXABAY版权声明/免责声明本文为团队原创文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn131亿美元！强生收购又一家心血管器械巨头，3年300亿美元收购，打算重当器械一哥？【药王启示录】K药、司美格鲁肽的故事 | 药时代视频荟萃中美关系能否扑灭ADC投资热潮？点击阅读原文，了解更多！