Comparing Oral Drug Dosing Strategies in Older Patients With Metastatic Breast Cancer to Maximize Tolerance and Reduce Discontinuation: The CDK4/6 Inhibitor Dosing Knowledge (CDK) Study

The purpose of this study is to generate evidence on an alternative dosing strategy for CDK4/6 inhibitors to help more patients with MBC (age ≥ 65 years) tolerate side effects and stay on treatment longer, to derive the most clinical benefit from these drugs.
The primary objective of the CDK Study is to compare TTD on the approved dosing for palbociclib (125 mg orally daily on days 1-21 of 28-day cycle) or ribociclib (600 mg orally daily on days 1-21 of 28-day cycle) vs. TTD using titrated dosing approach with the same schedule but starting at a lower dose of palbociclib (100 mg or 75 mg) or ribociclib (400 mg or 200 mg) and escalating the dose if well-tolerated in combination with provider/patient choice endocrine therapy (AI or fulvestrant) in patients age 65 or older with HR+/HER2- MBC. The secondary and exploratory objectives will generate evidence needed to personalize treatment decisions by comparing patient-centric secondary outcomes and evaluating baseline factors.
Together with their treating physician, participants will choose the CDK4/6 inhibitor (palbociclib or ribociclib) and which endocrine therapy (aromatase inhibitor or fulvestrant) of their choice but will be randomized to either Arm 1 (indicated dosing) or Arm 2 (titrated dosing).

开始日期2024-10-28

申办/合作机构

American Society of Clinical Oncology, Inc.

[+1]

NCT05843253 / Not yet recruiting临床2期IIT

PhaseII Study of Ribociclib and Everolimus Following Radiotherapy in Pediatric and Young Adult Patients Newly Diagnosed With HGG Including DIPG, Which Harbor Alterations of the Cell Cycle and/or PI3K/mTOR Pathways

The goal of this study is to determine the efficacy of the study drugs ribociclib and everolimus to treat pediatric and young adult patients newly diagnosed with a high-grade glioma (HGG), including DIPG, that have genetic changes in pathways (cell cycle, PI3K/mTOR) that these drugs target.
The main question the study aims to answer is whether the combination of ribociclib and everolimus can prolong the life of patients diagnosed with HGG, including DIPG.

开始日期2024-06-28

申办/合作机构

Nationwide Children's Hospital

[+1]

NCT06409390 / Recruiting早期临床1期IIT

A Pilot Study of Sequential ("First Strike, Second Strike") Therapies, Modeled on Evolutionary Dynamics of Anthropocene Extinctions, for Hormone Positive Metastatic Breast Cancer

The purpose of the study is to test a treatment strategy with currently approved drugs to see if it is practical to administer the available drugs in a new way that researchers hope could be more effective in treating metastatic breast cancer.

开始日期2024-04-26

申办/合作机构

H. Lee Moffitt Cancer Center & Research Institute, Inc.

100 项与琥珀酸瑞波西利相关的临床结果

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100 项与琥珀酸瑞波西利相关的转化医学

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100 项与琥珀酸瑞波西利相关的专利（医药）

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660

项与琥珀酸瑞波西利相关的文献（医药）

2024-03-01·Journal of evidence-based medicine

First‐line CDK4/6 inhibitor‐based combinations for HR+/HER2– advanced breast cancer: A Bayesian network meta‐analysis

Article

作者: Zhou, Yunxiang ; Zhang, Kun ; Lu, Wei ; Guo, Xianan ; Chen, Yiding ; Wu, Shijie ; Zhong, Xi ; Shen, Lu ; Chen, Huihui

Abstract:

Background:

International guidelines recommend cyclin‐dependent kinase 4/6 inhibitor (CDK4/6i)‐based first‐line therapy for hormone receptor‐positive, human epidermal growth factor receptor 2‐negative (HR+/HER2−) advanced breast cancer (ABC). However, direct drug comparisons are lacking. We aimed to identify the most effective and safe therapy through network meta‐analysis (NMA).

Methods:

We searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and OpenGrey up to September 30, 2023. Eligible studies included randomized controlled trials (RCTs) assessing endocrine therapy alone or in combination with CDK4/6i as first‐line endocrine treatment for HR+/HER2− ABC patients. The hazard ratios for progression‐free survival (PFS) and overall survival (OS) and relative risks for objective response rate and adverse events (AEs) were available in selected trials. We performed a Bayesian NMA following PRISMA guidelines.

Results:

Thirteen RCTs, involving 10 treatments, were included. Most studies were at low risk of bias. Regarding PFS, ribociclib+fulvestrant ranked first with a surface under the cumulative ranking curve (SUCRA) of 85.0%, followed by dalpiciclib+nonsteroidal aromatase inhibitor (NSAI) (SUCRA = 78.9%). Considering OS, the top three ranked treatments were ribociclib+fulvestrant (SUCRA = 94.1%), abemaciclib+NSAI (SUCRA = 69.9%), and ribociclib+NSAI (SUCRA = 68.5%). Out of four CDK4/6is, ribociclib minimized the grade 3/4 AEs, while dalpiciclib demonstrated the worst safety. Publication bias could not be ignored in our analyses, and the certainty of evidence was downgraded primarily due to imprecision.

Conclusions:

Ribociclib+fulvestrant probably represents the best option in a first‐line setting. When combined with NSAI, dalpiciclib likely showed the best efficacy but the worst safety. Abemaciclib+NSAI and ribociclib+NSAI could also be promising treatments, while palbociclib presented inferiority. (PROSPERO Registration No. CRD42022370271)

2024-02-16·Clinical cancer research : an official journal of the American Association for Cancer Research

Intrinsic Subtype and Overall Survival of Patients with Advanced HR+/HER2− Breast Cancer Treated with Ribociclib and ET: Correlative Analysis of MONALEESA-2, -3, -7

Article

作者: O'Shaughnessy, Joyce ; Partridge, Ann H. ; Janni, Wolfgang ; Su, Fei ; Prat, Aleix ; Zarate, Juan Pablo ; Yap, Yoon-Sim ; Carey, Lisa A. ; Cameron, David A. ; Sonke, Gabe S. ; Lteif, Agnes ; André, Fabrice ; Yardley, Denise A. ; Solovieff, Nadia ; Thuerigen, Astrid

Abstract:

Purpose::

The MONALEESA-2, -3, -7 trials demonstrated statistically significant and clinically meaningful progression-free survival and overall survival (OS) benefits with ribociclib plus endocrine therapy (ET) versus ET alone in hormone receptor–positive, HER2-negative (HR+/HER2−) advanced breast cancer (ABC). Understanding the association of intrinsic subtypes with survival outcomes could potentially guide treatment decisions. Here, we evaluated the association of intrinsic subtypes with OS in MONALEESA-2, -3, -7.

Experimental Design::

Tumor samples from MONALEESA-2, -3, -7 underwent PAM50-based subtyping. The relationship between subtypes and OS was assessed using univariable and multivariable Cox proportional hazards models. Multivariable models were adjusted for clinical prognostic factors.

Results::

Overall, 990 tumors (among 2,066 patients) from ribociclib (n = 580) and placebo (n = 410) arms were profiled. Subtype distribution was luminal A, 54.5%; luminal B, 28.0%; HER2-enriched (HER2E) 14.6%; and basal-like, 2.8%; and was consistent across treatment arms. The luminal A subtype had the best OS outcomes in both arms, while basal-like had the worst. Patients with HER2E (HR, 0.60; P = 0.018), luminal B (HR, 0.69; P = 0.023), and luminal A (HR, 0.75; P = 0.021) subtypes derived OS benefit with ribociclib. Patients with basal-like subtype did not derive benefit from ribociclib (HR, 1.92; P = 0.137); however, patient numbers were small (n = 28).

Conclusions::

The prognostic value of intrinsic subtypes for OS was confirmed in this pooled analysis of the MONALEESA trials (largest dataset in HR+/HER2− ABC). While basal-like subtype did not benefit, a consistent OS benefit was observed with ribociclib added to ET across luminal and HER2E subtypes.

2024-02-01·European journal of cancer (Oxford, England : 1990)

Efficacy, safety, and prognosis prediction in patients treated with ribociclib in combination with letrozole: Final results of phase 3b RIBECCA study in hormone receptor positive, human epidermal growth factor receptor-2 negative, locally advanced or metastatic breast cancer

Article

作者: Hartkopf, Andreas ; Kurbacher, Christian ; Krabisch, Petra ; Fuchs, Roswitha ; Nusch, Arnd ; Heinrich, Bernhard J ; Huober, Jens ; Kuemmel, Sherko ; Voges, Claudia ; Brucker, Sara ; Janni, Wolfgang ; Fehm, Tanja ; Fasching, Peter A ; Lüftner, Diana ; Reinisch, Mattea ; Kreuzeder, Julia ; Quiering, Claudia ; Decker, Thomas ; Tesch, Hans ; Schneeweiss, Andreas ; Schuler, Martin

BACKGROUND:

In MONALEESA-2, addition of ribociclib to letrozole resulted in significantly longer progression-free survival (PFS) in postmenopausal women with HR+HER2- advanced breast cancer (ABC). RIBociclib for the treatment of advanCed breast CAncer (RIBECCA) study investigated ribociclib plus letrozole in a patient population reflecting routine clinical practice.

PATIENTS AND METHODS:

In this multicenter, open-label, single-arm, phase 3b study, patients with HR+HER2- ABC not amenable to curative therapy and ECOG performance status ≤ 2 received ribociclib plus letrozole (cohort A: postmenopausal women and men in first-line; cohort B: pre-/perimenopausal women in first-line [B1], patients pretreated for advanced disease [B2]). The primary endpoint was clinical benefit rate (CBR) by week 24; secondary endpoints included overall response rate (ORR), PFS, overall survival (OS), and safety. Association of patient and tumor characteristics with PFS was analyzed by multivariable Cox regression analysis.

RESULTS:

Overall, 487 patients were evaluable for efficacy, 502 for safety. By week 24, CBR was 60.8 % (95 % CI, 56.3-65.1), ORR was 19.3 % (95 % CI, 15.9-23.1). Median PFS was 21.8 months (95 % CI, 13.9-25.3) in first-line postmenopausal patients and 11.0 months (95 % CI, 8.2-16.4) in premenopausal and pretreated patients. Median OS was not reached. Higher baseline ECOG performance status, higher histological grade, and negative progesterone receptor status showed an unfavorable effect on PFS. Most common adverse events were neutropenia (50.0 %), nausea (42.0 %), and fatigue (39.2 %).

CONCLUSION:

In this broad population of patients with HR+HER2- ABC, efficacy and safety results of ribociclib plus letrozole were similar to those observed in pivotal trials.

437

项与琥珀酸瑞波西利相关的新闻（医药）

2024-06-28

·FiercePharma

Pfizer poaches Novartis exec to succeed retiring Suneet Varma as oncology commercial chief

Pfizer has appointed Novartis' U.S. oncology head Tina Deignan, Ph.D., as its own oncology commercial president. Pfizer has hired a new oncology commercialization leader to help the business reach its goal of marketing eight blockbuster drugs by 2030. Suneet Varma, currently the commercial president of Pfizer’s oncology unit, has decided to retire after 15 years with the pharma giant. Pfizer’s chief oncology officer, Chris Boshoff, M.D., Ph.D., announced the move Friday on LinkedIn. Filing Varma’s position will be Tina Deignan, Ph.D., who was most recently a senior VP leading Novartis’ U.S. oncology business. In between her latest two-year stint and a prior seven-year stop at Novartis, Deignan worked for 15 years at Bristol Myers Squibb, spending much of that time in the company's oncology division. At BMS, Deignan led “the launch of iconic cancer immunotherapy indications,” Boshoff said in the LinkedIn post. Deignan will officially start this fall, and Varma will stay with Pfizer until early 2025 to ensure a smooth transition, according to Boshoff. Rodney Gillespie, who had been Novartis’ international oncology therapeutic area head, has taken on the U.S. oncology chief role, a company spokesperson told Fierce Pharma. Varma joined Pfizer through the Wyeth acquisition in 2009, originally in a consumer health capacity. In 2022, he was reassigned from Pfizer’s rare disease department to serve as global oncology and U.S. president. Then, as part of an organizational overhaul in late 2023 that made oncology a separate unit within Pfizer, Boshoff became the leader of that franchise, with Varma serving as the unit's commercial chief. The reorg that elevated the oncology group at Pfizer was triggered by the company’s $43 billion acquisition of antibody-drug conjugate specialist Seagen. Since the buyout, Pfizer has unveiled a goal to market eight blockbuster cancer drugs by 2030, compared with five today. During an interview on the sidelines of American Society of Clinical Oncology’s annual meeting earlier this month, Varma said Pfizer expects the blockbusters to come from each of its four focus areas, namely breast, genitourinary, hematology and thoracic cancers. At the time, Varma said Pfizer’s ongoing cost-cutting initiatives wouldn’t affect oncology, as the department had already finished its own post-merger consolidations. He also said Pfizer Oncology’s commercial infrastructure is at the right scale with the ability to take on additional products. Novartis and Pfizer share some overlapping business segments in oncology. One of the imminent tasks for Deignan includes managing the decline of the CDK4/6 inhibitor Ibrance, an in-class competitor to Novartis’ Kisqali. Ibrance has been losing market share after several negative phase 3 readouts, but, as of 2023, it was still Pfizer’s largest oncology asset with $4.75 billion in annual sales. By comparison, Kisqali saw sales jump 69% last year to $2.08 billion. In addition, Pfizer’s Braftovi-Mektovi duo is a direct rival to Novartis’ Tafinlar-Mekinist combo in the BRAF-MEK field, with the Novartis regimen clearly ahead in terms of sales. There’s also Pfizer’s Astellas-partnered Xtandi, which, like Novartis’ radioligand therapy Pluvicto, plays in the prostate cancer arena. The two drugs could clash soon, as Novartis is readying an FDA filing for Pluvicto in PSMA-positive, metastatic castration-resistant prostate cancer. The transition also comes amid the high-profile rollout of the Astellas-partnered ADC Padcev, used in combination with Merck’s Keytruda, in first-line bladder cancer. There, Deignan will lead the charge against an Opdivo-chemo regimen by her old employer, BMS, and another immunotherapy by Merck KGaA. Deignan is leaving her U.S. oncology job at Novartis as the Swiss pharma puts an increased emphasis on the U.S. market. Besides Pluvicto’s potential expansion into the pre-chemo prostate cancer setting, the company is also awaiting an FDA decision for Kisqali as a post-surgery adjuvant therapy in HR-positive, HER2-negative breast cancer.

高管变更临床3期并购ASCO会议

2024-06-23

·药渡

欧洲杯来了！哪些国家最有望夺得“最佳药物管道”奖杯？

来源：药渡撰文：Maskey 编辑：哦呼欧洲杯激战正酣，各国球队为了荣誉和胜利而奋力拼搏。但如果换个角度，设想一下，若是让这些参加欧洲杯的国家在“最佳药物管道”这一特殊领域展开角逐，谁又将脱颖而出，问鼎桂冠呢？目前，世界各地的制药公司都在竞相开发最具创新性和最有效的常见人类疾病治疗方法。他们进行临床前研究和临床试验，希望他们的治疗方法能得到监管机构的批准。监管机构会为可能治疗严重疾病的新型试验药物授予突破性疗法认定和快速通道认定。近年来，越来越多的新型治疗方法（如细胞和基因疗法、单克隆抗体和抗体-药物偶联物）已获得监管机构的批准[1]。因此，制药公司正在加大对这些创新疗法的开发投入。一些最大的制药公司位于欧洲，所有这些公司都在建立庞大的创新疗法药物管线。图1.近年来美国食品药品监督管理局(FDA)批准的新分子实体（NME）和生物制剂的数量【1】图2.获得批准的单克隆抗体百分比【2】德国拜耳是德国领先的制药公司之一。老年性黄斑变性药物阿柏西普、前列腺癌药物达罗他胺、抗凝药物利伐沙班和慢性肾病药物Finerenone是其产品组合中最有价值的药物。该公司正在开发33种新疗法，其中19种疗法正在进行1期临床试验，3种疗法正在进行2期临床试验[3]。该公司正在测试几种创新的重组腺相关病毒 (rAAV) 基因疗法，用于治疗亨廷顿氏病、帕金森氏病和庞贝氏病。另一家德国制药公司勃林格殷格翰正在临床试验中测试40多种药物[4]。该公司已经开发出用于治疗多种疾病的小分子药物、T细胞接合剂和癌症疫苗。该公司的产品组合中包括有效的治疗药物，包括肺纤维化药物尼达尼布和抗糖尿病药物恩格列净。默克集团是另一家德国制药公司，正在开发10多种用于治疗癌症、自身免疫性疾病和疟疾的药物[5]。其药物管线中一些有前景的在研药物包括小分子药物Enpatoran、抗体药物偶联物M9140和免疫检查点抑制剂avelumab。 BioNtech也是一家德国大型生物制药公司，与辉瑞公司成功开发了COVID-19疫苗BNT162b2(Comirnaty)。该公司还在对患有不同类型癌症（如结直肠癌和胰腺导管腺癌）的患者测试癌症疫苗Autogene Cevumeran[6]。BioNTech SE正在临床试验中测试30多种治疗方法，包括mRNA治疗、细胞疗法、基于蛋白质的疗法和小分子免疫调节剂。这些治疗方法旨在治疗癌症和传染病。其管道中最有前途的候选药物之一是单克隆抗体Gotistobart，正在非小细胞肺癌患者中进行测试。该公司开发的其他重要药物包括双特异性抗体Acasunlimab、BNT312/GEN1042和BNT327/PM8002。德国规模较小的生物制药公司也在努力扩大其药物研发线。Ethris开发了一种新型吸入式mRNA治疗药物ETH47，用于治疗呼吸道病毒感染。海德堡制药公司研发线中的一种主要候选药物是用于治疗多发性骨髓瘤的抗体-药物偶联物HDP-101。Affimed开发了用于治疗非小细胞肺癌的双特异性先天细胞接合剂AFM24。Atai Life Sciences研发线中有几种用于治疗抑郁症和焦虑症的药物。法国法国最大的制药公司赛诺菲拥有庞大的药物管线，包括60多种临床阶段治疗药物[7]。该公司正在开发双特异性抗体、疫苗、单克隆抗体、NK细胞接合剂、酶替代疗法和基因疗法。其最畅销的药物是与Regeneron合作开发的单克隆抗体度匹鲁单抗。该药物已被批准用于多种适应症，例如特应性皮炎、嗜酸性食管炎和哮喘。其投资组合中的另一项重要资产是与阿斯利康合作开发的呼吸道合胞病毒 (RSV) 疫苗nirsevimab。其管线中的几种药物，如小分子药物SAR441566、单克隆抗体Amlitelimab和单克隆抗体Frexalimab，都有可能获得监管部门的批准并成为变革性的治疗方法。法国还有几家不太知名的制药公司，包括Genfit、Abivax和Enterome，它们正在研发新的创新疗法。Genfit正在开发治疗胆管癌和高氨血症的新疗法。今年6月，FDA加速批准其药物Elafibranor，用于治疗原发性胆汁性胆管炎。Amolyt Pharma的药物管线包括治疗肢端肥大症和甲状旁腺功能减退症的药物。Enterome正在开发新的基于肽的免疫疗法，用于治疗惰性非霍奇金淋巴瘤和胶质母细胞瘤。Abivax已开发小分子药物obefazimod，用于治疗溃疡性结肠炎和克罗恩病。Antabio正在开发治疗铜绿假单胞菌感染和医院内感染的药物。Ipen的临床阶段管线中有10多种药物，包括治疗偏头痛、阿拉吉耶综合征、多发性骨髓瘤和胆道闭锁的药物[8]。英国英国-瑞典制药公司阿斯利康拥有最大的药物管线之一，拥有超过90种不同的临床阶段治疗药物[9]。该公司正在开发用于治疗癌症、呼吸系统疾病、代谢疾病、肾脏疾病和心血管疾病的新药。它拥有非常强大的肿瘤学产品组合，包括抗体药物偶联物trastuzumab deruxtecan和酪氨酸激酶抑制剂奥希替尼。该公司还通过购买和公司收购在其管线中增加了嵌合抗原受体T细胞(CAR-T)疗法、呼吸道合胞病毒疫苗和2型糖尿病药物。其与第一三共联合开发的抗体药物偶联物Datopotamab deruxtecan可能很快会在美国获得监管部门的批准。葛兰素史克 (GSK) 已开发出60多种用于治疗艾滋病毒、癌症、传染病以及呼吸道和免疫疾病的药物。该公司最近开发的最成功的治疗方法之一是呼吸道合胞病毒疫苗Arexvy，该疫苗已获得FDA批准用于50岁以上的人群[10]。该公司在开发高效疫苗方面有着良好的记录，例如Gardasil、Arexvy和 Shingrix。今年，GSK收购了一家新兴生物制药公司Aiolos Bio，该公司开发了一种新型哮喘药物。 Verona Pharma开发了一种用于治疗慢性阻塞性肺病的药物Ensifentrine，今年可能会获得FDA的批准。Ellipses Pharma正在对2期临床试验中的四种药物进行评估[11]。该公司正在研发不同类别的药物，例如用于治疗癌症的双重抑制剂、纳米颗粒-药物偶联物和选择性雄激素受体调节剂 (SARM)。Evox Therapeutics正在临床前研究中开发外泌体递送的腺相关病毒(AAV) 基因疗法，用于治疗苯丙酮尿症和心血管疾病[12]。瑞士罗氏的研发管线中有70多种药物[13]。该公司开发的转化疗法之一是双特异性单克隆抗体Faricimab，用于治疗糖尿病性黄斑水肿和新生血管性年龄相关性黄斑变性。其他成功获得监管部门批准的重要治疗方法是抗体-药物偶联物polatuzumab vedotin-piiq双特异性单克隆抗体Emicizumab和双特异性抗体glofitamab-gxbm。其阿尔茨海默氏症药物gantenerumab在3期临床试验中未能显示出疗效。该公司已将小分子抑制剂camonsertib和双特异性抗体RG6286等抗癌药物从其管线中移除。罗氏正在优先考虑那些更有可能获得监管机构批准的治疗方法。诺华是全球销售额最大的制药公司之一。其药物研发管线中有超过60种治疗方法[14]。其研发管线包括单克隆抗体、CAR-T疗法、基因疗法、小分子抑制剂、合成小干扰RNA (siRNA) 和其他治疗不同疾病的药物。其产品组合中的重要资产是心力衰竭组合药物Sacubitril/valsartan、多发性硬化症药物 Ofatumumab、乳腺癌药物ribociclib和高脂血症药物inclisiran。其布鲁顿氏酪氨酸激酶(BTK)抑制剂remibrutinib很有可能被批准用于治疗慢性自发性荨麻疹。 ADC Therapeutics正在临床试验中测试大约3种治疗方法[14]。该公司开发了抗体药物偶联物loncastuximab tesirine-lpyl，该药物已获得FDA加速批准，用于治疗大B细胞淋巴瘤。Alentis Therapeutics的研发管线中有大约4种治疗方法，包括抗体药物偶联物和单克隆抗体[15]。图3.销售额最高的制药公司和治疗方法【16】丹麦丹麦制药公司诺和诺德是欧洲最大的制药公司之一。诺和诺德的药物管线包括35多种药物，其中大多数药物正在对患有非酒精性脂肪性肝炎和糖尿病等慢性疾病的患者进行测试[17]。其最成功的药物是用于治疗肥胖症和糖尿病的索马鲁肽。诺和诺德开发了一种每周一次的糖尿病药物胰岛素Icodec，该药物已获准在欧洲使用。Genmab有10多种治疗方法正在临床试验中测试。它与辉瑞联合开发了抗体-药物偶联物tisotumab vedotin，该药物已获准用于治疗宫颈癌。其T细胞结合双特异性抗体epcoritamab也已获准用于治疗弥漫性大B细胞淋巴瘤。比利时比利时生物制药公司Union Chimique Belge (UCB)正在开发用于治疗系统性红斑狼疮和严重纤维肌痛综合征等神经和自身免疫性疾病的药物。其研发管线中有大约10种小分子药物和单克隆抗体[18]。其药物bimekizumab已在美国获批用于治疗斑块状银屑病。荷兰荷兰制药公司Argenx开发了抗体片段efgartigimod，该片段已获批用于治疗全身性重症肌无力。该公司正在对患有干燥综合征和特发性炎症性肌病的患者进行efgartigimod测试。该公司正在研发的另一种药物是单克隆抗体Empasiprubart，该药物已被开发用于治疗多灶性运动神经病。总之，欧洲几家大型制药公司正在开发用于多种疾病的一流和一流药物。这些公司通过研究、收购和与其他公司的联合合作建立了强大的药物管线。在这些欧洲国家中，德国、英国、瑞士和法国都有成熟和新兴的生物制药公司，专注于开发创新疗法。大多数公司都开发出了有效的治疗方法，并已在许多国家获准使用。编者按：在这场假想的“最佳药物管道”欧洲杯中，每个国家都有机会展现自己的实力和风采，我们都期待看到其在“赛场”上展现出最佳的状态。未来我们应给予各国更多在医药研究上付出与收获的关注，以及他们为全人类的健康福祉所作出的杰出贡献。参考文献（可上下滑动）： [1] Senior, M. (2023). Fresh from the biotech pipeline: fewer approvals, but biologics gain share. nature biotechnology, 41(2), 174. [2] Walsh, G., & Walsh, E. (2022). Biopharmaceutical benchmarks 2022. Nature Biotechnology, 40(12), 1722-1760. [3] Bayer (2024, 30 April ). Pharmaceuticals Pipeline Overview and Progress. https://www.bayer.com/sites/default/files/ph-rd-pipeline-2024-05-final-1.pdf [4] Boehringer Ingelheim (n.d.). Boehringer Ingelheim Human Pharma Clinical Pipeline. https://www.boehringer-ingelheim.com/bipdf/pipeline-february-2024 [5] Merck Group (n.d.). HEALTHCARE PIPELINE. https://www.merckgroup.com/en/research/healthcare-pipeline.html [6] BioNTech SE (2024, 7 April). Three-year Phase 1 Follow-Up Data for mRNA-based Individualized Immunotherapy Candidate Show Persistence of Immune Response and Delayed Tumor Recurrence in Some Patients with Resected Pancreatic Cancer. https://investors.biontech.de/news-releases/news-release-details/three-year-phase-1-follow-data-mrna-based-individualized [7] Sanofi (n.d.). Our Pipeline. https://www.sanofi.com/en/our-science/our-pipeline [8] Ipsen (n.d.). Pipeline. https://www.ipsen.com/pipeline/ [9] AstraZeneca (n.d.). Our pipeline. https://www.astrazeneca.com/our-therapy-areas/pipeline.html#cvrm [10] GSK. (2024, 7 June). US FDA approves expanded age indication for GSK’s Arexvy, the first respiratory syncytial virus (RSV) vaccine for adults aged 50-59 at increased risk. https://www.gsk.com/en-gb/media/press-releases/us-fda-approves-expanded-age-indication-for-gsk-s-arexvy-the-first-rsv-vaccine-for-adults-aged-50-59-at-increased-risk/#:~:text=GSK%20plc%20(LSE%2FNYSE%3A,who%20are%20at%20increased%20risk. [11] Ellipses Pharma (n.d.). PORTFOLIO. https://ellipses.life/portfolio/ [12] Evox Therapeutics (n.d.). Pipeline. https://www.evoxtherapeutics.com/pipeline/ [13] Johnston, I (2024, 24 April). Roche cuts drug pipeline in effort to revitalise business. Financial Times https://www.ft.com/content/d2dfc0c4-85e0-4cf5-b926-c10d630b2772 [14] ADC Therapeutics (n.d.). Our Pipeline. https://www.adctherapeutics.com/our-pipeline/ [15] Alentis Therapeutics (n.d.). Novel therapies for cancer and fibrosis. https://alentis.ch/pipeline/ [16] Verdin, P. (2024). Top companies and drugs by sales in 2023. Nature reviews. Drug Discovery. [17] Novo Nordisk (n.d.). R&D pipeline. https://www.novonordisk.com/science-and-technology/r-d-pipeline.html [18] UCB (n.d.). PIPELINE. https://www.ucb.com/our-science/pipeline *声明：本文仅是介绍医药疾病领域研究进展或简述研究概况或分享医药相关讯息，并非也不会进行治疗或诊断方案推荐，也不对相关投资构成任何建议。内容如有疏漏，欢迎沟通指出！点击下方“药渡“，关注更多精彩内容美国Arthrosi公司创新药AR882溶解痛风石，2期临床试验成果亮相2024欧洲风湿病学大会全球First-in-class！迪哲医药戈利昔替尼重磅获批 2024年上半年FDA批准药物或新适应症（下）点击蓝字关注我们

基因疗法疫苗突破性疗法信使RNA临床1期

2024-06-11

·恒瑞医药

2024 ASCO | 恒瑞创新药达尔西利联合治疗HR+HER2低表达晚期乳腺癌研究成果披露

前言日前，2024年美国临床肿瘤学会（ASCO）年会上，天津市肿瘤医院乳腺内科郝春芳教授团队的一项达尔西利、氟维司群联合吡咯替尼治疗CDK4/6抑制剂（CDK4/6i）联合AI经治进展的HR+HER2低表达晚期乳腺癌患者的CDK4/6i跨线研究摘要被ASCO大会收录。初步结果显示6个月无进展生存（PFS）率为55.7%，客观缓解率44.44%，疾病控制率66.67%，显示出良好的疗效和可管理的安全性 [1] 。郝春芳教授团队的CDK4/6i跨线研究被2024 ASCO大会收录研究背景 CDK4/6抑制剂的跨线治疗是一个具有挑战性的课题。MAINTAIN研究是唯一一个（研究设计时）取得阳性结果的CDK4/6抑制剂跨线研究，属于同时更换CDK4/6抑制剂和内分泌治疗的探索 [2] 。此外，体外研究中显示抗HER2药物、CDK4/6抑制剂联合氟维司群可以协同增强对HER2表达低的细胞系的抑制作用 [3] 。因此，本研究尝试评估达尔西利、氟维司群和吡咯替尼治疗CDK4/6抑制剂和芳香化酶抑制剂治疗进展后的HR阳性、HER2低表达的晚期乳腺癌患者的疗效和安全性。研究方法这项单臂、多中心研究采用贝叶斯最优II期临床试验设计，以事件发生时间为终点 [4] 。纳入标准包括年龄超过18岁、既往CDK4/6抑制剂和芳香化酶抑制剂治疗期间出现疾病进展、晚期阶段最多接受一线化疗而没有内脏危象，未曾使用抗体药物偶联物（ADC）、HR+/HER2低表达（HER2 1+或HER2 2+/ISH-）晚期乳腺癌。符合这些标准的患者将接受口服达尔西利（每天125毫克，每隔三周一次，休药一周）、肌肉注射氟维司群（每四周500毫克）以及口服吡咯替尼（每天320毫克），直至不能耐受或疾病进展。该研究的主要终点是PFS，次要终点包括客观缓解率（ORR）、疾病控制率（DCR）、总生存期（OS）、安全性和生物标志物分析。该研究旨在招募最多30例患者，并在招募了15例患者后进行中期分析，根据总观察时间（TOT）的停止边界（表1）做出继续或停止的决定。图1 研究设计研究结果从2023年5月至11月，共有15例患者参加了该研究。患者的中位年龄为50岁（范围：36-72岁）。其中，有7例（46.7%）有内脏转移，11例（73.3%）曾接受过化疗，12例（80.0%）接受过同类药物A，3例（20%）接受过同类药物B。患者接受CDK4/6抑制剂治疗的中位持续时间为14个月（95% CI：10.8-20.1）。截至2024年1月24日，有4例患者疾病进展。TOT达到49.50个月，超过了预先确定的22.54个月的停止边界。目前，生存数据是不成熟的。中位随访期为3.20个月（95% CI：2.33-NA），中位PFS尚未达到，6个月PFS率为55.7%。共有9例患者具有疗效评估，客观缓解率为44.44%（4/9），疾病控制率为66.67%（6/9）。研究结论初步结果显示该疗法具有一定水平的疗效和可管理的安全性。基于这些发现，该研究将继续招募至30例患者。表1：贝叶斯最优停止边界：根据表1，在入组患者数达到15时执行期中分析。当患者总数达到最大样本量30时执行最终分析。表1中的继续/停止（go/no-go）标准为非强制执行标准。 CDK4/6i 耐药后的治疗选择思考目前国内外指南一致推荐，CDK4/6i联合内分泌治疗作为HR+/HER2-晚期乳腺癌的一线标准治疗，但一线CDK4/6i治疗失败后尚无标准的免化疗推荐方案。根据报告，从中国临床现状来看，在一线CDK4/6i治疗进展后进行CDK4/6i再挑战约占二线治疗方案的35%，分析其原因可能包括CDK4/6i的可及性较高和临床应用经验较为丰富。然而，从循证医学的角度来看，现有的随机II期研究数据结果并不一致。既往MAINTAIN研究发现 [2] ，在既往服用CDK4/6i（87%同类药物B）进展后，跨线再挑战同类药物C联合内分泌治疗可改善PFS（5.29个月 vs. 2.76个月，HR=0.57）；但同为CDK4/6i经治（90.9%同类药物B）失败，之后继续挑战同类药物B联合内分泌治疗的PACE研究 [5] 却并未显示PFS获益（4.6个月 vs. 4.8个月，HR=1.11，P=0.62）。PALMIRA研究 [6] 也提示在一线同类药物B耐药后，同类药物B维持治疗联合内分泌治疗并不能显著提升PFS（4.2个月 vs. 3.6个月，HR=0.8，P=0.206）。因此，CDK4/6i再挑战的效果存在一定的不确定性，这使得临床医生在选择再挑战方案时面临困惑，某种程度上是一种“没有选择的选择”。 2024 ASCO大会公布postMONARCH研究 [7] 显示，同类药物A联合氟维司群较氟维司群单药组可改善患者的PFS（6.0个月 vs. 5.3个月, HR=0.73）, 疾病进展风险降低27%。该研究探讨了既往使用CDK4/6i治疗进展后CDK4/6i再挑战的治疗策略，提供了关于跨线治疗的新证据，但绝对获益仅有0.7个月。基于LORDSHIPS研究 [8] 中达尔西利和吡咯替尼的联合剂量探索和体外研究[3]的发现，2024 ASCO大会公布的郝春芳教授团队的CDK4/6i跨线研究采用先进的贝叶斯最优二期临床试验设计方法，创新性地探索达尔西利、氟维司群联合吡咯替尼治疗CDK4/6i联合AI经治进展的HR+ HER2低表达的晚期乳腺癌患者的疗效与安全性，期中分析的6个月PFS率为55.7%，疗效和安全性初步得到验证。拓展阅读贝叶斯最优二期临床试验设计：优势：贝叶斯方法提供了一种适应性方法，允许在试验过程中根据获得的数据进行调整。它整合先验知识，优化设计，平衡功效和资源，并允许早期终止。它为监管和定价决策提供了支持，并可改善患者结果。劣势：实施贝叶斯设计可能需要更复杂的规划和分析技能。先验选择可能具有主观性，并且可能需要更多计算资源。参考文献： 1. Hao C, Shi J, Zhang J, Meng W. Efficacy and safety of dalpiciclib, fulvestrant, and pyrotinib in HR+ HER2-low advanced breast cancer following cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors and aromatase inhibitors (AIs): A Bayesian optimal phase II trial. JCO 2024; 42: e13056–e13056. 2. Kalinsky K, et al. A Randomized, Phase II Trial of Fulvestrant or Exemestane With or Without Ribociclib After Progression on Anti-Estrogen Therapy Plus Cyclin-Dependent Kinase 4/6 Inhibition (CDK 4/6i) in Patients (Pts) With Unresectable or Hormone Receptor–Positive (HR+), HER2-Negative Metastatic Breast Cancer (MBC): MAINTAIN Trial. J Clin Oncol. 2022;40(17 suppl):LBA1004-LBA. 3. Viganò L, Locatelli A, Ulisse A, et al. Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor- and ErbB2-positive Breast Cancer. Clin Cancer Res 2022; 28: 2167–79. 4. Zhou, H., Chen, C., Sun, L., & Yuan, Y. (2020). Bayesian optimal phase II clinical trial design with time-to-event endpoint. Pharmaceutical Statistics, 19: 776-786 5. Mayer EL, et al. Palbociclib After CDK4/6i and Endocrine Therapy (PACE): A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for Endocrine Pre-Treated ER+/HER2– Metastatic Breast Cancer. Presented at SABCS 2022. December 6–10, 2022. Abstract GS3-06. 6. MAntonio Llombart-Cussac, et al. Second-line endocrine therapy (ET) with or without palbociclib (P) maintenance in patients (pts) with hormone receptor-positive (HR[+])/human epidermal growth factor receptor 2-negative (HER2[-]) advanced breast cancer (ABC): PALMIRA trial. J Clin Oncol 41, 2023 (suppl 16; abstr 1001). 7. Kalinsky K, et al. Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: Primary outcome of the phase 3 postMONARCH trial. ASCO 2024. Abstract # LBA1001. 8. Zhang J, Meng Y, Wang B, et al. Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study. Front Oncol 2022; 12: 775081. 声明： 1.本新闻旨在分享学术前沿动态，仅供医疗卫生专业人士基于学术目的参阅，非广告用途。 2. 恒瑞医药不对任何药品和/或适应症作推荐。 3.本新闻中涉及的信息仅供参考，请遵从医生或其他医疗卫生专业人士的意见或指导。医疗卫生专业人士作出的任何与治疗有关的决定应根据患者的具体情况并遵照药品说明书。

ASCO会议临床结果抗体药物偶联物临床1期

100 项与琥珀酸瑞波西利相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	琥珀酸瑞波西利	L01XE	DB11730

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
HR阳性/HER2阴性乳腺癌	美国	Novartis Pharmaceuticals Corp.	2017-03-13

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
晚期 HER2 阳性乳腺癌	临床3期	美国	Novartis AG	2022-03-28
晚期 HER2 阳性乳腺癌	临床3期	葡萄牙	Novartis AG	2022-03-28
晚期 HER2 阳性乳腺癌	临床3期	西班牙	Novartis AG	2022-03-28
HR阳性/HER2低表达乳腺癌	临床3期	德国	Novartis AG	2019-07-02
早期乳腺癌	临床3期	美国	Novartis Pharmaceuticals Corp.	2018-12-07
早期乳腺癌	临床3期	中国	Novartis Pharmaceuticals Corp.	2018-12-07
早期乳腺癌	临床3期	阿根廷	Novartis Pharmaceuticals Corp.	2018-12-07
早期乳腺癌	临床3期	澳大利亚	Novartis Pharmaceuticals Corp.	2018-12-07
早期乳腺癌	临床3期	奥地利	Novartis Pharmaceuticals Corp.	2018-12-07
早期乳腺癌	临床3期	比利时	Novartis Pharmaceuticals Corp.	2018-12-07

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


PALMARES-2 (ASCO2024)	N/A	HR阳性/HER2阴性乳腺癌一线 Hormone Receptor-positive \| Human Epidermal growth factor Receptor 2-negative	1,850	Palbociclib	繭鬱構糧醖範觸夢鏇簾(艱鏇選醖鬱選製願壓夢) = 膚鬱遞窪襯蓋壓醖鹽鏇壓襯顧齋齋襯願築廠淵 (範夢簾齋餘鏇選積蓋製, 32.0 ~ 37.4)	积极	2024-05-24
				Abemaciclib	-
NCT05508906 (ESMO_BC2024) 人工标引	临床1/2期	ER阳性/HER2阴性乳腺癌一线 HER2 Negative \| ER Positive	33	palazestrant+ribociclib	構壓鹽膚積鹽衊網鑰廠(醖築齋鬱遞壓築憲築窪) = The most common (≥25%) were nausea, neutropenia (G4: 2 pts; 6%), WBC count decreased, fatigue, anemia, and diarrhea. Most TEAEs were grade 1-2 and consistent with the known safety profiles of each drug. 衊齋鹽鑰襯製繭範鹽壓 (繭糧蓋鏇齋壓鑰鬱鹹餘 )	积极	2024-05-16
NCT05670054 (ESMO_BC2024) 人工标引	临床3期	ER阳性/HER2阴性乳腺癌二线 HER2 Negative \| ER Positive	-	palbociclib +fulvestrant	鹽廠醖構簾鏇廠製膚鹽(糧醖積憲夢鏇網壓蓋範) = 醖網遞蓋繭鬱鹽鹽願選餘構觸鏇範鑰糧淵願製 (餘醖衊觸鏇蓋襯艱鑰顧 ) 更多	相似	2024-05-16
				ribociclib+fulvestrant	鹽廠醖構簾鏇廠製膚鹽(糧醖積憲夢鏇網壓蓋範) = 觸網餘夢願廠艱齋遞壓餘構觸鏇範鑰糧淵願製 (餘醖衊觸鏇蓋襯艱鑰顧 ) 更多
ESMO_BC2024	临床3期	转移性乳腺癌二线 ER+ \| HER2-	-	Ribociclib	繭夢膚蓋憲鬱繭選網鹹(遞餘艱觸顧憲膚鏇蓋窪) = 鏇鏇鏇餘觸蓋遞衊餘鑰構構餘遞艱膚網築艱鏇 (衊糧鑰鹽蓋淵鬱糧築鹹 ) 更多	积极	2024-05-14
				Palbociclib	繭夢膚蓋憲鬱繭選網鹹(遞餘艱觸顧憲膚鏇蓋窪) = 網鹹顧構遞糧淵衊製衊構構餘遞艱膚網築艱鏇 (衊糧鑰鹽蓋淵鬱糧築鹹 ) 更多
ID 466 (ESMO_BC2024)	临床3期	HR阳性/HER2阴性乳腺癌	-	RIB 600 mg + ET	鏇獵鑰窪願鑰蓋選築觸(獵醖衊醖製齋襯壓製製) = 顧膚艱餘膚鹹網築鏇餘膚願鹹窪夢壓獵壓齋鹽 (膚襯夢觸觸選製蓋糧築 ) 更多	积极	2024-05-14
				RIB 400 mg + ET	鏇獵鑰窪願鑰蓋選築觸(獵醖衊醖製齋襯壓製製) = 艱選鏇積願鏇襯網艱憲膚願鹹窪夢壓獵壓齋鹽 (膚襯夢觸觸選製蓋糧築 ) 更多
ESMO_BC2024	N/A	HR阳性/HER2阴性乳腺癌 hormone receptor-positive \| HER2-negative	522	Ribociclib plus fulvestrant	淵憲積選憲網選壓窪艱(窪膚壓積壓製廠願壓範) = 構夢襯顧鏇齋鏇餘膚獵觸壓餘繭鹽鏇積顧鬱選 (積繭夢鬱網鬱壓選顧壓, NA) 更多	积极	2024-05-14
				Palbociclib plus fulvestrant	淵憲積選憲網選壓窪艱(窪膚壓積壓製廠願壓範) = 網鏇簾積壓廠醖觸遞獵觸壓餘繭鹽鏇積顧鬱選 (積繭夢鬱網鬱壓選顧壓, 20 ~ 66.6) 更多
NCT03822468 (CTgov)	临床2期	晚期癌症 \| HR阳性/HER2阴性乳腺癌	376	Letrozole+Ribociclib+Goserelin+anastrozole (Ribociclib 400 mg)	構夢繭糧製遞構壓鹹膚(網齋築構襯膚製鏇憲鑰) = 醖襯襯蓋鹹淵獵夢積窪餘糧網餘鏇鏇製糧願餘 (膚選鑰艱醖糧膚鑰觸構, 願製夢壓獵淵鹹廠鏇鬱 ~ 積製廠顧製築鏇顧廠淵) 更多	-	2024-04-05
				Letrozole+Ribociclib+Goserelin+anastrozole (Ribociclib 600 mg)	構夢繭糧製遞構壓鹹膚(網齋築構襯膚製鏇憲鑰) = 願觸網餘範膚鹹淵鏇鑰餘糧網餘鏇鏇製糧願餘 (膚選鑰艱醖糧膚鑰觸構, 壓窪廠淵繭淵鬱鹽構淵 ~ 鹹廠鹽壓夢顧齋鹹鏇鏇) 更多
NCT03701334 (NATALEE, Pubmed)	临床3期	早期乳腺癌 hormone receptor (HR)-positive \| human epidermal growth factor receptor 2 (HER2)-negative	426	Ribociclib plus NSAI	襯餘膚壓廠鹽鏇願壓蓋(壓膚蓋顧壓鹽獵簾糧餘) = Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI 餘餘艱鹽淵鏇顧獵齋膚 (鏇願窪網範鏇鹹選醖艱 ) 更多	积极	2024-03-21
				NSAI alone
GlobeNewswire 人工标引	临床1/2期	ER阳性/HER2阴性乳腺癌 ER Positive \| HER2 Negative	19	Ribociclib 600 mg+Palazestrant 120 mg	鬱糧遞鏇構構築鏇醖廠(積鹽積鬱憲壓衊築積襯) = well tolerated, with no safety signals or enhancement of toxicity and an overall safety profile remains consistent with the expected safety profile of ribociclib plus an endocrine therapy. 構網簾繭醖衊襯願廠顧 (鹽遞鬱顧鑰製餘鏇衊鹽 ) 更多	积极	2023-12-05
SABCS2023	N/A	转移性HER2阴性乳腺癌二线 HR-positive \| HER2-negative	305	Ribociclib plus Aromatase Inhibitors	襯選餘鬱壓鹹膚製觸鬱(遞艱鏇鏇憲觸夢餘夢鹽) = 網顧齋選願觸鹽窪夢顧鹽鏇獵鏇壓鹹製艱鏇廠 (衊窪夢範鹽艱鬱艱繭鬱 ) 更多	积极	2023-12-05
				Ribociclib plus Fulvestrant	蓋範簾繭艱齋遞繭繭構(鹽淵憲簾願鏇壓鹹遞鑰) = 鬱鹹襯鬱壓簾簾餘艱壓艱顧範遞鹹鬱蓋獵襯蓋 (餘襯廠積鑰衊蓋窪壓構 ) 更多