A Randomized Phase III Trial of Checkpoint Blockade in Lung Cancer Patients in the Adjuvant Setting Based on Pathologic Response Following Neoadjuvant Therapy (CLEAR)

This phase III trial compares the effect of adding AZD6738 to durvalumab versus durvalumab alone to increase time without cancer in patients with non-small cell lung cancer, following treatment with chemotherapy and surgery. AZD6738 may stop the growth of tumor cells and may kill them by blocking some of the enzymes needed for cell growth. Durvalumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Adding AZD6738 to durvalumab may increase time without cancer in patients with non-small cell lung cancer, following treatment with chemotherapy and surgery.

开始日期2025-03-14

申办/合作机构

National Cancer Institute

NCT06680050 / Not yet recruiting临床2期IIT

AUSTRAL Trial: An Open-Label, Multicenter, Phase II Study Of Radiotherapy Followed By Durvalumab (MEDI4736) And Ceralasertib (AZD6738) In Stage III NSCLC Patients With Thoracic Relapses +/- Oligometastases After PACIFIC Regimen

Aim of this phase 2 study is to explore the safety and efficacy of thoracic re-irradiation +/- SBRT to oligometastases (<3) followed after an interval of 2 weeks by durvalumab and ceralasertib for patients with thoracic relapses +/- oligometastases after PACIFIC or PACIFIC-like (concurrent or sequential chemo-radiotherapy followed by maintenance durvalumab) regimens.

开始日期2025-01-01

申办/合作机构

Istituto di Ricerche Farmacologiche Mario Negri

NCT05941897 / Active, not recruiting临床2期

A Phase II, Open-label, Multicentre, Non-comparative, Single-arm Local Study of Ceralasertib Plus Durvalumab in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer Without Actionable Genomic Alterations, and Whose Disease Has Progressed On or After Prior Anti-PD-(L)1 Therapy and Platinum-based Chemotherapy

A study to investigate efficacy and safety of ceralasertib plus durvalumab in participants aged ≥ 18 years with advanced or metastatic non-small cell lung cancer whose disease progressed on or after prior anti-PD-(L)1 therapy and platinum-based chemotherapy.

开始日期2023-06-21

申办/合作机构

AstraZeneca PLC

100 项与 Ceralasertib 相关的临床结果

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100 项与 Ceralasertib 相关的转化医学

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100 项与 Ceralasertib 相关的专利（医药）

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项与 Ceralasertib 相关的文献（医药）

2025-02-01·BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

Molecular mechanisms restoring olaparib efficacy through ATR/CHK1 pathway inhibition in olaparib-resistant BRCA1/2MUT ovarian cancer models

Article

作者: Mikula, Michał ; Statkiewicz, Małgorzata ; Gajek, Arkadiusz ; Rusetska, Natalia ; Szymczak-Pajor, Izabela ; Biegała, Łukasz ; Rogalska, Aneta ; Marczak, Agnieszka ; Śliwińska, Agnieszka

Resistance to olaparib inevitably develops in ovarian cancer (OC) patients, highlighting the necessity for effective strategies to improve its efficacy. Here, we established a novel olaparib-resistant patient-derived xenograft model of high-grade serous OC with BRCA1/2 mutations and examined the molecular characteristics of acquired resistance and resensitization to olaparib in treatment-naïve tumors in vivo. Olaparib-resistant xenografts were treated with olaparib, ATR inhibitor (ATRi, ceralasertib), CHK1 inhibitor (CHK1i, MK-8776) or their combinations. Proliferation, apoptosis, ATR/CHK1 activity, PARP signaling, DNA damage response (DDR), epithelial-to-mesenchymal transition (EMT), and MDR1 expression, were examined via RT-qPCR, western blot, and immunohistochemistry. Resistant tumors exhibited defects in PARP and ATR/CHK1 signaling, accompanied by altered expression of proteins involved in DDR and EMT. Olaparib rechallenge combined with ATR/CHK1 inhibitors showed promising synergistic effects on tumor growth inhibition. Mechanistically, combined treatments suppressed tumor proliferation without increasing apoptosis or necrosis, while inducing tumor cell vacuolization indicative of cell death. ATRi combined with olaparib induced or augmented downregulation of ATR, CHK1, PARP1, PARG, BRCA1, γH2AX, and PARylated protein expression, while reversing olaparib-induced upregulation of vimentin, BRCA2, and 53BP1. Our collective findings indicate that ATR/CHK1 pathway inhibition restores the olaparib efficacy in resistant BRCA1/2^MUT high-grade serous OC, highlighting promising approach for olaparib rechallenge of non-responsive patients. Uncovered mechanisms might improve our understanding of acquisition and overcoming resistance to olaparib in ovarian cancer.

2024-12-01·GYNECOLOGIC ONCOLOGY

ATR inhibition increases reliance on PARP-mediated DNA repair revealing an improved therapeutic strategy for cervical cancer

Article

作者: Benbrook, Doris M. ; Elayapillai, Sugantha Priya ; Parker, Madison ; Hannafon, Bethany N ; Hannafon, Bethany N. ; Kennedy, Amy ; Moxley, Katherine M ; Lausen, James ; Moxley, Katherine M. ; Dogra, Samrita ; Benbrook, Doris M

OBJECTIVE:

Cervical cancer results from persistent infection with high-risk human papillomavirus (HR-HPV) and the expression of E6 and E7 oncoproteins. E6 and E7 compromise the activity of p53 and Rb, the G1-S cell cycle checkpoint, and ATM-mediated DNA damage repair (DDR), which in turn increases reliance on ATR- and PARP-mediated DDR at the G2 cell cycle checkpoint. This study aimed to determine the effects of an ATR inhibitor (ATRi, AZD6738) and a PARP-inhibitor (PARPi, AZD2281) on HR-HPV+ cervical cancer cell lines.

METHODS:

The effects of ATRi and PARPi, alone and in combination, on metabolic viability, cell cycle arrest, apoptosis, and DDR pathways in cervical cancer cell lines were evaluated in vitro, and the in vivo tumor response was evaluated using a xenograft model.

RESULTS:

Cervical cancer cells were sensitive to ATRi and PARPi monotherapy. The combination therapy was only synergistic in reducing metabolic viability when exposed to ATRi first, followed by PARPi, owing to ATRi-mediated upregulation of PARP expression. Combination of ATRi and PARPi induced G2 cell cycle arrest and apoptosis. PARPi induced DNA damage and γH2AX phosphorylation, which was further increased by ATRi treatment. However, PARPi-induced Rad51 foci formation was reduced by ATRi treatment, suggesting the inhibition of homologous recombination repair. ATRi significantly reduced cervical cancer xenograft tumor growth and was not affected by simultaneous PARPi treatment at the doses studied.

CONCLUSIONS:

Our findings show that ATRi increased reliance on PARP for metabolic viability, the combination of ATRi and PARPi induced synthetic lethality in cervical cancer in vitro, and reduced tumor burden in vivo.

2024-12-01·CANCER CHEMOTHERAPY AND PHARMACOLOGY

Combination of S-1 and the oral ATR inhibitor ceralasertib is effective against pancreatic cancer cells

Article

作者: Nakano, Ami ; Hirohara, Masayoshi ; Takeuchi, Osamu ; Watanabe, Kazuhiro ; Masuda, Yutaka ; Morimoto, Yoshihito ; Takada, Kimihiko

PURPOSE:

In our previous study, we found that the Chk1 inhibitor prexasertib enhances the antitumour effect of the oral anticancer drug S-1 against pancreatic cancer cells. In this study, we investigated the effect of combining S-1 and ceralasertib, an oral inhibitor of ATR, which is located upstream of Chk1. Ceralasertib is currently being investigated in multiple clinical trials for various cancers.

METHODS:

The cell-proliferation inhibitory effect was measured by MTT assay, using the pancreatic cancer cell lines BxPC-3, SUIT-2, PANC-1, and MIA PaCa-2, while apoptosis was measured by flow cytometry using PI/Annexin staining. The mechanism underlying the combined effect was analysed using western blotting, and the antitumor effect was analysed using a mouse xenograft model.

RESULTS:

MTT assay revealed that the combination of S-1 and ceralasertib had a synergistic effect, leading to the suppression of cell proliferation. Measurement with PI/Annexin staining revealed that the combination of S-1 and ceralasertib induced apoptosis more efficiently than either drug alone. Western blotting results showed that ceralasertib inhibited S-1-induced activation of ATR and Chk1. The average estimated tumour volume after 3 weeks of administration was 601 mm³ in the S-1 group, 580 mm³ in the ceralasertib group, and 298 mm³ in the combination group.

CONCLUSION:

The combination of S-1 and ceralasertib demonstrated a high antiproliferative effect in inhibiting tumour growth in vitro.

项与 Ceralasertib 相关的新闻（医药）

2024-11-04

·ioncology

ESMO 2024丨多西他赛仍是PD-（L）1抑制剂耐药晚期NSCLC患者的标准治疗

点上方蓝字“ioncology”关注我们，然后点右上角“…”菜单，选择“设为星标” 编者按：抗PD-(L)1已获批用于晚期非小细胞肺癌（NSCLC）的治疗。然而，大多数患者因治疗选择有限在接受抗PD-(L)1治疗期间会出现疾病进展。在2024欧洲肿瘤内科学会（ESMO）年会上，来自法国马赛Pascale Tomasini教授分享了PD-(L)1抑制剂耐药的晚期非小细胞肺癌(NSCLC)患者的精准免疫肿瘤治疗(PIONeeR)：一项靶向确定耐药通路的Ib/IIa期临床试验的研究结果。《肿瘤瞭望》在现场采访了Pascale Tomasin教授，分享主要研究成果以及 PD - (L)1 抑制剂耐药的晚期非小细胞肺癌患者当下的治疗策略、未来展望。这项开放标签、多中心、对照随机研究使用了贝叶斯自适应设计。在序贯或同时接受PD-(L)1和铂类化疗后疾病进展的晚期NSCLC患者符合纳入标准。患者随机为4组，A组：度伐利尤单抗（Du）+ Monalizumab，B组：Du + Oleclumab，C组：Du + Ceralasertib，E组：Du +赛沃替尼或对照组：多西他赛。主要终点是12周疾病控制率（12-w DCR）根据RECIST 1.1。主要次要终点包括缓解持续时间（DoR）、总缓解率（ORR）、无进展生存期（PFS）、总生存期（OS）和安全性。中期分析使用了30%的无效边界。如果存在高概率（P ≥ 90%）12-w DCR达到D组的12-w DCR，则认为联合治疗有效。 114例患者被随机分配到A组，n=28；B组，n=3；C组，n=32；D组，n=31；E组，n=20。由于缺乏疗效，B组和E组提前关闭。在D组中，11例患者在接受治疗前退出。有效性层面，对照组的12-w DCR为54.5%（95%CI [34.0%; 74.3%]），A组为24.1% [10.7%; 41.0%]，B组为0%，C组为50% [33.1%; 66.9%]，E组为13.6% [3.0%; 30.4%]；A组和C组的P值分别为1.2%和36.8%。与D组相比，实验组在PFS或OS方面没有显著获益。然而，C组中有5例患者根据RECIST达到了部分缓解（PR），中位DoR为5.6个月[2.1; 9.7]。安全性相当。 PIONeeR 试验是学术合作的成功案例，通过使用创新的自适应设计来识别新型免疫治疗（IO）组合的疗效信号，探索克服晚期 NSCLC 对 PD-(L) 1 抑制剂耐药性的方法。虽然没有实验组正式达到疗效目标，但一些患者从包括 ceralasertib 和 monalizumab 的组合中获得了长期临床益处。目前，综合生物标志物分析正在进行中，以预测受益于这些联合治疗的患者。 01 《肿瘤瞭望》：2024 ESMO发布了一项针对已确定耐药途径的 Ib/IIa 期临床试验结果，请问您如何看待 PD - (L)1 抑制剂耐药的晚期非小细胞肺癌患者的治疗策略?（LBA8） Dr. Pascale Tomasini：多西他赛目前仍是 PD - (L)1 抑制剂耐药的晚期非小细胞肺癌（NSCLC）标准治疗方法，这表明在某些情况下，对于患者的治疗需求还未得到充分满足。在过去的十年里，人们研究了几种不同的方案，试图通过不同的组合来克服对 PD - 1 和 PD - (L)1 抑制剂的耐药性。尽管进行了多种尝试，但到目前为止，还没有一种组合被证明比多西他赛更好。 Dr. Pascale Tomasini: I think there is a real unmet need in these situations, as docetaxel is still the standard-of-care. During the last decade, several different options were studied in order to overcome resistance to PD-1 and PD-L1 inhibitors with several different combinations, but no combination has been shown to be better than docetaxel so far. 02 《肿瘤瞭望》：可供患者参加的临床试验越来越多。加入PD-L1免疫组化检测是否有助于为PD-L1耐药NSCLC患者选择治疗方式？ Dr. Pascale Tomasini: 目前，许多不同的组合正在与其他检查点抑制剂（如 TIGIT 抑制剂、LAG - 3 抑制剂）以及一些靶向疗法进行研发。但我认为仅靠 PD - (L)1 不足以预测这些药物的疗效。因此，我认为需要进行大型生物标志物分析，并整合多种生物标志物，以确定哪些患者可能从这些组合治疗中受益，与仍然是标准治疗方法的多西他赛相比，找到更优的治疗方案。 Dr. Pascale Tomasini: Many different combinations are being tested with other checkpoint inhibitors, TIGIT inhibitors and LAG-3 inhibitors, or even with some targeted therapies. I don’t think PD-(L)1 alone would be enough to predict the efficacy of these drugs. I think there is a need for a large biomarker analysis, and to integrate all these biomarkers to be able to find who among the patients are likely to respond and derive benefit from these combinations as compared to docetaxel, which is still the standard. 03 《肿瘤瞭望》：您能否谈谈PD-L1抑制剂耐药NSCLC领域未满足的需求？ Dr. Pascale Tomasini: 对于晚期非小细胞肺癌且对 PD - 1 和 PD - (L)1 抑制剂耐药的患者来说，目前除了多西他赛之外没有其他更好的选择。这些患者迫切需要找到毒性更小、疗效更好的治疗方法。许多新的治疗选择正在被开发，我希望通过这些治疗选择及进行许多生物标志物分析，能够改善这些患者的治疗策略。 Dr. Pascale Tomasini: Again, there is nothing else other than docetaxel for now in this setting of patients with advanced non-small cell lung cancer resistant to PD-1 and PD-L1 inhibitors. There is a real need for these patients to find something else with less toxicity and better efficacy. Many options are being tested, and I hope with these options and many biomarker analyses, we will be able to improve the strategy for these patients. （来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

临床结果ASCO会议

2024-05-23

·药通社

绝地翻盘：阿斯利康的转型与管线建设

对话决策层！如何打剂型差和产品差？产品立项和开发如何塑造壁垒？创新药企业都是产品为王，产品决定一个企业的胜败。小企业的成功靠产品，中型企业的成功靠一条产品管线，而大企业的成功靠管线管理——不同管线的推陈出新、各管线内产品的生命周期维持与延续。管线强则企业强，管线差则企业弱，制药巨头亦是如此。本文以阿斯利康为例，介绍管线管理的重要性、以及管线搭建与维护的方法。因为创新乏力，管线青黄不接，阿斯特拉与捷利康在1998年进行了合并，组建了阿斯利康。通过合并与整合，两个公司的资源与能力产生了很大的协同性，并推出了洛赛克（奥美拉唑）的迭代品耐信（埃索美拉唑，奥美拉唑的一种手性单体），形成以了以消化、中枢神经、抗肿瘤、心血管，呼吸和抗感染为特色的六大管线，具体产品如下表所示：虽然合并之后，阿斯利康的管线得到了明显的强化，业绩在强化销售力量和耐信等核心产品的带动下，实现了持续、稳步增长，但是创新乏力的问题并未得到解决，专利悬崖始终是挥之不去的阴影。2010年之后，阿斯利康陷入了爆品后时代的危机——销售额下滑，产品管线青黄不接，研发管线储备不足，股价一蹶不振。在阿斯利康最黑暗的时候，辉瑞曾两次报价欲收购该公司。然而令阿斯利康更为气愤的是，辉瑞对这家百年巨头的两次报价均远远不及新生的“牛犊”艾尔建。这样的阿斯利康，要么接受被收购的命运，要么背水一战——逐步完成管线的升级与延伸。幸运的是，阿斯利康在至暗的时刻迎来了救世主——总裁Pascal Soriot和研发副总裁Mene Pangalos。Pascal Soriot霸气回绝了辉瑞的收购邀约，并放出豪言，要让阿斯利康的销售额在未来的十年里翻两倍，随后便对阿斯利康进行了大刀阔斧地改革。Mene Pangalos则提出5R决策框架，在该框架的影响下，阿斯利康的研发效率在短短几年间发生了显著的变化，研发成功率几乎翻了5倍。The 5R framework2012年10月，原罗氏首席运营官Pascal Soriot加入了阿斯利康，出任阿斯利康的CEO。2013年3月，阿斯利康制定了实现销售额恢复增长和建立科学领导者地位的战略目标，其核心内容包括以下六点：1）扭转因专利悬崖和收入下滑所致的不利局面，驱动业绩恢复增长；2）加速二期临床管线的开发，以扩充三期临床管线的规模和提升生物制品管线的潜力；3）坚定不移地推出专科药，以抹平阿斯利康在普药领域的历史优势；4）通过各地团队的共同努力和获取全球认可的科学集群，以创新和差异化定位的科研重塑阿斯利康的研发平台；5）显著性简化业务，提高生产力，建立支持长期成功的文化；6）利用商务拓展和收购机遇，强化产品管线。为了达成该战略目标，阿斯利康停掉了大量夕阳性领域的产品研发，聚焦于朝阳性的领域。在开发新分子实体的同时，也不断投资产品的生命周期管理（如，开发埃索美拉唑新剂型、新规格、新用法、新适应症、新复方、OTC等）。为了支持研发，阿斯利康大幅增加了研发投入，平均研发投入强度从2008-2012年间的16.4%，迅速提升至2013-2017年间的25.5%；为了在专利悬崖之下提振业绩，阿斯利康也大幅增加了销售投入，通过在专利悬崖效应不显著的区域市场提升销售力量来最大化产品价值。为此，该公司的平均市场&一般管理费投入强度从2008-2012年间的34.2%，迅速提高至2013-2017年间的50.2%（在跨国巨头中，几乎已是最高水平）。除此以外，阿斯利康还以“不惜血本”的态度引进、投资或收购产品或管线资产。在2013-2017年间，阿斯利康收购了Ardea Biosciences、百时美施贵宝的糖尿病业务部门、Amplimmune、Spirogen、Pearl Therap、Omthera Pharma、Definiens、ZS pharma、阿特维斯在北美的呼吸系统品牌药管线，控股了Acerta Pharma，总合同金额高达140亿美元。除了企业兼并，阿斯利康还花掉了41亿美元，用以授权引进了纳洛西醇、罗沙司他、monalizumab（phase 3）等20多个产品或研发项目。高强度的研发投入、高强度的销售费用和高频率的收购，必然导致阿斯利康的利润下跌。平均净利润水平从2008-2012年间的15.3%下降至2013-2017年间的10.7%，加之销售额的逐渐下滑，年平均净利润也从2008-2012年间的48.71亿美元下降至25.81亿美元。为此，阿斯利来不得不在2016年进行资产重组，剥离大量的非核心资产套现，以推动战略的继续执行。2016年阿斯利康集中甩出的资产：2016年2月，将高血压药非洛地平和单硝酸异山梨酯缓释片的中国权益以5亿美元卖给康哲；2016年3月，将便秘药Naloxegol的欧洲权益卖给ProStrakan，交易金额未知；2016年4月，将痛风药lesinurad的美国权益以2.65亿美元卖给Ironwood；2016年6月，将麻醉部门的区域权益以7.7亿美元转让给Aspen；2016年6月，将痛风药lesinurad的欧洲和拉美权益以2.3亿美元卖给Gruenenthal；2016年8月，将小分子感染部门以15.75亿美元卖给辉瑞；2016年7月，将tralokinumab和brodalumab以10亿美元卖给Leo pharma；2016年10月，将在研的IL-23单抗MEDI2070以15.2亿美元卖给艾尔建；2016年10月，将在研的COPD药物AZD7986以1.5亿美元卖给强生子公司；2016年10月，将Rhinocourt Aqua的美国以外权益以3.3亿美元卖给强生子公司；2016年10月，将艾塞那肽的中国权益以1亿美元卖给三生制药。通过资产重组，阿斯利康完成了二次战略聚焦，不仅大幅压缩了人员规模，而且显著提升了资产利用率和运营效率。经过资产的重组，阿斯利康仅剩下抗肿瘤、心血管&代谢、呼吸三条特色管线，2017年总销售额分别为40.42亿美元，72.66亿美元和47.06亿美元，其它无法归类、低收益或专利失效的产品，进行了集中化管理，总销售额为41.56亿美元。因为资产的大量剥离和长期的产品管线青黄不接，阿斯利康的销售收入在2017年达到2004年以来的历史低谷，仅为201.52亿美元。但相比2012年，阿斯利康不仅基本完成了产品管线的推陈出新，而且研发管线中储备了多个高潜力值的产品。经过2016年的资产重组，阿斯利康放弃了夕阳性的抗感染、消化管线，整合了心血管和糖尿病等普药管线，强化了朝阳性的抗肿瘤管线。随着管线的不断强化，阿斯利康在随后的几年里，大量甩出了老旧的产品权益或管线资产，用以套现并换取新的管线资源。除此以外，阿斯利康为了最大化资产的价值，除了生命周期管理（如奥拉帕利开发新适应症、新疗法），还将部分产品的权益授权给了其它公司。例如，将奥拉帕利的部分适应症权益授权给默沙东，让其与Keytruda形成捆绑销售，从而提升经济效益。2017年的形势虽然有了明显的好转，但仍需坚持才能达到战略意义上的成功。为此，阿斯利康在研发投入强度保持不变的前提下，大幅增加了产品引进的强度。2018-2022年间，阿斯利康的项目交易总金额达329亿美元，引进了Evusheld（Cilgavimab/tixagevimab）、Vimovo（奥美拉唑/碳酸氢钠）、Wainua（eplontersen）、Andexxa（andexanet alfa）、Enhertu（trastuzumab deruxtecan）、新冠疫苗等产品，以及Sipavibart（phase 3）、camizestrant（phase 3）、ceralasertib（phase 3）、IPH5201（phase 2）、monalizumab（phase 3）等重要研发项目。除此以外，阿斯利康在此期间还兼并了5家公司，总合同金额约为425亿美元。通过对Alexion的收购，阿斯利康不仅快速布局了罕见病，还成为了赛道的领头羊。经过10年的苦心经营，阿斯利康的变化是显而易见的。通过对老化的、非核心的产品的剥离与出售，产品管线实现了推陈，通过内部研发、投资引进、交易并购等多重方式，产品管线又实现了出新。如今的阿斯利康，不仅形成了以抗肿瘤、心血管&肾病与代谢、呼吸与免疫、疫苗与免疫、罕见病为特色的五大管线。而且还在抗肿瘤、罕见病等领域建立了领先的优势，不论是产品管线还是研发管线的稀缺性都有了显著的提升。正因为此，最近两年来，阿斯利康逐渐降低了销售投入，市场&一般管理费支出已经下降至销售额的42%左右。对于创新药企业而言，现有的产品管线只能代表过去和现在的成功，而能代表未来的是研发管线。所以，相比现有产品，研发管线是影响企业市值高低的最重要因素。根据阿斯利康2023年年报披露的数据，该公司一共有178个产品处于研发管线中，项目高度聚焦于抗肿瘤、生物制药和罕见病三大领域，其中处于开发晚期阶段的新分子实体有17个，123个新分子实体或产品生命周期管理的项目处于临床二期或三期阶段。因为阿斯利康逐渐形成了强大产品管线和研发管线，股价也一路飙升，2023年的市值已相比2014年翻了两倍有余，销售额方面，该公司2023年的总营收达458亿美元，相比2014年几乎也翻了两倍，Soriot成功兑现了他的承诺。本文作者：魏利军，北京药眼信息咨询有限公司创始人，著有《跨国药企成功启示录》和《仿制药企兴衰启示录》，本文内容来自正在撰写新书《制药企业的战略设计与产线规划》中的实例。因为内容是初稿，可能存在表达和内容的轻微偏误，欢迎广大朋友提供宝贵的意见。推荐阅读

并购临床3期临床2期

2024-05-22

·BioSpace

AstraZeneca furthers ambition to transform outcomes in early lung cancer and redefine metastatic breast cancer treatment at ASCO 2024

Back-to-back plenary presentations from LAURA and ADRIATIC Phase III trials reinforce the potential of TAGRISSO® (osimertinib) and IMFINZI® (durvalumab) in early lung cancer settings DESTINY-Breast06 data underscore potential of ENHERTU® (fam-trastuzumab deruxtecan-nxki) earlier in HR-positive, HER2-low breast cancer treatment, and in a broader population including HER2-ultralow WILMINGTON, Del.--(BUSINESS WIRE)-- AstraZeneca advances its ambition to redefine cancer care with new data across its industry-leading portfolio and pipeline at the American Society of Clinical Oncology (ASCO) Annual Meeting, May 31 to June 4, 2024. More than 100 abstracts will feature 25 approved and potential new medicines across the Company’s diverse oncology portfolio and pipeline, including two late-breaking plenary presentations, a special late-breaking abstract session presentation and 15 oral presentations. Highlights include: LAURA Phase III trial of TAGRISSO® (osimertinib) in unresectable, Stage III epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after chemoradiotherapy (CRT) (Plenary LBA4). ADRIATIC Phase III trial of IMFINZI® (durvalumab) in patients with limited-stage small cell lung cancer (LS-SCLC) who had not progressed following concurrent CRT (cCRT) (Plenary LBA5). DESTINY-Breast06 Phase III trial of ENHERTU® (fam-trastuzumab deruxtecan-nxki) in patients with metastatic hormone receptor (HR)-positive HER2-low and HER2-ultralow metastatic breast cancer following one or more lines of endocrine therapy (LBA1000). First-in-human, investigator-initiated trial of C-CAR031, a novel autologous armored Glypican 3 (GPC3) targeting chimeric antigen receptor T cell (CAR-T) therapy, in patients with liver cancer. The CAR-T is based on AZD5851, a novel cell therapy designed by AstraZeneca (Rapid Oral Abstract 4019). Two late-breaking presentations from the externally sponsored I-SPY2.2 Phase II trial of neoadjuvant datopotamab deruxtecan (Dato-DXd), alone and in combination with IMFINZI, in patients with breast cancer (LBA501 and LBA509). Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “Our plenary data at ASCO show the pioneering role of our medicines in curative-intent lung cancer treatment and highlight progress toward our continued ambition to have a medicine for more than half of all patients treated for lung cancer by 2030. The overwhelming efficacy in the LAURA trial will add to the extensive body of evidence for TAGRISSO in EGFR-mutated non-small cell lung cancer, and the impressive survival data from ADRIATIC will show the potential of IMFINZI to transform outcomes in limited-stage small cell lung cancer.” Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “Data from our antibody drug conjugates at ASCO underscore the opportunity to replace traditional chemotherapy with these medicines for many patients as we expand their use to new populations. DESTINY-Breast06 results will demonstrate the potential to treat patients across a broader spectrum of HR-positive metastatic breast cancer with ENHERTU, including those with HER2-ultralow expression who have never had access to HER2-directed therapy before. We're also excited by the I-SPY2.2 efficacy and tolerability data for datopotamab deruxtecan plus IMFINZI, which will show the potential of combining antibody drug conjugates with immunotherapy in the early-stage setting.” Transforming treatment expectations across earlier-stage lung cancer settings Several presentations will reinforce the Company’s progress toward moving lung cancer treatment to earlier stages of disease. These include: A late-breaking plenary presentation showcasing progression-free survival (PFS) results from the LAURA Phase III trial evaluating TAGRISSO in unresectable, Stage III EGFRm NSCLC after CRT. In February, high-level results showed a statistically significant and highly clinically meaningful PFS benefit for TAGRISSO in this setting. A late-breaking plenary presentation highlighting overall survival (OS) and PFS results from the ADRIATIC Phase III trial of IMFINZI in patients with LS-SCLC who had not progressed following cCRT. In April, high-level results from an interim analysis showed a statistically significant and clinically meaningful OS and PFS benefit for IMFINZI in this setting. An oral presentation of an analysis from the ADAURA Phase III trial of TAGRISSO in the adjuvant treatment of early-stage (IB, II and IIIA) EGFRm NSCLC, assessing the potential for circulating tumor DNA-based molecular residual disease to predict disease recurrence. A rapid oral presentation of an exploratory analysis from the AEGEAN Phase III trial of IMFINZI-based treatment before and after surgery in patients with resectable early-stage (IIA-IIIB) NSCLC, evaluating efficacy in patients with N2 disease (cancer in the lymph nodes on the same side as the affected lung or between the lungs). A poster presentation of updated OS, PFS and safety results from the COAST Phase II trial of IMFINZI in combination with novel immunotherapies oleclumab, an anti-CD73 monoclonal antibody, and monalizumab, an anti-NKG2A monoclonal antibody, in unresectable, Stage III NSCLC, supporting the PACIFIC-9 Phase III trial in this patient population. In metastatic lung cancer, the Company will present data that underscore its commitment to extending the benefits of antibody drug conjugates (ADCs) to more patients. A poster presentation will share updated safety and efficacy results, including PD-L1 expression, from the TROPION-Lung02 Phase Ib trial of datopotamab deruxtecan plus pembrolizumab with or without platinum chemotherapy as 1st-line treatment for patients with advanced NSCLC without actionable genomic alterations. These data build on previously presented results from the TROPION-Lung-1 Phase III trial demonstrating the potential of this novel ADC in advanced disease. Datopotamab deruxtecan in combination with immunotherapies is being further explored in multiple Phase III trials in this setting, including AVANZAR, TROPION-Lung07 and TROPION-Lung08. Redefining the breast cancer treatment landscape with ADCs across subtypes and stages of disease A late-breaking presentation will showcase efficacy and safety outcomes from the DESTINY-Breast06 Phase III trial. In April, high-level results showed ENHERTU demonstrated a statistically significant and clinically meaningful improvement in PFS versus standard-of-care chemotherapy in patients with HR-positive, HER2-low metastatic breast cancer. A clinically meaningful PFS improvement was also seen in patients with HER2-ultralow expression. An oral presentation will spotlight data from an interim analysis of the dose-expansion phase of the DESTINY-Breast07 Phase 1b/II trial assessing ENHERTU alone or in combination with pertuzumab as 1st-line treatment in HER2-positive metastatic breast cancer. These regimens are being further explored in the DESTINY-Breast09 Phase III clinical trial. Additionally, a poster presentation will share updated OS and PFS results from the DESTINY-Breast03 Phase III trial of ENHERTU versus trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. An oral presentation will feature patient-reported outcomes data from the TROPION-Breast01 Phase III trial of datopotamab deruxtecan in patients with inoperable or metastatic HR-positive, HER2-low or negative breast cancer previously treated with endocrine-based therapy and at least one systemic therapy. Previously presented primary results from TROPION-Breast01 showed datopotamab deruxtecan demonstrated a statistically significant and clinically meaningful improvement in PFS versus investigator’s choice of chemotherapy. Two late-breaking presentations of results from the externally sponsored I-SPY2.2 Phase II trial will highlight the rates of pathological complete response associated with neoadjuvant datopotamab deruxtecan, alone and in combination with IMFINZI, across breast cancer subtypes. Advancing the next wave of medicines and combination therapies to attack cancer from multiple angles A rapid oral presentation will spotlight safety and preliminary efficacy results from an investigator-initiated Trial of C-CAR031, a novel autologous armored Glypican 3 (GPC3) targeting chimeric antigen receptor T cell (CAR-T) therapy that is being investigated for hepatocellular carcinoma. The CAR-T is based on AZD5851, a novel cell therapy designed by AstraZeneca using their transforming growth factor-beta receptor II (TGFβRII) dominant negative armoring platform and is manufactured by AbelZeta Pharmaceuticals Inc. C-CAR031 is being developed in China under a co-development agreement between AbelZeta and AstraZeneca. AstraZeneca’s TGFβRII dominant negative armoring is designed to resist the immuno-suppressive tumor microenvironment and enhance the potential effectiveness of CAR-Ts in solid tumors. A rapid abstract update will feature updated efficacy data from a Phase I trial of AZD0901, a potential first-in-class ADC targeting Claudin 18.2, which has shown promise as a therapeutic target in gastric cancer. First results were presented at the ASCO Plenary Series 2023. Additionally, a clinical science symposium presentation of the externally sponsored CAPRI Phase II trial will share efficacy and safety results for ceralasertib, an ataxia telangiectasia and rad3-related (ATR) kinase inhibitor, plus LYNPARZA (olaparib) in patients with platinum-sensitive recurrent high-grade serious ovarian cancer. Collaboration in the scientific community is critical to improving outcomes for patients. AstraZeneca is collaborating with Daiichi Sankyo Company Limited to develop and commercialize ENHERTU and datopotamab deruxtecan, and with Merck & Co., Inc. (MSD outside of the US and Canada) to develop and commercialize LYNPARZA. AstraZeneca obtained full oncology rights to monalizumab from Innate Pharma in October 2018 through a co-development and commercialization agreement initiated in 2015. Key AstraZeneca presentations during ASCO 2024 Lead Author Abstract Title Presentation details (CDT) Lung Cancers Ramalingam, SS Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: Primary results of the phase 3 LAURA study. Abstract #LBA4 Plenary Session June 2, 2024 2:47pm Spigel, DR ADRIATIC: durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). Abstract #LBA5 Plenary Session June 2, 2024 3:21pm John, T Molecular residual disease (MRD) analysis from the ADAURA trial of adjuvant (adj) osimertinib in patients (pts) with resected EGFR‑mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC). Abstract #8005 Oral Abstract Session June 3, 2024 9:12am Heymach, J Outcomes with perioperative durvalumab (D) in pts with resectable NSCLC and baseline N2 lymph node involvement (N2 R-NSCLC): An exploratory subgroup analysis of AEGEAN. Abstract #8011 Rapid Oral Abstract Session June 2, 2024 4:36pm Aggarwal, C Updated results from COAST, a phase 2 study of durvalumab (D) ± oleclumab (O) or monalizumab (M) in patients (pts) with stage III unresectable non-small cell lung cancer (uNSCLC). Abstract #8046 Poster Session June 3, 2024 1:30pm Levy, BP Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC): Subgroup analysis from TROPION-Lung02. Abstract #8617 Poster Session June 3, 2024 1:30pm Janne, PA Trastuzumab deruxtecan (T-DXd) in patients with HER2-mutant metastatic non–small cell lung cancer (mNSCLC): Final analysis results of DESTINY-Lung02. Abstract #8543 Poster Session June 3, 2024 1:30pm Sun, Y Datopotamab deruxtecan (Dato-DXd) in Chinese patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Results from the phase 1/2 TROPION-PanTumor02 study. Abstract #8548 Poster Session June 3, 2024 1:30pm Lisberg, A Intracranial efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously treated advanced/metastatic non-small cell lung cancer (a/m NSCLC) with actionable genomic alterations (AGA): Results from TROPION-Lung05. Abstract #8593 Poster Session June 3, 2024 1:30pm Sands, J Analysis of drug-related interstitial lung disease (ILD) inpatients (pts) treated with datopotamab deruxtecan (Dato-DXd). Abstract #8623 Poster Session June 3, 2024 1:30pm Breast Cancers Curigliano, G Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06). Abstract #LBA1000 Oral Abstract Session June 2, 2024 7:30am Pernas, S Datopotamab deruxtecan (Dato-DXd) vs chemotherapy (CT) in previously treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Patient-reported outcomes (PROs) from the TROPION-Breast01 study. Abstract #1006 Oral Abstract Session June 1, 2024 4:24pm Andre, F DESTINY-Breast07: Dose-expansion interim analysis of T-DXd monotherapy and T-DXd + pertuzumab in patients with previously untreated HER2+ mBC. Abstract #1009 Oral Abstract Session June 1, 2024 5:24pm Shatsky, RA Rates of pathologic complete response (pCR) after datopotamab deruxtecan (Dato) plus durvalumab (Durva) in the neoadjuvant setting: Results from the I-SPY2.2 trial. Abstract #LBA501 Oral Abstract Session June 3, 2024 3:12pm Meisel, J Rates of pathologic complete response (pCR) after neoadjuvant datopotamab deruxtecan (Dato): Results from the I-SPY2.2 trial. Abstract #LBA509 Rapid Oral Abstract Session May 31, 2024 2:45pm Hamilton, EP Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Updated survival results of DESTINY-Breast03. Abstract #1025 Poster Session June 2, 2024 9:00am Gastrointestinal Cancers Zhang, Q Phase I study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR-T, in patients with advanced hepatocellular carcinoma (HCC). Abstract #4019 Rapid Oral Abstract Session June 3, 2024 10:51am Xu, RH Updates on Abstract 434420: A Phase 1 Trial of Claudin 18.2-Specific Antibody-Drug Conjugate CMG901 in Patients with Advanced Gastric/Gastroesophageal Junction Cancer Education Session June 1, 2024 12:42pm Chan, SL Safety analysis by treatment periods from EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization with durvalumab with/without bevacizumab in participants with embolization-eligible unresectable hepatocellular carcinoma. Abstract #4122 Poster Session June 1, 2024 1:30pm Kelley, RK T cell receptor and immune gene expression pharmacodynamics for durvalumab monotherapy and in combination with tremelimumab or bevacizumab in unresectable hepatocellular carcinoma (uHCC). Abstract #4022 Poster Session June 1, 2024 1:30pm Hamilton, A ATHENA: A phase 1/2 study of AZD5851, a chimeric antigen receptor (CAR) T-cell therapy directed against GPC3 in adult patients with advanced/recurrent hepatocellular carcinoma (HCC). Abstract #TPS2675 Poster Session June 1, 2024 9:00am Shen, L GEMINI-Gastric: A phase 2 study of novel treatment combinations in patients with locally advanced unresectable or metastatic gastric cancers. Abstract #TPS4182 Poster Session June 1, 2024 1:30pm Zhou, J GEMINI-Hepatobiliary: A phase 2 study of novel first-line immuno-oncology-based treatments in patients with advanced hepatobiliary cancers. Abstract #TPS4187 Poster Session June 1, 2024 1:30pm Gynecological Cancers Simpkins, F Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-sensitive epithelial ovarian cancer (cohort A). Abstract #5510 Clinical Science Symposium June 1, 2024 1:39pm Pan-Tumor Raufi, AG CLARITY-PanTumor01: A phase 2 trial of the claudin 18.2-specific antibody-drug conjugate AZD0901 (CMG901) in patients with CLDN18.2-expressing advanced solid tumors. Abstract #TPS3163 Poster Session June 1, 2024 9:00am Punekar, SR An open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT‑112 in human leukocyte antigen-C*08:02–positive adult patients with unresectable, advanced, and/or metastatic solid tumors that are positive for the KRAS G12D mutation. Abstract #TPS2677 Poster Session June 1, 2024 9:00am Spira, AI PRIMROSE: A modular phase 1/2a study of AZD3470, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP deficient advanced solid tumors. Abstract #TPS3179e Poster Session June 1, 2024 9:00am Perez, A Non-clinical evaluation of NT-175, an autologous T cell product engineered to express an HLA-A*02:01-restricted TCR targeting TP53 R175H and resistant to TGF-b inhibition. Abstract #2560 Poster Session June 1, 2024 9:00am IMPORTANT SAFETY INFORMATION FOR TAGRISSO® (osimetinib) There are no contraindications for TAGRISSO Interstitial lung disease (ILD)/pneumonitis occurred in 4% of the 1813 TAGRISSO-treated patients; 0.4% of cases were fatal. In the FLAURA2 study, ILD/pneumonitis occurred in 3.3% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 0.4% of cases were fatal. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (eg, dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD/pneumonitis is confirmed Heart rate-corrected QT (QTc) interval prolongation occurs in TAGRISSO-treated patients. Of the 1813 TAGRISSO monotherapy-treated patients in clinical trials, 1.1% were found to have a QTc >500 msec, and 4.3% of patients had an increase from baseline QTc >60 msec. Of the 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy in the FLAURA2 study, 1.8% were found to have a QTc >500 msec, and 10.5% of patients had an increase from baseline QTc >60 msec. No QTc-related arrhythmias were reported. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia Cardiomyopathy occurred in 3.8% of the 1813 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. In the FLAURA2 study, cardiomyopathy occurred in 9% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 1.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) ≥10% from baseline and to <50% LVEF occurred in 4.2% of 1557 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of TAGRISSO-treated patients experienced LVEF decreases ≥10% from baseline and a drop to <50%. In the FLAURA2 study, 8% (21/262) of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, who had baseline and at least one follow-up LVEF assessment, experienced LVEF decreases ≥10% and a drop to less than 50%. For patients receiving TAGRISSO monotherapy, conduct cardiac monitoring in patients with cardiac risk factors, including assessment of LVEF at baseline and during treatment. For patients receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, conduct cardiac monitoring in all patients, including assessment of LVEF at baseline and during treatment. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO Keratitis was reported in 0.6% of 1813 patients treated with TAGRISSO monotherapy in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist Postmarketing cases consistent with erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if EMM, SJS, or TEN is suspected and permanently discontinue if confirmed Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation of TAGRISSO based on severity Aplastic anemia has been reported in patients treated with TAGRISSO in clinical trials (0.06% of 1813) and postmarketing. Some cases had a fatal outcome. Inform patients of the signs and symptoms of aplastic anemia including but not limited to, new or persistent fevers, bruising, bleeding, and pallor. If aplastic anemia is suspected, withhold TAGRISSO and obtain a hematology consultation. If aplastic anemia is confirmed, permanently discontinue TAGRISSO. Perform complete blood count with differential before starting TAGRISSO, periodically throughout treatment, and more frequently if indicated Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose Because of the potential for serious adverse reactions in breastfed infants from TAGRISSO, women should not breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose Most common (≥20%) adverse reactions, including laboratory abnormalities, were: TAGRISSO monotherapy: leukopenia, lymphopenia, thrombocytopenia, anemia, diarrhea, rash, musculoskeletal pain, neutropenia, nail toxicity, dry skin, stomatitis, and fatigue TAGRISSO in combination with pemetrexed and platinum-based chemotherapy: leukopenia, thrombocytopenia, neutropenia, lymphopenia, rash, diarrhea, stomatitis, nail toxicity, dry skin, and increased blood creatinine INDICATIONS TAGRISSO is indicated as adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated in combination with pemetrexed and platinum-based chemotherapy, for the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated for the treatment of adult patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy Please see complete Prescribing Information, including Patient Information for TAGRISSO. IMPORTANT SAFETY INFORMATION FOR IMFINZI® (durvalumab) There are no contraindications for IMFINZI® (durvalumab) or IMJUDO® (tremelimumab-actl). Severe and Fatal Immune-Mediated Adverse Reactions Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI and IMJUDO depending on severity. See USPI Dosing and Administration for specific details. In general, if IMFINZI and IMJUDO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Immune-Mediated Pneumonitis IMFINZI and IMJUDO can cause immune-mediated pneumonitis, which may be fatal. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. IMFINZI as a Single Agent In patients who did not receive recent prior radiation, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions. In patients who received recent prior radiation, the incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% were fatal and 2.7% were Grade 3 adverse reactions. The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar in patients who received IMFINZI as a single agent or with ES-SCLC or BTC when given in combination with chemotherapy. IMFINZI with IMJUDO Immune‑mediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMFINZI and IMJUDO, including fatal (0.3%) and Grade 3 (0.2%) adverse reactions. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated pneumonitis occurred in 3.5% (21/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including fatal (0.5%), and Grade 3 (1%) adverse reactions. Immune-Mediated Colitis IMFINZI with IMJUDO and platinum-based chemotherapy can cause immune-mediated colitis, which may be fatal. IMFINZI and IMJUDO can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. IMFINZI as a Single Agent Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (<0.1%) and Grade 3 (0.4%) adverse reactions. IMFINZI with IMJUDO Immune‑mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (3.6%) adverse reactions. Intestinal perforation has been observed in other studies of IMFINZI and IMJUDO. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated colitis occurred in 6.5% (39/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy including fatal (0.2%) and Grade 3 (2.5%) adverse reactions. Intestinal perforation and large intestine perforation were reported in 0.1% of patients. Immune-Mediated Hepatitis IMFINZI and IMJUDO can cause immune-mediated hepatitis, which may be fatal. IMFINZI as a Single Agent Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions. IMFINZI with IMJUDO Immune‑mediated hepatitis occurred in 7.5% (29/388) of patients receiving IMFINZI and IMJUDO, including fatal (0.8%), Grade 4 (0.3%) and Grade 3 (4.1%) adverse reactions. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated hepatitis occurred in 3.9% (23/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including fatal (0.3%), Grade 4 (0.5%), and Grade 3 (2%) adverse reactions. Immune-Mediated Endocrinopathies Adrenal Insufficiency: IMFINZI and IMJUDO can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. IMFINZI as a Single Agent Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. IMFINZI with IMJUDO Immune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3%) adverse reactions. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated adrenal insufficiency occurred in 2.2% (13/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.8%) adverse reactions. Hypophysitis: IMFINZI and IMJUDO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. IMFINZI as a Single Agent Grade 3 hypophysitis/hypopituitarism occurred in <0.1% (1/1889) of patients who received IMFINZI. IMFINZI with IMJUDO Immune-mediated hypophysitis/hypopituitarism occurred in 1% (4/388) of patients receiving IMFINZI and IMJUDO. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated hypophysitis occurred in 1.3% (8/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.5%) adverse reactions. Thyroid Disorders (Thyroiditis, Hyperthyroidism, and Hypothyroidism): IMFINZI and IMJUDO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. IMFINZI as a Single Agent Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI. Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. IMFINZI with IMJUDO Immune-mediated thyroiditis occurred in 1.5% (6/388) of patients receiving IMFINZI and IMJUDO. Immune-mediated hyperthyroidism occurred in 4.6% (18/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3%) adverse reactions. Immune-mediated hypothyroidism occurred in 11% (42/388) of patients receiving IMFINZI and IMJUDO. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated thyroiditis occurred in 1.2% (7/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy. Immune-mediated hyperthyroidism occurred in 5% (30/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.2%) adverse reactions. Immune-mediated hypothyroidism occurred in 8.6% (51/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.5%) adverse reactions. Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. IMFINZI as a Single Agent Grade 3 immune-mediated Type 1 diabetes mellitus occurred in <0.1% (1/1889) of patients receiving IMFINZI. IMFINZI with IMJUDO Two patients (0.5%, 2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated Type 1 diabetes mellitus occurred in 0.5% (3/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy including Grade 3 (0.3%) adverse reactions. Immune-Mediated Nephritis with Renal Dysfunction IMFINZI and IMJUDO can cause immune-mediated nephritis. IMFINZI as a Single Agent Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. IMFINZI with IMJUDO Immune-mediated nephritis occurred in 1% (4/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.5%) adverse reactions. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated nephritis occurred in 0.7% (4/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.2%) adverse reactions. Immune-Mediated Dermatology Reactions IMFINZI and IMJUDO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 and CTLA-4 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. IMFINZI as a Single Agent Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions. IMFINZI with IMJUDO Immune-mediated rash or dermatitis occurred in 4.9% (19/388) of patients receiving IMFINZI and IMJUDO, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Immune-mediated rash or dermatitis occurred in 7.2% (43/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.3%) adverse reactions. Immune-Mediated Pancreatitis IMFINZI in combination with IMJUDO can cause immune-mediated pancreatitis. Immune-mediated pancreatitis occurred in 2.3% (9/388) of patients receiving IMFINZI and IMJUDO, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. Other Immune-Mediated Adverse Reactions The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI and IMJUDO or were reported with the use of other immune-checkpoint inhibitors. Cardiac/vascular: Myocarditis, pericarditis, vasculitis. Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy. Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis. Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic. Endocrine: Hypoparathyroidism. Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection. Infusion-Related Reactions IMFINZI and IMJUDO can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI and IMJUDO based on the severity. See USPI Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. IMFINZI as a Single Agent Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions. IMFINZI with IMJUDO Infusion-related reactions occurred in 10 (2.6%) patients receiving IMFINZI and IMJUDO. IMFINZI with IMJUDO and Platinum-Based Chemotherapy Infusion-related reactions occurred in 2.9% (17/596) of patients receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy, including Grade 3 (0.3%) adverse reactions. Complications of Allogeneic HSCT after IMFINZI Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT. Embryo-Fetal Toxicity Based on their mechanism of action and data from animal studies, IMFINZI and IMJUDO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. In females of reproductive potential, verify pregnancy status prior to initiating IMFINZI and IMJUDO and advise them to use effective contraception during treatment with IMFINZI and IMJUDO and for 3 months after the last dose of IMFINZI and IMJUDO. Lactation There is no information regarding the presence of IMFINZI and IMJUDO in human milk; however, because of the potential for serious adverse reactions in breastfed infants from IMFINZI and IMJUDO, advise women not to breastfeed during treatment and for 3 months after the last dose. Adverse Reactions In patients with Stage III NSCLC in the PACIFIC study receiving IMFINZI (n=475), the most common adverse reactions (≥20%) were cough (40%), fatigue (34%), pneumonitis or radiation pneumonitis (34%), upper respiratory tract infections (26%), dyspnea (25%), and rash (23%). The most common Grade 3 or 4 adverse reactions (≥3%) were pneumonia (7%) and pneumonitis/radiation pneumonitis (3.4%). In patients with Stage III NSCLC in the PACIFIC study receiving IMFINZI (n=475), discontinuation due to adverse reactions occurred in 15% of patients in the IMFINZI arm. Serious adverse reactions occurred in 29% of patients receiving IMFINZI. The most frequent serious adverse reactions (≥2%) were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in <2% of patients and were similar across arms. In patients with mNSCLC in the POSEIDON study receiving IMFINZI and IMJUDO plus platinum-based chemotherapy (n=330), the most common adverse reactions (occurring in ≥20% of patients) were nausea (42%), fatigue (36%), musculoskeletal pain (29%), decreased appetite (28%), rash (27%), and diarrhea (22%). In patients with mNSCLC in the POSEIDON study receiving IMFINZI in combination with IMJUDO and platinum-based chemotherapy (n=330), permanent discontinuation of IMFINZI or IMJUDO due to an adverse reaction occurred in 17% of patients. Serious adverse reactions occurred in 44% of patients, with the most frequent serious adverse reactions reported in at least 2% of patients being pneumonia (11%), anemia (5%), diarrhea (2.4%), thrombocytopenia (2.4%), pyrexia (2.4%), and febrile neutropenia (2.1%). Fatal adverse reactions occurred in a total of 4.2% of patients. In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), the most common adverse reactions (≥20%) were nausea (34%), fatigue/asthenia (32%), and alopecia (31%). The most common Grade 3 or 4 adverse reaction (≥3%) was fatigue/asthenia (3.4%). In patients with extensive-stage SCLC in the CASPIAN study receiving IMFINZI plus chemotherapy (n=265), IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%), and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy. In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), the most common adverse reactions (occurring in ≥20% of patients) were fatigue (42%), nausea (40%), constipation (32%), decreased appetite (26%), abdominal pain (24%), rash (23%), and pyrexia (20%). In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), discontinuation due to adverse reactions occurred in 6% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients), and upper gastrointestinal hemorrhage (2 patients). In patients with unresectable HCC in the HIMALAYA study receiving IMFINZI and IMJUDO (n=388), the most common adverse reactions (occurring in ≥20% of patients) were rash (32%), diarrhea (27%), fatigue (26%), pruritus (23%), musculoskeletal pain (22%), and abdominal pain (20%). In patients with unresectable HCC in the HIMALAYA study receiving IMFINZI and IMJUDO (n=388), serious adverse reactions occurred in 41% of patients. Serious adverse reactions in >1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8% of patients who received IMFINZI and IMJUDO, including death (1%), hemorrhage intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%). Permanent discontinuation of treatment regimen due to an adverse reaction occurred in 14% of patients. The safety and effectiveness of IMFINZI and IMJUDO have not been established in pediatric patients. Indications: IMFINZI is indicated for the treatment of adult patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. IMFINZI, in combination with IMJUDO and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC). IMFINZI in combination with IMJUDO is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). Please see Full Prescribing Information including Medication Guide for IMFINZI and IMJUDO. IMPORTANT SAFETY INFORMATION FOR LYNPARZA® (olaparib) CONTRAINDICATIONS There are no contraindications for LYNPARZA. WARNINGS AND PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.2% of patients with various BRCAm, gBRCAm, HRR gene-mutated or HRD-positive cancers who received LYNPARZA as a single agent or as part of a combination regimen, consistent with the approved indications, and the majority of events had a fatal outcome. The median duration of therapy in patients who developed MDS/AML was approximately 2 years (range: <6 months to >4 years). All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. In SOLO-1, patients with newly diagnosed advanced BRCAm ovarian cancer, the incidence of MDS/AML was 1.9% (5/260) in patients who received LYNPARZA and 0.8% (1/130) in patients who received placebo based on an updated analysis. In PAOLA-1, of patients with newly diagnosed advanced ovarian cancer with HRD-positive status, the incidence of MDS/AML was 1.6% (4/255) in patients who received LYNPARZA and 2.3% (3/131) in the control arm. In SOLO-2, patients with BRCAm platinum-sensitive relapsed ovarian cancer, the incidence of MDS/AML was 8% (15/195) in patients who received LYNPARZA and 4% (4/99) in patients who received placebo. The duration of LYNPARZA treatment prior to the diagnosis of MDS/AML ranged from 0.6 years to 4.5 years. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed. Pneumonitis: Occurred in 0.8% of patients exposed to LYNPARZA monotherapy, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately. Venous Thromboembolism (VTE): Including severe or fatal pulmonary embolism (PE) occurred in patients treated with LYNPARZA. In the combined data of two randomized, placebo-controlled clinical studies (PROfound and PROpel) in patients with metastatic castration-resistant prostate cancer (N=1180), VTE occurred in 8% of patients who received LYNPARZA, including pulmonary embolism in 6%. In the control arms, VTE occurred in 2.5%, including pulmonary embolism in 1.5%. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated. Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. Verify pregnancy status in females of reproductive potential prior to initiating treatment. Females Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose. Males Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time. ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), urinary tract infection (13%), thrombocytopenia (11%), and stomatitis (11%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%). ADVERSE REACTIONS—First-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab Most common adverse reactions (Grades 1-4) in ≥10% of patients treated with LYNPARZA/bevacizumab and at a ≥5% frequency compared to placebo/bevacizumab in the first-line maintenance setting for PAOLA-1 were: nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%), and leukopenia (18%). In addition, the most common adverse reactions (≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were: diarrhea (18%), neutropenia (18%), urinary tract infection (15%), and headache (14%). In addition, venous thromboembolism occurred more commonly in patients receiving LYNPARZA/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients for LYNPARZA in combination with bevacizumab in the first-line maintenance setting for PAOLA-1 were: decrease in hemoglobin (79%), decrease in lymphocytes (63%), increase in serum creatinine (61%), decrease in leukocytes (59%), decrease in absolute neutrophil count (35%), and decrease in platelets (35%). ADVERSE REACTIONS—Maintenance gBRCAm Recurrent Ovarian Cancer Most common adverse reactions (Grades 1-4) in ≥20% of patients who received LYNPARZA in the maintenance setting for SOLO-2 were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the maintenance setting for SOLO-2 were: increase in mean corpuscular volume (89%), decrease in hemoglobin (83%), decrease in leukocytes (69%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), increase in serum creatinine (44%), and decrease in platelets (42%). ADVERSE REACTIONS—Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early Breast Cancer Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the adjuvant setting for OlympiA were: nausea (57%), fatigue (including asthenia) (42%), anemia (24%), vomiting (23%), headache (20%), diarrhea (18%), leukopenia (17%), neutropenia (16%), decreased appetite (13%), dysgeusia (12%), dizziness (11%), and stomatitis (10%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the adjuvant setting for OlympiA were: decrease in lymphocytes (77%), increase in mean corpuscular volume (67%), decrease in hemoglobin (65%), decrease in leukocytes (64%), and decrease in absolute neutrophil count (39%). ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast Cancer Most common adverse reactions (Grades 1-4) in ≥20% of patients who received LYNPARZA in the metastatic setting for OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the metastatic setting for OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%). ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic Pancreatic Adenocarcinoma Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the first-line maintenance setting for POLO were: fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the first-line maintenance setting for POLO were: increase in serum creatinine (99%), decrease in hemoglobin (86%), increase in mean corpuscular volume (71%), decrease in lymphocytes (61%), decrease in platelets (56%), decrease in leukocytes (50%), and decrease in absolute neutrophil count (25%). ADVERSE REACTIONS—HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA for PROfound were: anemia (46%), fatigue (including asthenia) (41%), nausea (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%), and dyspnea (10%). Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA for PROfound were: decrease in hemoglobin (98%), decrease in lymphocytes (62%), decrease in leukocytes (53%), and decrease in absolute neutrophil count (34%). ADVERSE REACTIONS—Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA/abiraterone with a difference of ≥5% compared to placebo for PROpel were: anemia (48%), fatigue (including asthenia) (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%), and abdominal pain (13%). Most common laboratory abnormalities (Grades 1-4) in ≥20% of patients who received LYNPARZA/abiraterone for PROpel were: decrease in hemoglobin (97%), decrease in lymphocytes (70%), decrease in platelets (23%), and decrease in absolute neutrophil count (23%). DRUG INTERACTIONS Anticancer Agents: Clinical studies of LYNPARZA with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. CYP3A Inhibitors: Avoid coadministration of strong or moderate CYP3A inhibitors when using LYNPARZA. If a strong or moderate CYP3A inhibitor must be coadministered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment. CYP3A Inducers: Avoid coadministration of strong or moderate CYP3A inducers when using LYNPARZA. USE IN SPECIFIC POPULATIONS Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose. Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients. Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C). Renal Impairment: No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min). INDICATIONS LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated: First-Line Maintenance BRCAm Advanced Ovarian Cancer For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. First-Line Maintenance HRD-Positive Advanced Ovarian Cancer in Combination with Bevacizumab In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: a deleterious or suspected deleterious BRCA mutation, and/or genomic instability Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. Maintenance BRCA-mutated Recurrent Ovarian Cancer For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early Breast Cancer For the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative, high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. gBRCAm, HER2-Negative Metastatic Breast Cancer For the treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer For the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer For the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. BRCAm Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone In combination with abiraterone and prednisone or prednisolone (abi/pred) for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA. Please see complete Prescribing Information, including Medication Guide. IMPORTANT SAFETY INFORMATION FOR ENHERTU® (fam-trastuzumab deruxtecan-nxki) Indications ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with: Unresectable or metastatic HER2-positive (IHC 3+ or ISH positive) breast cancer who have received a prior anti-HER2-based regimen either: – In the metastatic setting, or – In the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen Unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms. Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception. Contraindications None. Warnings and Precautions Interstitial Lung Disease / Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks. HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU. HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21). Neutropenia Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level. HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 63% of patients. Seventeen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1% of patients. HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients. Left Ventricular Dysfunction Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment. HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.8% of patients, of which 0.6% were Grade 3. HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF. Embryo-Fetal Toxicity ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU. Additional Dose Modifications Thrombocytopenia For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by one level. Adverse Reactions HER2-Positive and HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg) The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 1799 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 65% were exposed for >6 months and 38% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (73%), decreased white blood cell count (70%), decreased hemoglobin (66%), decreased neutrophil count (63%), decreased lymphocyte count (58%), fatigue (56%), decreased platelet count (48%), increased aspartate aminotransferase (47%), increased alanine aminotransferase (43%), vomiting (40%), increased blood alkaline phosphatase (38%), alopecia (34%), constipation (33%), decreased appetite (32%), decreased blood potassium (31%), diarrhea (29%), musculoskeletal pain (24%), and abdominal pain (20%). HER2-Positive Metastatic Breast Cancer DESTINY-Breast03 The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg intravenously once every three weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30). Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each). ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (74%), decreased neutrophil count (70%), increased aspartate aminotransferase (67%), decreased hemoglobin (64%), decreased lymphocyte count (55%), increased alanine aminotransferase (53%), decreased platelet count (52%), fatigue (49%), vomiting (49%), increased blood alkaline phosphatase (49%), alopecia (37%), decreased blood potassium (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), headache (22%), respiratory infection (22%), abdominal pain (21%), increased blood bilirubin (20%), and stomatitis (20%). HER2-Low Metastatic Breast Cancer DESTINY-Breast04 The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast04. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU. Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each). ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (70%), decreased hemoglobin (64%), decreased neutrophil count (64%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (44%), alopecia (40%), vomiting (40%), increased aspartate aminotransferase (38%), increased alanine aminotransferase (36%), constipation (34%), increased blood alkaline phosphatase (34%), decreased appetite (32%), musculoskeletal pain (32%), diarrhea (27%), and decreased blood potassium (25%). HER2-Mutant Unresectable or Metastatic NSCLC (5.4 mg/kg) DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis. The safety of ENHERTU was evaluated in 101 patients with HER2-mutant unresectable or metastatic NSCLC who received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity in DESTINY‑Lung02. Nineteen percent of patients were exposed for >6 months. Serious adverse reactions occurred in 30% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I. Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%). ENHERTU was permanently discontinued in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, decreased blood potassium, hypomagnesemia, myocarditis, and vomiting. Dose interruptions of ENHERTU due to adverse reactions occurred in 23% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia and ILD/pneumonitis. Dose reductions due to an adverse reaction occurred in 11% of patients. The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (61%), decreased white blood cell count (60%), decreased hemoglobin (58%), decreased neutrophil count (52%), decreased lymphocyte count (43%), decreased platelet count (40%), decreased albumin (39%), increased aspartate aminotransferase (35%), increased alanine aminotransferase (34%), fatigue (32%), constipation (31%), decreased appetite (30%), vomiting (26%), increased alkaline phosphatase (22%), and alopecia (21%). HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) for patients who received ENHERTU. Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%). ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and decreased blood potassium. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (75%), decreased white blood cell count (74%), decreased neutrophil count (72%), decreased lymphocyte count (70%), decreased platelet count (68%), nausea (63%), decreased appetite (60%), increased aspartate aminotransferase (58%), fatigue (55%), increased blood alkaline phosphatase (54%), increased alanine aminotransferase (47%), diarrhea (32%), decreased blood potassium (30%), vomiting (26%), constipation (24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia (22%). HER2-Positive (IHC3+) Unresectable or Metastatic Solid Tumors The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. The median duration of treatment was 8.3 months (range 0.7 to 30.2). Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in one patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock. ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%. Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis. Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea. The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (75%), nausea (69%), decreased hemoglobin (67%), decreased neutrophil count (66%), fatigue (59%), decreased lymphocyte count (58%), decreased platelet count (51%), increased aspartate aminotransferase (45%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (36%), vomiting (35%), decreased appetite (34%), alopecia (34%), diarrhea (31%), decreased blood potassium (29%), constipation (28%), decreased sodium (22%), stomatitis (20%), and upper respiratory tract infection (20%). Use in Specific Populations Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU. Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose. Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose. Infertility: ENHERTU may impair male reproductive function and fertility. Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients. Geriatric Use: Of the 1287 patients with HER2-positive or HER2-low breast cancer treated with ENHERTU 5.4 mg/kg, 22% were ≥65 years and 3.8% were ≥75 years. No overall differences in efficacy within clinical studies were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (59%) as compared to younger patients (49%). Of the 101 patients with HER2-mutant unresectable or metastatic NSCLC treated with ENHERTU 5.4 mg/kg, 40% were ≥65 years and 8% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 192 patients with HER2-positive (IHC 3+) unresectable or metastatic solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02, DESTINY-Lung01, or DESTINY-CRC02, 39% were 65 years or older and 9% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min). Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST). To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch. Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide. Notes AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. About AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit and follow us on social media @AstraZeneca. US-89716 Last Updated 5/24 View source version on businesswire.com: Contacts Media Inquiries Brendan McEvoy, +1 302 885 2677 Chelsea Tressler, +1 302 885 2677 US Media Mailbox: usmediateam@astrazeneca.com Source: AstraZeneca View this news release online at:

临床3期临床1期ASCO会议临床结果临床2期

100 项与 Ceralasertib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11787	-	-	DB14917

研发状态

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
非小细胞肺癌	临床3期	美国	阿斯利康制药有限公司	2023-05-18
非小细胞肺癌	临床3期	美国	阿斯利康全球研发（中国）有限公司	2023-05-18
非小细胞肺癌	临床3期	中国	阿斯利康全球研发（中国）有限公司	2023-05-18
非小细胞肺癌	临床3期	中国	阿斯利康制药有限公司	2023-05-18
非小细胞肺癌	临床3期	日本	阿斯利康制药有限公司	2023-05-18
非小细胞肺癌	临床3期	日本	阿斯利康全球研发（中国）有限公司	2023-05-18
非小细胞肺癌	临床3期	阿根廷	阿斯利康制药有限公司	2023-05-18
非小细胞肺癌	临床3期	阿根廷	阿斯利康全球研发（中国）有限公司	2023-05-18
非小细胞肺癌	临床3期	澳大利亚	阿斯利康全球研发（中国）有限公司	2023-05-18
非小细胞肺癌	临床3期	澳大利亚	阿斯利康制药有限公司	2023-05-18

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临床结果

适应症

分期

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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


ASH2024	N/A	慢性粒单核细胞白血病 \| 骨髓增生异常综合征	-	Ceralasertib 160mg BID 7on/7off	淵廠鬱願鏇遞範鹹獵積(築繭繭鑰範蓋簾淵築選) = n=1, grade 3 or higher AEs with 7on/7off dosing 蓋廠窪廠顧積鹹廠獵壓 (鹹網範鏇齋餘壓衊憲艱 ) 更多	-	2024-12-07
				Ceralasertib 160mg BID 14on/14off
NCT03787680 (CTgov)	临床2期	转移性去势抵抗性前列腺癌	49	Olaparib+AZD6738 (Cohort 1 (DRPro))	鬱鑰遞夢築顧餘蓋齋夢(築鑰鹽鹹簾願醖範鏇網) = 餘憲簾網築積膚簾選壓築鬱襯艱獵製顧餘構選 (齋壓遞醖淵鬱範選膚獵, 觸餘憲憲夢遞壓觸鬱艱 ~ 鑰鏇製築積壓簾蓋構選) 更多	-	2024-08-12
				Olaparib+AZD6738 (Cohort 2 (DRDef))	壓簾餘鏇窪繭襯鏇鏇憲(鹽觸餘夢鬱艱廠餘壓鬱) = 選艱願醖廠糧蓋淵願憲築築衊獵餘襯築製鏇壓 (糧餘蓋鏇觸鬱衊餘鹹窪, 築壓夢蓋顧築鑰積簾遞 ~ 糧憲築鬱淵鹹簾繭廠選) 更多
NCT04564027 (PLANETTE, CTgov)	临床2期	晚期恶性实体瘤 \| 晚期癌症	54	Ceralasertib (Cohort A (aST): 160 mg of Ceralasertib)	淵艱鏇鑰繭範鑰選鬱艱(顧糧憲鑰鏇遞繭願壓願) = 窪窪夢壓窪鏇鏇繭鏇簾蓋夢獵積蓋齋窪餘鑰獵 (窪鹹獵獵顧獵衊鏇築範, 遞鑰夢網鏇窪築廠築醖 ~ 餘淵餘夢築鬱製積鏇鹽) 更多	-	2024-06-25
				Ceralasertib (Cohort B (mCRPC): 160 mg of Ceralasertib)	範蓋選簾餘夢遞範範構(顧餘醖願齋鏇顧鹽窪網) = 鏇築膚醖鬱獵繭簾夢壓壓繭選遞鏇簾窪積蓋範 (獵獵鏇獵獵範遞夢衊襯, 窪鬱範製憲襯憲獵簾壓 ~ 憲觸簾齋簾遞繭製選積) 更多
NCT03462342 (CAPRI, ASCO2024)	临床2期	铂敏感性卵巢上皮癌 genomic instability \| HRD positive \| LOH	37	Ceralasertib 160mg	製鏇鏇獵鏇窪襯艱壓夢(齋憲獵壓觸繭艱壓廠餘) = 積獵壓艱膚築憲夢廠淵壓築選鑰窪獵顧餘淵糧 (製築觸選襯鹽糧鹹襯廠 ) 更多	积极	2024-05-24
NCT04564027 (PLANETTE, AACR2024) 人工标引	临床2期	实体瘤 \| 转移性去势抵抗性前列腺癌 ATM	45	Ceralasertib 160 mg BIDCeralasertib 160 mg BID	蓋繭憲衊鏇製蓋廠構顧(觸膚遞鹹鹽鏇鬱糧糧簾) = 膚願鏇艱築鹽窪範簾簾範鏇鬱繭憲繭獵願獵憲 (窪繭選鹽鹹願願壓襯顧, 1.9 ~ 17.9) 更多	不佳	2024-04-05
				Ceralasertib (mCRPC)	蓋繭憲衊鏇製蓋廠構顧(觸膚遞鹹鹽鏇鬱糧糧簾) = 壓醖糧範餘積觸憲繭獵範鏇鬱繭憲繭獵願獵憲 (窪繭選鹽鹹願願壓襯顧, 0.8 ~ 26.8) 更多
NCT02223923 (PATRIOT, Pubmed) 人工标引	临床1期	难治恶性实体肿瘤 Gene \| ARID1A Positive	67	Ceralasertib 20-240 mg BD	獵鬱淵繭製積膚淵艱襯(淵夢鹽淵範觸鹹鬱鏇網) = 糧憲鏇窪觸構淵憲醖選鑰鹽簾鏇醖鏇構憲窪築 (膚糧願衊膚廠齋衊壓繭 ) 更多	积极	2024-01-16
NCT02664935 (WCLC2023) 人工标引	临床2期	晚期非小细胞肺癌 RAS Mutations	31	Ceralasertib+Durvalumab (KRASmut patients received previous ICB)	鏇顧遞憲窪鹽繭憲願觸(繭蓋壓築鬱淵鹹繭獵顧) = 積膚獵範簾艱糧構壓壓膚夢繭壓範獵膚鹹鏇蓋 (壓蓋鏇積醖網製獵積醖 ) 更多	积极	2023-09-10
				Ceralasertib+Durvalumab (ICB exposed KRAS wild-type patients)	鏇顧遞憲窪鹽繭憲願觸(繭蓋壓築鬱淵鹹繭獵顧) = 選鏇齋鏇網鏇網蓋淵糧膚夢繭壓範獵膚鹹鏇蓋 (壓蓋鏇積醖網製獵積醖 ) 更多
NCT05450692 (LATIFY, ASCO2023)	临床3期	转移性非小细胞肺癌 \| 局部晚期非小细胞肺癌二线 \| 三线	580	Ceralasertib + Durvalumab	衊廠選繭淵醖壓壓鏇構(繭鹽觸製鑰顧鑰艱顧窪) = 鬱遞鬱窪繭夢醖鹽壓顧網築餘範鏇鑰築廠襯築 (積淵糧積艱鏇壓構膚簾, 14.1–20.3) 更多	-	2023-05-31
NCT03328273 (Pubmed)	临床1/2期	复发性慢性淋巴细胞白血病	11	Ceralasertib monotherapy	壓鹹餘範鹹遞蓋艱齋衊(艱醖繭醖觸製願觸鏇選) = 廠築鏇獵餘獵遞壓鹹選積製鹹壓夢鑰鏇齋繭憲 (醖襯觸廠遞範憲膚鏇網 ) 更多	-	2023-01-01
				Acalabrutinib plus ceralasertib	壓鹹餘範鹹遞蓋艱齋衊(艱醖繭醖觸製願觸鏇選) = 蓋鏇蓋觸膚鹹觸膚製醖積製鹹壓夢鑰鏇齋繭憲 (醖襯觸廠遞範憲膚鏇網 )
NCT02576444 (OLAPCO, CTgov)	临床2期	晚期恶性实体瘤	67	Olaparib AZD2881 (Olaparib AZD2881)	窪鏇壓鏇夢鹹窪鏇艱簾(願膚願製簾淵構積繭觸) = 積鹹鏇蓋襯選齋壓衊淵願齋鏇衊壓鬱遞夢艱製 (鑰醖鑰窪選鬱餘觸襯積, 鏇艱鹽糧遞範淵獵憲選 ~ 積築築夢餘遞夢夢選鬱) 更多	-	2022-12-28
				Capivasertib AZD5363+Olaparib (Olaparib & Capivasertib AZD5363)	窪鏇壓鏇夢鹹窪鏇艱簾(願膚願製簾淵構積繭觸) = 餘淵簾襯觸鹹範蓋積範願齋鏇衊壓鬱遞夢艱製 (鑰醖鑰窪選鬱餘觸襯積, 鏇淵鑰簾鬱蓋憲襯簾遞 ~ 觸顧壓淵襯鹹築蓋簾廠) 更多