LTK

Application based on results from the TRIDENT-1 and CARE trials, in which Augtyro demonstrated clinically meaningful response rates If approved, Augtyro will provide a new, next-generation option for patients with NTRK-positive locally advanced or metastatic solid tumors who have high unmet medical needs The U.S. Food and Drug Administration assigned a target action date of June 15, 2024 PRINCETON, N.J.--(BUSINESS WIRE)--Bristol Myers Squibb Company (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has accepted the supplemental New Drug Application (sNDA) for Augtyro™ (repotrectinib) for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, and are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity. The filing acceptance is based on results from the registrational Phase 1/2 TRIDENT-1 trial (adult patients with NTRK-positive solid tumors) and CARE study (pediatric patients with NTRK-positive solid tumors). The FDA granted the application Priority Review status and assigned a Prescription Drug User Fee Act (PDUFA) goal date of June 15, 2024. “While great advancements have been made over the last decade, patients with NTRK-positive locally advanced or metastatic solid tumors still experience significant unmet needs. New and effective treatment options that may improve durability of response and address resistance to existing tyrosine kinase inhibitors are critical to helping patients with these aggressive tumors,” said Joseph Fiore, vice president, global program lead, Augtyro, Bristol Myers Squibb. “We look forward to working closely with the FDA on the review of our application for Augtyro for this tumor-agnostic indication and potentially offering patients with NTRK-positive disease a new, durable treatment option.” The filing was based on the results from the TRIDENT-1 and CARE trials. In the TRIDENT-1 study, Augtyro demonstrated clinically meaningful response rates in patients with NTRK-positive locally advanced or metastatic solid tumors. Durability of response was robust, including among patients whose tumors harbor common resistance mutations, and intracranial responses were observed. Augtyro showed a safety pro was well tolerated and generally manageable. The study remains ongoing to assess long-term outcomes and additional endpoints. Results from TRIDENT-1 were supported by data from the CARE study, which evaluates Augtyro in pediatric and young adult patients with locally advanced or metastatic solid tumors harboring ALK, ROS1 or NTRK1-3 gene alterations. Additionally, in November 2023 the U.S. Food and Drug Administration approved Augtyro for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer NSCLC. Bristol Myers Squibb thanks the patients and investigators involved with the TRIDENT-1 and CARE clinical trials. Turning Point Therapeutics is a wholly owned subsidiary of the Bristol-Myers Squibb Company. As of August 2022, Bristol Myers Squibb acquired the company, including its asset repotrectinib. About TRIDENT-1 TRIDENT-1 is a global, multicenter, single-arm, open-label, multi-cohort Phase 1/2 clinical trial evaluating the safety, tolerability, pharmacokinetics and anti-tumor activity of Augtyro in patients with advanced solid tumors, including non-small cell lung cancer (NSCLC). Phase 1/2 includes patients with locally advanced or metastatic solid tumors harboring ROS1 or NTRK fusions. Additional analyses of the trial are still being conducted; asymptomatic central nervous system (CNS) metastases are allowed. The trial excludes patients with symptomatic brain metastases, among other exclusion criteria. Phase 1 of the trial included the dose escalation that determined the recommended Phase 2 dose. Phase 2 of the trial has a primary endpoint of overall response rate (ORR). Key secondary endpoints include duration of response (DOR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as assessed by Blinded Independent Central Review (BICR), progression-free survival (PFS), and intracranial response in six distinct expansion cohorts, including tyrosine kinase inhibitor (TKI)-naïve and TKI-pretreated patients with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive locally advanced or metastatic solid tumors. About CARE CARE is a Phase 1/2 open-label, safety, tolerability, pharmacokinetics and anti-tumor activity clinical trial evaluating Augtyro in pediatric and young adult patients with locally advanced or metastatic solid tumors harboring ALK, ROS1 or NTRK1-3 gene alterations. Phase 1 of the study aims to evaluate the safety and tolerability at different dose levels. Phase 1 of the trial has primary endpoints of dose limiting toxicities (DLTs) and pediatric recommended Phase 2 dose (RP2D). Secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), time to response (TTR), duration of response (DOR) and intracranial ORR (IC-ORR). Phase 2 of the study will seek to demonstrate the efficacy and anti-tumor activity of Augtyro in pediatric and young adult patients. The primary endpoint of Phase 2 is ORR and secondary endpoints include CBR, TTR, DOR, IC-ORR, progression-free survival (PFS), central nervous system PFS (CNS-PFS) and overall survival (OS). About NTRK-Positive Solid Tumors Neurotrophic tropomyosin kinase receptors (NTRK) are a family of receptors involved in neural development. NTRK gene fusions can play a role in the development of cancer. They are rare in patients with solid tumors with less than 1% of patients testing positive, though may be more frequent in patients with secretory breast cancer, infantile fibrosarcoma, thyroid cancer, gastrointestinal stromal tumors, spitzoid tumors and infantile fibrosarcoma, among other cancers. Per international treatment guidelines, targeted agents are part of the treatment armamentarium for patients with a tumor harboring this gene alteration. Bristol Myers Squibb: Creating a Better Future for People with Cancer Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research platforms uniquely position the company to approach cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. About Augtyro Augtyro (TPX-0005, BMS-986472) is a next-generation tyrosine kinase inhibitor (TKI) targeting ROS1-positive or NTRK-positive locally advanced or metastatic solid tumors, including non-small cell lung cancer (NSCLC), where there remain significant unmet medical needs for patients. Augtyro was designed to improve durability of response and with favorable properties for human brain penetration to enhance intracranial activity. It is being studied in a registrational Phase 1/2 trial in adults (TRIDENT-1) and a Phase 1/2 trial in pediatric patients (CARE). Augtyro has demonstrated clinically meaningful results and was granted three Breakthrough Therapy Designations (BTDs) by the FDA for the treatment of patients with: ROS1-positive metastatic NSCLC who have not been treated with a ROS1 TKI; ROS1-positive metastatic NSCLC who have been previously treated with one ROS1 TKI and who have not received prior platinum-based chemotherapy; and advanced solid tumors that have an NTRK gene fusion who have progressed following treatment with one or two prior tropomyosin receptor kinase (TRK) TKIs (with or without prior chemotherapy) and have no satisfactory alternative treatments. Augtyro was also previously granted four fast-track designations in patients with: ROS1-positive advanced NSCLC who have been treated with disease progression following one prior line of platinum-based chemotherapy and one prior line of a ROS1 TKI; ROS1-positive advanced NSCLC who have not been treated with a ROS1 TKI; ROS1-positive advanced NSCLC who have been previously treated with one ROS1 TKI and who have not received prior platinum-based chemotherapy; and advanced solid tumors that have an NTRK gene fusion who have progressed following treatment with at least one prior line of chemotherapy and one or two prior TRK TKIs and have no satisfactory alternative treatments. Augtyro was also granted an Orphan Drug designation by the U.S. Food and Drug Administration (FDA). INDICATION AUGTYROTM (repotrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). Warnings & Precautions IMPORTANT SAFETY INFORMATION Central Nervous System Adverse Reactions Among the 351 patients who received AUGTYRO in the TRIDENT-1 study, a broad spectrum of central nervous system (CNS) adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 75% with Grade 3 or 4 events occurring in 4%. Dizziness, including vertigo, occurred in 64% and Grade 3 dizziness occurred in 2.8% of patients. The median time to onset was 6 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 12% required dose reduction of AUGTYRO due to dizziness. Ataxia, including gait disturbance and balance disorder, occurred in 29% of the 351 patients; Grade 3 ataxia occurred in 0.3%. The median time to onset was 15 days (1 day to 1.4 years). Dose interruption was required in 6% of patients, 8% required dose reduction and one patient (0.3%) permanently discontinued AUGTYRO due to ataxia. Cognitive disorder, including memory impairment and disturbance in attention, occurred in 23% of the 351 patients. Cognitive disorders included memory impairment (13%), disturbance in attention (11%), and confusional state (2%); Grade 3 cognitive disorders occurred in 0.9% of patients. The median time to onset of cognitive disorders was 37 days (1 day to 1.4 years). Dose interruption was required in 2% of patients, 1.7% required dose reduction and 0.6% permanently discontinued AUGTYRO due to cognitive adverse reactions. Mood disorders occurred in 6% of the 351 patients. Mood disorders occurring in >1% of patients included anxiety (2.8%), irritability (1.1%), and depression (1.4%); Grade 4 mood disorders (mania) occurred in 0.3% of patients. Dose interruption was required in 0.3% of patients and 0.3% required a dose reduction due to mood disorders. Sleep disorders including insomnia and hypersomnia occurred in 15% of the 351 patients. Sleep disorders observed in >1% of patients were somnolence (8%), insomnia (6%) and hypersomnia (1.1%). Dose interruption was required in 0.9% of patients, and 0.3% required a dose reduction due to sleep disorders. The incidences of CNS adverse reactions reported were similar in patients with and without CNS metastases. Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity. Interstitial Lung Disease (ILD)/Pneumonitis Among the 351 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.6%] and interstitial lung disease [0.3%]) occurred in 2.9%; Grade 3 ILD/pneumonitis occurred in 1.1%. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.6% required dose reduction, and 1.1% permanently discontinued AUGTYRO due to ILD/pneumonitis. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold AUGTYRO in patients with suspected ILD/pneumonitis and permanently discontinue AUGTYRO if ILD/pneumonitis is confirmed. Hepatotoxicity Among the 351 patients treated with AUGTYRO, increased alanine transaminase (ALT) occurred in 35%, increased aspartate aminotransferase (AST) occurred in 40%, including Grade 3 or 4 increased ALT in 2% and increased AST in 2.6%. The median time to onset of increased ALT or AST was 15 days (range: 1 day to 1.9 years). Increased ALT or AST leading to dose interruptions or reductions occurred in 2.8% and 1.4% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.6%. Monitor liver function tests, including ALT, AST and bilirubin, every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue AUGTYRO based on the severity. Myalgia with Creatine Phosphokinase (CPK) Elevation Among the 351 patients treated with AUGTYRO, myalgia occurred in 13% of patients, with Grade 3 in 0.6%. Median time to onset of myalgia was 19 days (range: 1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.7% of patients. AUGTYRO was interrupted in one patient with myalgia and concurrent CPK elevation. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during AUGTYRO treatment and monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. Based on severity, withhold and then resume AUGTYRO at same or reduced dose upon improvement. Hyperuricemia Among the 351 patients treated with AUGTYRO, 18 patients (5%) experienced hyperuricemia reported as an adverse reaction, 0.9% experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication. Monitor serum uric acid levels prior to initiating AUGTYRO and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity. Skeletal Fractures Among 351 adult patients who received AUGTYRO, fractures occurred in 2.3%. Fractures involved the ribs (0.6%), feet (0.6%), spine (0.3%), acetabulum (0.3%), sternum (0.3%), and ankles (0.3%). Some fractures occurred at sites of disease and prior radiation therapy. The median time to fracture was 71 days (range: 31 days to 1.4 years). AUGTYRO was interrupted in 0.3% of patients. Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of AUGTYRO on healing of known fractures and risk of future fractures. Embryo-Fetal Toxicity Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose, since AUGTYRO can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AUGTYRO and for 4 months after the last dose. Adverse Reactions Among 351 patients who received AUGTYRO for ROS1-positive NSCLC and other solid tumors in the TRIDENT-1 trial, the most common (>20%) adverse reactions were dizziness (64%), dysgeusia (50%), peripheral neuropathy (47%), constipation (37%), dyspnea (30%), ataxia (29%), fatigue (29%), cognitive disorders (23%), and nausea (20%). In a subset of 264 patients who received AUGTYRO for ROS1-positive NSCLC, the most common (≥20%) adverse reactions were dizziness (63%), dysgeusia (48%), peripheral neuropathy (47%), constipation (36%), dyspnea (30%), ataxia (28%), fatigue (24%), cognitive disorders (23%), and muscular weakness (21%). Drug Interactions Effects of Other Drugs on AUGTYRO Strong and Moderate CYP3A Inhibitors Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO. P-gp Inhibitors Avoid concomitant use with P-gp inhibitors. Concomitant use of AUGTYRO with a P-gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Strong and Moderate CYP3A Inducers Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO. Effects of AUGTYRO on other Drugs Certain CYP3A4 Substrates Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling. Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates, which can reduce the efficacy of these substrates. Contraceptives Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives. Avoid concomitant use of AUGTYRO with hormonal contraceptives. Advise females to use an effective nonhormonal contraceptive. Please see U.S. Full Prescribing Information for AUGTYRO About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that Augtyro (repotrectinib) may not receive regulatory approval for the additional indication described in this release in the currently anticipated timeline or at all, that any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such treatment for such additional indication described in this release will be commercially successful. No forward-looking statement can be guaranteed. It should be noted that acceptance of the application does not change the standards for FDA approval. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2023 as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news

▎药明康德内容团队报道近日，香港证券交易所网站公示显示，同源康医药已向港交所递交IPO申请并获得受理。同源康医药成立于2017年，是一家临床阶段的生物制药公司，致力于发现、开发差异化靶向疗法并对其进行商业化，以满足癌症治疗中亟待满足的医疗需求。自成立以来，该公司已建立由11款候选药物组成的产品管线，其中有多款已处于临床试验阶段。截图来源：参考资料[1]同源康医药主要专注于小分子药物开发。根据招股书，该公司的产品管线包括核心产品TY-9591、关键产品TY-302和TY-2136b、多款创新临床产品以及4款处于临床前阶段的产品。TY-9591是同源康医药的核心产品。作为一款第三代EGFR-TKI，该药对EGFR突变具有抗肿瘤作用，并具有出色的血脑屏障渗透能力。同源康医药正在研究TY-9591在EGFR突变非小细胞肺癌（NSCLC）及NSCLC脑转移中的作用。根据招股书介绍，TY-9591可以不可逆地与某些EGFR突变体结合，包括L858R突变、19外显子缺失、L858R/T790M突变和19外显子缺失/T790M突变，从而通过阻断酪氨酸激酶的磷酸化和细胞内信号通路（如Ras/Raf/MEK/ERK或PI3K/AKT通路）来抑制下游信号级联反应，最终抑制癌细胞的增殖和转移。此外，TY-9591在安全性方面的提升预计将可提供更长的治疗窗口。临床试验数据显示，在入组1b期及2期临床研究的29例从未接受治疗的可评估NSCLC脑转移患者中，25例患者达到颅内部分缓解（PR）及4例患者达到完全缓解（CR），颅内客观缓解率（ORR）为100%。在2期研究中，研究人员观察到严重不良事件的总体发生率为8.3%，治疗相关严重不良事件的发生率低至8.3%，显示出良好的安全性。根据这些令人鼓舞的临床数据，同源康医药正在就TY-9591单一疗法进行一项关键的2期临床试验，作为EGFR突变NSCLC脑转移的一线治疗。此外，1b期研究临床数据显示，TY-9591在78例可评估患者中表现出了良好的疗效和安全性，EGFR突变（L858R/19外显子缺失）NSCLC患者的中位无进展生存期（PFS）为21.5个月，其中19外显子缺失患者为25.7个月，L858R突变患者为19.3个月。研究人员确认的ORR为85.9%，其中19外显子缺失患者为85.7%，L858R突变患者为86.1%。此外，未观察到DLT，而不良事件的发生率和严重程度均可接受。研究人员正在进行TY-9591单一疗法作为一线治疗EGFR L858R突变的局部晚期或转移性NSCLC的注册性3期临床试验。截图来源：参考资料[1]TY-302是一种强效、选择性口服CDK4/6抑制剂，拟开发治疗乳腺癌及前列腺癌等晚期实体瘤。该候选药以关键细胞周期调节因子CDK4/6为靶点， 抑制Rb的磷酸化，从而防止癌细胞增殖。根据从目前1/2期临床试验收集的初步安全性数据，在一般不良事件（尤其是有关传染病、皮肤及皮下组织以及胃肠道系统的不良事件）方面，TY-302实现了更高的安全性。此外，TY-302在乳腺癌方面取得了令人鼓舞的疗效。研究人员观察到TY-302在入组的既往二线或多线治疗失败的14例乳腺癌患者中，疾病控制（DCR）达71.4%。同源康医药预计将进一步研究TY-302与托瑞米芬联合治疗二线内分泌治疗后进展的三线或后线ER+/HER2−乳腺癌的效果。此外，该公司还计划于2024年下半年开始TY-302治疗前列腺癌的2期临床试验，探索联合阿比特龙的TY-302用于治疗mCRPC，这是一种难以治疗且对标准护理治疗（内分泌治疗）无反应的晚期前列腺癌。TY-2136b为该公司自主研发的一款口服ROS1/NTRK抑制剂，拟开发用于治疗实体瘤。该药被设计为有效结合活性激酶构象，并避免各种临床耐药突变引起的空间干扰。TY-2136b主要针对伴有ROS1或NTRK突变的NSCLC，在临床前研究中已表现出良好的安全性，且在解决对现有ROS1/NTRK药物获得性耐药方面具有显著疗效。美国FDA已授予TY-2136b孤儿药资格，用于治疗ROS1阳性、NTRK融合阳性、ALK阳性或LTK阳性NSCLC。该药目前正在美国进行1期临床试验。同源康医药已授予丽珠医药TY-2136b的大中华区权利许可。此外，同源康医药还在开发多个针对CDK家族的产品，包括：TY-2699a，一种CDK7抑制剂；TY-0540，一种CDK2/4/6抑制剂；TY-1210，一种CDK2抑制剂；TY-0609，一种CDK4抑制剂。肺癌是同源康医药的主要研究领域之一。该公司也正在开发多种以肺癌为适应症的候选药物，包括：TY-1091，用于RET阳性融合实体瘤；TY-4028，用于EGFR 20外显子插入突变的局部晚期或转移性NSCLC；TY-2699a，用于SCLC；以及TY-3200，用于NSCLC。聚焦前沿，群星璀璨！JPM大会期间于旧金山举行的“2024药明康德全球论坛”上，数千名行业人士齐聚现场，30多位行业领袖带来独家洞见。为了更多行业同仁能够跨越时空观看精彩内容，北京时间2月1日10:00-14:30，我们将提供“2024药明康德全球论坛”限时免费线上回放。产业大咖为何对2024年保持乐观？GLP-1激动剂的火热给我们带来了哪些启示？在癌症和更广泛的疾病领域，新兴疗法将如何重塑治疗格局？还有哪些技术和方向可能在新一年里迎来爆发？欢迎扫描结尾二维码查看完整议程并注册预约观看！▲本次论坛面向全球观众免费开放，长按识别上方二维码，即可申请观看。参考资料：[1]浙江同源康医药股份有限公司 - B的申请版本. Retrieved Jan 27，2024, from https://www1.hkexnews.hk/app/sehk/2024/106204/documents/sehk24012601281_c.pdf本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈。转发授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

Application based on data from the registrational TRIDENT-1 and CARE trials showing robust responses and durable activity in these patient populations If approved, repotrectinib will offer a potential best-in-class treatment for patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer and a new option for patients with NTRK-positive solid tumors, in the European Union PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb Company (NYSE: BMY) today announced that the European Medicines Agency (EMA) has validated its marketing authorization application for the next-generation tyrosine kinase inhibitor (TKI) repotrectinib as a treatment for ROS1 TKI-naïve and -pretreated adult patients with ROS1-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) and TKI-naïve and -pretreated adult and pediatric patients 12 years and older with NTRK-positive locally advanced or metastatic solid tumors. The application was based on results from the registrational Phase 1/2 TRIDENT-1 trial (adult patients with ROS1-positive NSCLC or NTRK-positive solid tumors) and CARE study (pediatric patients with NTRK-positive solid tumors). Validation of the application confirms the submission is complete and begins the EMA’s centralized review procedure. “While there are existing TKIs for the treatment of ROS1-positive non-small cell lung cancer and NTRK-positive solid tumors, there is still an undeniable need for new options that may offer patients more durable responses, including those with metastatic disease to the brain, and may address the issue of treatment resistance for patients with these aggressive and rare tumors,” said Joseph Fiore, executive director, global program lead, repotrectinib, Bristol Myers Squibb. “The clinical trial results with repotrectinib highlight the potential for this next-generation therapy to become a best-in-class option for patients with tumors harboring ROS1 fusions and a new option for those with NTRK-fusion positive tumors, two groups who each continue to face a high unmet medical need. Today’s validation by the European Medicines Agency brings us another step closer to our goal of making this new targeted therapy available to patients in Europe.” In the TRIDENT-1 and CARE trials, repotrectinib demonstrated clinically meaningful response rates in patients across ROS1-positive NSCLC and NTRK-positive solid tumor cohorts. Durability of response was robust and intracranial responses were observed in both settings, as well as in patients whose tumors harbor common resistance mutations. The safety pro repotrectinib was well characterized and generally manageable with routine standard-of-care treatments. The study remains ongoing to assess long-term outcomes and additional endpoints across patient populations with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive locally advanced or metastatic solid tumors. Additionally, in November 2023 the U.S. Food and Drug Administration approved Augtyro™ (repotrectinib) for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC. Bristol Myers Squibb thanks the patients and investigators involved with the TRIDENT-1 and CARE clinical trials. Turning Point Therapeutics is a wholly owned subsidiary of the Bristol-Myers Squibb Company. As of August 2022, Bristol Myers Squibb acquired the company, including its asset repotrectinib. About TRIDENT-1 TRIDENT-1 is a global, multicenter, single-arm, open-label, multi-cohort Phase 1/2 clinical trial evaluating the safety, tolerability, pharmacokinetics and anti-tumor activity of repotrectinib in patients with advanced solid tumors, including non-small cell lung cancer (NSCLC). Phase 1/2 includes patients with locally advanced or metastatic solid tumors harboring ROS1 fusions. Additional analyses of the trial are still being conducted; asymptomatic central nervous system (CNS) metastases are allowed. The trial excludes patients with symptomatic brain metastases, among other exclusion criteria. Phase 1 of the trial included the dose escalation that determined the recommended Phase 2 dose. Phase 2 of the trial has a primary endpoint of overall response rate (ORR). Key secondary endpoints include duration of response (DOR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as assessed by Blinded Independent Central Review (BICR), progression-free survival (PFS), and intracranial response in six distinct expansion cohorts, including tyrosine kinase inhibitor (TKI)-naïve and TKI-pretreated patients with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive locally advanced or metastatic solid tumors. About CARE CARE is a Phase 1/2 open-label, safety, tolerability, pharmacokinetics and anti-tumor activity clinical trial evaluating repotrectinib in pediatric and young adult patients with locally advanced or metastatic solid tumors harboring ALK, ROS1 or NTRK1-3 gene alterations. Phase 1 of the study aims to evaluate the safety and tolerability at different dose levels. Phase 1 of the trial has primary endpoints of dose limiting toxicities (DLTs) and pediatric recommended Phase 2 dose (RP2D). Secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), time to response (TTR), duration of response (DOR) and intracranial ORR (IC-ORR). Patients less than 12 years of age will initially be enrolled in Phase 1 to determine the RP2D for this age group. Once the pediatric RP2D is determined, patients less than 12 years of age may be enrolled into Phase 2 of the study. Patients ages 12 to 25 years will be directly enrolled into Phase 2 concurrent with Phase 1 enrollment. Phase 2 of the study will seek to demonstrate the efficacy and anti-tumor activity of repotrectinib in pediatric and young adult patients. The primary endpoint of Phase 2 is ORR and secondary endpoints include CBR, TTR, DOR, IC-ORR, progression-free survival (PFS), central nervous system PFS (CNS-PFS) and overall survival (OS). About ROS1-Positive Lung Cancer Lung cancer is the leading cause of cancer deaths in the United States. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) represents up to 85% of diagnoses. Survival rates vary depending on the stage and type of the cancer when diagnosed. ROS1 fusions are rare and occur in about 1-2% of patients with NSCLC. With a median age of 50, patients with tumors that are ROS1-positive tend to be younger than the average lung cancer patient, more often female than male and may have little to no smoking history. ROS1-positive lung cancer tends to be aggressive and can often spread to the brain. ROS1 tyrosine kinase inhibitor (TKI) therapy is the current standard of care for patients with a tumor harboring this gene alteration. About NTRK-Positive Solid Tumors NTRK gene fusions are rare in patients with solid tumors with less than 1% of patients testing positive. Per international treatment guidelines, targeted agents are part of the treatment armamentarium for patients with a tumor harboring this gene alteration. Bristol Myers Squibb: Creating a Better Future for People with Cancer Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research platforms uniquely position the company to approach cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. About Repotrectinib Repotrectinib (TPX-0005, BMS-986472) is a next-generation tyrosine kinase inhibitor (TKI) targeting ROS1- or NTRK-positive locally advanced or metastatic solid tumors, including non-small cell lung cancer (NSCLC), where there remain significant unmet medical needs for patients. Repotrectinib was designed to improve durability of response and with favorable properties for human brain penetration to enhance intracranial activity. It is being studied in a registrational Phase 1/2 trial primarily in adults and a Phase 1/2 trial in pediatric patients. In June 2017, repotrectinib was granted an Orphan Drug designation by the U.S. Food and Drug Administration (FDA). Since then, repotrectinib has demonstrated clinically meaningful results and was granted three Breakthrough Therapy Designations (BTDs) by the FDA for the treatment of patients with: ROS1-positive metastatic NSCLC who have not been treated with a ROS1 TKI; ROS1-positive metastatic NSCLC who have been previously treated with one ROS1 TKI and who have not received prior platinum-based chemotherapy; and advanced solid tumors that have an NTRK gene fusion who have progressed following treatment with one or two prior tropomyosin receptor kinase (TRK) TKIs (with or without prior chemotherapy) and have no satisfactory alternative treatments. Repotrectinib was also previously granted four fast-track designations in patients with: ROS1-positive advanced NSCLC who have been treated with disease progression following one prior line of platinum-based chemotherapy and one prior line of a ROS1 TKI; ROS1-positive advanced NSCLC who have not been treated with a ROS1 TKI; ROS1-positive advanced NSCLC who have been previously treated with one ROS1 TKI and who have not received prior platinum-based chemotherapy; and advanced solid tumors that have an NTRK gene fusion who have progressed following treatment with at least one prior line of chemotherapy and one or two prior TRK TKIs and have no satisfactory alternative treatments. U.S. FDA-APPROVED INDICATION AUGTYROTM (repotrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). Warnings & Precautions IMPORTANT SAFETY INFORMATION Central Nervous System Adverse Reactions Among the 351 patients who received AUGTYRO in the TRIDENT-1 study, a broad spectrum of central nervous system (CNS) adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 75% with Grade 3 or 4 events occurring in 4%. Dizziness, including vertigo, occurred in 64% and Grade 3 dizziness occurred in 2.8% of patients. The median time to onset was 6 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 12% required dose reduction of AUGTYRO due to dizziness. Ataxia, including gait disturbance and balance disorder, occurred in 29% of the 351 patients; Grade 3 ataxia occurred in 0.3%. The median time to onset was 15 days (1 day to 1.4 years). Dose interruption was required in 6% of patients, 8% required dose reduction and one patient (0.3%) permanently discontinued AUGTYRO due to ataxia. Cognitive disorder, including memory impairment and disturbance in attention, occurred in 23% of the 351 patients. Cognitive disorders included memory impairment (13%), disturbance in attention (11%), and confusional state (2%); Grade 3 cognitive disorders occurred in 0.9% of patients. The median time to onset of cognitive disorders was 37 days (1 day to 1.4 years). Dose interruption was required in 2% of patients, 1.7% required dose reduction and 0.6% permanently discontinued AUGTYRO due to cognitive adverse reactions. Mood disorders occurred in 6% of the 351 patients. Mood disorders occurring in >1% of patients included anxiety (2.8%), irritability (1.1%), and depression (1.4%); Grade 4 mood disorders (mania) occurred in 0.3% of patients. Dose interruption was required in 0.3% of patients and 0.3% required a dose reduction due to mood disorders. Sleep disorders including insomnia and hypersomnia occurred in 15% of the 351 patients. Sleep disorders observed in >1% of patients were somnolence (8%), insomnia (6%) and hypersomnia (1.1%). Dose interruption was required in 0.9% of patients, and 0.3% required a dose reduction due to sleep disorders. The incidences of CNS adverse reactions reported were similar in patients with and without CNS metastases. Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity. Interstitial Lung Disease (ILD)/Pneumonitis Among the 351 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.6%] and interstitial lung disease [0.3%]) occurred in 2.9%; Grade 3 ILD/pneumonitis occurred in 1.1%. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.6% required dose reduction, and 1.1% permanently discontinued AUGTYRO due to ILD/pneumonitis. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold AUGTYRO in patients with suspected ILD/pneumonitis and permanently discontinue AUGTYRO if ILD/pneumonitis is confirmed. Hepatotoxicity Among the 351 patients treated with AUGTYRO, increased alanine transaminase (ALT) occurred in 35%, increased aspartate aminotransferase (AST) occurred in 40%, including Grade 3 or 4 increased ALT in 2% and increased AST in 2.6%. The median time to onset of increased ALT or AST was 15 days (range: 1 day to 1.9 years). Increased ALT or AST leading to dose interruptions or reductions occurred in 2.8% and 1.4% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.6%. Monitor liver function tests, including ALT, AST and bilirubin, every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue AUGTYRO based on the severity. Myalgia with Creatine Phosphokinase (CPK) Elevation Among the 351 patients treated with AUGTYRO, myalgia occurred in 13% of patients, with Grade 3 in 0.6%. Median time to onset of myalgia was 19 days (range: 1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.7% of patients. AUGTYRO was interrupted in one patient with myalgia and concurrent CPK elevation. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor serum CPK levels during AUGTYRO treatment and monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. Based on severity, withhold and then resume AUGTYRO at same or reduced dose upon improvement. Hyperuricemia Among the 351 patients treated with AUGTYRO, 18 patients (5%) experienced hyperuricemia reported as an adverse reaction, 0.9% experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication. Monitor serum uric acid levels prior to initiating AUGTYRO and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity. Skeletal Fractures Among 351 adult patients who received AUGTYRO, fractures occurred in 2.3%. Fractures involved the ribs (0.6%), feet (0.6%), spine (0.3%), acetabulum (0.3%), sternum (0.3%), and ankles (0.3%). Some fractures occurred at sites of disease and prior radiation therapy. The median time to fracture was 71 days (range: 31 days to 1.4 years). AUGTYRO was interrupted in 0.3% of patients. Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of AUGTYRO on healing of known fractures and risk of future fractures. Embryo-Fetal Toxicity Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose, since AUGTYRO can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AUGTYRO and for 4 months after the last dose. Adverse Reactions Among 351 patients who received AUGTYRO for ROS1-positive NSCLC and other solid tumors in the TRIDENT-1 trial, the most common (>20%) adverse reactions were dizziness (64%), dysgeusia (50%), peripheral neuropathy (47%), constipation (37%), dyspnea (30%), ataxia (29%), fatigue (29%), cognitive disorders (23%), and nausea (20%). In a subset of 264 patients who received AUGTYRO for ROS1-positive NSCLC, the most common (≥20%) adverse reactions were dizziness (63%), dysgeusia (48%), peripheral neuropathy (47%), constipation (36%), dyspnea (30%), ataxia (28%), fatigue (24%), cognitive disorders (23%), and muscular weakness (21%). Drug Interactions Effects of Other Drugs on AUGTYRO Strong and Moderate CYP3A Inhibitors Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO. P-gp Inhibitors Avoid concomitant use with P-gp inhibitors. Concomitant use of AUGTYRO with a P-gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Strong and Moderate CYP3A Inducers Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO. Effects of AUGTYRO on other Drugs Certain CYP3A4 Substrates Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling. Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates, which can reduce the efficacy of these substrates. Contraceptives Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives. Avoid concomitant use of AUGTYRO with hormonal contraceptives. Advise females to use an effective nonhormonal contraceptive. Please see U.S. Full Prescribing Information for AUGTYRO About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results may not be consistent with the results to date, that repotrectinib may not receive regulatory approval for the indication described in this release in the currently anticipated timeline or at all, that any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such product candidate for such indication described in this release will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2022, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news