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FDA批准CAR-T疗法Yescarta治疗成年类型的巨B-细胞淋巴瘤

2017-10-19 01:15:26 作者：新特药房来源：互联网浏览次数：3 文字大小：【大】【中】【小】

简介： Yescarta（KTE-C19，axicabtagene ciloleucel）是Kite Pharma公司开发的一种靶向CD19的CAR-T疗法已获FDA批准上市2017年10月18日美国食品和药品监管局今天批准Yescarta (axicabtagene ciloleucel)，一个基 ...

关键字：KTE-C19 axicabtagene ciloleucel商标名Yescarta 第二个CAR-T疗法用于治疗B细胞淋巴瘤

Yescarta（KTE-C19，axicabtagene ciloleucel）是Kite Pharma公司开发的一种靶向CD19的CAR-T疗法已获FDA批准上市
2017年10月18日美国食品和药品监管局今天批准Yescarta (axicabtagene ciloleucel)，一个基于细胞基因治疗，治疗成年患者有某些类型的巨B-细胞淋巴瘤患者对或患者在至少两种其他类别治疗后已复发不反应。Yescarta，一种嵌合抗体受体(CAR)T细胞治疗，是被FDA批准的第二个基因治疗和首个为某些类型的非-何杰金氏淋巴瘤(NHL)。
FDA长官Scott Gottlieb，M.D.说：“今天标记在为严重疾病的治疗全新的科学范式的发展中另一个里程碑。在正好几十年，基因治疗已去从正是一种鼓舞人的概念至实际的解决对致命的和很大程度上不可治愈的癌症形式，”“这个批准显示这个有希望的新医学领域的持续发展势头和我们致力于支持和帮助加快这些产品的开发我们将很快发布一项全面政策，以解决我们计划如何支持基于细胞再生医学的发展。该政策也将澄清我们将如何对CAR-T细胞和其他基因治疗使用突破性产品应用我们的加快方案。我们仍然致力于支持利用这些新的科学平台有效开发安全有效的治疗方法。”
弥漫性巨B-细胞淋巴瘤(DLBCL)是在成年中最常见类型的NHL。NHLs是癌症开始在免疫系统的某些细胞和是或可能快速生长(侵袭性)或缓慢生长。在美国，每年接近72,000的NHL新病例被诊断，而DLBCL代表接近三个新诊断病例中的一个。Yescarta被批准为在有巨B-细胞淋巴瘤成年患者中至少两种其他类型治疗失败后使用，包括DLBCL，原发性纵隔巨B-细胞淋巴瘤，高级别B-细胞淋巴瘤和DLBCL来自滤泡性淋巴瘤。Yescarta是不适用为患者有原发性中枢神经系统淋巴瘤的治疗。.
Yescarta的每次剂量是使用患者自己的免疫系统创建的定制治疗，以帮助打击淋巴瘤平台。患者的T-细胞，白细胞的一种类型，被采集和遗传上被修饰已包括一个新基因靶向和杀死淋巴瘤细胞。一旦细胞被修饰，它们被回输至患者。
FDA的对生物制品评价和研究中心(CBER)主任Peter Marks，M.D.，Ph.D.说：“Yescarta的批准携带这个创新类别CAR-T细胞治疗至一个有少数其他选择附加组的癌症患者 – 那些成年对以前治疗没有反应的有某些类型的淋巴瘤，”
Yescarta的安全性和疗效是在超过100例成年有难治性或复发巨B-细胞淋巴瘤一项多中心临床试验被确定。用Yescarta治疗后完全缓解率为51%。
用Yescarta治疗有致严重副作用潜能。它携带一个黑框警告对细胞因子释放综合证(CRS)，它是一种全身性反应对CAR-T细胞的激活和增殖致高热和流感-样症状，和对神经毒性。 CRS和神经毒性两者均可能是致命或危及生命。其他副作用包括严重感染，低血细胞计数和一个被削弱的免疫系统。来自用Yescarta治疗副作用通常地出现在第一至二周内，但有些副作用可能出现以后。
因为CRS和神经毒性的风险，Yescarta正在有一个风险评价和缓解策略(REMS)被批准，它包括要素确保安全使用(ETASU)。FDA正在要求医院和他们的伴随诊所分发Yescarta被特别认证。作为该认证的一部分，涉及Yescarta处方，发送或给药的工作人员被要求是受过训练识别和处置CRS和神经系统毒性。还有，患者必须被告知潜在严重副作用和如果发生副作用及时返回治疗地点的重要性。
为进一步评价长期安全性，FDA还要求制造商进行上市后观察性研究涉及用Yescarta治疗患者。
FDA授权Yescarta 优先审评和突破性治疗指定。Yescarta还接受孤儿药物指定，它提供奖励帮助和鼓励对罕见疾病药物开发。Yescarta申请被审评用一个协同，交叉-机构方法。临床审评由FDA的卓越的肿瘤中心进行，而CBER进行所有审评的其他方面和做最后产品批准决定。
FDA授权Yescarta的批准给予Kite Pharma，有限公司。
Kite’s Yescarta™ (Axicabtagene Ciloleucel) Becomes First CAR T Therapy Approved by the FDA for the Treatment of Adult Patients With Relapsed or Refractory Large B-Cell Lymphoma After Two or More Lines of Systemic Therapy
U.S. Food and Drug Administration (FDA) has granted regular approval to Yescarta™ (axicabtagene ciloleucel), the first chimeric antigen receptor T cell (CAR T) therapy for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (transformed follicular lymphoma, or TFL). Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.
CAR T therapy is a breakthrough in hematologic cancer treatment in which a patient’s own T cells are engineered to seek and destroy cancer cells. CAR T therapy is manufactured specifically for each individual patient.
“The FDA approval of Yescarta is a landmark for patients with relapsed or refractory large B-cell lymphoma. This approval would not have been possible without the courageous commitment of patients and clinicians, as well as the ongoing dedication of Kite’s employees,” said Arie Belldegrun, MD, FACS, Founder of Kite. “We must also recognize the FDA for their ability to embrace and support transformational new technologies that treat life-threatening illnesses. We believe this is only the beginning for CAR T therapies.”
“Today is an important day for patients with relapsed or refractory large B-cell lymphoma who have run out of options and have been waiting for new treatments that may help them in their fight against cancer,” said John Milligan, PhD, President and Chief Executive Officer of Gilead Sciences. “With the combined innovation, talent and drive of the Kite and Gilead teams, we will rapidly advance cell therapy research and aim to bring new options to patients with many other types of cancer.”
Yescarta has a Boxed Warning in its product label regarding the risks of cytokine release syndrome (CRS) and neurologic toxicities. A Risk Evaluation and Mitigation Strategy (REMS) has been approved by the FDA for Yescarta. The REMS program will inform and educate healthcare professionals about the risks associated with Yescarta therapy. Training and certification on the REMS program will be an integral part of the final authorization for centers offering Yescarta. Additional information about the REMS program can be found at www.yescartarems.com. Please see below for Important Safety Information.
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), accounting for three out of every five cases. In the United States each year, there are approximately 7,500 patients with refractory DLBCL who are eligible for CAR T therapy. Historically, when treated with the current standard of care, patients with refractory large B-cell lymphoma had a median overall survival of approximately six months, with only seven percent attaining a complete response. Currently, patients with large B-cell lymphoma in second or later lines of therapy have poor outcomes and greater unmet need, since nearly half of them either do not respond or relapse shortly after transplant.
“With CAR T therapy, we are reengineering a patient’s own immune system to detect and kill cancer cells, and the results have been impressive,” said Frederick L. Locke, MD, ZUMA-1 Co-Lead Investigator and Vice Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida. “Many of the patients that received CAR T therapy had already relapsed several times with traditional treatments such as chemotherapy or hematopoietic stem cell transplant. Now, thanks to this new therapy many patients are in remission for months.”
“This therapy is a new option for patients with relapsed or refractory large B-cell lymphoma who have run out of treatment options and face a dire prognosis,” said Louis J. DeGennaro, PhD, President and Chief Executive Officer of The Leukemia & Lymphoma Society (LLS). “Early on, LLS recognized the potential of CAR T therapy and we are proud to be part of making this historic approval possible.”
“Engineered cell therapies like Yescarta represent the potential for a changing treatment paradigm for cancer patients,” said David Chang, MD, PhD, Worldwide Head of Research and Development and Chief Medical Officer at Kite. “Together, Gilead and Kite will accelerate studies of CAR T therapy in multiple blood cancers and advance other cell therapy approaches for solid tumors, with the goal of helping patients with diverse cancers benefit from this new era of personalized cancer therapy.”
Yescarta will be manufactured in Kite’s state-of-the-art commercial manufacturing facility in El Segundo, California. In the ZUMA-1 pivotal trial, Kite demonstrated a 99 percent manufacturing success rate with a median manufacturing turnaround time of 17 days, which is important to patients given the potential for rapid disease progression in this population.
Yescarta has been granted Priority Medicines (PRIME) regulatory support for DLBCL in the European Union. A Marketing Authorization Application (MAA) for axicabtagene ciloleucel is currently under review with the European Medicines Agency (EMA) and potential approval is expected in the first half of 2018.
Yescarta (axicabtagene ciloleucel) Pivotal Trial Results
The approval of Yescarta is supported by data from the ZUMA-1 pivotal trial. In this study, 72 percent of patients treated with a single infusion of Yescarta (n=101) responded to therapy (overall response rate) including 51 percent of patients who had no detectable cancer remaining (complete remission; 95% CI: 41, 62). At a median follow-up of 7.9 months, patients who had achieved a complete remission had not reached the estimated median duration of response (95% CI: 8.1 months, not estimable [NE]).
In the study, 13 percent of patients experienced grade 3 or higher cytokine release syndrome (CRS) and 31 percent experienced neurologic toxicities. The most common (≥ 10%) Grade 3 or higher reactions include febrile neutropenia, fever, CRS, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia and lung infections. Serious adverse reactions occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias (including neutropenia, thrombocytopenia and anemia), and serious infections. Fatal cases of CRS and neurologic toxicity occurred. FDA approved Yescarta with a Risk Evaluation and Mitigation Strategy.
Yescarta Indication
Yescarta is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma
IMPORTANT SAFETY INFORMATION
BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES
•Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
•Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
•Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS.
Cytokine Release Syndrome (CRS)
CRS, including fatal or life-threatening reactions, occurred following treatment with Yescarta. In Study 1, CRS occurred in 94% (101/108) of patients receiving Yescarta, including ≥ Grade 3 (Lee grading system) CRS in 13% (14/108) of patients. Among patients who died after receiving Yescarta, four had ongoing CRS events at the time of death. The median time to onset was 2 days (range: 1 to 12 days) and the median duration of CRS was 7 days (range: 2 to 58 days). Key manifestations of CRS include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
Ensure that 2 doses of tocilizumab are available prior to infusion of Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.
Neurologic Toxicities
Neurologic toxicities, that were fatal or life-threatening, occurred following treatment with Yescarta. Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks of Yescarta infusion, with a median time to onset of 4 days (range: 1 to 43 days). The median duration of neurologic toxicities was 17 days. Grade 3 or higher neurologic toxicities occurred in 31% of patients.
The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with Yescarta. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta.
Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.
Yescarta REMS
Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. The required components of the Yescarta REMS are:
•Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS.
•Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Yescarta are trained about the management of CRS and neurologic toxicities.
Further information is available at www.YescartaREMS.com or 1-844-454-KITE (5483).
Hypersensitivity Reactions
Allergic reactions may occur with the infusion of Yescarta. Serious hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.
Serious Infections
Severe or life-threatening infections occurred in patients after Yescarta infusion. In Study 1, infections (all grades) occurred in 38% of patients. Grade 3 or higher infections occurred in 23% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Yescarta infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines.
Febrile neutropenia was observed in 36% of patients after Yescarta infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated.
Viral Reactivation
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.
Prolonged Cytopenias
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. In Study 1, Grade 3 or higher cytopenias not resolved by Day 30 following Yescarta infusion occurred in (28%) of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after Yescarta infusion.
Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with Yescarta. In Study 1, hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment with Yescarta and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement.
The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment with Yescarta.
Secondary Malignancies
Patients treated with YESCARTA may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.
Effects on Ability to Drive and Use Machines
Due to the potential for neurologic events, including altered mental status or seizures, patients receiving Yescarta are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.
Adverse Reactions
The most common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias. Serious adverse reactions occurred in 52% of patients. The most common serious adverse reactions (> 2%) include encephalopathy, fever, lung infection, febrile neutropenia, cardiac arrhythmia, cardiac failure, urinary tract infection, renal insufficiency, aphasia, cardiac arrest, Clostridium difficile infection, delirium, hypotension, and hypoxia.
The most common (≥ 10%) Grade 3 or higher reactions include febrile neutropenia, fever, CRS, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia and lung infections.
About Kite
Kite, a Gilead Company, is a biopharmaceutical company based in Santa Monica, California. Kite is engaged in the development of innovative cancer immunotherapies. The company is focused on chimeric antigen receptor and T cell receptor engineered cell therapies. For more information on Kite, please visit www.kitepharma.com.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.
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