强生（JNJ）7月28日宣布，抗癌药Imbruvica（ibrutinib）补充新药申请（sNDA）获FDA批准，用于既往接受过至少一种疗法的慢性淋巴细胞白血病（CLL）患者的治疗。此外，FDA同时批准Imbruvica用于携带del 17p删除突变的CLL患者的治疗。del 17p删除突变是指17号染色体部分片段丢失，携带该突变的CLL患者被认为预后最差。Imbruvica由强生旗下杨森（Janssen）和Pharmacyclics公司联合开发和商业化。

Imbruvica标签更新是基于III期RESONATE（PCYC-1112-CA）研究的数据。该研究是一项随机、多中心、开放标签、头对头研究，在391例既往接受过至少一种疗法且不适合嘌呤类似物（purine analog）治疗或复治（retreatment）的慢性淋巴细胞白血病（CLL）和小淋巴细胞淋巴瘤（SLL）患者中开展，将Imbruvica与ofatumumab进行了对比。研究中，195例患者接受Imbruvica（420mg，每日一次）治疗至病情恶化或不可接受性毒性，196例患者接受静脉注射ofatumumab（起始剂量300mg，随后11次2000mg剂量）治疗24周。研究结果表明，与ofatumumab相比，Imbruvica显著改善了经治CLL或SLL患者的无进展生存期（PFS）和总生存期（OS）。

关于Imbruvica：

Imbruvica（ibrutinib）之一种首创的口服布鲁顿酪氨酸激酶（BTK）抑制剂。BTK是B细胞受体信号复合体中的一种关键信号分子，在恶性B细胞的生存及扩散中起着重要作用。Imbruvica能够阻断介导恶性B细胞不可控地增殖和扩散的信号通路。

FDA分别于2013年12月和2014年2月批准Imbruvica用于经治讨套细胞淋巴瘤（MCL）患者和经治慢性淋巴细胞白血病（CLL）患者的治疗。强生旗下杨森生物科技与Pharmacyclics于2011年12月签署授权协议，共同开发和商业化Imbruvica。

关于Arzerra（ofatumumab）：

Arzerra（ofatumumab）是葛兰素史克（GSK）的实验性药物，该药是一种创新的全人源化单克隆抗体，靶向B细胞表面CD20分子的一个抗原表位，该表位包含了CD20分子的胞外大环和小环结构。Arzerra分别于2009年和2010年获FDA和EMA批准，用于对标准药物【阿仑单抗（alemtuzumab，Campath）或氟达拉滨（fludarabine）】治疗无应答的慢性淋巴细胞白血病（CLL）患者的治疗。Arzerra已于2014年4月获FDA批准，联合苯丁酸氮芥（chlorambucil）用于初治且不适和氟达拉滨（fludarabine）化疗的慢性淋巴细胞白血病（CLL）患者的一线治疗。Arzerra由葛兰素史克（GSK）和Genmab联合开发。（生物谷Bioon.com）

英文原文：IMBRUVICA® (ibrutinib) Receives Regular Approval by U.S. FDA in Chronic Lymphocytic Leukemia (CLL) and CLL patients with del 17p
Approval based on Phase 3 RESONATE data with statistically significant improvements in progression-free and overall survival

HORSHAM, PA, July 28, 2014 – The U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) for IMBRUVICA® (ibrutinib) capsules for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.[1] The FDA also approved IMBRUVICA for CLL patients with del 17p,1 a genetic mutation that occurs when part of chromosome 17 has been lost. CLL patients with del 17p are considered to have the poorest prognosis.[2] IMBRUVICA is jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics, Inc.

The update to the IMBRUVICA label is based on data from the Phase 3 RESONATE™ study, which demonstrated IMBRUVICA significantly improved progression-free survival (PFS) and overall survival (OS) versus ofatumumab in patients with previously treated CLL or small lymphocytic leukemia (SLL).[3]

IMBRUVICA was initially approved in February 2014 under Subpart H regulation, the FDA’s accelerated approval process, based on data from a Phase 1b/2 study for patients with CLL who have received at least one prior therapy.1 This indication was based on an overall response rate (ORR). An improvement in survival or disease-related symptoms was not established. In accord with the accelerated approval process, confirmation of clinical benefit in a subsequent Phase 3 study was required, which has resulted in this updated indication for the use of IMBRUVICA in patients with CLL who have received at least one prior therapy and in CLL patients with del 17p.

“The RESONATE data expands our understanding of the efficacy and safety of IMBRUVICA to an even greater degree,” said John C. Byrd, M.D., director, Division of Hematology, The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital & Richard J. Solove Research Institute, and lead investigator for RESONATE.† “This approval is particularly exciting for people with del 17p CLL, considering IMBRUVICA is the first treatment to be approved specifically for this difficult-to-treat patient population.”

CLL is a slow-growing blood cancer of white blood cells called lymphocytes, most commonly B cells.[4] CLL is predominantly a disease of the elderly, with a median age of diagnosis of 72.4 In CLL, the genetic mutation del 17p occurs when part of chromosome 17 has been lost. CLL patients with del 17p have poor treatment outcomes.2 Del 17p is reported in seven percent of treatment-naïve CLL cases,[5] with approximately 20 to 40 percent of relapsed/refractory patients harboring the mutation.[6]

“We’re very pleased this approval came swiftly,” said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen Research & Development, LLC. “These Phase 3 results reinforce the data on which the original approval was granted; they also offer greater clinical understanding of the impact of efficacy related to progression-free and overall survival and, more importantly, the safety of IMBRUVICA in this patient population.”

Data from this study were recently presented during an oral session at the 50th annual meeting of the American Society of Clinical Oncology (ASCO), featured in the official ASCO press program and simultaneously published online in the New England Journal of Medicine. In January 2014, the RESONATE trial was halted early because results showed a statistically significant difference in PFS, the primary endpoint of the study, as well as in OS, a key secondary endpoint at the time of this interim analysis.

Janssen and Pharmacyclics are continuing an extensive clinical development program for IMBRUVICA, including Phase 3 study commitments in multiple patient populations.

IMBRUVICA in CLL1
The safety and efficacy of IMBRUVICA in CLL were evaluated in the randomized, international, multi-center, open-label Phase 3 PCYC-1112 (RESONATE) trial in 391 patients with CLL or SLL, who had received at least one prior therapy. Thirty-two percent of patients in the trial had del 17p. Patients were administered either 420 mg oral ibrutinib (n=195) once-daily until progression or unacceptable toxicity or intravenous ofatumumab for up to 24 weeks (n=196, initial dose of 300 mg followed by 11 doses at 2,000 mg per dose and schedule consistent with local labeling). Data showed single-agent, once-daily IMBRUVICA significantly prolonged PFS (median not reached vs. 8.1 months; HR 0.22, 95% CI, 0.15 to 0.32; P<0.0001) and OS (HR 0.43; 95% CI, 0.24 to 0.79; P=0.05) versus intravenous ofatumumab in previously treated patients with CLL or SLL. The OS results represent a 57 percent statistically significant reduction in the risk of death in patients receiving IMBRUVICA versus those in the ofatumumab arm.

PFS was the primary endpoint of the RESONATE study, with OS, ORR and safety as key secondary endpoints. PFS, as assessed by an independent review committee according to modified International Workshop on Chronic Lymphocytic Leukemia criteria, indicated IMBRUVICA was associated with a 78 percent statistically significant reduction in the risk of death or progression versus ofatumumab. ORR was shown to be 42.6 percent in the IMBRUVICA arm, versus 4.1 percent in the ofatumumab arm.  

The Warnings and Precautions for IMBRUVICA include hemorrhage, infections, cytopenias, atrial fibrillation, second primary malignancies and embryo-fetal toxicity.1 For more information about Warnings and Precautions, please see below in this release.

After an 8.6 month median duration of therapy, the most common Grade 3 or 4 adverse event (AE) was pneumonia* (10%). The most commonly occurring non-hematologic side effects during the RESONATE trial (AEs in 20 percent or more of patients) were diarrhea (48%), fatigue (28%), musculoskeletal pain* (28%), nausea (26%), pyrexia (fever; 24%) and rash* (24%). Hematologic adverse events included (all grades) platelet decrease (52%), neutrophil decrease (51%) and hemoglobin decrease (36%).1 *Includes multiple ADR terms.

Approximately five percent of patients receiving IMBRUVICA in the Phase 3 RESONATE (PCYC-1112-CA) and Phase 1b/2 PCYC-1102-CA studies discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately six percent of patients.1

The recommended dose of IMBRUVICA for CLL is 420 mg (three 140 mg capsules) orally once daily.1

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage - Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICAÒ.

The mechanism for the bleeding events is not well understood. IMBRUVICAÒ may increase the risk of hemorrhage in patients receiving anti-platelet or anti-coagulant therapies. Consider the benefit-risk of withholding IMBRUVICAÒ for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICAÒ. Twenty-six percent of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 26 to 29%), thrombocytopenia (range, 10 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICAÒ. Monitor complete blood counts monthly.

Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICAÒ, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICAÒ treatment and dose modification.

Second Primary Malignancies - Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICAÒ. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICAÒ can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICAÒ. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS
The most common adverse reactions (≥20%) in the clinical trials were thrombocytopenia (56%), neutropenia (51%), diarrhea (51%), anemia (37%), fatigue (28%), musculoskeletal pain (28%), upper respiratory tract infection (28%), rash (26%), nausea (25%), and pyrexia (24%). Approximately 5% of patients receiving IMBRUVICAÒ discontinued treatment due to adverse events. These included infections, subdural hematomas, and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients.

DRUG INTERACTIONS

CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICAÒ dose.

CYP3A Inducers - Avoid co-administration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment - Avoid use in patients with baseline hepatic impairment.