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罗氏抗癌药Gazyvaro获欧盟批准用于滤泡性淋巴瘤（FL）的治疗
2016年6月17日 -继今年2月底获得美国FDA批准之后，瑞士制药巨头罗氏（Roche）抗癌药obinutuzumab（美国品牌名Gazyva）近日在欧盟监管方面也传来了喜讯。欧盟委员会（EC）已批准obinutuzumab（欧洲品牌名Gazyvaro）联合苯达莫司汀（bendamustine）化疗治疗后紧接着obinutuzumab单药维持治疗，作为一种新的治疗方案，用于对罗氏自身已上市重磅抗癌药美罗华（品牌名：MabThera / Rituxan，通用名：rituximab，利妥昔单抗）或含美罗华方案治疗无缓解、或接受此类方案治疗期间或治疗后6个月内病情进展的滤泡性淋巴瘤（FL）患者。
据估计，在欧洲每年约有1.9万人确诊为滤泡性淋巴瘤（FL），这是一种最常见类型的惰性（生长缓慢）非霍奇金淋巴瘤（NHL），约占所有NHL病例的五分之一。FL被认为是不治之症，大多数患者会经历反复复发，而且病情每复发一次，就变得更加难以治疗，因此该领域存在着远未满足的巨大医疗需求。Gazyva联合苯达莫司汀提供了一种新的治疗选择，可用于病情复发的FL患者，能显著降低疾病进展或死亡风险。
Gazyva的成功，对罗氏意义重大，该药将减少生物仿制药对其已上市重磅药物美罗华（Rituxan）的冲击。目前，罗氏也正在其他一些类型癌症中评价Gazyva的疗效。
欧盟批准Gazyvaro治疗滤泡性淋巴瘤（FL），是基于III期GADOLIN研究的数据。研究表明，根据独立评审委员会（IRC）的评定，在接受含有Rituxan方案治疗期间或治疗后6个月内病情进展的滤泡性淋巴瘤（FL）患者中，与苯达莫司汀单药治疗组相比，Gazyva联合苯达莫司汀治疗后紧接着Gazyva单药维持治疗的患者组疾病恶化或死亡（无进展生存期，PFS）风险显著降低52%（HR=0.48，95%CI:0.34-0.68，p＜0.0001），Gazyva方案组中位PFS数据尚未获得，苯达莫司汀单药治疗组中位PFS为13.8个月。研究者评估结果显示，Gazyva方案组中位PFS是苯达莫司汀单药治疗组的2倍多（29.2个月 vs 13.7个月，HR=0.48，95%CI：0.35-0.67，p＜0.0001）。
在欧洲，Gazyvaro已于2014年7月获批联合苯丁酸氮芥（chlorambucil）用于因合并症而不适合全剂量氟达拉滨为基础治疗方案的初治慢性淋巴细胞白血病（CLL）患者。Gazyva获批治疗CLL，是基于III期CLL11研究的数据。数据表明，与美罗华（MabThera，通用名：rituximab，利妥昔单抗）+苯丁酸氮芥组合疗法相比，Gazyvaro+苯丁酸氮芥组合疗法使疾病恶化或死亡风险显著降低61%，显著延长了患者的疾病无进展生存期（PFS：26.7个月 vs 15.2个月，p＜0.001），同时也增加了缓解深度（以微小残留病（MRD）评价： 37.7% vs 3.3%），并取得了较高的完全缓解率（ 21% vs 7%）。此外，与苯丁酸氮芥单药疗法相比，Gazyvaro+苯丁酸氮芥组合疗法也增加了初治CLL患者的总生存期（OS）。
关于Gazyva/Gazyvaro（obinutuzumab）：
obinutuzumab又名GA101，是首个糖基化的II型抗CD20单克隆抗体，靶向B细胞表面的CD20分子，能够直接诱导B细胞死亡。obinutuzumab旨在增强抗体依赖性细胞毒性作用（Antibody-Dependent Cellular Cytotoxicity，ADCC）及直接的细胞死亡诱导作用（Direct Cell Death induction）。obinutuzumab在美国的品牌名为Gazyva，在欧洲的品牌名为Gazyvaro。
New Drugs Online Report for obinutuzumab
Information
Generic Name: obinutuzumab
Trade Name: Gazyvaro (EU), Gazyva (US)
Synonym: RG7159, GA101, RO5072759, afutuzumab
Entry Type: New molecular entity
Development and Regulatory status
UK: Launched
EU: Launched
US: Launched
UK launch Plans: Available only to registered users
Actual UK launch date: July 2014
Comments
Jul 14: Launched in the UK on 31 July [18].
26/08/2014 13:09:52
Jul 14: Approved in the EU [17].
31/07/2014 10:20:06
Obinutuzumab was launched in the US as Gazyva shortly after approval [16].
04/07/2014 17:41:14
May 14: EU Positive opinion for obtinutuzumab in combination with chlorambucil for the treatment of adult patients with previously untreated chronic lymphocytic leukemia (CLL) who have comorbidities making them unsuitable for a certain type of chemotherapy (full-dose fludarabine). [15]
27/05/2014 09:42:06
Nov 13: Approved in the US for use in combination with chlorambucil to treat patients with previously untreated CCL [13].
01/11/2013 17:26:23
Jul 13: Granted priority review status in the US, with an action date of Dec 20 [10].
04/07/2013 09:13:33
May 13: Filed in the EU & US, based on CLL11 data [8].
17/05/2013 11:48:34
May 13: Granted Breakthrough Therapy Designation by the FDA [8].
17/05/2013 11:45:05
Nov 12: Orphan designation (EU/3/12/1054) granted in the EU for obinutuzumab for the treatment of chronic lymphocytic leukaemia [5].
19/11/2012 09:14:42
Filing now anticipated 2013 (3)
07/09/2010 13:58:34
Roche expects to file for approval in 2011 (2)
16/03/2010 15:03:46
PIII (1)
16/03/2010 15:02:21
Trial or other data
Jun 15: NICE publishes final guidance recommending obinutuzumab alongside chlorambucil as a first-line treatment for CLL and co-existing medical conditions in patients who can’t take fludarabine-based therapy, and only if bendamustine-based therapy is also not suitable [22].
08/06/2015 15:46:58
Mar 15: In a Final Appraisal Determination NICE recommends obinutuzumab in combination with chlorambucil for previously-untreated adult patients with CLL and co-existing medical conditions who are unsuitable for full-dose fludarabine-based therapy, and only if bendamustine-based therapy is also not suitable [21].
11/03/2015 15:30:21
Dec 14: NICE issues further draft guidance for consultation recommending Gazyvaro for some people with untreated CLL, as long as Roche provides the treatment to the NHS at a (confidential) reduced price to secure value for money [20].
02/12/2014 10:04:38
Oct 14: NICE publishes preliminary guidance rejecting obinutuzumab because of uncertainties in the data. Although a clinically effective treatment, there are too many uncertainties in the company’s submission. The Appraisal Committee noted that the most likely incremental cost-effectiveness ratio (ICER) for Gazyvaro/chlorambucil compared with chlorambucil monotherapy was £31,000 per QALY gained, £28,000 per QALY gained compared with chlorambucil/MabThera (rituximab), £49,000 per QALY gained compared with bendamustine monotherapy, and £48,000 per QALY gained compared with bendamustine/MabThera, but it also said because of uncertainties these figures were likely to be higher [19].
03/10/2014 15:47:47
Nov 13: Results reported from the second stage of the PIII CLL11 study conducted in cooperation with the German CLL Study Group. For patients in the Gazyva arm, median PFS was 26.7 months vs 15.2 months for those in the MabThera/Rituxan arm (HR 0.39, CI 0.31-0.49, p<0.0001). Additional data comparing the Gazyva and MabThera/Rituxan treatment arms showed higher complete response rates (21% vs 7%) and a ten-fold increase in the % of people achieving minimal residual disease (MRD) negativity (29.4% vs 2.5%), which was defined as no detectable disease in the blood at the end of the treatment course [14].
07/11/2013 21:47:00
Nov 13: In an updated analysis from the first stage of the CLL11 study comparing Gazyva + chlorambucil vs chlorambucil alone, overall survival was longer in the combination group (HR 0.41, 95% CI 0.23-0.74 p=0.002) after a median observation time of 23 months; median overall survival has not yet been reached in any of the study arms [14].
07/11/2013 21:46:29
Jul 13: NCT01905943 is a PIII multicentre, open-label, single-arm study to eva luate the safety and efficacy of obinutuzumab alone or in combination with chemotherapy (bendamustine or chlorambucil,for 6 cycles) in 800 patients with previously untreated or relapsed/refractory CLL. Patients will receive obinutuzumab 1000 mg on Days 1/2 (split dose), 8 and 15 of Cycle 1, and on Day 1 of Cycles 2-6,. The study starts in Sep 13 and is due to complete Apr 18 (primary outcome data collection May 16) [12].
29/07/2013 11:31:21
Jul 13: In an interim analysis, the PIII CLL11 study met its primary endpoint with obinutuzumab + chlorambucil improving PFS vs rituximab + chlorambucil. These final data were reached ahead of the target completion date in 2014 as a result of the magnitude of difference between the two study arms. No new safety signals were identified and adverse events were similar to those observed in the first stage of the study which was reported earlier this year. Final data from the CLL11 study will be submitted to the ASH Meeting in Dec 2013 [11].
24/07/2013 21:47:50
GA101 is the first Type II anti-CD20 medicine that is glycoengineered, which means specific sugar molecules in GA101 were modified (using GlycoMAb technology) to change its interaction with the body´s immune cells with the goal of helping the immune system remove cancer cells from the body. In addition, as a type II anti-CD20 antibody, GA101 binds to CD20 with the aim of killing cancerous cells directly [8].
17/05/2013 11:46:42
May 13: Results from CLL11: GA101 combined with chlorambucil demonstrated a significant 86% reduction in the risk of disease progression, relapse or death. Additionally, the length of time during which people lived without their disease worsening (median progression-free survival, PFS) was more than doubled (23 months compared to 10.9 months, HR=0.14, 95% CI 0.09-0.21, p <.0001) when compared to chlorambucil alone. [7]
17/05/2013 08:47:18
Jan 13: Genentech reports positive PFS results from stage 1 of the PIII CLL11 trial in people with previously untreated CLL. The study includes two separate stages. Stage 1 eva luates obinutuzumab plus chlorambucil to chlormabucil alone, & includes a pre-planned PFS futility analysis comparing obinutuzumab plus chlorambucil to rituximab plus chlorambucil. The goal of this futility analysis was to eva luate the likelihood that the study would meet its pre-specified endpoint criteria during stage 2 analysis - improved efficacy (PFS) in the direct comparison of obinutuzumab plus chlorambucil to rituximab plus chlorambucil. The independent Data & Safety Monitoring Board (DSMB) concluded that stage 2 of the study should continue until its final analysis [6].
01/02/2013 11:30:22
Dec 11: Data expected from the PIII CLL11 (BO21004, NCT01010061) trial in 2013. The trial will recruit approximately 780 pts. Progression-free survival is the primary endpoint; patients will be followed up for at least 5 years [4].
06/03/2012 16:29:49
A PIII trial (BO21004, NCT01010061) began in Jan 2010 to eva luate the safety and efficacy of afutuzumab plus chlorambucil, vs. rituximab plus chlorambucil or chlorambucil alone in pts with previously untreated CLL (2).
16/03/2010 15:06:38
Evidence Based eva luations
NICE TA http://www.nice.org.uk/guidance/ta343
SMC http://www.scottishmedicines.org.uk/SMC_Advice/Advice/1008_14_obinutuzumab_Gazyvaro/obinutuzumab_Gazyvaro
NICE scope http://www.nice.org.uk/Guidance/InDevelopment/GID-TAG451/Documents
EPAR http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002799/WC500171596.pdf
FDA doc http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125486_s008lbl.pdf
NHSC http://www.nhsc-healthhorizons.org.uk/topics/obinutuzumab-with-chlorambucil-for-chronic-lymphoc/
References
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