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ASH2014:新基公布Revlimid关键III期FIRST研究深度分析数据

来源:生物谷 2014-12-09 19:15

2014年12月9日讯 /生物谷BIOON/ --2014年12月8日讯 /生物谷BIOON/ --2014年第56届美国血液学会年会(ASH)于12月6日-9日在美国旧金山举行。近日,生物技术巨头新基(Celgene)在会上公布了抗癌药物Revlimid(雷利米得,通用名:lenalidomide,来那度胺)关键III期FIRST研究的多个事后分析(post-hoc analyses)数据。该研究在新诊移植不合格多发性骨髓瘤(MM)患者中开展,将连续Revlimid+低剂量地塞米松组合疗法(cRd)与固定持续时间18周期Rd(Rd18)疗法或12周期美法仑+泼尼松+沙利度胺(MPT)疗法进行了比较。正如此前所报道的,所有随机患者的意向性治疗分析表明,该研究达到了无进展生存期(PFS)的主要终点(中位PFS:21.2个月 MPT vs 25.5个月 Rd, HR=0.72,p<0.01)。

年龄对PFS的影响:

在一项分析中,作者检查了年龄(75岁或以下 vs 75岁以上)对无进展生存期(PFS)和次要终点的的影响。总体而言,35%患者年龄超过75岁。在2个年龄组,与MPT和Rd18相比,PFS和OS结果对cRd有利。此外,与MPT相比,cRd缓解率较高;在2个年龄组,与MPT相比,缓解持续时间cRd较长。这些数据进一步验证了老年患者中cRd疗法相对于标准MPT疗法的相关研究数据。

肾功能对PFS的影响:

此外,研究者还针对肾功能不全(RI)患者进行了分析。该研究中,24%患者肾功能正常(肌酐清除率[CrCl]≥80毫升/分钟),44%患者轻度RI(80毫升/分钟>CrCl≥50毫升/分钟),23%患者中度RI(50毫升/分钟>CrCl≥30毫升/分钟),9%患者重度RI(CrCl<30毫升/分钟)。需要透析的患者被排除在外。Rd组来那度胺起始剂量(肾功能正常或轻度RI为25mg,中度RI为10mg,重度RI为每隔一天15mg),MPT组美法仑起始剂量(中度至重度RI剂量降低50%)在CrCl<50毫升/分钟患者中进行调整。分析结果表明,在所有伴有肾功能损害(RI)的所有患者组中,与MPT疗法相比,cRd疗法表现出更长的无进展生存期(PFS),尤其是肾功能正常患者(HR=0.71;P=0.05)、轻度RI患者(HR=0.74;P=0.02)、重度RI患者(HR=0.66;P<0.01)、重度RI患者(HR=0.76;P=0.31)。与Rd18相比,轻度或中度RI患者中PFS略微表现出对cRd有利(均P<0.01)。

缓解深度对PFS的影响:

在实现极佳部分缓解(VGPR)的患者中,与Rd18组(31.0个月;HR=0.46;P<0.01)和MPT组(34.7个月;HR=0.55;P<0.001)相比,cRd组中位PFS显著更长。在实现完全缓解(OR)的患者中,与Rd18组(45.2个月;HR=0.29;P<0.01)或MPT组(44.6个月;HR=0.28;P<0.01)相比,cRd组中位PFS显著更长。

新基分别于于2014年2和2014年4月向欧洲药品管理局(EMA)和FDA提交了Revlimid+地塞米松联合治疗新诊多发性骨髓瘤(MM)的新药申请。FDA已指定该药处方药用户收费法(PDUFA)目标日期为2015年2月22日。

目前,Revlimid+地塞米松联合疗法已获全球近70个国家批准,用于既往接受过至少一种疗法的多发性骨髓瘤(MM)患者的治疗;同时,Revlimid+地塞米松联合疗法已获澳大利亚和新西兰批准,用于经一种疗法治疗后病情恶化的多发性骨髓瘤(MM)患者的治疗。此外,Revlimid已获美国、加拿大、瑞士、澳大利亚、新西兰和几个拉美国家批准用于骨髓异常综合症(MDS)导致的贫血。在美国,FDA已批准Revlimi用于套细胞淋巴瘤(CML)的治疗。(生物谷Bioon.com)

英文原文:Age, Renal Impairment and Depth of Response Analyses of the First (MM-020/IFM 07-01) Study of Continuous REVLIMID® (lenalidomide) Plus Low-Dose dexamethasone in Newly-Diagnosed Multiple Myeloma Presented at ASH

Continuous REVLIMID® (lenalidomide) plus low-dose dexamethasone increased progression-free survival compared with fixed duration of Rd or melphalan, prednisone and thalidomide regardless of age, renal impairment, or depth of response

SAN FRANCISCO--(BUSINESS WIRE)-- Celgene Corporation (NASDAQ:CELG) today announced that results were presented from multiple post-hoc analyses of its pivotal phase III FIRSTTM (MM-020/IFM 07-01) trial, comparing continuous REVLIMID® (lenalidomide) plus low-dose dexamethasone (continuous Rd) to a fixed duration of 18 cycles of Rd (Rd18) or 12 cycles of melphalan, prednisone and thalidomide (MPT) for the treatment of newly diagnosed, transplant-ineligible multiple myeloma. The studies were presented during the 56th American Society of Hematology (ASH) annual meeting.

As previously reported, the study met the primary endpoint of progression-free survival (PFS) in the intent-to-treat analysis of all randomized patients (Median PFS 21.2 months MPT vs 25.5 months Rd, Hazard Ratio (HR) 0.72, p < 0.01).

In one analysis, the authors examined the impact of age (75 years or younger vs. over 75 years) on PFS and secondary endpoints. Overall, 35% of patients were over 75 years of age.

PFS and overall survival (OS) outcomes favored continuous Rd over MPT and over Rd18 in both age groups.

In addition, response rates were higher with continuous RD vs MPT and duration of response was longer in the continuous Rd arm compared to MPT in both age groups.

"These analyses continue to validate the published data for certain older patients receiving continuous therapy with lenalidomide and dexamethasone compared to a standard triplet regimen," said Prof. Thierry Facon, MD, University of Lille and primary investigator of the study.

Additionally, an analysis of patients with renal impairment (RI) was presented. In the study, 24% had normal renal function (creatinine clearance [CrCl] ≥ 80 mL/min), 44% presented with mild RI (CrCl ≥ 50 and < 80 mL/min), 23% had moderate RI (CrCl ≥ 30 and < 50 mL/min), and 9% had severe RI (CrCl < 30 mL/min). Patients requiring dialysis were excluded. The starting doses of lenalidomide (25 mg for pts with normal renal function or mild RI, 10 mg QD for moderate RI, and 15 mg every other day for severe RI) in the Rd arms and of melphalan (reduced by 50% in patients with moderate or severe RI) in the MPT arm were adjusted for patients with CrCl < 50 mL/min.

Continuous Rd demonstrated a longer PFS compared with MPT in all groups of patients with renal impairment, in particular, in patients with normal renal function (HR = 0.71; P = 0.05), in patients with mild RI (HR = 0.74; P = 0.02), patients with moderate RI (HR = 0.66; P < 0.01) and in patients with severe RI (HR 0.76; P=0.31). A slight PFS benefit was also seen with continuous Rd compared to Rd18 (a secondary comparison) in patients with mild or moderate RI (P < 0.01 for both).

An analysis of the impact of depth of response on PFS was also presented. In patients who achieved at least a very good partial response (VGPR), median PFS was significantly longer (not reached (NR) with continuous Rd compared with Rd18 (31.0 months; HR = 0.46; P < 0.01) or MPT (34.7 months; HR = 0.55; P < 001). A benefit of continuous Rd was observed compared with Rd18 or MPT in patients who achieved a complete response (CR), where the median PFS with continuous Rd was NR vs. 45.2 months with Rd18 (HR = 0.29; P < 0.01) and 44.6 months with MPT (HR = 0.28; P < 0.01).

Safety results in the FIRST study (N Engl J Med 2014) showed that grade 3/4 adverse events that occurred in at least 8% of patients in the continuous Rd arm, Rd18 arm or MPT arm included neutropenia (28%, 26% and 45%, respectively), anemia (18%, 16% and 19%, respectively), thrombocytopenia (8%, 8% and 11%, respectively), febrile neutropenia (1%, 3% and 3%, respectively), leukopenia (5%, 6% and 10%, respectively), infection (29%, 22% and 17%, respectively), pneumonia (8%, 8% and 6%, respectively), deep-vein thrombosis and/or pulmonary embolism (8%, 6% and 5%, respectively), asthenia (8%, 6% and 6%, respectively), fatigue (7%, 9% and 6%, respectively), and peripheral sensory neuropathy (1%, < 1% and 9%, respectively). Rates of grade 3/4 cardiac disorders for patients in the continuous Rd, Rd18 and MPT arms were 12%, 7% and 9%, respectively. The incidence of invasive second primary malignancies was 3% in patients taking continuous Rd, 6% in patients taking Rd18 and 5% in patients taking MPT. The overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm.

Celgene has submitted applications for approval of REVLIMID in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients with the European Medicines Agency (EMA) in February 2014 and with the U.S. Food and Drug Administration (FDA) in April 2014. The U.S. Food and Drug Administration has set a Prescription Drug User Fee Act (PDUFA) date of Feb. 22, 2015.

REVLIMID plus low-dose dexamethasone is not indicated for the treatment of newly diagnosed multiple myeloma in any country.

About REVLIMID®

REVLIMID is approved in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy in nearly 70 countries, encompassing Europe, the Americas, the Middle-East and Asia, and in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy in Australia and New Zealand.

REVLIMID is also approved in the United States, Canada, Switzerland, Australia, New Zealand and several Latin American countries, as well as Malaysia and Israel, for transfusion-dependent anaemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities and in Europe for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

In addition, REVLIMID is approved in the United States for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

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