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多发性骨髓瘤药物Empliciti获美国优先评审

2015-11-05 02:57:36 作者：新特药房来源：互联网浏览次数：0 文字大小：【大】【中】【小】

简介： 2015年9月2日，美国FDA将优先审查Empliciti（elotuzumab）的生物制品许可申请（BLA），用于既往已接受一种或多种治疗方案的复发或难治性多发性骨髓瘤（MM）患者的治疗。FDA将在6个月内完成审查，而非常规 ...

关键字：elotuzumab 商品名Empliciti 用于复发或难治性多发性骨髓瘤

2015年9月2日，美国FDA将优先审查Empliciti（elotuzumab）的生物制品许可申请（BLA），用于既往已接受一种或多种治疗方案的复发或难治性多发性骨髓瘤（MM）患者的治疗。FDA将在6个月内完成审查，而非常规的10个月。之前，FDA已授予elotuzumab突破性药物资格。在欧洲，EMA最近也已受理elotuzumab的上市许可申请，也将进行加速评估。
elotuzumab是一种免疫调节性抗体，靶向信号淋巴细胞激活分子家族成员7（SLAMF7，也称为CS1），这是一种表达于骨髓瘤细胞和自然杀伤（NK）细胞上的糖蛋白，但在正常组织中未检测到。
根据提交至FDA的一项III期临床研究（ELOQUENT-2）的数据，与Revlimid（来那度胺）+地塞米松联合疗法相比，elotuzumab+Revlimid+地塞米松联合疗法使复发或难治性多发性骨髓瘤（MM）患者无进展生存期显著延长（中位PFS：19.4 vs 14.9个月，p＜0.001），疾病进展或死亡风险显著降低30%，总缓解率显著提高（ORR：79% vs 66%，p＜0.001）。
关于Empliciti
百时美施贵宝公司建议，如果Empliciti能通过评审，Empliciti将作为埃罗妥珠单抗的品牌名称。百时美施贵宝公司埃罗妥珠单抗Elotuzumab是一个针对SLAMF7的实验性免疫调节抗体。SLAMF7是一个在骨髓瘤细胞和NK细胞表面高表达而在正常组织和造血干细胞表面没有表达的的糖蛋白。埃罗妥珠单抗Elotuzumab的安全性和有效性还没有接受FDA及其他安全健康部门的评估，百时美施贵宝公司和ABBY共同研发了埃罗妥珠单抗elotuzumab，而百时美施贵宝公司将独自承担埃罗妥珠单抗elotuzumab的商业运作。
关于多发性骨髓瘤
多发性骨髓瘤是一种发生于骨髓中的血癌，通常是由骨髓中的浆细胞癌变后增殖失控所导致。尽管过去的十年中在多发性骨髓瘤的治疗方法上已经有了长足的进步，但是它在很大程度上仍然是一种难以治愈的疾病，只有45%的患者在确诊后能活过5年。许多患者都有一个共同特点，暂停治疗之后病情会反复复发，最终导致他们继续接受治疗。复发之后，患者的5年内存活率不足20%。据估计，多发性骨髓瘤全球每年有114,200新增病例，并且每年有超过79,000人因此丧命。
Empliciti, elotuzumab (BMS-901608, HuLuc63)
Elotuzumab Granted Priority Review by FDA for Multiple Myeloma
Elotuzumab (Empliciti) was recently granted a priority review by the FDA for use in combination therapy in patients who have multiple myeloma, following the failure of one or more prior therapies, according to the drug’s co-developers, Bristol-Myers Squibb and AbbVie.
In late July, a separate regulatory filing for the same indication was accepted and given an accelerated review by the European Medicines Agency (EMA). Reviews from both the FDA and EMA will be based primarily on data from the phase III ELOQUENT-2 trial, with supporting data from the phase II study CA204-009.
“Bristol-Myers Squibb is delighted by the approach both agencies have taken to review the Empliciti applications as it underscores the unmet medical need in the treatment of multiple myeloma and the role Immuno-Oncology may play,” said Michael Giordano, MD, senior vice president, head of Oncology Development, Bristol-Myers Squibb, in a statement. “The acceptance of our applications by the FDA and EMA brings Bristol-Myers Squibb’s Immuno-Oncology science a step closer to helping patients with hematologic malignancies.”
The open-label phase III ELOQUENT-2 trial randomized 646 patients who have relapsed/refractory multiple myeloma to lenalidomide and dexamethasone alone (n = 325), or in combination with elotuzumab (n = 321). Elotuzumab was administered weekly at 10 mg/kg IV for the first two cycles, and then biweekly thereafter; lenalidomide was dosed at 25 mg orally on days 1 to 21 of each cycle. Across the study, patients were given 40 mg of oral dexamethasone in weeks without elotuzumab. In weeks in the experimental arm, when elotuzumab was administered, dexamethasone was dosed at 28 mg orally, plus 8 mg IV. The cycle length for all three drug regimens was 28 days, and treatment was administered to the point of disease progression or unacceptable toxicity.
The median patient age in the trial was 66 years, and patients received a median of two prior therapies (range, 1-3), including bortezomib (70%), thalidomide (48%), and lenalidomide (6%). Thirty-five percent of patients were refractory to their most recent therapy; however, none of the patients were lenalidomide refractory. High-risk patient subgroups were identified, with 32% and 9% of patients having a 17p deletion (del[17p]) or t(4;14) translocation, respectively.
The primary outcome measures for this study were progression-free survival (PFS) and overall response rate (ORR); overall survival (OS) was a secondary endpoint. Tumor response was assessed every 4 weeks, whereas survival was assessed every 12 weeks following disease progression.
At a median follow-up of 2 years, PFS with the elotuzumab regimen was 19.4 months (95% CI, 16.6-22.2) versus 14.9 months (95% CI, 12.1-17.2) with lenalidomide and dexamethasone alone (hazard ratio [HR], 0.70; 95% CI, 0.57-0.85; P <.001). The 1-year PFS for the elotuzumab arm was 68%, while the control arm was 57%; the difference in 2-year PFS rates increased to 41% and 27%, respectively.
“What I think is quite striking about this progression-free survival curve...is that the two curves do not appear to come back together with longer follow-up,” said lead author Sagar Lonial, MD, when discussing the results during a presscast held in advance of the ASCO 2015 Annual Meeting.
“This idea of the maintenance of benefit over time really speaks to the power of an immune-mediated based approach when we treat cancer. We’ve seen this, for instance, with PD-1 and other immune-based approaches,” added Lonial, who is chief medical officer of the Winship Cancer Institute of Emory University, and professor and executive vice chair of the Department of Hematology and Medical Oncology of Emory University School of Medicine.
In the overall study, the PFS benefit with elotuzumab was observed across the high-risk del(17p) and t(4;14) subgroups, with HRs of 0.65 and 0.53, respectively.
ORR was 79% with elotuzumab and 66% for the control group (P = .0002). The OS data for the trial are not yet mature.
Elotuzumab was well-tolerated overall, according to Lonial. “The improvement in clinical parameters occurred without a significant increase in adverse events or toxicities. In fact, there was no reduction in quality of life for the group receiving the three drugs.”
At the time of the interim analysis, 35% of patients who were receiving the elotuzumab regimen, as well as 20% of patients receiving lenalidomide and dexamethasone alone, remained on therapy. The most commonly reported all-grade adverse events (AEs) in the elotuzumab arm versus the control arm were lymphocytopenia (99% vs 98%) anemia (96% vs 95%), thrombocytopenia (84% vs 78%), neutropenia (82% vs 89%), fatigue (47% vs 39%), diarrhea (47% vs 36%), and pyrexia (37% vs 25%).
Serious AEs occurred in 65% versus 57% of the elotuzumab versus control arms, respectively. Grade 3/4 lymphocytopenia rates were higher with elotuzumab at 77% versus 49%; however, high-grade neutropenia rates were higher in the control arm, at 44% versus 34%. Ten percent of patients (n = 33) in the elotuzumab arm had infusion reactions, most of which were grade 1/2 (n = 29).
Data from study CA204-009 were presented in June at the 20th Congress of the European Hematology Association (EHA). In the phase II trial, 152 patients with relapsed/refractory multiple myeloma received bortezomib plus dexamethasone with (n = 77) or without (n = 75) elotuzumab. The median patient age was 66 years and patients had received 1 to 3 prior therapies.
Treatment cycles 1 through 8 were 21 days, with all regimens administered on 28-day cycles thereafter. Elotuzumab at 10 mg/kg IV was administered weekly in cycles 1 and 2, on days 1 and 11 of cycles 3 to 8, and on days 1 and 15 thereafter; patients received bortezomib at 1.3 mg/m2 either IV or subcutaneous on days 1, 4, 8, and 11 of cycles 1 to 8, then on days 1, 8, and 15 thereafter; dexamethasone was administered at 20 mg orally on “non-elotuzumab” days and 8 mg orally, plus 8 mg IV on elotuzumab days.
All treatments were administered until disease progression or unacceptable toxicity. The primary endpoint was PFS. Based on the study design, a P value ≤.3 was considered statistically significant.
At the data cutoff, 18% of patients who received the elotuzumab combination remained on therapy, compared to 10% of patients in the control group. The median number of treatment cycles was 12 and 7, respectively.
The median PFS observed with the addition of elotuzumab was 9.7 months versus 6.9 months with bortezomib and dexamethasone alone (HR, 0.71; 70% CI, 0.58-0.87; P = .08). When adjusting for prognostic factors, the HR for PFS was 0.58 (70% CI, 0.47-0.72; P = .01). One- and 2-year PFS rates were 39% versus 32% and 24% versus 6%, respectively.
ORR was 66% with elotuzumab, compared with 63% in the control arm. Early survival data showed an HR of 0.61 (70% CI, 0.43-0.85), which favored the elotuzumab group, with 1-year OS rates of 85% versus 74% in patients receiving bortezomib and dexamethasone alone. OS follow-up is ongoing.
Sixty-eight percent of patients (n = 51) in the elotuzumab arm reported grade 3/4 AEs, compared with 60% (n = 45) in the control arm. The most common AEs of grade 3 or higher were thrombocytopenia (9% [n = 7] with elotuzumab vs 17% [n = 13] in the control arm) and infections (19% [n = 4] versus 15% [n = 11], respectively).
There was an occurrence of grade 1/2 infusion reactions in 7% of the elotuzumab arm; however, there were no infusion reactions at the maximum planned infusion rate of 5 mL/min.
Elotuzumab binds to the SLAMF7 protein found on the surface of both myeloma cells and natural killer (NK) lymphocytes in the immune system. “One of the unique attributes of elotuzumab is that it appears to have a dual mechanism through which it targets both the myeloma cell and appears to enhance the activation of natural killer cells,” Lonial said on the ASCO presscast.
Elotuzumab was given a breakthrough therapy designation by the FDA in May 2014 for use in combination with lenalidomide and dexamethasone for patients who have multiple myeloma, following one or more prior therapies.
The ongoing phase III ELOQUENT-1 trial is examining elotuzumab plus lenalidomide and dexamethasone in the frontline setting for relapsed/refractory multiple myeloma. Other ongoing trials are examining elotuzumab in various combinations with existing therapies.