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美国FDA加速批准Lartruvo注射剂为软组织肉瘤的治疗新药

2016-10-20 08:54:01 作者：来源：互联网浏览次数：16 文字大小：【大】【中】【小】

简介： 新型抗癌药LARTRUVO（olaratumab）注射剂与多柔比星的组合，是四十年来第一个获得FDA批准的一线治疗软组织肉瘤2016年10月19日,美国食品和药品监管局(FDA)授予加速批准Lartruvo(olaratumab)与多柔比星[dox ...

关键字：注射剂olaratumab 商品名lartruvo 与多柔比星治肉瘤加速比准突破治疗孤儿药物

新型抗癌药LARTRUVO（olaratumab）注射剂与多柔比星的组合，是四十年来第一个获得FDA批准的一线治疗软组织肉瘤
2016年10月19日,美国食品和药品监管局(FDA)授予加速批准Lartruvo(olaratumab)与多柔比星[doxorubicin]治疗有的某种类型软组织肉瘤(STS)成年，它是在肌肉，脂肪，肌腱或其他软组织发生癌症。Lartruvo被批准与FDA-被批准化疗药物多柔比星对用辐射或手术不能治愈和患者有一种类型STS对它一种蒽环类(化疗)是一种适当治疗有STS患者的治疗使用。
FDA药品评价和研究中心中血液学和肿瘤产品室主任和FDA的肿瘤学中心的代理主任Richard Pazdur，M.D.说：“对这些患者，Lartruvo，添加至多柔比星，提供一种新治疗选择”。“这是自从在40年多年以前多柔比星的批准软组织肉瘤初始的治疗被FDA批准的第一个新治疗。”
美国癌症研究所估计在2016年有12,310的STS新病例和接近5,000可能因此病死亡。对不能通过手术去除的STS最常用治疗是单独用多柔比星或用其他药物治疗。STS包括一个广泛来自肌肉，脂肪，血管，神经，肌腱或关节村里各种肿瘤。
Lartruvo是一种血小板衍生长因子(PDGF)受体-α阻断抗体。当受刺激时，PDGF受体引起肿瘤生长。Lartruvo通过阻断这些受体起作用，它可能有助减慢或停止肿瘤生长。
在一项随机化临床试验涉及133 患者有多于25种不同亚型的转移STS中研究Lartruvo的安全性和疗效。患者接受或Lartruvo与多柔比星或单独多柔比星。这项试验测量治疗后患者生存的时间长度 (总体生存)，治疗后肿瘤不生长的时间长度(无进展生存)和其肿瘤经历皱缩的患者的百分率(总体反应率)。在这个试验中接受Lartruvo与多柔比星患者在总体生存有统计显著改善：中位生存为26.5个月与之比较对单独接受多柔比星患者为14.7个月。接受Lartruvo与多柔比星患者有中位无进展生存8.2个月相比较对患者单独接受多柔比星为4.4个月。接受Lartruvo与多柔比星患者肿瘤皱缩为18.2%和单独接受多柔比星患者7.5%。
Lartruvo有严重风险包括输注相关反应和胚胎胎儿危害。输注相关反应包括低血压，发热，发冷和皮疹。用Lartruvo治疗的最常见副作用是恶心，疲乏，血细胞的低水平(中性粒细胞减少)，肌肉骨骼痛，粘膜炎，脱发，呕吐，腹泻，食欲减低，腹痛，神经病变和头痛。
FDA 授予Lartruvo申请快速通道指定，突破性治疗指定和优先审评状态因为初步临床证据表明它在某种严重或危及生命疾病或情况的治疗中有效性中提供一个实质上改善。FDA正在监管局的加速批准程序下批准，它根据临床数据显示该药物对某个药物治疗某种严重或危及生命或情况某个替代性终点的影响是有理由可能预测有临床获益允许批准。承办单位正在进行一项较大研究，当前它正在进行中，以进一步开拓跨越STS多种亚型Lartruvo的有效性。
Lartruvo还接受孤儿药物指定，它提供奖励例如税收减免，用户费用免除和对专有权资格以帮助和鼓励意向治疗罕见病药物的开发。
Lartruvo由总部在印第安纳州印第安纳波利斯的Eli Lilly和公司上市。
规格
10毫克/毫升
FDA Approves Lilly's LARTRUVO™ (olaratumab) in Combination with Doxorubicin for Soft Tissue Sarcoma
- LARTRUVO, in combination with doxorubicin, is the first FDA-approved front-line therapy for soft tissue sarcoma in four decades
- The approval was based on results from the positive Phase 2 JGDG trial
- LARTRUVO received the FDA's Breakthrough Therapy Designation and was approved under the Agency's Accelerated Approval program
U.S. Food and Drug Administration (FDA) has granted approval of LARTRUVO™ (olaratumab injection, 10 mg/mL), in combination with doxorubicin, for the treatment of adults with soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery. LARTRUVO's indication is approved under Accelerated Approval, and is based on data from the Phase 2 portion of the pivotal JGDG trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. LARTRUVO, in combination with doxorubicin, is the first FDA-approved front-line therapy for STS in four decades. The confirmatory Phase 3 trial, ANNOUNCE, is fully enrolled.
"LARTRUVO represents an important step forward in soft tissue sarcoma treatment," said William D. Tap, M.D., chief of the sarcoma medical oncology services at Memorial Sloan Kettering Cancer Center in New York and the principal investigator of the JGDG registration trial. "We are pleased with this approval, which will provide patients with a treatment option that offers new hope in their battle against this difficult disease."
Soft tissue sarcoma is a complex disease with multiple subtypes, making it hard to diagnose and difficult to treat. For decades, there have been no first-line therapeutic advancements for STS that have improved overall survival (OS). According to the American Cancer Society, in 2015, there were an estimated 12,000 new STS cases diagnosed and nearly 5,000 deaths in the U.S. alone, representing an unmet medical need.
LARTRUVO is the first monoclonal antibody approved to treat STS. It also received Fast Track, Orphan Drug and Breakthrough Therapy designations from the FDA for this indication, and was reviewed and approved under the FDA's Accelerated Approval program. This program allows for earlier approval of drugs that treat serious conditions and that fill an unmet medical need.
"The approval of LARTRUVO is based on an encouraging and positive study for patients, and represents progress in soft tissue sarcoma treatment. For the first time in four decades, we now have a combination regimen – LARTRUVO and doxorubicin – that offers progress over doxorubicin alone in the front-line setting, by improving overall survival for people with soft tissue sarcoma," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "This continues our commitment to discovering new ways to treat cancer, including for people who have rare types of cancer."
"The entire sarcoma patient community is excited to have an innovative medicine approved for the treatment of advanced soft tissue sarcoma," said Bert E. Thomas IV, PhD, MBA, CEO of the Sarcoma Foundation of America. "We are confident that the approval of LARTRUVO may help these patients live longer."
The approval of LARTRUVO is based on the results of JGDG, an open-label, randomized, active-controlled study of 133 patients, which compared LARTRUVO, in combination with doxorubicin chemotherapy, to doxorubicin alone in patients with STS with a histologic subtype for which an anthracycline-containing regimen was appropriate and which is not amenable to curative treatment with surgery or radiotherapy. The efficacy outcome measures were OS, progression-free survival (PFS), and objective response rate (ORR).
Median OS was improved by 11.8 months in patients randomized to receive LARTRUVO plus doxorubicin compared to patients randomized to doxorubicin alone, and was statistically significant. Median OS was 26.5 months (95% CI: 20.9, 31.7) on the LARTRUVO-doxorubicin arm compared to 14.7 months (95% CI: 9.2, 17.1) on the doxorubicin-only arm (stratified hazard ratio [HR], 0.52; 95% CI: 0.34, 0.79, <0.05). The study met its prespecified protocol-defined endpoint for PFS. Patients treated on the LARTRUVO and doxorubicin arm achieved 8.2 months (95% CI: 5.5, 9.8) of median PFS compared to 4.4 months (95% CI: 3.1, 7.4) on the doxorubicin-only arm (stratified hazard ratio [HR], 0.74; 95% CI: 0.46, 1.19), based on independent review. The number of events at the time of analysis was 37 (56%) on the LARTRUVO-doxorubicin arm and 34 (51%) on the doxorubicin-only arm. The number of deaths at the time of analysis was 39 (59%) on the LARTRUVO-doxorubicin arm and 52 (78%) on the doxorubicin-only arm. Objective response rate (ORR), based on independent review and defined as complete response (CR) plus partial response (PR), was also assessed with an ORR of 18.2 percent (95% CI: 9.8, 29.6) (CR, 4.5%; PR, 13.6%) on the LARTRUVO-doxorubicin arm and 7.5 percent (95% CI: 2.5, 16.6) (CR, 1.5%; PR, 6%) on the doxorubicin-only arm.
The labeling for LARTRUVO contains Warnings and Precautions for infusion-related reactions and embryo-fetal toxicity. The most commonly reported adverse reactions (all grades) occurring in ≥20 percent of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were nausea (73% vs 52%), fatigue (69% vs 69%), musculoskeletal pain (64% vs 25%), mucositis (53% vs 35%), vomiting (45% vs 19%), diarrhea (34% vs 23%) and headache (20% vs 9%). The most common laboratory abnormalities (all grades) occurring in ≥20% of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were lymphopenia (77% vs 73%), neutropenia (65% vs 63%), thrombocytopenia (63% vs 44%), hyperglycemia (52% vs 28%), elevated aPTT (33% vs 13%), hypokalemia (21% vs 15%) and hypophosphatemia (21% vs 7%). Febrile neutropenia was reported in 13% of LARTRUVO plus doxorubicin-treated patients versus 12% of doxorubicin-treated patients.
Adverse reactions resulting in permanent discontinuation of LARTRUVO occurred in 8% (5/64) of patients. The most common adverse reaction leading to LARTRUVO discontinuation was infusion-related reaction (3%). Dose reductions of LARTRUVO for adverse reactions occurred in 25% (16/64) of patients; the most common adverse reaction leading to dose reduction was Grade 3 or 4 neutropenia (20%). Dose delays of LARTRUVO for adverse reactions occurred in 52% (33/64) of patients; the most common adverse reactions resulting in dose delays were neutropenia (33%), thrombocytopenia (8%) and anemia (5%).
IMPORTANT SAFETY INFORMATION FOR LARTRUVO
Warnings and Precautions
Infusion-Related Reactions
•Infusion-related reactions (IRR) occurred in 70 (14%) of 485 patients who received at least one dose of LARTRUVO across clinical trials. For 68 of these 70 patients (97%), the first occurrence of IRR was in the first or second cycle. Grade =3 IRR occurred in 11 (2.3%) of 485 patients, with one (0.2%) fatality. Symptoms of IRR included flushing, shortness of breath, bronchospasm, or fever/chills, and in severe cases symptoms manifested as severe hypotension, anaphylactic shock, or cardiac arrest. Infusion-related reactions required permanent discontinuation in 2.3% of patients and interruption of infusion in 10% of patients. All 59 patients with Grade 1 or 2 IRR resumed LARTRUVO; 12 (20%) of these patients had a Grade 1 or 2 IRR with rechallenge. The incidence of IRR in the overall safety database (N = 485) was similar (18% versus 12%) between those who did (56%) and those who did not (44%) receive premedication. Monitor patients during and following LARTRUVO infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Immediately and permanently discontinue LARTRUVO for Grade 3 or 4 IRR.
Embryo-Fetal Toxicity
•Based on animal data and its mechanism of action, LARTRUVO can cause fetal harm when administered to a pregnant woman. Animal knockout models link disruption of platelet-derived growth factor receptor alpha (PDGFR-a) signaling to adverse effects on embryo-fetal development. Administration of an anti-murine PDGFR-a antibody to pregnant mice during organogenesis caused malformations and skeletal variations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LARTRUVO and for 3 months after the last dose.
Most Common Adverse Reactions/Lab Abnormalities
•The most commonly reported adverse reactions (all grades; grade 3-4) occurring in =20% of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were nausea (73% vs 52%; 2% vs 3%), fatigue (69% vs 69%; 9% vs 3%), musculoskeletal pain (64% vs 25%; 8% vs 2%), mucositis (53% vs 35%; 3% vs 5%), alopecia (52% vs 40%; 0% vs 0%), vomiting (45% vs 19%; 0% vs 0%), diarrhea (34% vs 23%; 3% vs 0%) decreased appetite (31% vs 20%; 2% vs 0%), abdominal pain (23% vs 14%; 3% vs 0%), neuropathy (22% vs 11%; 0% vs 0%), and headache (20% vs 9%; 0% vs 0%).
•The most common laboratory abnormalities (all grades; grade 3-4) occurring in =20% of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were lymphopenia (77% vs 73%; 44% vs 37%), neutropenia (65% vs 63%; 48% vs 38%) and thrombocytopenia (63% vs 44%; 6% vs 11%), hyperglycemia (52% vs 28%; 2% vs 3%), elevated aPTT (33% vs 13%; 5% vs 0%), hypokalemia (21% vs 15%; 8% vs 3%), and hypophosphatemia (21% vs 7%; 5% vs 3%).
Use in Specific Populations
•Lactation: Because of the potential risk for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment with LARTRUVO and for at least 3 months following the last dose.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761038lbl.pdf