新型抗癌药物Lartruvo（olaratumab）注射液联合阿霉素获FDA加速批准至新治疗.
近日，美国食品和药物管理局FDA已加速批准抗癌新药Lartruvo（olaratumab注射液，10mg/mL）联合阿霉素（doxorubicin）用于组织学亚型为适合含蒽环类方案并且不适合采用放疗或手术根治的软组织肉瘤（STS）成人患者。
Lartruvo是一种人血小板衍生生长因子受体α（platelet-derived growth factor recepter α，PDGFRα）拮抗剂，该药是FDA批准治疗STS的首个单克隆抗体药物。
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。” 加速批准，快速通道指定，突破性治疗指定和优先审评，加速批准程序孤儿药物指定
批准日期：2016年10月19；公司: Eli Lilly和公司
LARTRUVO(olaratumab)注射液，为静脉使用
美国初始批准：2016
一般描述
Olaratumab是一个重组人IgG1单克隆阻断抗体特异性地结合至人血小板衍生长因子受体 α(PDGFR-α)。LARTRUVO有一个约分子量154 kDa。LARTRUVO在遗传工程的哺乳动物NS0细胞中生产。
LARTRUVO是一种无菌，无防腐剂，清澈至略微乳光，和无色至略微浅黄色溶液。LARTRUVO注射液是在单剂量小瓶中供应为稀释后静脉使用。每个小瓶含500 mg LARTRUVO在50 mL(10 mg/mL)。每mL含10 mg olaratumab，甘氨酸(7.5 mg)，L-组氨酸(0.3 mg)，L-组氨酸一盐酸盐(1.7 mg)，甘露醇(13.7 mg)，聚山梨醇20(0.2 mg)，氯化钠(2.9 mg)，和注射用水，USP，pH 5.2至
作用机制
Olaratumab是一种人IgG1抗体结合血小板衍生长因子受体α(PDGFR-α)。PDGFR-α是一种受体表达在间充质来源的细胞上酪氨酸激酶。通过这个受体信号在细胞生长，趋化作用，和间充质干细胞分化中起作用。在某些肿瘤和基质细胞，包括肉瘤也曽检测到受体和其中信号可能对癌细胞增殖，转移，和zhong流微环境的维持有贡献。Olaratumab和PDGFR-α间相互作用阻止受体被PDGF-AA和-BB配体以及PDGF-AA，-BB，和-CC-诱导的受体结合激活和下游PDGFR-α通路信号。Olaratumab表现在体外和在体内对选定肉瘤细胞系抗-肿瘤活性和在体内肿瘤植入模型破坏PDGFR-α信号通路。
适应证和用途
LARTRUVO™是一种血小板衍生长因子受体α(PDGFR-α)阻断抗体使用，与多柔比星联用，为有软组织肉瘤(STS)一种组织学亚型为含蒽醌方案是适当成年患者的治疗和是不适于用放射治疗或手术治疗治愈。
这个适应证是在加速批准下被批准的。继续批准这个适应证可能取决于在验证性试验中临床获益的证实和描述
剂量和给药方法
● 在每21天疗程的天1和8历时60分钟静脉输注给予LARTRUVO在15 mg/kg直至疾病进展或不能接受毒性。
● 对头8个疗程，LARTRUVO被与多柔比星给予。
● 疗程1的天1用LARTRUVO前静脉用预先给药苯海拉明[diphenhydramine]和地塞米松[dexamethasone]。
● 仅为静脉输注。不要静脉推注或丸注。
剂型和规格
注射液：500mg/50mL(10mg/mL)溶液在单剂量小瓶中。
禁忌证
无。
警告和注意事项
●输注相关反应：输注期间和后对体征和症状监视。对3或4级输注相关反应终止LARTRUVO。
●胚胎-胎儿毒性：可能致胎儿危害。劝告对胎儿潜在风险的女性和用LARTRUVO治疗期间和末次剂量后共3个月使用有效避孕
不良反应
LARTRUVO加多柔比星最常见(≥20%)不良反应是恶心，疲乏，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。
最常见(≥20%)实验室异常是淋巴细胞减少，中性粒细胞减少，血小板减少，高血糖，升高的aPTT，低钾血症，和低磷血症。
在特殊人群中使用
哺乳：劝告妇女不要哺乳喂养。
供应/贮存和处置
LARTRUVO是在单次-剂量小瓶作为一个无菌，无防腐剂，清澈至略微乳光和无色至略微浅黄色溶液供应。
● NDC 0002-8926-01 500 mg/50 mL(10 mg/mL)单次-剂量小瓶，在一纸盒中个体包装。
贮存小瓶在冰箱在2°C至8°C(36°F至46°F)直至使用时。避光保护保持小瓶在外部纸盒内。不要冻结或摇晃小瓶。

FDA Approves Eli Lilly (LLY)'s LARTRUVO (Olaratumab) In Combination With Doxorubicin For Soft Tissue Sarcoma
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%). See the full Important Safety Information at the end of this press release and the Prescribing Information. 
LARTRUVO is indicated, in combination with doxorubicin, for the treatment of adult patients 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.
This indication is approved under Accelerated Approval. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.
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-) signaling to adverse effects on embryo-fetal development. Administration of an anti-murine PDGFR- 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.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6a5bff43-f922-46ae-a727-d54d9138c46e