1月13日，礼来制药（纽约证券交易所代码：LLY）和信达生物制药（香港联交所股票代码：01801），共同宣布：双方共同开发的创新PD-1抑制剂达伯舒（信迪利单抗注射液）的一项随机、双盲、3期对照临床研究（ORIENT-11）——达伯舒（信迪利单抗注射液）联合力比泰(注射用培美曲塞二钠) 和铂类用于无EGFR敏感突变或ALK基因重排的晚期或复发性非鳞状非小细胞肺癌（nsqNSCLC）一线治疗期中分析达到主要研究终点。
基于由独立数据委员会（IDMC）进行的期中分析，达伯舒（信迪利单抗注射液）联合力比泰（注射用培美曲塞二钠）和铂类对比安慰剂联合力比泰（注射用培美曲塞二钠）和铂类，显著延长了无进展生存期（PFS），达到预设的优效性标准，安全性特征与既往报道的达伯舒（信迪利单抗注射液）研究结果一致，无新的安全性信号。
相关研究结果将在近期的学术会议上予以公布。根据独立数据委员会（IDMC）建议，礼来将在近期与信达启动就向国家药品监督管理局递交注册申请的讨论。
中山大学肿瘤防治中心内科主任张力教授表示：“国家癌症中心公布了的中国癌症数据，其中肺癌总体发病率为20%，死亡率约为27%，均位列所有癌症之首。对于无EGFR敏感突变或ALK基因重排的非鳞状非小细胞肺癌患者而言，他们需要更多的治疗方案，抗PD-1单克隆抗体联合化疗为这一类患者带来了更大的生存获益。我们非常欣喜地看到，达伯舒（信迪利单抗注射液）这一研究在期中分析达到了预设的主要研究终点。”
“该项研究结果令人振奋，显示了达伯舒（信迪利单抗注射液）联合力比泰（注射用培美曲塞二钠）和铂类能够在此类患者人群中显著延缓疾病进展。它也再次体现了礼来和信达为肺癌患者提供创新治疗方案的承诺，”礼来中国高级副总裁，药物发展与医学事务中心负责人王莉博士说道，“在此我们想感谢所有参与此次研究的受试患者、研究人员和临床试验中心以及信达的各位同事。我们期待未来能早日将这一新型治疗方案带给中国的肺癌患者。”
信达生物制药集团医学科学与战略肿瘤部副总裁周辉博士表示：“目前达伯舒（信迪利单抗注射液）是唯一列入国家医保目录的抗PD-1单克隆抗体药物。它于12月24日获得国家药品监督管理局批准，用于至少经过二线系统化疗的复发或难治性经典型霍奇金淋巴瘤的治疗。目前我们正在开展多项肺癌3期随机对照研究。ORIENT-11研究期中分析结果令人鼓舞，我们预见达伯舒（信迪利单抗注射液）有能力惠及更多肺癌患者，让他们有更多时间陪伴家人。”
关于ORIENT-11研究
ORIENT-11研究是一项评估达伯舒（信迪利单抗注射液）或安慰剂联合力比泰（注射用培美曲塞二钠）和铂类用于晚期或复发性非鳞状非小细胞肺癌（nsqNSCLC）一线治疗有效性和安全性的随机、双盲、3期对照临床研究（ClinicalTrials.gov, NCT03607539）。主要研究终点是由独立影像学评审委员会（IRRC）根据RECIST v1.1标准评估的无进展生存（PFS）。次要研究终点包括总生存期（OS）、安全性等。
本研究共入组397例受试者，按照2:1随机入组，分别接受达伯舒（信迪利单抗注射液）200mg或安慰剂联合力比泰（注射用培美曲塞二钠）和铂类治疗，每3周给药1次，完成4个周期治疗后，进入达伯舒（信迪利单抗注射液）或安慰剂联合力比泰（注射用培美曲塞二钠）维持阶段，治疗直至疾病进展、毒性不可耐受或其他需要终止治疗的情况。对照组疾病进展后可有条件交叉至达伯舒（信迪利单抗注射液）单药治疗。
关于非鳞状非小细胞肺癌
(nsqNSCLC)
肺癌是我国目前发病率和死亡率均排名第一的恶性肿瘤。在所有肺癌中NSCLC大约占80%至85%，约70%的NSCLC患者在诊断时已是不适于根治性手术的局部晚期或转移性肿瘤。同时，在接受手术治疗的早期NSCLC患者中也有相当比例会发生复发或远处转移，后因疾病进展而死亡。中国NSCLC患者中约70%为非鳞状NSCLC，其中接近50%的NSCLC患者无EGFR敏感突变或ALK基因重排，这部分晚期肺癌患者不适用靶向治疗，治疗手段有限，存在巨大的未被满足的医疗需求。
关于达伯舒
（信迪利单抗注射液）
达伯舒（信迪利单抗注射液）是礼来制药和信达生物制药在中国共同合作研发的具有国际品质的创新生物药。其上市申请已正式获得国家药品监督管理局的批准，获批的第一个适应症是复发/难治性经典型霍奇金淋巴瘤，并入选版中国临床肿瘤学会（CSCO）淋巴瘤诊疗指南。医保国谈中，达伯舒（信迪利单抗注射液）是唯一进入国家医保的具有国际品质PD-1抑制剂。
达伯舒（信迪利单抗注射液）是一种人类免疫球蛋白G4（IgG4）单克隆抗体，能特异性结合T细胞表面的PD-1分子，从而阻断导致肿瘤免疫耐受的 PD-1/程序性死亡受体配体1（Programmed Death-Ligand 1, PD-L1）通路，重新激活淋巴细胞的抗肿瘤活性，从而达到治疗肿瘤的目的。目前有超过二十多个临床研究（其中8项是注册临床试验）正在进行，以探讨信迪利单抗在其它实体肿瘤上的抗肿瘤作用。信达生物同时正在美国开展信迪利单抗注射液的临床研究工作。
IMPORTANT SAFETY INFORMATION FOR ALIMTA (pemetrexed for injection)
CONTRAINDICATION
ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.
WARNINGS AND PRECAUTIONS
Myelosuppression and Increased Risk of Myelosuppression Without Vitamin Supplementation
ALIMTA can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation.Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued during treatment and for 21 days after the last dose of ALIMTA as they may reduce the severity of treatment-related hematologic and gastrointestinal toxicities. Obtain a complete blood count at the beginning of each cycle. Do not administer ALIMTA until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce ALIMTA in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles.In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the ALIMTA arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%.
Renal Failure
ALIMTA can cause severe, and sometimes fatal, renal toxicity. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with ALIMTA.The incidences of renal failure in clinical studies in which patients received ALIMTA with cisplatin were 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received ALIMTA as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI).Withhold ALIMTA in patients with a creatinine clearance of less than 45 mL/min.
Bullous and Exfoliative Skin Toxicity
Serious and sometimes fatal, bullous, blistering, and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/toxic epidermal necrolysis, can occur with ALIMTA. Permanently discontinue ALIMTA for severe and life-threatening bullous, blistering, or exfoliating skin toxicity.
Interstitial Pneumonitis
Serious interstitial pneumonitis, including fatal cases, can occur with ALIMTA treatment. Withhold ALIMTA for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue ALIMTA.
Radiation Recall
Radiation recall can occur with ALIMTA in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue ALIMTA for signs of radiation recall.
Increased Risk of Toxicity With Ibuprofen in Patients With Renal Impairment
Exposure to ALIMTA is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of ALIMTA. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for ALIMTA adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity.
Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ALIMTA and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose.
DRUG INTERACTIONS
Ibuprofen increases exposure (AUC) of pemetrexed. In patients with creatinine clearance between 45 mL/min and 79 mL/min:Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA.Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.
ADVERSE REACTIONS
Severe adverse reactions (Grade 3-4) occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin) versus ALIMTA with platinum chemotherapy + placebo for initial treatment (KEYNOTE-189), respectively, were fatigue (12% vs 6%); diarrhea (5% vs 3%); dyspnea (3.7% vs 5%); vomiting (3.7% vs 3%); nausea (3.5% vs 3.5%); rash (2% vs 2.5%); decreased appetite (1.5% vs 0.5%); constipation (1% vs 0.5%); and pyrexia (0.2% vs 0%).Common adverse reactions (all grades) occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin) versus ALIMTA with platinum chemotherapy + placebo for initial treatment (KEYNOTE-189), respectively, were nausea (56% vs 52%); fatigue (56% vs 58%); constipation (35% vs 32%); diarrhea (31% vs 21%); decreased appetite (28% vs 30%); rash (25% vs 17%); vomiting (24% vs 23%); cough (21% vs 28%); dyspnea (21% vs 26%); and pyrexia (20% vs 15%).
USE IN SPECIFIC PATIENT POPULATIONS
Lactation: There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from ALIMTA, advise women not to breastfeed during treatment with ALIMTA and for one week after the last dose.Males of Reproductive Potential: ALIMTA may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible.Pediatric Use: The safety and effectiveness of ALIMTA in pediatric patients have not been established. Adverse reactions observed in pediatric patients studied were similar to those observed in adults.Patients with Renal Impairment: ALIMTA is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function. No dose is recommended for patients with creatinine clearance less than 45 mL/min.Geriatric: The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials.
PM_HCP_ISI_NSCLC1L_Combo_30JAN
For safety and dosing guidelines for ALIMTA, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the full Prescribing Informationand Patient Prescribing Information.
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ALIMTA is a registered trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.
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