新型抗癌药PD-L1抗体Bavencio(avelumab)冻干粉注射剂获FDA批准为第一个治疗罕见型皮肤癌
2017年3月23日，美国食品和药品监管局授权加速批准Bavencio(avelumab)为成年和12岁和以上儿童有转移Merkel细胞癌(MCC)的治疗，包括未曽接受以前化疗。这是为转移MCC，一种罕见，侵袭性皮肤癌FDA-批准的第一个治疗。
FDA的药品评价和研究中心和中血液学肿瘤学办公室代理主任FDA的卓越肿瘤学中心主任Richard Pazdur，M.D.说：“皮肤癌是最常见癌之一，有一种罕见型被称为Merkel细胞癌患者迄今未曽有被批准的治疗选择，” “科学社会继续使靶向对各种类型癌症治疗的机体免疫系统机制进展。这些进展正在导致新治疗—即使在癌症的罕见型其中治疗选择是有限或不-存在。”
按照美国癌症研究所，在美国每年约1,600人被诊断有MC。而患者的大多数存在有可用手术切除的局部化肿瘤，所有的约半数将经历复发，和超过30%最终将发生转移疾病。在有转移MCC患者中，癌症已播散超出皮肤至机体的其他部分。
Bavencio靶向PD-1/PD-L1途径(在机体免疫细胞和有些癌症细胞发现的蛋白)。通过阻断这些相互作用，Bavencio可能帮助机体免疫系统袭击癌症细胞。
Bavencio接到一个加快批准，它利用临床试验数据被认为预测对患者一种临床获益使FDA批准药物对严重情况以满足未满足的医药需求。承办单位被要求进行进一步临床试验确证Bavencio的临床获益和当前正在进行这些研究。
Bavencio的今天批准是根据来自一项88例有转移MCC患者的单-臂试验，患者以前曽用至少一种以前化疗方案治疗过。
试验测量他们的肿瘤经历完全或部分缩小患者的百分率(总体反应率)和，对有一个反应患者，肿瘤被控制的时间长度(反应的时间)。在本试验中接受Bavencio的88例患者中，他们的肿瘤33 %经历完全或部分缩小。反应患者的86 %反应持续共超过6个月和反应患者的45%反应时间超过12个月。
Bavencio的常见副作用包括疲乏，肌肉骨骼痛，腹泻，恶心，输注-相关反应，皮疹，食欲减退和肢体肿胀(周围水肿)。Bavencio的最严重的风险是免疫-介导的，其中机体免疫系统攻击健康细胞或器官，例如肺(肺炎)，肝(肝炎)，结肠(结肠炎)，激素-产生腺体(内分泌病变)和肾(肾炎)。此外，有严重的输注-相关反应的风险。
经受严重或危及生命输注-相关反应患者应停止使用Bavencio。妊娠或哺乳喂养妇女不应服用Bavencio因为它可能致危害至发育中胎儿或一个新生的婴儿。
FDA授权这项申请优先审评和突破性治疗指定。 Bavencio还接到孤儿罕见药物指定，它提供鼓励帮助和鼓励对罕见疾病药物的开发。
FDA授权赋予EMD Serono Inc 公司Bavencio的加快批准。
包装规格
20mg/10ml(20mg/nl)/瓶

生产厂家：辉瑞联合德国默克
FDA Grants Approval for BAVENCIO(avelumab), the First Immunotherapy Approved for Metastatic Merkel Cell Carcinoma
•Only FDA-approved treatment for metastatic Merkel cell carcinoma, a rare and aggressive skin cancer      
•First indication for BAVENCIO, a human anti-PD-L1 antibody   
 US Food and Drug Administration (FDA) has approved BAVENCIO® (avelumab) Injection 20mg/mL, for intravenous use, for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC). This indication is approved under accelerated approval based on tumor response and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.BAVENCIO will be co-commercialized by EMD Serono, the biopharmaceutical business of Merck in the US and Canada, and Pfizer. BAVENCIO was developed, reviewed and approved through the FDA's Breakthrough Therapy Designation and Priority Review programs.
BAVENCIO, a human anti-PD-L1 antibody, is the first FDA-approved therapy for patients with mMCC.Metastatic MCC is a rare and aggressive skin cancer, with fewer than half of patients surviving more than one year and fewer than 20% surviving beyond five years。
"At the heart of this FDA approval is our drive to make a meaningful difference for patients with hard-to-treat cancers like metastatic Merkel cell carcinoma," said Belén Garijo, CEO Healthcare and Member of the Executive Board of Merck. "BAVENCIO's journey has included years of hard work - from the scientists who discovered this molecule in our labs, to our alliance with Pfizer and to the study participants and investigators worldwide. We are grateful to all who have made it possible for us to bring this important new treatment option to patients."
"Today is a significant milestone for people fighting metastatic Merkel cell carcinoma, who until now have not had any options beyond chemotherapy," said Albert Bourla, Group President, Pfizer Innovative Health. "This approval demonstrates the power of collaboration to accelerate meaningful new choices for cancer patients."
"Merkel cell carcinoma is rarer than some of the more well-known skin cancers, however, it's very aggressive and the proportion of people who die from MCC is much higher than that of people with melanoma," said Deborah S. Sarnoff, MD, President of the Skin Cancer Foundation. "With this approval, I believe there is new hope for people and their families touched by this rare form of skin cancer."
The efficacy and safety of BAVENCIO was demonstrated in the JAVELIN Merkel 200 trial, an open-label, single-arm, multi-center study conducted in 88 patients with histologically confirmed metastatic MCC whose disease had progressed on or after chemotherapy administered for distant metastatic disease. Sixty-five percent of patients were reported to have had one prior anti-cancer therapy for metastatic MCC and 35% had two or more prior therapies. The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by a blinded independent central review committee (IRC) and IRC-assessed duration of response.
The overall response rate (ORR) was 33% (95% confidence interval [CI]: 23.3-43.8%).Eleven percent of patients experienced a complete response (95% CI: 6.6-19.9%) and 22% of patients experienced a partial response (95% CI: 13.5-31.7%). Tumor responses were durable, with 86% of responses lasting for at least six months (n=25).Forty-five percent of responses lasted at least 12 months (n=13).Duration of response ranged from 2.8 to over 23.3 months.
The warnings and precautions for BAVENCIO include immune-mediated adverse reactions (such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis and renal dysfunction, and other adverse reactions), infusion-related reactions and embryo-fetal toxicity. The most common adverse reactions (reported in at least 20% of patients) included fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reactions (22%), rash (22%), decreased appetite (20%) and peripheral edema (20%).For more information, please see Important Safety Information for BAVENCIO below.
BAVENCIO is designed to potentially engage both the adaptive and innate immune systems. By binding to PD-L1, BAVENCIO is thought to prevent tumor cells from using PD-L1 for protection against white blood cells, such as T-cells, exposing them to anti-tumor responses.BAVENCIO has been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.
IMPORTANT SAFETY INFORMATION and INDICATION   
BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade.
BAVENCIO can cause immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis was reported in 0.9% (16/1738) of patients, including two (0.1%) patients with Grade 5 and 11 (0.6 %) with Grade.
BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis and permanently discontinue for life-threatening (Grade 4) or recurrent Grade 3 colitis upon re-initiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade.
BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.
Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% (8/1738) of patients, including one (0.1%) with Grade 3.
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life threatening (Grade 4) thyroid disorders. Thyroid disorders including hypothyroidism, hyperthyroidism, and thyroiditis were reported in 6% (98/1738) of patients, including three (0.2%) with Grade 3.
Type 1 diabetes mellitus, including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade 3 or greater) hyperglycemia and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3 hyperglycemia.
BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% (1/1738) of patients.
BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high dose corticosteroids, and initiate hormone replacement therapy if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO: myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.
BAVENCIO can cause severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Patients should be premedicated with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade.
BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least one month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least one month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.
The most common adverse reactions (all grades, greater than or equal to 20%) in patients with metastatic MCC were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reactions (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%). The most common adverse reaction requiring dose interruption was anemia.
Selected treatment-emergent laboratory abnormalities (all grades, greater than or equal to 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%). and increased alanine aminotransferase (20%). Selected treatment-emergent Grade 3-4 laboratory abnormalities (greater than or equal to 2%) were lymphopenia (19%), anemia (9%), hyperglycemia (7%), increased alanine aminotransferase (5%), and increased lipase (4%).
INDICATION   
BAVENCIO is indicated for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
About BAVENCIO® (avelumab)   
BAVENCIO is a human programmed death ligand-1 (PD-L1) blocking antibody indicated in the US for the treatment of adults and pediatric patients 12 years of age and older with metastatic Merkel cell carcinoma.This indication is approved under accelerated approval based on tumor response and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf