Impact !! XALKORI(R) (crizotinib) for NSCLC !!!!

Pfizer To Present New Data in Lung And Kidney Cancers at The European Society For Medical Oncology 2  By BusinessWirevia The Motley Fool Posted 1:22PM 09/17/12 Pfizer To Present New Data in Lung And Kidney Cancers at The European Society For Medical Oncology 2012 Congress First Phase 3 Data Presentation on XALKORI® (crizotinib) versus Standard Chemotherapy in Previously Treated Patients with ALK-Positive Advanced Non-Small Cell Lung Cancer  Data on Kidney Cancer Portfolio Broaden Clinical Understanding of the Continuum of Care for Renal Cell Carcinoma Patients NEW YORK--(BUSINESS WIRE)-- Pfizer Oncology today announced that important data from its lung cancer and renal cell carcinoma (RCC) portfolios will be presented at the upcoming European Society for Medical Oncology (ESMO) Congress in Vienna, Austria, September 28 - October 2, 2012. "We believe that the clinical trial results to be shared at ESMO 2012 substantially enhance our knowledge of both marketed and investigational therapies from our lung and kidney cancer portfolios," said Mace Rothenberg, MD, senior vice president of clinical development and medical affairs for Pfizer's Oncology Business Unit. "We are especially pleased to be able to share, for the first time, detailed results of PROFILE 1007, a randomized trial comparing XALKORI to standard chemotherapy in patients with recurrent, ALK-positive non-small cell lung cancer (NSCLC). These results, which will be presented at the Presidential Symposium, reinforce the value of Pfizer's precision medicine approach to drug development, and demonstrate the benefit that targeted, efficient and science-driven cancer drug development can have on patient outcomes."

Treating Lung Cancer Through a Targeted Approach Data highlights relating to Pfizer's lung cancer portfolio include: Phase 3 randomized study of crizotinib versus pemetrexed or docetaxel chemotherapy in advanced, ALK-positive NSCLC (PROFILE 1007) (Presidential Symposium, Abstract #LBA1, September 30, 16:00-18:00)1 Updated results of a global Phase 2 study with crizotinib in advanced ALK-positive NSCLC (Poster Discussion, Abstract #1230PD, September 30, 12:45-14:15)2 Clinical activity of crizotinib in patients with advanced NSCLC harboring ROS1 gene rearrangement (Poster Discussion, Abstract #1191PD, September 30, 12:45-14:15)3 Updated data will be presented on dacomitinib, an investigational, irreversible pan-HER tyrosine kinase inhibitor (TKI), for first-line treatment of EGFR-mutant, HER2-mutant or amplified lung cancers (Oral Presentation, Abstract #1228O, September 30, 9:00-11:00).4 Additionally, data from a Phase 1 trial of dacomitinib in combination with XALKORI (crizotinib) in previously treated advanced NSCLC will be presented (Poster Presentation, Abstract #1290P, September 29, 13:00-14:00).5

Pfizer Oncology Leadership in Renal Cell Carcinoma Pfizer Oncology is committed to contributing to the science of advanced RCC and continues to support a number of studies evaluating established and novel compounds for the disease. Pfizer will present data from new and ongoing analyses of its RCC clinical trial program at ESMO 2012, broadening clinical understanding of INLYTA® (axitinib), SUTENT® (sunitinib malate) and TORISEL® (temsirolimus) across the spectrum of renal cancer. INLYTA is an oral kinase inhibitor designed to inhibit tyrosine kinases including vascular endothelial growth factor (VEGF) receptors 1, 2 and 3. Data presentations for INLYTA include: Clinic and home blood pressure measurements are reliable for guiding therapy in patients with metastatic RCC receiving axitinib as first-line therapy (Poster Presentation, Abstract #811P, September 29, 13:00-14:00)6 Axitinib vs sorafenib for advanced RCC: Phase 3 overall survival results and analysis of prognostic factors (Poster Discussion, Abstract #793PD, October 1, 13:00-14:00)7 As part of the continued evaluation of SUTENT, data to be presented at the meeting include: Comparative assessment of sunitinib-associated adverse events (AEs) as potential biomarkers of efficacy in metastatic mRCC (Oral Presentation, Abstract #785O, October 1, 14:00-15:00)8 Sunitinib dosing schedule and data collection timepoints: impact on quality of life outcomes in metastatic RCC (Poster Presentation, Abstract #815P, September 29, 13:00-14:00)9 Late breaking data will be presented in oral sessions from two randomized Phase 3 studies evaluating TORISEL in patients with advanced RCC at different stages of disease, including results from the INTORSECT trial in previously treated patients compared with sorafenib. (Proffered Papers Session, Abstract #LBA22_PR, October 1, 14:00-15:50).10 Pfizer will also present results from the INTORACT trial evaluating TORISEL in combination with bevacizumab in treatment-naïve patients (Proffered Papers Session, Abstract #LBA21_PR, October 1, 14:00-15:50).11 Pfizer previously announced that the INTORSECT and INTORACT trials did not meet their primary endpoints in May 2012 and August 2012, respectively. About XALKORI ® (crizotinib) XALKORI received an accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with XALKORI. XALKORI also has received approval in a number of other countries including Canada, South Korea, Japan and Switzerland. In June 2012, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion recommending that XALKORI be granted conditional approval in the European Union (EU) for the treatment of adults with previously treated ALK-positive advanced NSCLC. Additional applications are under regulatory review in several countries worldwide. Important XALKORI ® (crizotinib) Safety Information 12 Drug-induced hepatotoxicity with fatal outcome has occurred. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including alanine aminotransferase (ALT) and total bilirubin once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated. XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes and permanently discontinue XALKORI in patients with treatment-related pneumonitis. QTc prolongation has been observed. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI for grade 4 QTc prolongation. XALKORI should be withheld for grade 3 QTc prolongation until recovery to ≤ grade 1. Permanently discontinue XALKORI if grade 3 QTc prolongation recurs. Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI in the United States. XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI. If the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. Among the 397 patients for whom information on deaths and serious adverse reactions is available, deaths within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9), and other (4). Safety of XALKORI was evaluated in 255 patients with locally advanced or metastatic ALK-positive NSCLC in 2 single-arm clinical trials (Studies A and B). The most common adverse reactions (≥25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3-4 adverse reactions in ≥4% of patients in both studies included ALT increased and neutropenia. Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia were reported in 159 (62%) patients in clinical trials. Consider ophthalmological evaluation, particularly if patients experience photopsia or experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or photopsia could also be signs of a retinal hole or pending retinal detachment. Advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder.

About INLYTA ® (axitinib) In January 2012, INLYTA® was approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy. INLYTA was approved by the European Commission on September 3, 2012, for the treatment of adult patients with advanced RCC after failure of prior treatment with sunitinib or a cytokine. INLYTA has also been approved in a number of other countries and regions, including Switzerland, Japan, Canada, Australia, and South Korea. INLYTA, a kinase inhibitor, is an oral therapy that was designed to selectively inhibit vascular endothelial growth factor (VEGF) receptors 1, 2 and 3, which are proteins that can influence tumor growth, vascular angiogenesis and progression of cancer (tumor spread).

Important INLYTA ® (axitinib) Safety Information 13 Serious adverse reactions reported in patients receiving INLYTA were arterial embolic and thrombotic events, venous embolic and thrombotic events, haemorrhage (including gastrointestinal haemorrhage, cerebral haemorrhage and haemoptysis), gastrointestinal perforation and fistula formation, hypertensive crisis, and posterior reversible encephalopathy syndrome. The most common (≥ 20%) adverse reactions observed following treatment with INLYTA were diarrhoea, hypertension, fatigue, dysphonia, nausea, decreased appetite, and palmar-plantar erythrodysaesthesia (hand-foot) syndrome.

About SUTENT ® (sunitinib malate) SUTENT® is approved for gastrointestinal stromal tumors (GIST) after disease progression on or intolerance to imatinibmesylate, for advanced RCC, and for progressive, well-differentiated pancreatic neuroendocrine tumors (NET) in patients with unresectable locally advanced or metastatic disease. SUTENT is an oral multi-kinase inhibitor that works by blocking multiple molecular targets implicated in the growth, proliferation and spread of cancer.8b Two important SUTENT targets, vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) are expressed by many types of solid tumors and are thought to play a crucial role in angiogenesis, the process by which tumors acquire blood vessels, oxygen and nutrients needed for growth. SUTENT also inhibits other targets important to tumor growth, including KIT, FLT3 and RET.

Important SUTENT ® (sunitinib malate) Safety Information 14 Serious adverse reactions associated with sunitinib are renal failure, heart failure, pulmonary embolism, intestinal perforation, and haemorrhages (e.g. respiratory, gastrointestinal, tumour haemorrhages). The most common (≥20%) adverse events (AEs) in patients receiving SUTENT were decreased appetite, taste disturbance, hypertension, fatigue, gastrointestinal disorders, skin discoloration, and hand-foot syndrome. Fatal events, other than those listed, included multi-system organ failure, disseminated intravascular coagulation, peritoneal hemorrhage, rhabdomyolysis, cerebrovascular accident, dehydration, adrenal insufficiency, renal failure, respiratory failure, pleural effusion, pneumothorax, shock, and sudden death.

About TORISEL ® (temsirolimus) TORISEL® is the only intravenous mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of advanced renal cell carcinoma (RCC). TORISEL inhibits the activity of mTOR, an intracellular protein implicated in multiple growth-related cellular functions including proliferation, growth and survival. The inhibition of mTOR also reduces levels of certain growth factors, such as vascular endothelial growth factor (VEGF), which are overexpressed in solid tumors like kidney cancer and are thought to play a crucial role in angiogenesis, the process by which tumors acquire blood vessels, nutrients and oxygen needed for growth.

Important TORISEL ® (temsirolimus) Safety Information 15 Serious reactions observed with TORISEL are hypersensitivity/infusion reactions (including some life-threatening and rare fatal reactions), hyperglycaemia/glucose intolerance, infections, interstitial lung disease (pneumonitis), hyperlipaemia, intracerebral bleeding, renal failure, bowel perforation, and wound healing complication. The most common (≥30%) adverse reactions (all grades) observed with TORISEL include anaemia, nausea, rash (including rash, pruritic rash, maculopapular rash, pustular rash), anorexia, oedema (including facial oedema and peripheral oedema), and asthenia. Cataracts have been observed in some patients who received the combination of temsirolimus and interferon α. For more information on XALKORI (crizotinib), INLYTA (axitinib), SUTENT (sunitinib malate) and TORISEL (temsirolimus), including full prescribing information, please visit www.pfizer.com. 

个体化变革舞台静候中国药企 发布时间：2012-9-19 来源：药品资讯网信息中心Crizotinb作为个体化医学的重要成果以创纪录的速度通过FDA审批，也成为重新思考靶向治疗药物临床试验的重要依据。 今年2月的国际顶尖科学杂志《细胞》(Cell）报道了这样一段故事： "当真野裕之医生走进韩国国立首尔大学医院的肿瘤病房，他惊讶地发现，那位几天前还卧床不起的病人竟能走路并正在兴致勃勃地打听当地最好的菜馆。而不久前，这位日本病人因肺癌而难以呼吸和吞咽，卧床不起。他不得不从日本飞到韩国参加辉瑞新药Crizotinb的临床试验。" 间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂Crizotinb的神奇疗效代表了个体化靶向治疗药物的又一成功。 由于先天遗传带来某些基因亚型的不同，饱受同一种疾病折磨的两个人接受同一种药物治疗，一位可能很快就恢复健康，而另一位可能需要每天服用更大剂量的同种药片来对抗疾病，或饱受药物副作用的折磨，还可能无法享受到药物的福祉而病情久未有起色。 近年，源于转化医学成果的个体化医学通过甄别基因生物标记物，筛选合适的人群给予个性化的给药治疗，给我国制药业带来新的思考和变革方向。

临床优势突出 用于HER-2基因呈阳性的乳腺癌患者，上市已14年、2011年全球销售收入达52.53亿美元的赫赛汀仍然是当前全球最畅销的抗肿瘤药，其成功打开了全球制药产业个体化医学方向发展的时代大门。 阿斯利康的表皮生长因子受体（EGFR）靶向药物易瑞沙（吉非替尼）曾经走过6年曲折的上市前临床研究之路，直到2009年后，4项大规模Ⅲ期临床研究才确证其对EGFR阳性患者的非小细胞肺癌（NSCLC）患者人群的效果。易瑞沙的开发过程启示了研发人员，通过生物标记物筛选合适的获益人群，并将其纳入临床研究设计中将大大优化临床试验效率。 辉瑞开发的Crizotinb则是个体化药物激动人心的新惊喜。其临床试验并没有包括服用安慰剂的对照组，医生只纳入ALK基因检测阳性（大约占欧美肺癌病人的4%）的病人，却能显著快速地缩小肿瘤。在2011年12月5日，中国科技大学校友、华裔女科学家崔景荣博士凭借此项发明成果获得第36届年度美国国家发明大奖。 Crizotinb是FDA 6年内首批的治疗肺癌新药，从NSCLC中发现ALK融合基因到FDA批准仅耗时4年——自2011年3月30日该药被FDA受理，到8月26日被FDA批准，仅仅基于两项无对照Ⅰ期和Ⅱ期研究数据（但同时，FDA要求辉瑞在药物上市后进一步验证其长期生存益处）。如此快速的审批皆因该药的显著临床疗效，相对现有困境具有突出的临床优势。Crizotinb作为个体化医学的重要成果以创纪录的速度通过FDA审批，也成为重新思考靶向治疗药物临床试验的重要依据。 通常，药物上市前需经历三期临床试验，而采用随机对照试验来评估药物耗时持久，花费巨大。在没有合适的标准对照治疗药物的时候，纳入药物反应良好的生物标记物阳性亚组患者进行临床试验如果能更好地证明达到治疗终点时的疗效，基于良好的试验设计和具有说服力的结果，也将赢得FDA的认可，由此将大大加速靶向治疗药物的研发效率。 诚然，今天个体化医学对药物治疗的贡献不仅仅应用于靶向抗肿瘤药物中。 干扰素联合利巴韦林治疗丙型肝炎，药物的响应与病毒的基因型以及患者白介素28的基因型有很大关系，根据此基因亚组的分型，还能预测患者是对治疗响应好而可以继续目前治疗，还是对治疗响应差需等待更好的治疗方案，从而避免不必要的经济负担和治疗毒副作用。 个体化基因信息还能应用于对药物不良反应的预测与易感人群的筛选排除。如治疗癫痫药物卡马西平的主要不良反应是药疹及可能恶化至严重皮肤过敏反应，当前研究发现人类白细胞抗原HLA-B*1502的相关基因型与药疹的发生有极显著的相关性，在使用之前借助这一基因生物标记物能有效预测患者不良反应的发生，优化药物的临床使用。

适合国人的个体化药物 以个体基因生物标记信息为参考，为患者选择个体化的靶向治疗药物，是当下全球制药工业研发人员努力的方向。作为根植于中国市场的国内药企，在个体化医学的浪潮下更要借此东风破浪远航。 目前，全球创新药的研发大多基于西方人群的基因特点，如EGFR阳性突变在欧洲人群中的发生率大约是10%，但东亚人群发生率高达35%，使得以此生物标记物为靶向的抗肿瘤药在东亚国家中具有不可比拟的应用价值。针对中国人群相关基因特点研发制定药物治疗方案、设计优化临床试验已是共识。如近日默沙东在北京建立中国人群心血管和代谢生物样品库就说明了这一点。 2011年Crizotinb凭借其在ALK阳性亚组NSCLC患者人群中的良好效果而快速通过FDA的审批引发人们新的思考，至少在靶向抗肿瘤领域，一些有识之士在呼吁临床试验的初期阶段采取对入组观察病人相关基因型的预筛选来优化临床研究设计，聚焦准确目标，及时避免不成功药物带来不必要的时间和投资损失，并加速药物评估时间。诚然，这样振奋人心的革新是基于FDA已有快速审批通道对创新药物的鼓励，但却足以激发我国药物审评机构及研发机构对变革的新思考。 目前，在广州检测EGFR呈现阳性的NSCLC患者，医保将承担易瑞沙疗程内每月15，000元费用中的14，000元。据当地医生的一些说法，这是医保体系的一种尝试，希望以此鼓励和个人精确匹配的个体化治疗的发展。这说明通过精细的个体化医疗推动有限的公共医保资源的节约，将是未来国家医保的发展趋势，这无疑是制药企业的新动力。 基于FDA对靶向治疗药物和相搭配的诊断方法相关指导意见，辉瑞和雅培在Crizotinb上合作研发药物和推出相应的诊断试剂盒，同时提交审查并获得FDA批准是靶向治疗领域首发性的创新。当前，通过基因的诊断解决方案配合高效个体化药物将是理想的商业模式。同时，随着人类基因测序技术的不断完善和优化，几年内人类全基因测序成本将降低至1000美元以下。