Nintedanib(BIBF1120)相关信息

Nintedanib (BIBF 1120)简介

bibf1120 Ofev(nintedanib)使用说明书2014年第一版.pdf (373.03 KB, 下载次数: 248)

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Nintedanib (BIBF 1120)是一种有效的三重血管激酶抑制剂，对VEGFR1/2/3， FGFR1/2/3和PDGFRα/β均有抑制作用，其IC50分别为34 nM/13 nM/13 nM， 69 nM/37 nM/108 nM和59 nM/65 nM。目前EMA和FDA已经接受了1120的上市申请（适应症是特发性肺间质纤维化）

EMA accepts marketing authorisation application for nintedanib in IPF
EMA接受了nintedanib对IPF的上市申请
http://www.boehringer-ingelheim. ... _june_2014_ipf.html

U.S. FDA Accepts NDA Filing for Boehringer Ingelheim’s Investigational Nintedanib and Grants Priority Review Designation for the Treatment of Idiopathic Pulmonary Fibrosis
FDA接受了BI的在研药物Nintedanib的新药上市申请，并且授予了其在特发性肺纤维化的优先审查资格
http://us.boehringer-ingelheim.c ... onary-fibrosis.html

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靶点	VEGFR1	VEGFR2	VEGFR3	FGFR1	FGFR2	FGFR3	PDGFRα	PDGFRβ
IC50	34nM	21nM	13nM	69nM	37nM	108nM	59nM	65nM

从BI的资料来看，1120除了以上靶点外，还有一些额外的靶点：

附加靶点	Flt-3	Ret	Src	Lck	Lyn
IC50	26nM	35nM	156nM	16nM	195nM

各靶点IC50值引用自以下资料：
BIBF 1120 (Nintedanib).pdf (1.15 MB, 下载次数: 185)

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BIBF1120 (Vargatef).pdf (126.46 KB, 下载次数: 165)

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1.体外研究        
BIBF1120对酪氨酸激酶受体如EGFR, HER2, InsR, IGF1R 或者细胞周期激酶 CDK1, CDK2 和CDK4抑制效果不大， IC50都大于1x103nM。BIBF1120强抑制VEGF-刺激的HUVEC 和VEGF-刺激的HSMEC，EC50分别为9 和 7 nM。相反，BIBF1120 作用于FaDu, Calu-6 和Hela时EC50则大到几百倍。[1]

2.体内研究       
在小鼠的Fadu 移植瘤中，按鼠体重，每千克处理100mg BIBF1120,结果显示肿瘤血管密度降低76%。BIBF1120 作用于移植瘤模型Caki-1, HT-29, SKOV-3, Calu6 和PAC-120同样有显著的抑制效果。BIBF1120已用于治疗多种癌症，包括：非小细胞肺癌，前列腺癌，卵巢癌，及结肠直肠癌。且BIBF1120目前处于二期临床实验阶段。[1]

3.激酶实验        
VEGFR-2的胞质酪氨酸激酶域克隆到pFastBac载体上，与谷胱甘肽巯基转移酶 (GST)相融合。 GST融合蛋白在SF-9昆虫细胞中表达，用重元素萃取分离法提取。HEPEX萃取液包括20 mM HEPES （pH 为7.4）, 100 mM NaCl, 10 mM ss-甘油磷酸盐, 10 mM 聚硝基磷酸单苯酯, 30mM NaF, 5 mM EDTA, 5% 甘油, 1% Triton X-100, 1 mM Na3VO4, 0.1% SDS, 0.5μg/ml 抑肽素A, 2.5 μg/ml 3,4-二氯异香豆素(丝氨酸蛋白酶的不可逆抑制剂), 2.5 μg/ml反式-环氧琥珀酰-L-亮氨酰-L-氨基丁烷, 20 KIU/ml 抑肽酶, 2 μg/ml 亮抑肽酶, 1 mM苯甲脒，和0.002% PMSF。谷氨酸和酪氨酸按4:1比例随机组成的聚合物作为基底物，每组50ul的反应液包括5 % DMSO, 40 mM HEPES （pH 为 7.4）, 5 mM MgCl2, 5 mM MnCl2, 0.5 mg/ml 聚谷氨酸/酪氨酸, 0.05% Triton X-100, 100 μM ATP, 1 μCi [γ-33P]ATP ，和 10 μl酶制剂。实验在室温下进行20分钟，最后加入10 μl 5 % H3PO4终止反应。沉淀物转移到GF/B 过滤器中，使用与96孔过滤器相配的万能采集器收集。通过闪烁计数器测定混合物的放射能。

4.临床组   

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT01684111	Recruiting	Carcinoma, Non-Small-Cell Lung	Aktion Bronchialkarzinom e.V.|Boehringer Ingelheim	2013-06	Phase 1
NCT01907100	Recruiting	Mesothelioma	Boehringer Ingelheim	2013-09	Phase 2
NCT01979952	Recruiting	Idiopathic Pulmonary Fibrosis	Boehringer Ingelheim	2013-11	Phase 3
NCT02009579	Not yet recruiting	Uterine Cervical Neoplasms	Belgian Gynaecological Oncology Group; Grupo Español de Investigación en Cáncer de Ovario; Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens; Mario Negri Gynecologic Oncology group; Multicenter Italian Trials in Ovarian Cancer; Institute of Cancer Research, United Kingdom	2013-12	Phase 2
NCT01948141	Recruiting	Recurrent Non-small Cell Lung Cancer|Squamous Cell Lung Cancer|Stage III Non-small Cell Lung Cancer|Stage IV Non-small Cell Lung Cancer	Roswell Park Cancer Institute|National Cancer Institute (NCI)|Boehringer Ingelheim	2014-01	Phase 2

5.化学数据

分子量	539.62
化学式	C31H33N5O4
CAS号	656247-17-5

6.相关信息
抗血管生成药治疗非小细胞肺癌
成纤维细胞生长因子受体（FGFR）
尼达尼布（BIBF1120）联合多西他赛化疗可延长肺腺癌患者的生存期
希望获得BIBF1120的相关情况
bibf2992 bibf1120 两项肿瘤III期临床试验结果引关注


[1] Hilberg F, et al. Cancer Res, 2008, 68(12), 4774-4782.
[2] Frank H, et al. J Thorac Oncol, 2007, 2(8), S380. doi: 10.1097/01.JTO.0000283231.76336.01

这是当时马哥非常看好的吧？期待中！

Pro：第一个在NSCLC临床试验中证实有OS获益的抗血管生成TKI

Con：与其他抗血管生成药物相似，没有可预测疗效的biomarker

勃林格殷格翰向EMA提交nintedanib（BIBF1120）上市许可申请

2013年10月16日讯 /生物谷BIOON/ --勃林格殷格翰（Boehringer Ingelheim）10月14日宣布，已向欧洲药品管理局（EMA）提交了口服三联血管激酶抑制剂nintedanib的上市许可申请，寻求批准与多西紫杉醇（docetaxel）联合用药，用于一线化疗后腺癌肿瘤学为局部晚期或转移性复发性非小细胞肺癌（NSCLC）患者的治疗。

Nintedanib联合化疗，是首个在起始化疗失败的广泛腺癌群体中延长患者生存期超过1年的肺癌药物。

nintedanib上市许可申请的提交，是基于一项国际性、双盲III期LUME-Lung 1研究的数据，这是在广泛的二线腺癌患者群体所开展的、附加疗法表现出相对于活性对照组具有生存利益的首个试验。该项试验在NSCLC患者中开展，与安慰剂+多西紫杉醇组相比，nintedanib+多西紫杉醇治疗组疾病无进展生存期（PFS）表现出统计学意义的显着延长（3.4个月 vs 2.7个月），肿瘤再度生长风险降低21%，总生存期（OS）显着延长（12.6个月 vs 10.3个月），平均延长20%。

此外，数据还表明，腺癌患者越早发生一线化疗失败，nintedanib所带来的临床益处越大，在初始一线治疗后9个月内（T＜9个月）疾病恶化的患者，平均总生存期取得了3个月的临床益处（10.9个月 vs 7.9个月）。

关于Nintedanib：

Nintedanib是一种口服三联血管激酶抑制剂，可同时阻断3种生长因子受体：血管内皮生长因子受体（VEGFR 1-3）、血小板源性生长因子受体（PDGFR α和β）、成纤维细胞生长因子受体（FGFR 1-3）。所有这3种受体在血管生成和肿瘤生长过程中均发挥着重要作用。这些受体的阻断，可能导致血管生成的抑制，而血管生成在肿瘤生长中起着关键作用。

目前，勃林格殷格翰正在多种实体瘤中评价nintedanib，包括晚期非小细胞肺癌、卵巢癌、肝癌（肝细胞癌）、肾癌（肾细胞癌）、大肠癌等。（生物谷Bioon.com）

EMA接受BI提交的Nintedanib用于IPF的上市申请

2014年6月5日，勃林格殷格翰（BI）宣布其提交的Nintedanib用于治疗特发性肺纤维化(IPF)的上市申请被欧洲药品管理局接受，并被授予加速审评资格。该公司首席医疗官Dugi表示，此举“使我们在满足这一未满足的医疗需求及为IPF患者提供一种新的治疗选择上向前迈进了一步。”
这次的上市申请资料提交包括3期临床研究INPULSIS-1和INPULSIS-2的数据，临床研究显示这款口服酪氨酸激酶抑制剂可明显延缓IPF患者的疾病进程。试验结果最近在《新英格兰医学杂志》上得到发布，结果证实Nintedanib达到了主要目标，与安慰剂相比，可使最大肺活量的年度下降明显减少50%。
勃林格殷格翰指出，这款药物对可以使急性加重期风险降低38%，使确诊或疑似急性加重期风险明显降低68%。Nintedanib以生长因子受体为靶点，这款药物在临床开发中还作为一种治疗选择用于某些肿瘤，包括非小细胞肺癌、卵巢癌、结肠癌和肝癌。
2011年，欧盟委员会批准InterMune公司的吡非尼酮(Pirfenidone)用于成人患者轻度至中度IPF治疗。Nintedanib与吡非尼酮均未在美国获得上市批准，但InterMune最近表示，该公司会很快计划向FDA再次提交这款药物的上市申请，该药物于2010年曾被FDA拒绝。

信源：http://www.bioon.com/industry/drug/584355.shtml

BIBF 1120: Triple Angiokinase Inhibitor with Sustained Receptor Blockade and Good Antitumor Efficacy
BIBF 1120: 具有持续的受体拮抗作用和良好的抗肿瘤效果的三重血管激酶抑制剂

Abstract
Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC50, 20–100 nmol/L). BIBF 1120 inhibits mitogenactivated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC50, 10–80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25– 100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development. [Cancer Res 2008;68(12):4774–82]

摘要
通过阻断血管内皮生长因子(vascular endothelial growth factor, VEGF)信号通路来抑制肿瘤血管生成是肿瘤学领域一种新的治疗手段。临床前研究表明，通过阻断额外的血管生成受体酪氨酸激酶能够提高长期的临床收益，这些激酶包括：血小板源生长因子受体(platelet-derived growth factor receptors, PDGFR)和成纤维细胞生长因子受体(fibroblast growth factor receptors, FGFR)。BIBF1120是一种吲哚酮类衍生物，其在酶反应分析中能够有效阻断VEFG受体(VEFGR)、PDGFR以及FGFR激酶(IC50, 20–100 nmol/L)。BIBF1120在三种类型的细胞（内皮细胞、周细胞和平滑肌细胞）中通过抑制促使血管上传的丝裂原活化蛋白激酶(mitogenactivated protein kinase, MAPK)和Akt通路，从而抑制细胞的增值EC50, 10–80 nmol/L()和促进其凋亡。在所有已经测试的肿瘤模型中，包括生长在裸鼠体内的人类肿瘤异种移植物以及同源兔肿瘤模型，BIBF1120在可耐受的剂量(25– 100 mg/kg daily p.o.)内都具有高度的活性。

Cancer Res-2008-Hilberg-4774-82.pdf (752.29 KB, 下载次数: 122)

2014-6-30 14:14 上传

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Randomized Phase II Placebo-Controlled Trial of Maintenance Therapy Using the Oral Triple Angiokinase Inhibitor BIBF 1120 After Chemotherapy for Relapsed Ovarian Cancer

Purpose
Inhibiting angiogenesis is one of the most promising avenues for new therapies for ovarian cancer. We investigated the efficacy and safety of a novel agent, BIBF 1120, a triple angiokinase inhibitor, after chemotherapy for relapsed disease.

Patients and Methods
We conducted a randomized, double-blind, controlled phase II trial in 83 patients who had just completed chemotherapy for relapsed ovarian cancer, with evidence of response, but at high risk of further early recurrence. The patients were randomly assigned to receive maintenance therapy using BIBF 1120 250 mg or placebo, twice per day, continuously for 36 weeks. End points were progression-free survival (PFS), toxicity, and overall survival.

Results
Thirty-six–week PFS rates were 16.3% and 5.0% in the BIBF 1120 and placebo groups, respectively (hazard ratio, 0.65; 95% CI, 0.42 to 1.02; P
.06). Four patients continued on BIBF 1120, including two patients for another year or more. The proportion of patients with any grade 3 or 4 adverse events was similar between the groups (34.9% for BIBF 1120 v 27.5% for placebo; P
.49; mostly grade 3). However, more patients on BIBF 1120 experienced diarrhea, nausea, or vomiting (mainly grade 1 or 2 and no grade 4). There was a higher rate of grade 3 or 4 hepatotoxicity in patients on BIBF 1120 (51.2%) compared with patients on placebo (7.5%; P  .001), but this was rarely of clinical significance, and patients continued with the trial treatment. A single-level dose reduction to 150 mg was made in 15 patients, all on active drug.

Conclusion
BIBF 1120 is well tolerated and associated with a potential improvement in PFS. The observed treatment effect is sufficient to justify further study within a large phase III trial.

JCO-2011-Ledermann-3798-804.pdf (265.69 KB, 下载次数: 116)

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Phase I Open-Label Study of Continuous Treatment with BIBF 1120, a Triple Angiokinase Inhibitor, and Pemetrexed in Pretreated Non-Small Cell Lung Cancer Patients

Abstract
Introduction: BIBF 1120 (planned brand name Vargatef) is a novel, oral, triple angiokinase inhibitor targeting three receptor classes involved in blood vessel formation. The objectives of this phase I, openlabel dose-escalation study were to determine the safety, tolerability, and maximum tolerated dose (MTD) of BIBF 1120 with pemetrexed in patients with recurrent advanced-stage non–small cell lung carcinoma.

Patients and Methods: Patients harboring a tumor of any non–small cell lung carcinoma histology, previously treated with one first-line platinum-based chemotherapy regimen, received a BIBF 1120 starting dose of 100 mg bid (days 2-21) with pemetrexed 500 mg/m2 (day 1) over a 21-day cycle. Previous pemetrexed treatment was not permitted. BIBF 1120 dose was escalated until the MTD was determined.

Results: Twenty-six patients were treated. During treatment cycle (TC) 1, dose-limiting toxicities were experienced by one patient receiving 100 mg bid, one patient receiving 150 mg bid, one patient receiving 200 mg bid, and two patients receiving 250 mg bid BIBF 1120. Two additional dose-limiting toxicities were observed in TC 1 in an expanded patient cohort receiving 200 mg bid. Gastrointestinal disorders (84.6%), general disorders, and administration site conditions (76.9%) were the most frequent drugrelated adverse events. One patient had a complete response 44 days after initiating trial medication; 50% had stable disease as the best overall response. No clinically relevant pharmacokinetic interactions between BIBF 1120 and pemetrexed were observed.

Conclusion: The MTD of BIBF 1120 in combination with standard-dose pemetrexed was 200 mg bid. Continuous daily treatment with BIBF 1120 in this combination was tolerable, with promising signs of efficacy. Clin Cancer Res; 16(10); 2881–9. ©2010 AACR.

Clin Cancer Res-2010-Ellis-2881-9.pdf (248.8 KB, 下载次数: 115)

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Antiangiogenic-specific adverse events (AEs) in patients with non-small cell lung cancer (NSCLC) treated with nintedanib (N) and docetaxel (D).(2014 ASCO)
Abstract:
Background: Antiangiogenic treatments, including monoclonal antibodies and TKIs, have shown activity in tumors; however, their use is limited in part by their characteristic side effects (eg, bleeding, thrombosis, perforation, serious skin reactions, hypertension). N is an oral, twice-daily, triple angiokinase inhibitor. Here we extend our investigation of the LUME-Lung 1 study (ClinicalTrials.gov NCT00805194) and evaluate whether adding N to standard second-line D increases the frequency of characteristic adverse events (AEs) associated with antiangiogenic agents and whether these AEs restrict the use of N. Methods: LUME-Lung 1, a randomized, placebo-controlled Phase III trial investigating N + D in patients with advanced NSCLC after failure of first-line chemotherapy, demonstrated significant PFS improvement regardless of histology and showed significant survival improvement for patients with adenocarcinoma histology. The incidence and intensity of antiangiogenic-associated AEs according to the common terminology criteria for AEs (CTCAE version 3.0) were evaluated in all patients who received at least one dose of N, D, or Placebo (Pl). Results: AEs linked to VEGF inhibition that were more common (≥2% difference) in the N vs Pl arm were bleeding (all grades: 14.1% vs 11.6%; grade ≥3: 2.3% vs 1.8%) and hypertension (all grades: 3.5% vs 0.9%; grade ≥3: 0.6% vs 0.2%). When we compared histologic differences in antiangiogenic-associated AEs, we found nominal differences. More bleeding events were reported for N- treated squamous cell carcinoma (SCC) patients (all grades: 17.1% vs 10.9%; grade ≥3: 2.9% vs 1.3%) than for those with adenocarcinoma (all grades: 10.9% vs 11.1%; grade ≥3: 1.5% vs 1.3%). Fatal bleeding events, serious skin reactions, thrombosis, and perforations occurred at a low frequency and were balanced between both arms, regardless of histology. Conclusions: We demonstrated that adding N to standard second-line D for NSCLC therapy did not increase the frequency of AEs associated with antiangiogenic treatment to a relevant extent, except for grade 1-2 bleeding events in SCC patients. These AEs were balanced regardless of histology in LUME-Lung 1. Clinical trial information: NCT00805194.

Antiangiogenic-specific adverse events (AEs) in patients with non-small cell lung cancer (NSCLC) treated with nintedanib (N) and docetaxel (D).(2014 ASCO)
Abstract:
Background: Antiangiogenic treatments, including monoclonal antibodies and TKIs, have shown activity in tumors; however, their use is limited in part by their characteristic side effects (eg, bleeding, thrombosis, perforation, serious skin reactions, hypertension). N is an oral, twice-daily, triple angiokinase inhibitor. Here we extend our investigation of the LUME-Lung 1 study (ClinicalTrials.gov NCT00805194) and evaluate whether adding N to standard second-line D increases the frequency of characteristic adverse events (AEs) associated with antiangiogenic agents and whether these AEs restrict the use of N. Methods: LUME-Lung 1, a randomized, placebo-controlled Phase III trial investigating N + D in patients with advanced NSCLC after failure of first-line chemotherapy, demonstrated significant PFS improvement regardless of histology and showed significant survival improvement for patients with adenocarcinoma histology. The incidence and intensity of antiangiogenic-associated AEs according to the common terminology criteria for AEs (CTCAE version 3.0) were evaluated in all patients who received at least one dose of N, D, or Placebo (Pl). Results: AEs linked to VEGF inhibition that were more common (≥2% difference) in the N vs Pl arm were bleeding (all grades: 14.1% vs 11.6%; grade ≥3: 2.3% vs 1.8%) and hypertension (all grades: 3.5% vs 0.9%; grade ≥3: 0.6% vs 0.2%). When we compared histologic differences in antiangiogenic-associated AEs, we found nominal differences. More bleeding events were reported for N- treated squamous cell carcinoma (SCC) patients (all grades: 17.1% vs 10.9%; grade ≥3: 2.9% vs 1.3%) than for those with adenocarcinoma (all grades: 10.9% vs 11.1%; grade ≥3: 1.5% vs 1.3%). Fatal bleeding events, serious skin reactions, thrombosis, and perforations occurred at a low frequency and were balanced between both arms, regardless of histology. Conclusions: We demonstrated that adding N to standard second-line D for NSCLC therapy did not increase the frequency of AEs associated with antiangiogenic treatment to a relevant extent, except for grade 1-2 bleeding events in SCC patients. These AEs were balanced regardless of histology in LUME-Lung 1. Clinical trial information: NCT00805194.

Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-blind phase III trial.(2013 ASCO)
Abstract:
Background: Nintedanib (N) inhibits VEGFRs, PDGFRs, and FGFRs. LUME Lung 1 is a placebo (P) controlled phase III trial of N + docetaxel (D) in patients (pts) with locally advanced/metastatic NSCLC progressing after first-line therapy. Methods: Stage IIIB/IV or recurrent NSCLC pts (stratified by histology, ECOG PS, prior bevacizumab, and brain metastases) were randomized to N 200 mg bid + D 75 mg/m2 q21d (n=655) or P + D (n=659). 1° endpoint was centrally reviewed PFS after 713 events (2 sided stratified log-rank, α=5%, β=10%). Key 2° endpoint of OS was analyzed hierarchically after 1,121 events (2 sided, adjusted α=4.98%, β=20%), first in adenocarcinoma (adeno) pts <9 mo since start of first-line therapy (T<9mo; identified as a prognostic/predictive biomarker [ASCO ‘13]), followed by all adeno pts and then all pts. Predefined sensitivity analyses added sum of longest diameters of target lesions (SLD) to stratification factors in the Cox model. Results: Pt characteristics were balanced between the arms. N + D significantly prolonged PFS vs P + D (HR 0.79; CI: 0.68, 0.92; p=0.0019; median 3.4 vs 2.7 mo) regardless of histology (squamous HR 0.77, p=0.02; adeno HR 0.77, p=0.02). OS was significantly prolonged in all adeno pts (HR 0.83; p=0.0359; median 12.6 vs 10.3 mo) with the greatest improvement seen in T<9mo adeno pts (HR 0.75; p=0.0073; median 10.9 vs 7.9 mo). A trend for improved OS was seen in all pts (HR 0.94; p=0.272; median 10.1 vs 9.1). When adjusted for SLD, a significant OS benefit was seen in all pts (HR 0.88; CI: 0.78, 0.99; p=0.0365). Disease control rates were significantly improved with N + D in all adeno pts (odds ratio [OR] 1.93; p<0.0001), T<9mo adeno pts (OR 2.90; p<0.0001) and all pts (OR 1.68; p<0.0001). The most common AEs were diarrhea (any: 42.3 vs 21.8%; Gr ≥3: 6.6 vs 2.6%) and ALT elevations (any: 28.5 vs 8.4%; Gr ≥3: 7.8 vs 0.9%). Incidence of CTCAE Gr ≥3 AEs was 71.3 vs 64.3%. Withdrawals due to AEs (22.7 vs 21.7%) were similar in both arms, as were Gr ≥3 hypertension, bleeding or thrombosis. Conclusions: N + D significantly improved PFS independent of histology, and prolonged OS for adeno pts. AEs were generally manageable with dose reductions and symptomatic treatment. Clinical trial information: NCT00805194.