抗血管生成药治疗非小细胞肺癌

其它小分子抗血管生成药：
BIBF 1120BIBF 1120 is a novel, oral, potent, triple angiokinase inhibitor that simultaneously acts on three key receptor families involved in angiogenesis, VEGFRs, PDGFRs and FGFRs, binding in a competitive way to the ATP-binding site of receptor tyrosine kinases and inhibiting downstream intracellular signaling (Table 1).[37]

BIBF 1120 inhibits a narrow range of kinases at pharmacologically relevant concentrations and has a sustained duration of cellular action blocking, indicating the potential for a long-lasting antiangiogenic effect.

From clinical investigation, the cleavage of [14C]BIBF 1120 by esterase-catalyzed hydrolysis is the prevalent metabolic reaction; CYP450-dependent metabolism was found to be minor. The terminal half-life of BIBF 1120 was determined to be 19 h. BIBF 1120 is mainly excreted via the liver.[38,39]

Based on Phase I trials, the MTD of BIBF 1120 as a single agent was defined as: 250 mg b.i.d. in Caucasian patients and 200 mg (b.i.d) in Japanese ones.[40,41] The most common side effects were represented by nausea, diarrhea, vomiting, abdominal pain, fatigue of a mild-to-moderate intensity and reversible liver enzyme elevations (alanine aminotransferase and aspartate aminotransferase). Even in combination with standard chemotherapy regimens,[42,43] the MTD of continuous oral treatment was maintained at 200 mg b.i.d either in combination with standard-dose pemetrexed (500 mg/m2) or with carboplatin (AUC 6) and paclitaxel (200 mg/m2), obtaining a good safety profile, without any new AEs different from those related to the chemotherapy agent.

In the pemetrexed Phase I trial of the 26 patients treated, 13 patients (50%) had SD as the best overall response, nine patients completed four cycles of combination therapy and seven patients went on to receive BIBF 1120 monotherapy. One patient with a CR obtained 44 days after initiating treatment completed the study and has remained on 100 mg b.i.d. BIBF 1120 monotherapy for more than 3 years.

In a Phase II double-blind, two-arm, randomized monotherapy study (ECOG PS 0–2), 73 patients with advanced pretreated NSCLC were randomized between continuous b.i.d. treatment with 150 (37 patients) or 250 mg (36 patients) BIBF 1120 until PD.[43,44]

The median PFS of all patients (n = 73) was 6.9 weeks and the median OS was 21.9 weeks with no significant difference between the two groups; the DCR was 59%, with an advantage for patients with good PS (ECOG 0–1), improving symptoms such as cough or dyspnea, maintaining a good quality of life and with a good toxicity profile (Table 3).

These Phase II data confirmed the promising single-agent activity of BIBF 1120 in patients suffering from recurrent NSCLC, warranting further development of BIBF 1120 in the Phase III setting.

Furthermore, there are two Phase III trials that are still ongoing, LUME-Lung 1 and 2, where BIBF 1120 is combined with docetaxel[104] or pemetrexed,[105] respectively (Table 2).

CediranibCediranib (AZD2171) targets VEGFR, c-KIT and PDGFR signaling (Table 1)[45,46] and has been evaluated only in combination with chemotherapy.

In the Phase I setting, cediranib (30 mg or 45 mg) was combined with carboplatin (AUC 6) and paclitaxel 200 mg/m2 in 20 patients of one trial[47] and with cisplatin 80 mg/m2 and gemcitabine 1250 mg/m2 in 15 patients of a second trial.[48] No dose-limiting toxicities (DLTs) were reported in any study, with a toxicity profile represented by fatigue, nausea, diarrhea, anorexia and hypertension (Table 3).[49]

In a Canadian randomized Phase II/III study (BR.24; n = 296), the addition of cediranib 30 mg/day to carboplatin/paclitaxel (Table 2) improved RR (38 vs 16%; p < 0.0001) with respect to placebo, but not the median PFS.[50]

In the BR.29 trial (NCT00795340), carboplatin plus paclitaxel were combined with cediranib at a lower dose (20 mg/day) or placebo.[107] This trial is ongoing.
Another two Phase II trials are evaluating the combination of cediranib with pemetrexed,[51] or with gemcitabine and carboplatin.[52]

MotesanibMotesanib (AMG 706) is a small oral, multikinase inhibitor, molecule antagonist of VEGFR-1, -2 and -3, PDGFR, kit and Ret. Preclinical studies demonstrated inhibition of VEGF-induced angiogenesis and inhibition of tumor growth in vivo (Table 1).[61]

Several Phase I trials have investigated motesanib in combination with other antineoplastic agents.

Motesanib was combined with panitumumab, a fully human anti-EGFR mAb, cisplatin and gemcitabine in a Phase I trial including 36 patients with advanced solid tumors (19 NSCLC). Among the 29 patients evaluable, one CR, 31% PR (six NSCLC patients) and 59% SD were observed. The most common toxicities reported included nausea, fatigue and hypertension. A 39% of thromboembolism and one grade 5 pulmonary embolism was seen. (Table 3).[62]

A Phase Ib study assessed the safety, MTD, pharmacokinetics and activity of motesanib plus carboplatin/paclitaxel and/or panitumumab, in advanced NSCLC (Table 2).

Patients received sequentially escalating doses of motesanib (50 and 125 mg once daily; 75 mg b.i.d.) orally continuously plus carboplatin/paclitaxel (arm A; first line) or panitumumab (arm B; first and second line) once every 21-day cycle or 125 mg daily plus carboplatin/paclitaxel and panitumumab (arm C; first line). Three DLTs were reported including grade 4 pulmonary embolism and grade 3 deep vein thrombosis, and the MTD was 125 mg once daily. Common motesanib-related adverse events observed were fatigue (60% of patients), diarrhea (53%), hypertension (38%), anorexia (27%) and nausea (22%). The RRs were 17, 0 and 17% in arm A, B and C, respectively.[63] In a Phase II trial, 181 patients were randomly assigned to three treatment arms: paclitaxel/carboplatin for six cycles maximum plus motesanib orally from day 1 of cycle one at either (arm A) 125 mg once daily continuously or (arm B) 75 mg b.i.d. for 5 days followed by 2 treatment-free days; or the same chemotherapy plus bevacizumab (arm C). ORR was 30, 23 and 37% in arm A, B and C, respectively and no CR was reported; median PFS was 8.4, 6.2 and 9.0 months and OS was 15.2, 13.9 and 15.2, respectively. In arms A/B/C, grade 3 AEs occurred in 46, 58 and 50%, grade 4 AEs in 10, 3 and 5%, and grade 5 AEs (excluding NSCLC progression) in 7, 16 and 7% of patients, respectively. The most interesting of all grades toxicities included cholecystitis (5, 8 and 0%), hemorrhagic events (22, 24 and 18%), deep vein thrombosis (3, 0 and 2%), and pulmonary embolism (3, 2 and 3%).[64]

A Phase III, multicenter, randomized, placebo-controlled, double-blind trial (MONET-1)[108] is ongoing to evaluate the addition of motesanib to paclitaxel and carboplatin compared with the same chemotherapy regimen plus placebo in advanced NSCLC patients. The primary end point of this trial is OS (Table 2). In November 2008 the data monitoring committee recommended treatment discontinuation in subjects with squamous histology and enrollment suspension in patients with nonsquamous histology. This recommendation was based on an observation of higher early mortality rates in the motesanib compared with the placebo group and a higher incidence of hemoptysis in the squamous population. The data monitoring committee guidance recommends the trial be reopened only to patients with nonsquamous cell histology and this trial is recruiting patients.[65]

这个BIBF 1120有FGFRS靶点可能是适合乳腺癌病人的抗血管生成药， 而且没有C-KIT靶点，不影响血象。

哈，刚要查资料又看见强帖，老马帅！

学习了，感谢分享。

XL184是有入脑能力的。
Additionally, in whole-brain lysates of non-tumor-bearing mice, XL-184 attained 20% of peak plasma levels, indicating the ability of the drug to penetrate the blood-brain barrier
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268517/

1. 补充说明：
   
2. 阿西替尼的抑制血管作用，如果停药，24-32小时就恢复了。如果停药超过一周，影响效果蛮大的。阿西替尼一天吃二次和一天吃三次区别很小。阿西替尼有人种区别，日本人的最大剂量要小25%

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这样说来，是不是咱们中国人也应该减到日本人的量啊？

我也想问同样的问题。

中国人的剂量可以参考日本人的。

谢谢老马！

好东西，学习了！T药跟阿西应该是一类的吧？