新药讨论：Axitinib(阿西替尼)
本帖最后由 成长的烦恼 于 2012-1-29 18:06 编辑Axitinib or bevacizumab (bev) plus FOLFOX or FOLFIRI as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC).
Background: Axitinib (AG-013736, AG), an oral selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, shows activity in multiple tumor types including those refractory to front-line chemotherapy. Methods: This multicenter, open-label, randomized phase II trial compared AG and bev in combination with FOLFOX or FOLFIRI in second-line mCRC. Pts previously treated with irinotecan were randomized to mFOLFOX6 plus AG 5 mg BID or bev 5 mg/kg q2wk; pts who received oxaliplatin were randomized to FOLFIRI with AG or bev at the same doses, with stratification by performance status and prior bev therapy. Primary endpoint was progression-free survival (PFS). Results: 171 pts were randomized from March 2008 to July 2009. There were no significant differences in PFS or median overall survival (mOS) between the AG and bev arms with FOLFOX or FOLFIRI. However, there was a trend towards reduced mOS in the FOLFIRI arms with AG compared to bev, and a trend towards improved mOS with AG+FOLFOX vs bev+FOLFOX. There were more treatment discontinuations (DCs) and a higher incidence of grade ≥3 adverse events (AEs) in the AG arms (diarrhea, asthenia, fatigue; Table). Conclusions: This study did not meet the primary endpoint, showing similar PFS with AG compared to bev when added to second-line chemotherapy. A potential factor in these results was earlier DCs in the AG versus bev arms, likely secondary to increased AEs. While VEGF inhibitors may have a role in second-line treatment of mCRC, at current dosing regimens AG-based chemotherapy shows no improvement in outcome compared to bev.
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Arm A: Arm B: Arm C: Arm D:
AG+FOLFIRI Bev+FOLFIRI AG+FOLFOX Bev+FOLFOX
n=49 n=51 n=36 n=35
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Median PFS, mo 5.7 6.9 7.5 6.4
HR (95% CI)
A vs. B/C vs. D 1.19 (0.72, 1.96) 1.10 (0.57, 2.12)
P 0.75 0.61
Median OS, mo 12.9 15.7 17.1 14.1
HR (95% CI)
A vs. B/C vs. D 1.39 (0.84, 2.30) 0.66 (0.35, 1.23)
P 0.90 0.09
OS rate at 12 mo, % 54.9 64.1 58.3 51.0
Overall response rate, % 24.5 23.5 22.2 20.0
Median no. of cycles received 10.5 14 12.5 12
DC due to AEs (AG or bev), % of pts 17.4 5.9 16.7 8.6
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AEs, % All gr Gr ≥3 All gr Gr ≥3 All gr Gr ≥3 All gr Gr ≥3
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Diarrhea 70 28 49 12 44 11 31 6
Fatigue 48 11 35 4 33 11 26 3
Asthenia 30 20 22 2 17 3 17 3
Hypertension 35 9 16 4 61 8 20 3
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阿西替尼（Axitinib）是由辉瑞公司研发的多靶向小分子口服靶向药，以VEGF1、2、3为主要靶点，还包括PDGF，这和西地尼布比较类似。上述临床是阿西做为转移性结直肠癌在二线治疗方面联合FOLFOX、FOLFIRI与阿瓦斯汀的一个对比性二期实验。从ASCO2011年的公告来看其设计终点PFS并没有超越阿瓦，但在联合FOLFOX的方案中，阿西在PFS和OS方面都占有优势。毒性方面阿西明显比阿瓦要大，这需要特别引起注意。
A Trial of Single Agent Axitinib as Maintenance Therapy for Patients With First Line Metastatic Colorectal Cancer (mCRC)
Purpose
This is a non-randomized, open-label, Phase II trial investigating axitinib as a single-agent maintenance therapy following standard first-line FOLFOX/bevacizumab therapy for patients with mCRC.
Estimated Enrollment: 69
Study Start Date: December 2011
Estimated Study Completion Date: January 2014
Estimated Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
阿西替尼正在做的转移性结直肠癌维持性治疗的二期临床，在病患接受一线阿瓦+FOXFOL的治疗之后。
同问，用不用吃抗甲减的药？ 不好意思，这个问题不懂啊，是否提到憨氏服务台会更合适呢。 本帖最后由 成长的烦恼 于 2012-6-30 16:55 编辑
Early outcome of a phase I study of interrupted pulse-dosed axitinib combined with FOLFOX or FOLFIRI in refractory metastatic colorectal cancer.
Background: Therapeutic inhibition of angiogenesis pathways may improve response of chemotherapy refractory malignancies. We evaluated the combination of axitinib, a multi-target VEGF receptor inhibitor, used intermittently with 5-FU based chemotherapy for refractory mCRC. We hypothesized that intermittent pulse dosed axitinib may improve response by delivering chemotherapy during tumor reperfusion after release from angiogenesis inhibition. We present preliminary data of the Phase I portion evaluating the safety and efficacy of interrupted pulse dosed axitinib + FOLFIRI. Methods: Initially, Pfizer A4061020 was a phase IB study of axitinib + bevacizumab + FOLFOX vs. FOLFIRI to evaluate potential overlapping toxicities. A4061020 was expanded to determine the MTD of 7 days of intermittent pulse dosed axitinib + FOLFIRI or FOLFOX; while secondary outcomes include TTP and OS. Enrollment was open to mCRC with progression on both oxaliplatin and irinotecan-based regimens. Results: Preliminary data of 10 mCRC subjects show intermittent pulse dosed axitinib at 14mg and 20mg in combination chemotherapy treatment is safe and tolerable (few grade 3 and one grade 4 AE). The MTD is 20mg daily. We observed a median clinical TTP of 10.1 mos (0.8 to 21.5 mos) vs. a median TTP of 5 mos on last line of chemotherapy (1 to 13 mos). Subjects treated with pulse dose axitinib appear to demonstrate a favorable OS, however these data are still immature. Conclusions: In 10 heavily pre-treated mCRC subjects, intermittent pulse dosed axitinib demonstrates safety, tolerability, and improved TTP. Subjects treated with this approach demonstrated a favorable TTP compared to the prior line of therapy and OS. Intermittent, pulse dosed axitinib warrants further study in a larger population.
Subject Age Gender # Prior lines Axitinib TTP on last line TTP on study OS (mos) RECIST
of chemo dose (mg)of chemo (mos) (mos)
1 60 M 3 14 2 17.5 61.5+ PD
2 47 M 6 14 7 21.5 75.2+ PD
3 51 M 5 10 3 18.6 53.1 PD
4 50 M 3 20 5 5.4 32.4 PD
5 50 F 4 20 10 10 118.2+ SD
6 64 M 2 20 5 2.9 21.2 PD
7 55 M 4 20 3 9.6 39.8 PD
8 58 M 2 20 13 10.6 90.8 PD
9 67 M 3 20 11 10.1 57.4+ PD
10 41 F 6 20 1 0.8 34.8 PD
Median 5 mos 10.1 mos TBD 都太有才了，俺一句也看不懂！:dizzy: 俺看得懂阿拉伯数字，比5楼的稍好点，哈哈！:P:P:P
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