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卡博替尼治疗晚期和进展性肝细胞癌
Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma


Ghassan K. Abou-Alfa ... 肿瘤 • 2018.07.05
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• 选择性内照射与索拉非尼治疗肝细胞癌的比较 • 卡博替尼治疗晚期肝细胞癌 • 肝细胞癌 • 肝细胞癌诊断和治疗的最新实践指南 • ASCO 2017报告——胃肠道癌症

摘要


背景

卡博替尼(cabozantinib)能够抑制酪氨酸激酶,包括血管内皮生长因子受体-1、2和3以及MET和AXL,这些酪氨酸激酶与肝细胞癌进展和索拉非尼(sorafenib)耐药的发生相关,而索拉非尼是晚期肝细胞癌的标准初始治疗。这项随机、双盲、3期试验在既往接受过治疗的晚期肝细胞癌患者中评价了卡博替尼,并与安慰剂进行了比较。

 

方法

本研究以2∶1的比例将总共707例患者随机分组,接受卡博替尼(60 mg每日1次)或匹配的安慰剂治疗。符合条件的患者既往接受过索拉非尼治疗,在接受至少1次肝细胞癌全身治疗后疾病进展,并且既往可接受过最多2种晚期肝细胞癌全身治疗方案。主要终点为总生存期。次要终点为无进展生存期和客观缓解率。

 

结果

在第2次计划的期中分析时,试验显示与安慰剂组相比,卡博替尼组的总生存期显著较长。卡博替尼组和安慰剂组的中位总生存期分别为10.2个月和8.0个月(死亡的风险比,0.76;95%置信区间[CI],0.63~0.92;P=0.005)。卡博替尼组和安慰剂组的中位无进展生存期分别为5.2个月和1.9个月(疾病进展或死亡的风险比,0.44;95% CI,0.36~0.52;P<0.001),客观缓解率分别为4%和<1%(P=0.009)。卡博替尼组68%的患者和安慰剂组36%的患者出现了3级或4级不良事件。最常见的高级别事件包括掌跖感觉丧失性红斑(卡博替尼组17% vs.安慰剂组0)、高血压(16% vs. 2%)、谷草转氨酶水平升高(12% vs. 7%)、疲劳(10% vs. 4%)和腹泻(10% vs. 2%)。

 

结论

在既往接受过治疗的晚期肝细胞癌患者中,卡博替尼组的总生存期和无进展生存期比安慰剂组长。卡博替尼组中高级别不良事件发生率约为安慰剂组的2倍(由伊克力西斯[Exelixis]资助;CELESTIAL在ClinicalTrials.gov注册号为NCT01908426)。





作者信息

Ghassan K. Abou-Alfa, M.D., Tim Meyer, M.D., Ann-Lii Cheng, M.D., Anthony B. El-Khoueiry, M.D., Lorenza Rimassa, M.D., Baek-Yeol Ryoo, M.D., Irfan Cicin, M.D., Philippe Merle, M.D., YenHsun Chen, M.D., Joong-Won Park, M.D., Jean-Frederic Blanc, M.D., Luigi Bolondi, M.D., Heinz-Josef Klümpen, M.D., Stephen L. Chan, M.D., Vittorina Zagonel, M.D., Tiziana Pressiani, M.D., Min-Hee Ryu, M.D., Alan P. Venook, M.D., Colin Hessel, M.S., Anne E. Borgman-Hagey, M.D., Gisela Schwab, M.D., and Robin K. Kelley, M.D.
From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (G.K.A.-A.); Royal Free Hospital and University College London, London (T.M.); National Taiwan University Hospital, Taipei (A.-L.C.), and the Department of Medical Oncology, Liouying Chi Mei Hospital, Tainan (Y.C.) — both in Taiwan; USC Norris Comprehensive Cancer Center, Los Angeles (A.B.E.-K.), UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco (A.P.V., R.K.K.), and Exelixis, Alameda (C.H., A.E.B.-H., G.S.) — all in California; Humanitas Cancer Center, Humanitas Clinical and Research Center, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano (L.R., T.P.), the Department of Medical and Surgical Sciences, University of Bologna, Bologna (L.B.), and Medical Oncology Unit 1, Istituto Oncologico Veneto, IRCCS, Padua (V.Z.) — all in Italy; Asan Medical Center, University of Ulsan College of Medicine, Seoul (B.-Y.R., M.-H.R.), and the National Cancer Center, Goyang (J.-W.P.) — both in South Korea; Trakya University School of Medicine, Edirne, Turkey (I.C.); Groupement Hospitalier Nord, Lyon (P.M.), and Hôpital Haut-Lévêque, Centre Hospitalier Universitaire Bordeaux, Bordeaux (J.-F.B.) — both in France; the Department of Medical Oncology, Academic Medical Center, Amsterdam (H.-J.K.); and the Chinese University of Hong Kong, State Key Laboratory in Oncology in South China, Hong Kong (S.L.C.). Address reprint requests to Dr. Abou-Alfa at the Memorial Sloan Kettering Cancer Center, 300 E. 66th St., New York, NY 10065, or at abou-alg@mskcc.org.

 

参考文献

1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136(5):E359-E386.

2. Ryerson AB, Eheman CR, Altekruse SF, et al. Annual report to the nation on the status of cancer, 1975-2012, featuring the increasing incidence of liver cancer. Cancer 2016;122:1312-1337.

3. Abou-Alfa GK, Jarnagin W, Lowery M, et al. Liver and bile duct cancer. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff’s clinical oncology. 5th ed. Philadelphia: Saunders, 2014:1373-96.

4. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hepatobiliary cancers, version 4. 2017 (https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf).

5. European Association for the Study of the Liver, European Organisation for Research and Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908-943.

6. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390.

7. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34.

8. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56-66.

9. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389:2492-2502.

10. Opdivo. Princeton, NJ: Bristol-Myers Squibb, July 2017 (package insert).

11. Abou-Alfa GK, Venook AP. The antiangiogenic ceiling in hepatocellular carcinoma: does it exist and has it been reached? Lancet Oncol 2013;14(7):e283-e288.

12. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 2003;3:347-361.

13. Rankin EB, Giaccia AJ. The receptor tyrosine kinase AXL in cancer progression. Cancers (Basel) 2016;8(11):E103-E103.

14. Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G. Targeting MET in cancer: rationale and progress. Nat Rev Cancer 2012;12:89-103.

15. Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer 2014;14:769-785.

16. Shojaei F, Lee JH, Simmons BH, et al. HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res 2010;70:10090-10100.

17. Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2012;2:270-287.

18. Zhou L, Liu XD, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene 2016;35:2687-2697.

19. Ueki T, Fujimoto J, Suzuki T, Yamamoto H, Okamoto E. Expression of hepatocyte growth factor and its receptor, the c-met proto-oncogene, in hepatocellular carcinoma. Hepatology 1997;25:619-623.

20. Liu J, Wang K, Yan Z, et al. Axl expression stratifies patients with poor prognosis after hepatectomy for hepatocellular carcinoma. PLoS One 2016;11(5):e0154767-e0154767.

21. Rimassa L, Abbadessa G, Personeni N, et al. Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib. Oncotarget 2016;7:72622-72633.

22. Rimassa L, Assenat E, Peck-Radosavljevic M, et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol 2018;19:682-693.

23. Xiang Q, Chen W, Ren M, et al. Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET. Clin Cancer Res 2014;20:2959-2970.

24. Firtina Karagonlar Z, Koc D, Iscan E, Erdal E, Atabey N. Elevated hepatocyte growth factor expression as an autocrine c-Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells. Cancer Sci 2016;107:407-416.

25. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 2011;10:2298-2308.

26. Kelley RK, Verslype C, Cohn AL, et al. Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study. Ann Oncol 2017;28:528-534.

27. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247.

28. Llovet JM, Decaens T, Raoul JL, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol 2013;31:3509-3516.

29. DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med 1994;13:1341-1352.

30. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17:917-927.

31. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814-1823.

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