Brivanib versus sorafenib v terapii první linie pacientů s neresekovatelným pokročilým hepatocelulárním karcinomem: výsledky ...
Brivanib versus sorafenib v terapii první linie pacientů s neresekovatelným pokročilým hepatocelulárním karcinomem: výsledky randomizované studie fáze III BRISK‑FL
Philip J. Johnson, Shukui Qin, Joong‑Won Park, Ronnie T. P. Poon, Jean‑Luc Raoul, Philip A. Philip, Chih‑Hung Hsu, Tsung‑Hui Hu, Jeong Heo, Jianming Xu, Ligong Lu, Yee Chao, Eveline Boucher, Kwang‑Hyub Han, Seung‑Woon Paik, Jorge Robles‑Aviña, Masatoshi Kudo, Lunan Yan, Abhasnee Sobhonslidsuk, Dmitry Komov, Thomas Decaens, Won‑Young Tak, Long‑Bin Jeng, David Liu, Rana Ezzeddine, Ian Walters a Ann‑Lii Cheng
SOUHRN
Cíl
Brivanib je duální inhibitor receptorů vaskulárního endoteliálního růstového faktoru a fibroblastového růstového faktoru, které se podílejí na patogenezi hepatocelulárního karcinomu (HCC). Naše mezinárodní, randomizovaná, dvojitě zaslepená studie fáze III srovnávala brivanib se sorafenibem jako terapii HCC první linie.
Pacienti a metody
Pacienti s pokročilým HCC, kteří dosud nebyli léčeni systémovou terapií, byli náhodným způsobem zařazeni (v poměru 1 : 1) k léčbě sorafenibem v perorální dávce 400 mg dvakrát denně (n = 578) nebo brivanibem v dávce 800 mg jednou denně (n = 577). Primárním výsledným ukazatelem bylo celkové přežití (OS). Sekundární výsledné ukazatele byly doba do progrese (TTP), četnost objektivních odpovědí (ORR), četnost kontroly onemocnění (DCR) podle modifikovaných kritérií RECIST (mRECIST) a bezpečnost.
Výsledky
Studie neuspěla při dosažení primárního výsledného ukazatele, tedy non‑inferiority OS pro brivanib ve srovnání se sorafenibem, v populaci podle protokolu (n = 1 150; poměr rizik [HR] 1,06; 95,8% interval spolehlivosti [CI] 0,93–1,22), protože byl překročen předem definovaný interval (horní mez CI pro HR ≤ 1,08). Medián OS byl 9,9 měsíce pro sorafenib a 9,5 měsíce pro brivanib. TTP, ORR a DCR byly v obou ramenech studie podobné. Nejčastější nežádoucí příhody 3./4. stupně pro sorafenib a brivanib byly hyponatrémie (9 %, resp. 23 %), zvýšení AST (17 % a 14 %), únava (7 % a 15%), syndrom palmoplantární erytrodysestezie (15 % a 2 %) a hypertenze (5 % a 13 %). K přerušení léčby v důsledku nežádoucích příhod došlo u 33 % pacientů v rameni sorafenibu a 43 % pacientů v rameni brivanibu; ke snížení dávek došlo v 50 %, resp. 49 %.
Závěr
Naše studie nedosáhla svého primárního výsledného ukazatele, non‑inferiority brivanibu ve srovnání se sorafenibem z hlediska OS. Oba léky však měly podle dosažených sekundárních výsledných ukazatelů podobnou protinádorovou aktivitu. Brivanib měl přijatelný profil bezpečnosti, ale byl snášen hůře než sorafenib.
J Clin Oncol 31:3517‑3524. © 2013 by American Society of Clinical Oncology
Celý článek naleznete v časopise Journal of Clinical Oncology číslo 3/2013 na straně 137-145
Literatura
1. Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin 61:69‑90, 2011
2. Cao H, Phan H, Yang LX: Improved chemotherapy for hepatocellular carcinoma. Anticancer Res 32:1379‑1386, 2012
3. 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 56:908‑943, 2012
4. Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378‑390, 2008
5. 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 10:25‑34, 2009
6. Presta M, Dell’Era P, Mitola S, et al: Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16:159‑178, 2005
7. Grose R, Dickson C: Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev 16:179‑186, 2005
8. Mise M, Arii S, Higashituji H, et al: Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumor. Hepatology 23:455‑464, 1996
9. Ogasawara S, Yano H, Iemura A, et al: Expressions of basic fibroblast growth factor and its receptors and their relationship to proliferation of human hepatocellular carcinoma cell lines. Hepatology 24:198‑205, 1996
10. El‑Assal ON, Yamanoi A, Ono T, et al: The clinicopathological significance of heparanase and basic fibroblast growth factor expressions in hepatocellular carcinoma. Clin Cancer Res 7:1299‑1305, 2001
11. Uematsu S, Higashi T, Nouso K, et al: Altered expression of vascular endothelial growth factor, fibroblast growth factor‑2 and endostatin in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 20:583‑588, 2005
12. Poon RT, Ng IO, Lau C, et al: Correlation of serum basic fibroblast growth factor levels with clinicopathologic features and postoperative recurrence in hepatocellular carcinoma. Am J Surg 182:298‑304, 2001
13. Casanovas O, Hicklin DJ, Bergers G, et al: Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late‑stage pancreatic islet tumors. Cancer Cell 8:299‑309, 2005
14. Bergers G, Hanahan D: Modes of resistance to anti‑angiogenic therapy. Nat Rev Cancer 8:592‑603, 2008
15. Pàez‑Ribes M, Allen E, Hudock J, et al: Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220‑231, 2009
16. Ebos JM, Lee CR, Cruz‑Munoz W, et al: Accelerated metastasis after short‑term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232‑239, 2009
17. Wang L, Park H, Chhim S, et al: A novel monoclonal antibody to fibroblast growth factor 2 effectively inhibits growth of hepatocellular carcinoma xenografts. Mol Cancer Ther 11:864‑872, 2012
18. Cai ZW, Zhang Y, Borzilleri RM, et al: Discovery of brivanib alaninate ((S)‑((R)‑1‑(4‑(4‑fluoro‑2‑met hyl‑1H‑indol‑5‑yloxy)‑5‑methylpyrrolo[2,1‑f][1,2,4] triazin‑6‑yloxy)propan‑2‑yl)2‑aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor‑2 and fibroblast growth factor receptor‑1 kinase inhibitor (BMS‑540215). J Med Chem 51:1976‑1980, 2008
19. Huynh H, Ngo VC, Fargnoli J, et al: Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res 14:6146‑6153, 2008
20. Bhide RS, Lombardo LJ, Hunt JT, et al: The antiangiogenic activity in xenograft models of brivanib, a dual inhibitor of vascular endothelial growth factor receptor‑2 and fibroblast growth factor receptor‑1 kinases. Mol Cancer Ther 9:369‑378, 2010
21. Allen E, Walters IB, Hanahan D: Brivanib, a dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition. Clin Cancer Res 17:5299‑5310, 2011
22. Tovar V, Cornella, Villanueva A: FGF signaling is involved in acquired resistance to sorafenib in an in vivo model of hepatocellular carcinoma. Presented at the International Liver Cancer Association Conference, Hong Kong, China, September 2‑4, 2011 (abstr 0‑006)
23. Park JW, Finn RS, Kim JS, et al: Phase II, open‑label study of brivanib as first‑line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res 17:1973‑1983, 2011
24. Finn RS, Kang YK, Mulcahy M, et al: Phase II, open‑label study of brivanib as second‑line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res 18:2090‑2098, 2012
25. Llovet JM, Decaens T, Raoul J‑L, 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 doi: 10.1200/ JCO.2012.47.3009
26. Edeline J, Boucher E, Rolland Y, et al: Comparison of tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST in patients treated with sorafenib for hepatocellular carcinoma. Cancer 118:147‑156, 2012
27. Lencioni R, Llovet JM: Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 30:52‑60, 2010
28. Clopper CJ, Pearson ES: The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 26:404‑413, 1934
29. Garrett CR, Siu LL, El‑Khoueiry A, et al: Phase I dose‑escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full‑dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy. Br J Cancer 105:44‑52, 2011
30. Kaye SB, Siu LL, Jassem J, et al: Brivanib (B) in advanced ovarian cancer (OC): Subset results of a phase 2 randomized discontinuation trial (RDT). Ann Oncol 23:ix319, 2012 (suppl 9; abstr 9660)
31. Ratain MJ, Schwartz GK, Oza AM, et al: Brivanib (BMS‑582664) in advanced solid tumors (AST): Results of a phase II randomized discontinuation trial (RDT). J Clin Oncol 29:213s, 2011(suppl; abstr 3079)
32. Schwartz GK, Maki RG, Ratain MJ, et al: Brivanib (BMS‑582664) in advanced soft‑tissue sarcoma (STS): Biomarker and subset results of a phase II randomized discontinuation trial. J Clin Oncol 29:605s, 2011 (suppl; abstr 10000)
33. Osoba D, Rodrigues G, Myles J, et al: Interpreting the significance of changes in health‑related quality‑of‑life scores. J Clin Oncol 16:139‑144, 1998
34. Cheng A, Kang Y, Lin D, et al: Phase III trial of sunitinib (Su) versus sorafenib (So) in advanced hepatocellular carcinoma (HCC). J Clin Oncol 29:256s, 2011 (suppl; abstr 4000)
35. MaverickNY: Pharma Strategy Blog: Why does sorafenib work in HCC but sunitinib does not? http://pharmastrategyblog.com/2011/01/why‑does‑sorafenibwork‑in‑hcc‑but‑sunitinib‑does‑not.html/ (weblog) Accessed on November 29, 2012
Pracoviště autorů
Philip J. Johnson, University of Birmingham, Birmingham, United Kingdom; Shukui Qin, Nanjing Bayi Hospital, Nanjing; Jianming Xu, 307 Hospital of PLA, Beijing; Ligong Lu, Guangdong Provincial People’s Hospital, Guangdong; Lunan Yan, West China Hospital of Sichuan University, Chengdu; Ronnie T. P. Poon, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; Joong Won Park, Center for Liver Cancer, National Cancer Center, Goyang; Jeong Heo, Pusan National University School of Medicine, Pusan; KwangHyubHan, Yonsei University College of Medicine; Seung Woon Paik, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; WonYoung Tak, Kyungpook National University Hospital, Daegu, Republic of Korea; Jean‑Luc Raoul, Institut Paoli Calmettes, Marseille; Eveline Boucher, Central EugeneMarquis, RennesCedex, Rennes; ThomasDecaens, HôpitalHenriMondor, University of Paris‑Est, and INSERM, CreteilCedex, Creteil, France; Philip A. Philip, Karmanos Cancer Center, Detroit, MI; David Liu, Rana Ezzeddine, Ian Walters, Bristol‑Myers Squibb, Princeton, NJ; Chih‑HungHsu, Ann‑Lii Cheng, National Taiwan University Hospital; Yee Chao, Cancer Center, Taipei Veterans General Hospital, Taipei; Tsung‑Hui Hu, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung; Long‑Bin Jeng, China Medical University Hospital, Taichung, Taiwan, Republic of China; Jorge Robles‑Aviña, High Specialty Central South Hospital, Mexico City, Mexico; Masatoshi Kudo, Kinki University School of Medicine, Osaka, Japan; Abhasnee Sobhonslidsuk, Ramathibodi Hospital, Bangkok, Thailand; Dmitriy Komov, N. N. Blokhin Cancer Research Center, Moscow, Russia.
Zdroj: Journal of Clinical Oncology