BOOST: a phase 3 trial of sorafenib vs. best supportive care in first line treatment of hepatocellular carcinoma in patients with deteriorated liver function

Abstract

Aim: Only patients with good liver function {[Child-Pugh (CP)] A class} were eligible for trials testing sorafenib as first-line treatment of hepatocellular carcinoma (HCC); nevertheless, the drug was authorized without restrictions based on liver function. Therefore, we planned to test sorafenib efficacy and safety in patients with HCC and deteriorated liver function (CP-B).

Methods: This was an open-label, multicenter, randomized phase 3 trial. Patients with HCC, no previous systemic therapy, and CP-B score 7-9 were assigned 1:1 to best supportive care alone (control arm) or with standard dose sorafenib (experimental arm). Overall survival (OS) was the primary endpoint. To detect a 0.70 HR of death, with 80% power, and two-tailed α error 0.05, 234 events were required. The study closed prematurely because of slow accrual. Descriptive analyses are reported.

Results: From 2012 to 2017, 13 Italian centers randomized 35 patients. In total, 28 deaths were recorded, 12 without and 16 with sorafenib; median OS was 4.9 (95%CI: 1.2-5.6) and 3.5 months (95%CI: 1.3-5.3), respectively. At least one severe adverse event was reported in 2/15 (13.3%) without and 9/17 (52.9%) patients with sorafenib.

Conclusions: This trial failed its planned enrolment goal, showing the difficulty in performing clinical trials with drugs already registered with a label broader than what available evidence supports.

Keywords

Hepatocellular carcinoma / Child-Pugh B class / sorafenib

References

[1] Cancer today - IARC database. Available from: https://gco.iarc.fr [Last accessed on 2 Aug 2021]

[2] Siegel RL,Jemal A.Cancer statistics, 2019.CA A Cancer J Clin2018;69:7-34

[3] new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators.Hepatology1998;28:751-5

[4] Llovet JM,Bruix J.Prognosis of hepatocellular carcinoma: the BCLC staging classification.Semin Liver Dis1999;19:329-38

[5] validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. The Cancer of the Liver Italian Program (CLIP) Investigators.Hepatology2000;31:840-5

[6] Lu LC,Chan SY,Cheng AL.Clinical characteristics of advanced hepatocellular carcinoma patients with prolonged survival in the era of anti-angiogenic targeted-therapy.Anticancer Res2014;34:1047-52

[7] Wilhelm SM,Tang L.BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis.Cancer Res2004;64:7099-109

[8] Llovet JM,Mazzaferro V.SHARP Investigators Study GroupSorafenib in advanced hepatocellular carcinoma.N Engl J Med2008;359:378-90

[9] Cheng A,Chen Z.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 Oncol2009;10:25-34

[10] Granito A.Non-transplant therapies for patients with hepatocellular carcinoma and Child-Pugh-Turcotte class B cirrhosis.Lancet Oncol2017;18:e101-12

[11] Bruix J.Practice Guidelines CommitteeAmerican Association for the Study of Liver DiseasesManagement of hepatocellular carcinoma.Hepatology2005;42:1208-36

[12] Aaronson NK,Bergman B.The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.J Natl Cancer Inst1993;85:365-76

[13] Blazeby JM,Zee BC,Poon RT.EORTC Quality of Life GroupDevelopment of a questionnaire module to supplement the EORTC QLQ-C30 to assess quality of life in patients with hepatocellular carcinoma, the EORTC QLQ-HCC18.Eur J Cancer2004;40:2439-44

[14] Eisenhauer EA,Bogaerts J.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer2009;45:228-47

[15] Schemper M.A note on quantifying follow-up in studies of failure time.Control Clin Trials1996;17:343-6

[16] Perrone F,Daniele B.Cancer of Liver Italian Program (CLIP) InvestigatorsTamoxifen in the treatment of hepatocellular carcinoma: 5-year results of the CLIP-1 multicentre randomised controlled trial.Curr Pharm Des2002;8:1013-9

[17] Pinter M,Graziadei I.Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis.Oncologist2009;14:70-6

[18] Abou-Alfa GK,Santoro A.Safety and efficacy of sorafenib in patients with hepatocellular carcinoma (HCC) and Child-Pugh A versus B cirrhosis.Gastrointest Cancer Res2011;4:40-4 PMCID:PMC3109886

[19] Kim JE,Ryu MH.Sorafenib for hepatocellular carcinoma according to Child-Pugh class of liver function.Cancer Chemother Pharmacol2011;68:1285-90

[20] Pressiani T,Rimassa L.Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis.Ann Oncol2013;24:406-11

[21] Marrero JA,Venook AP.Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study.J Hepatol2016;65:1140-7

[22] Ganten TM,Schott E.Sorafenib in patients with hepatocellular carcinoma-results of the observational INSIGHT study.Clin Cancer Res2017;23:5720-8

[23] McNamara MG,Nuttall C.Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis.Eur J Cancer2018;105:1-9

[24] Blanc JF,Bronowicki JP.PRODIGE 21 collaboratorsPhase 2 trial comparing sorafenib, pravastatin, their combination or supportive care in HCC with Child-Pugh B cirrhosis.Hepatol Int2021;15:93-104

[25] Vogel A,Sung MW.Baseline liver function and outcomes in the phase III REFLECT study in patients with unresectable hepatocellular carcinoma (uHCC).J Clin Oncol2020;38:524

[26] Chan S,Cicin I.Outcomes based on albumin-bilirubin (ALBI) grade in the phase III CELESTIAL trial of cabozantinib versus placebo in patients with advanced hepatocellular carcinoma (HCC).Ann Oncol2019;30:ix45-6

[27] Kudo M,Brandi G.Effect of ramucirumab on ALBI grade in patients with advanced HCC: results from REACH and REACH-2.JHEP Rep2021;3:100215 PMCID:PMC7772786

[28] Labeur TA,Takkenberg B,Mathôt R.Sorafenib for patients with hepatocellular carcinoma and Child-Pugh B liver cirrhosis: lessons learned from a terminated study.Oncologist2020;25:e1274-9 PMCID:PMC7485346

[29] Bruix J,Merle P.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet2017;389:56-66

[30] Kudo M,Qin S.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.Lancet2018;391:1163-73

[31] Kudo M,Santoro A.CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis.J Hepatol2021;S0168-8278(21)00313:

[32] El-Khoueiry AB,Llovet J.Cabozantinib: an evolving therapy for hepatocellular carcinoma.Cancer Treat Rev2021;98:102221

[33] Daniele G,Lorusso V,Pache I.Methodological assessment of HCC literature.Ann Oncol2013;24 Suppl 2:ii6-14 PMCID:PMC3695643