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. 2022 Aug 15;14(8):1510-1527.
doi: 10.4251/wjgo.v14.i8.1510.

Second-line therapy for advanced hepatocellular carcinoma with regorafenib or cabozantinib: Multicenter French clinical experience in real-life after matching

Xavier Adhoute  1 , Marie De Matharel  2 , Laurent Mineur  3 , Guillaume Pénaranda  4 , Dann Ouizeman  2 , Clemence Toullec  3 , Albert Tran  2 , Paul Castellani  5 , Armelle Rollet  3 , Valérie Oules  5 , Hervé Perrier  5 , Si Nafa Si Ahmed  5 , Marc Bourliere  5 , Rodolphe Anty  2
Affiliations

Second-line therapy for advanced hepatocellular carcinoma with regorafenib or cabozantinib: Multicenter French clinical experience in real-life after matching

Xavier Adhoute et al. World J Gastrointest Oncol. .

Abstract

Background: Starting a second-line systemic treatment for hepatocellular carcinoma (HCC) is a common situation. The only therapeutic options in France are two broad-spectrum tyrosine kinase inhibitors (TKIs), regorafenib (REG) and cabozantinib (CBZ), but no comparative real-life studies are available.

Aim: To evaluate the progression-free survival (PFS) of patients treated with REG or CBZ, we investigated the disease control rate (DCR), overall survival (OS), and safety of both drugs. To identify the variables associated with disease progression over time.

Methods: A retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers (Avignon, Marseille, and Nice) between January 2017 and March 2021 using propensity score matching. PFS and OS were assessed using the Kaplan-Meier method. Multivariate analysis (MA) of progression risk factors over time was performed in matched-pair groups.

Results: Fifty-eight patients 68 (62-74) years old with HCC, Barcelona clinic liver cancer (BCLC) B/C (86%), Child-Pugh (CP)-A/B (24%) received REG for 3.4 (1.4-10.5) mo as second-line therapy. Twenty-eight patients 68 (60-73) years, BCLC B/C (75%), CP-A/B (25%) received CBZ for 3.7 (1.8-4.9) mo after first-line treatment with sorafenib [3 (2-4) (CBZ) vs 4 (2.9-11.8) mo (REG), P = 0.0226]. Twenty percent of patients received third-line therapy. After matching, PFS and DCR were not significantly different after a median follow-up of 6.2 (2.7-11.7) mo (REG) vs 5.2 (4-7.2) mo (CBZ), P = 0.6925. There was no difference in grade 3/4 toxicities, dose reductions, or interruptions. The OS of CP-A patients was 8.3 (5.2-24.8) vs 4.9 (1.6-11.7) mo (CP-B), P = 0.0468. The MA of risk factors for progression over time identified C-reactive protein (CRP) > 10 mg/L, neutrophil-to-lymphocyte ratio (NLR) > 3, and aspartate aminotransferase (AST) > 45 IU as predictive factors.

Conclusion: This multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC. Elevated levels of inflammatory markers (CRP and NLR) and AST were associated with non-control of TKIs over time. A 2-mo online progression risk calculation is proposed.

Keywords: C-reactive protein; Cabozantinib; Hepatocellular carcinoma; Neutrophil-lymphocyte ratio; Regorafenib.

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Conflict of interest statement

Conflict-of-interest statement: Xavier Adhoute: Board member, Consultancy (Bayer, Ipsen, Eisai, Servier); Laurent Mineur: Board member, Consultancy (Ipsen, Amgen, Travel, Mundipharma, Eisai); Clemence Toullec: Board member, Consultancy (Amgen, Bayer, BMS, Ipsen, Merck-Serono, MSD, Pierre-Fabre, Sanofi, Servier); Albert Tran: Board member, Consultancy (Gilead, Bayer, Eisai, Intercept, Abbvie, MSD, Ipsen); Valérie Oules: Consultancy (Gilead, Abbvie); Paul Castellani: Consultancy (Gilead, Abbvie); Marc Bourlière: Board member, Consultancy (Merck-Schering Plow, Gilead, Janssen, Vertex, Boehringer-Ingelheim, BMS, Roche, Abbvie, GSK); Si Nafa Si Ahmed: Consultancy (Gilead); Hervé Perrier: Consultancy (Sanofi); Rodolphe Anty: Board member, Consultancy (Gilead, Bayer, Eisai, Intercept, Abbvie, MSD, Ipsen); Guillaume Pénaranda, Armelle Rollet, Dann Ouizeman and Marie De Matharel have no conflicts of interest.

Figures

Figure 1
Figure 1
Study flowchart.
Figure 2
Figure 2
Kaplan-Meier curves. A: Median overall survival in hepatocellular carcinoma (HCC) patients receiving regorafenib (REG) or cabozantinib (CBZ) (entire cohort n = 86); B: Median progression-free survival in HCC patients receiving REG vs CBZ as second-line therapy: matching-adjusted indirect comparison study; C: Median progression-free survival in HCC patients receiving second- or third-line CBZ. HCC: Hepatocellular carcinoma; REG: Regorafenib; CBZ: Cabozantinib.
See this image and copyright information in PMC

References

    1. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390. - PubMed
    1. McNamara MG, Le LW, Horgan AM, Aspinall A, Burak KW, Dhani N, Chen E, Sinaei M, Lo G, Kim TK, Rogalla P, Bathe OF, Knox JJ. A phase II trial of second-line axitinib following prior antiangiogenic therapy in advanced hepatocellular carcinoma. Cancer. 2015;121:1620–1627. - PubMed
    1. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V, Mathurin P, Fartoux L, Lin DY, Bruix J, Poon RT, Sherman M, Blanc JF, Finn RS, Tak WY, Chao Y, Ezzeddine R, Liu D, Walters I, Park JW. 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. - PubMed
    1. Rimassa L, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, Rota Caremoli E, Porta C, Daniele B, Bolondi L, Mazzaferro V, Harris W, Damjanov N, Pastorelli D, Reig M, Knox J, Negri F, Trojan J, López López C, Personeni N, Decaens T, Dupuy M, Sieghart W, Abbadessa G, Schwartz B, Lamar M, Goldberg T, Shuster D, Santoro A, Bruix J. 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. - PubMed
    1. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G RESORCE Investigators. 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. - PubMed