Nivolumab As Second-Line Therapy Improves Survival in Patients with Unresectable Hepatocellular Carcinoma

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2024 Jun 27

PMID 38927902

Authors

Faisal M Sanai

Hassan O Odah

Kanan Alshammari

Adnan Alzanbagi

Murooj Alsubhi

Hani Tamim

Ashwaq Alolayan

Ahmed Alshehri

Saleh A Alqahtani

Affiliations

Soon will be listed here.

Abstract

Background: Limited data exists for the efficacy and outcomes of nivolumab as a second-line treatment for unresectable hepatocellular carcinoma (uHCC). We aimed to assess the efficacy and safety of nivolumab in patients with uHCC who experienced disease progression during sorafenib treatment.

Methods: In this retrospective, observational, multicenter study, adult Child-Turcotte-Pugh A/7B patients with uHCC who tolerated sorafenib therapy but showed disease progression switched to second-line intravenous nivolumab ( = 42). A similar number of consecutive, unselected patients who were maintained on sorafenib therapy, regardless of tumoral response or progression, served as historical controls ( = 38). The primary endpoint was overall survival (OS, defined as the time from starting sorafenib in either group up to death due to any cause) and analyzed by intention-to-treat.

Results: The mean age of the overall cohort was 72.4 ± 10.1 years, of whom 87.5% were males and 58.8% had underlying viral etiology. Patients in the two cohorts were similar, except those who received nivolumab had more co-morbidities (70.0% vs. 15.4%), ECOG-2 status (21.4% vs. 15.8%), BCLC stage C (81.0% vs. 47.4%), and extravascular invasion (54.4% vs. 21.8%) ( < 0.05 for all). More patients in the nivolumab arm were Child-Turcotte-Pugh B (35.7% vs. 21.1%, = 0.15). Median OS was 22.2 months (95% CI: 8.9-49.8) on second-line nivolumab and 11.0 months (95% CI: 3.6-18.4) on sorafenib alone (HR 1.93; 95% CI: 1.1-3.3, = 0.014). Median OS after starting nivolumab was 10.2 months, and time-to-progression was 4.9 months (95% CI: 3.2-6.3).

Conclusion: Nivolumab is an effective second-line treatment option in patients with uHCC who progress on sorafenib, with significantly improved OS. These early real-life data offer encouraging results, similar to those shown in Phase I/IIa clinical trials. Further investigations are warranted for the use of nivolumab as a monotherapy.

References

Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J . Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359(4):378-90. DOI: 10.1056/NEJMoa0708857. View

Pinter M, Peck-Radosavljevic M . Review article: systemic treatment of hepatocellular carcinoma. Aliment Pharmacol Ther. 2018; 48(6):598-609. PMC: 6120553. DOI: 10.1111/apt.14913. View

Yau T, Park J, Finn R, Cheng A, Mathurin P, Edeline J . Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2021; 23(1):77-90. DOI: 10.1016/S1470-2045(21)00604-5. View

Kudo M, Finn R, Galle P, Zhu A, Ducreux M, Cheng A . IMbrave150: Efficacy and Safety of Atezolizumab plus Bevacizumab versus Sorafenib in Patients with Barcelona Clinic Liver Cancer Stage B Unresectable Hepatocellular Carcinoma: An Exploratory Analysis of the Phase III Study. Liver Cancer. 2023; 12(3):238-250. PMC: 10521324. DOI: 10.1159/000528272. View

Scheiner B, Kirstein M, Hucke F, Finkelmeier F, Schulze K, von Felden J . Programmed cell death protein-1 (PD-1)-targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real-world cohort. Aliment Pharmacol Ther. 2019; 49(10):1323-1333. PMC: 6593858. DOI: 10.1111/apt.15245. View

Gadaleta R, Moschetta A . Dark and bright side of targeting fibroblast growth factor receptor 4 in the liver. J Hepatol. 2021; 75(6):1440-1451. DOI: 10.1016/j.jhep.2021.07.029. View

Yang Y, Chen D, Zhao B, Ren L, Huang R, Feng B . The predictive value of PD-L1 expression in patients with advanced hepatocellular carcinoma treated with PD-1/PD-L1 inhibitors: A systematic review and meta-analysis. Cancer Med. 2023; 12(8):9282-9292. PMC: 10166972. DOI: 10.1002/cam4.5676. View

Bruix J, Qin S, Merle P, Granito A, Huang Y, Bodoky G . Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2016; 389(10064):56-66. DOI: 10.1016/S0140-6736(16)32453-9. View

Kudo M, Finn R, Cheng A, Zhu A, Ducreux M, Galle P . Albumin-Bilirubin Grade Analyses of Atezolizumab plus Bevacizumab versus Sorafenib in Patients with Unresectable Hepatocellular Carcinoma: A Post Hoc Analysis of the Phase III IMbrave150 Study. Liver Cancer. 2023; 12(5):479-493. PMC: 10601852. DOI: 10.1159/000529996. View

10.

Finn R, Merle P, Granito A, Huang Y, Bodoky G, Pracht M . Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial. J Hepatol. 2018; 69(2):353-358. DOI: 10.1016/j.jhep.2018.04.010. View

11.

Fessas P, Kaseb A, Wang Y, Saeed A, Szafron D, Jun T . Post-registration experience of nivolumab in advanced hepatocellular carcinoma: an international study. J Immunother Cancer. 2020; 8(2). PMC: 7462152. DOI: 10.1136/jitc-2020-001033. View

12.

Alqahtani S, Sanai F, Alolayan A, Abaalkhail F, Alsuhaibani H, Hassanain M . Saudi Association for the Study of Liver diseases and Transplantation practice guidelines on the diagnosis and management of hepatocellular carcinoma. Saudi J Gastroenterol. 2020; 26(Suppl 1):S1-S40. PMC: 7768980. DOI: 10.4103/sjg.SJG_477_20. View

13.

Finkelmeier F, Czauderna C, Perkhofer L, Ettrich T, Trojan J, Weinmann A . Feasibility and safety of nivolumab in advanced hepatocellular carcinoma: real-life experience from three German centers. J Cancer Res Clin Oncol. 2018; 145(1):253-259. DOI: 10.1007/s00432-018-2780-8. View

14.

Marrero J, Kudo M, Venook A, Ye S, Bronowicki J, Chen X . Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study. J Hepatol. 2016; 65(6):1140-1147. DOI: 10.1016/j.jhep.2016.07.020. View

15.

Shi F, Shi M, Zeng Z, Qi R, Liu Z, Zhang J . PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer. 2010; 128(4):887-96. DOI: 10.1002/ijc.25397. View

16.

El-Khoueiry A, Sangro B, Yau T, Crocenzi T, Kudo M, Hsu C . 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(10088):2492-2502. PMC: 7539326. DOI: 10.1016/S0140-6736(17)31046-2. View

17.

Hsu C, Lee Y, Hsia C, Huang Y, Su C, Lin H . Performance status in patients with hepatocellular carcinoma: determinants, prognostic impact, and ability to improve the Barcelona Clinic Liver Cancer system. Hepatology. 2012; 57(1):112-9. DOI: 10.1002/hep.25950. View

18.

Lee C, Lee Y, Kim M, Jang H, Oh H, Kim S . Effectiveness of nivolumab versus regorafenib in hepatocellular carcinoma patients who failed sorafenib treatment. Clin Mol Hepatol. 2020; 26(3):328-339. PMC: 7364358. DOI: 10.3350/cmh.2019.0049n. View

19.

Kudo M, Finn R, Qin S, Han K, Ikeda K, Piscaglia F . Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018; 391(10126):1163-1173. DOI: 10.1016/S0140-6736(18)30207-1. View

20.

Greten T, Wang X, Korangy F . Current concepts of immune based treatments for patients with HCC: from basic science to novel treatment approaches. Gut. 2015; 64(5):842-8. PMC: 6311419. DOI: 10.1136/gutjnl-2014-307990. View