Efficacy and Safety of TKI Plus PD-1 Inhibitors in Elderly uHCC Patients: A Retrospective Study

Bowen Chen, Jin Lei, Haitao Zhao, Jinghui Dong, Zhen Zeng, Yinyin Li, Lingxiang Yu, Lin Zhou, Aiying Jia, Yinying Lu, Jiamin Cheng, Bowen Chen, Jin Lei, Haitao Zhao, Jinghui Dong, Zhen Zeng, Yinyin Li, Lingxiang Yu, Lin Zhou, Aiying Jia, Yinying Lu, Jiamin Cheng

Abstract

Purpose: To explore the efficacy and safety of sorafenib- or lenvatinib-based combination therapy with PD-1 inhibitors in elderly patients aged ≥75 years with unresectable hepatocellular carcinoma (uHCC).

Patients and methods: Systemic therapy-naïve uHCC patients who received first-line sorafenib- or lenvatinib-based combination therapy with PD-1 inhibitors were continually reviewed. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) in accordance with the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events (AEs) and immune-related AEs (irAEs) were also evaluated. Groups and subgroups were separated at the ages of 65 and 75 years and compared with 1:1 matching.

Results: Total 169 eligible patients were enrolled, including 24 aged ≥75 years. Median progression-free survival (PFS) and overall survival (OS) in these 24 elderly patients were 4.6 (95% CI: 2.6-6.6) months, and 17.0 (95% CI: 11.2-22.8) months, with 3-, 6-, 12-month OS rate at 82.90%, 73.70%, and 57.50%. Age ≥75 years was confirmed to be a risk factor influencing PFS among patients aged ≥65 years. Adverse events (AEs) were recorded in all these 24 elderly patients, with seven patients experiencing immune-mediated AEs (irAEs). Nearly 30% of elderly patients stopped treatment due to AEs (16% of these due to irAEs). No statistical differences were found in all efficacy endpoints at the cutoff age of 65 years.

Conclusion: For patients aged ≥75 years, application of PD-1 inhibitors in combination with sorafenib or lenvatinib is promising, but this has to be done with caution and needs to be confirmed by future prospective studies.

Keywords: PD-1 inhibitors; efficacy; elderly; hepatocellular carcinoma; safety.

Conflict of interest statement

The authors have no conflicts of interest to declare in this work.

© 2022 Chen et al.

Figures

Figure 1
Figure 1
Survival outcomes for different groups of patients who received first-line sorafenib or lenvatinib plus PD-1 inhibitors. (A) OS for all patients before matching; (B) OS for all patients after matching; (C) PFS for all patients before matching; (D) PFS for all patients after matching; (E) OS for elderly patients; (F) PFS for elderly patients.

References

    1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi:10.3322/caac.21660
    1. Villanueva A, Longo DL. Hepatocellular carcinoma. N Engl J Med. 2019;380(15):1450–1462. doi:10.1056/nejmra1713263
    1. Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017;8:561. doi:10.3389/fphar.2017.00561
    1. Jiang Y, Chen M, Nie H, Yuan Y. PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum Vaccin Immunother. 2019;15(5):1111–1122. doi:10.1080/21645515.2019.1571892
    1. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022;76(3):681–693. doi:10.1016/j.jhep.2021.11.018
    1. Zhao HT, Cai JQ. Chinese expert consensus on neoadjuvant and conversion therapies for hepatocellular carcinoma. World J Gastroenterol. 2021;27(47):8069–8080. doi:10.3748/wjg.v27.i47.8069
    1. Chinese Chapter of the International Hepato-Pancreato-Biliary Association;Group of Liver Surgery, Surgical Society of Chinese Medical Association;Expert Committee on Liver Cancer, Chinese Society of Clinical Oncology. Chinese multidisciplinary expert consensus on combined immunotherapy based on immune checkpoint inhibitors for hepatocellular carcinoma(2021 version). Zhonghua Gan Zang Bing Za Zhi. 2021;29(7):636–647. doi:10.3760/cma.j.cn501113-20210604-00261
    1. Professional Committee for Prevention and Control of Hepatobiliary and Pancreatic Diseases of Chinese Preventive Medicine Association, Chinese Society of Liver Cancer, Liver Study Group of Surgery Committee of Beijing Medical Association, Editorial Board of Chinese Journal of Hepatobiliary Surgery. Chinese expert consensus on conversion therapy of immune checkpoint inhibitors combined antiangiogenic targeted drugs for advanced hepatocellular carcinoma(2021 Edition) [J]. Zhonghua Gan Dan Wai Ke Za Zhi. 2021;27(4):241251. Chinese. doi:10.3760/cma.j.cn113884-20210415-00138
    1. Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020;38(26):2960–2970. doi:10.1200/JCO.20.00808
    1. Wu JY, Yin ZY, Bai YN, et al. Lenvatinib combined with anti-PD-1 antibodies plus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: a multicenter retrospective study. J Hepatocell Carcinoma. 2021;8:1233–1240. doi:10.2147/JHC.S332420
    1. Zhu XD, Huang C, Shen YH, et al. Downstaging and resection of initially unresectable hepatocellular carcinoma with tyrosine kinase inhibitor and anti-PD-1 antibody combinations. Liver Cancer. 2021;10(4):320–329. doi:10.1159/000514313
    1. He MK, Liang RB, Zhao Y, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2021;13:17588359211002720. doi:10.1177/17588359211002720
    1. Chen S, Xu B, Wu Z, et al. Pembrolizumab plus lenvatinib with or without hepatic arterial infusion chemotherapy in selected populations of patients with treatment-naive unresectable hepatocellular carcinoma exhibiting PD-L1 staining: a multicenter retrospective study. BMC Cancer. 2021;21(1):1126. doi:10.1186/s12885-021-08858-6
    1. Huang C, Zhu XD, Shen YH, et al. Organ specific responses to first-line lenvatinib plus anti-PD-1 antibodies in patients with unresectable hepatocellular carcinoma: a retrospective analysis. Biomark Res. 2021;9(1):19. doi:10.1186/s40364-021-00274-z
    1. Li Q, Cao M, Yuan G, et al. Lenvatinib plus camrelizumab vs. lenvatinib monotherapy as first-line treatment for unresectable hepatocellular carcinoma: a multicenter retrospective cohort study. Front Oncol. 2022;12:809709. doi:10.3389/fonc.2022.809709
    1. Chen S, Wu Z, Shi F, et al. Lenvatinib plus TACE with or without pembrolizumab for the treatment of initially unresectable hepatocellular carcinoma harbouring PD-L1 expression: a retrospective study. J Cancer Res Clin Oncol. 2022;148(8):2115–2125. doi:10.1007/s00432-021-03767-4
    1. Cai M, Huang W, Huang J, et al. Transarterial chemoembolization combined with lenvatinib plus PD-1 inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study. Front Immunol. 2022;13:848387. doi:10.3389/fimmu.2022.848387
    1. Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156(2):477–491.e1. doi:10.1053/j.gastro.2018.08.065
    1. Ramani A, Tapper EB, Griffin C, Shankar N, Parikh ND, Asrani SK. Hepatocellular carcinoma-related mortality in the USA, 1999–2018. Dig Dis Sci. 2022;67(8):4100–4111. doi:10.1007/s10620-022-07433-8
    1. Tateishi R, Uchino K, Fujiwara N, et al. A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011–2015 update. J Gastroenterol. 2019;54(4):367–376. doi:10.1007/s00535-018-1532-5
    1. Wang F, Mubarik S, Zhang Y, et al. Long-term trends of liver cancer incidence and mortality in China 1990–2017: a joinpoint and age-period-cohort analysis. Int J Environ Res Public Health. 2019;16(16):2878. doi:10.3390/ijerph16162878
    1. Partridge L, Deelen J, Slagboom PE. Facing up to the global challenges of ageing. Nature. 2018;561(7721):45–56. doi:10.1038/s41586-018-0457-8
    1. Macias RIR, Monte MJ, Serrano MA, et al. Impact of aging on primary liver cancer: epidemiology, pathogenesis and therapeutics. Aging. 2021;13(19):23416–23434. doi:10.18632/aging.203620
    1. Lyu N, Yi JZ, Zhao M. Immunotherapy in older patients with hepatocellular carcinoma. Eur J Cancer. 2022;162:76–98. doi:10.1016/j.ejca.2021.11.024
    1. Tada T, Kumada T, Hiraoka A, et al. Safety and efficacy of lenvatinib in elderly patients with unresectable hepatocellular carcinoma: a multicenter analysis with propensity score matching. Hepatol Res. 2020;50(1):75–83. doi:10.1111/hepr.13427
    1. Hajiev S, Allara E, Motedayеn Aval L, et al. Correction: impact of age on sorafenib outcomes in hepatocellular carcinoma: an international cohort study. Br J Cancer. 2021;124(9):1611. doi:10.1038/s41416-020-01241-5
    1. Marta GN, da Fonseca LG, Braghiroli MI, Moura F, Hoff PM, Sabbaga J. Efficacy and safety of sorafenib in elderly patients with advanced hepatocellular carcinoma. Clinics. 2021;76(e2498):e2498. doi:10.6061/clinics/2021/e2498
    1. Vithayathil M, D’Alessio A, Fulgenzi CAM, et al. Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma. Liver Int. 2022;42(11):2538–2547. doi:10.1111/liv.15405
    1. Corbaux P, Maillet D, Boespflug A, et al. Older and younger patients treated with immune checkpoint inhibitors have similar outcomes in real-life setting. Eur J Cancer. 2019;121:192–201. doi:10.1016/j.ejca.2019.08.027
    1. Charlson ME, Carrozzino D, Guidi J, Patierno C. Charlson comorbidity index: a critical review of clinimetric properties. Psychother Psychosom. 2022;91(1):8–35. doi:10.1159/000521288
    1. Subirana I, Sanz H, Vila J. Building bivariate tables: the comparegroups package for R. J Stat Softw. 2014;57(12):1–6. doi:10.18637/jss.v057.i12
    1. Ho DE, Imai K, King G, Stuart EA. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat Softw. 2011;42:8. doi:10.18637/jss.v042.i08
    1. Therneau TM. A package for survival analysis in R: R Package Version 3.1-12. Rochester, MN: Mayo Clinic. 2021.
    1. Kassambara A, Kosinski M, Biecek P, Fabian S survminer: drawing survival curves using ‘ggplot2’. R package version 0.4. 3. Google Scholar; 2018.
    1. Wickham H. ggplot2: Elegant Graphics for Data Analysis. springer; 2016.
    1. Wnvabd R. Modern Applied Statistics with S. Springer; 2002.
    1. Kudo M, Finn RS, Qin S, et al. 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
    1. Osa A, Uenami T, Koyama S, et al. Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients. JCI Insight. 2018;3:19. doi:10.1172/jci.insight.59125
    1. Xie D, Sun Q, Wang X, et al. Immune checkpoint inhibitor plus tyrosine kinase inhibitor for unresectable hepatocellular carcinoma in the real world. Ann Transl Med. 2021;9(8):652. doi:10.21037/atm-20-7037
    1. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. doi:10.1056/NEJMoa0708857
    1. Muchnik E, Loh KP, Strawderman M, et al. Immune checkpoint inhibitors in real-world treatment of older adults with non-small cell lung cancer: immune checkpoint inhibitors and older adults. J Am Geriatr Soc. 2019;67(5):905–912. doi:10.1111/jgs.15750
    1. Fukui T, Okuma Y, Nakahara Y, et al. Activity of nivolumab and utility of neutrophil-to-lymphocyte ratio as a predictive biomarker for advanced non-small-cell lung cancer: a prospective observational study. Clin Lung Cancer. 2019;20(3):208–214.e2. doi:10.1016/j.cllc.2018.04.021
    1. Baldini C, Martin Romano P, Voisin AL, et al. Impact of aging on immune-related adverse events generated by anti-programmed death (ligand)PD-(L)1 therapies. Eur J Cancer. 2020;129:71–79. doi:10.1016/j.ejca.2020.01.013
    1. Betof AS, Nipp RD, Giobbie-Hurder A, et al. Impact of age on outcomes with immunotherapy for patients with melanoma. Oncologist. 2017;22(8):963–971. doi:10.1634/theoncologist.2016-0450
    1. Hunt NJ, Kang SWS, Lockwood GP, Le Couteur DG, Cogger VC. Hallmarks of aging in the liver. Comput Struct Biotechnol J. 2019;17:1151–1161. doi:10.1016/j.csbj.2019.07.021
    1. Cantarini MC, Trevisani F, Morselli-Labate AM, et al. Effect of the etiology of viral cirrhosis on the survival of patients with hepatocellular carcinoma. Am J Gastroenterol. 2006;101(1):91–98. doi:10.1111/j.1572-0241.2006.00364.x
    1. Lee SH, Choi HC, Jeong SH, et al. Hepatocellular carcinoma in older adults: clinical features, treatments, and survival: hepatocellular carcinoma in older adults. J Am Geriatr Soc. 2011;59(2):241–250. doi:10.1111/j.1532-5415.2010.03273.x
    1. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label Phase 2 trial. Lancet Oncol. 2018;19(7):940–952. doi:10.1016/S1470-2045(18)30351-6

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner