Efficacy of Immune Checkpoint Inhibitors and Their Combinations in Previously Treated Advanced Hepatocellular Carcinoma: A Systematic Review of Clinical Trials

Introduction: Hepatocellular carcinoma (HCC) is increasing worldwide and is often diagnosed at an advanced stage with no curative treatment and are unresectable. HCC frequently has immunosuppressed microenvironment and therefore, immune checkpoint inhibitors (ICI) can be effective in these tumors. In this systematic review, we will assess the efficacy of ICIs and its combinations with tyrosine kinase inhibitors (TKIs) in previously treated HCC. Methods: Literature search was performed on PubMed and Embase with Mesh and Emtree terms, “Hepatocellular Carcinoma”, AND “ICI” from the inception of data till 2/30/23. We screened 3,741 articles and included 1 randomized clinical trial (RCT, N=413) and 10 nonrandomized clinical trials (nRCTs, N=1534) based on inclusion criteria. Prisma guidelines were followed conducting this systematic review. Results: In an RCT by Finn et al. (N=413), hazard ratios of overall survival (OS) and progression free survival (PFS)s were 0.781 (95% CI, 0.611 to 0.998; P = .0238) and 0.718 (95% CI, 0.570 to 0.904; P=.0022), respectively in favor of pembrolizumab in comparison to placebo. In 6 clinical trials on ICI monotherapies (N=1056), overall response rate (ORR), complete response (CR), and partial response (PR) were 14.2%, 0.37%, and 13.8%, respectively. In 2 clinical trials on combination of 2 ICIs (N=307), ORR, CR, and PR were 23.45%, 3.25%, and 20.2%, respectively. In 3 clinical trials ICI combination with tyrosine kinase inhibitors (TKIs) (N=171), ORR, CR, and PR were 21%, 1.1%, and 20%, respectively (Table 1). Conclusion: Pembrolizumab was significantly more effective than placebo in improving survival rates. ICI monotherapies, 2 checkpoint inhibitors combination and ICI combination with TKI has shown clinically significant response in previously treated HCC patients and was relatively better with 2 checkpoint inhibitors combination on indirect comparison. More randomized double blind RCTs are needed to confirm these results. Table 1. - Efficacy of Immune Checkpoint inhibitors and its combinations NCT # Author et. al. year Total number of patients (N) Medications Prior therapy Median OS ORR CR PR SD PD Median PFS NCT01658878 El-Khoueiry et al. 2017 268 Nivolumab, 0·1–10 mg/kg; n=48 Sorafenib 15.0 months 20% 3 4 NA 42 (88%) NA Nivolumab, 3 mg/kg; n =214 5% NA NA NA 132 (62%) NA NCT01658878 Yau et al. 2020 50 Nivolumab 1mg/kg plus Ipilimumab 3mg/kg Sorafenib 22.8 mo 16 (32%) 4 (8%) 12 (24%) 9 (18%) 20 (40%) NA 49 Nivolumab 3mg/kg plus Ipilimumab 1mg/kg 12.5 mo 13 (27%) 3 (6%) 12 (24%) 5 (10%) 24 (49%) 49 Nivolumab 3mg/kg plus Ipilimumab 1mg/kg 12.7 mo 14 (29%) 0 15 (31%) 9 (18%) 21 (43%) NCT02519348 Kelley et al., 2021 332 Tremelimumab + Durvalumab, n = 75 Sorafenib 18.7 mo 24.0 (14.9 to 35.3 1 (1.3) 17 (22.7) 16 (21.3) NA 2.17 Durvalumab n=104 13.6 mo 10.6 (5.4 to 18.1 0 11 (10.6) 28 (26.9) NA 2.07 Tremelimumab n=69 15.1 mo 7.2 (2.4 to 16.1 0 5 (7.2) 29 (42.0) NA 2.69 Tremelimumab + Durvalumab n=84 11.3 mo 9.5 (4.2 to 17.9) 2 (2.4 6 (7.1) 23 (27.4) NA 1.87 NCT02702401 Finn et al., 2021 413 Pembrolizumab Sorafenib 13.9 mo 51 (18%) 6 (2.2%) 45 (16.2%) 122 (44%) 90 (32.4%) 3.0 months Placebo 10.6 mo 6(4.4%) 0 6 (4.4%) 66 (49%) 57 (42.2%) 2.8 months NCT02702414 Zhu et al., 2018 169 Pembrolizumab n =104 Sorafenib 12.9 mo 18 (17%) 1 (1%) 17 (16%) 46 (44%) 34 (33%) 4.9 mo NCT02989922 Qin et al., 2020 220 Camrelizumab n=217 Sorafenib 13.8 mo 32 (14.7%) 0 32 (14.7%) 19 (63%) 99 (45.6%) 2.1 mo NCT03389126 Lee et al., 2021 30 Avelumab, n = 30 Sorafenib 14.2 mo (3) 10% 0 (0%) 3 (10%) 19 (63%) 8 (27%) 3.5 mo NCT03419897 Merle et al., 2022 249 Tislelizumab Sorafenib 12-13.2 mo 32 (13%) 5 (2%) 27 (11%) 100 (40%) 107 (43%) 2.7 mo NA NA NA NA NA NCT03941873 Zhang et al., 2022 43 Sitravatinib alone n =21 1 or 2 prior lines 71.4 mo 4 (10%) NA 4 (10%) NA NA 4.8 mo Sitravatinib+ Tislelizumab n=22 NA 52.7 mo NA NA NA NA NA NCT04072679 Zhang et al, 2020 50 Sintilimab + IBI305 n = 29 NA NA 7 (24%) 0 7 (24%) 15 (52%) 7 (24%) 60.5% IBI305 alone n=21 NA NA 6 (33%) 0 6 (33%) 9 (43%) 3 (14%) 75.8% NCT03463876 Xu et al., 2021 120 Camrelizumab + Apatinib NA NA 27(22.5%) 2 25 NA NA 5.5 months OS; overall survival, ORR: overall response rate, CR: complete response, PR: partial response, SD: Stable disease, PD: Progressive disease, PFS: progression free survival.