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Meta-Analysis
. 2021 Dec 1;4(12):e2136128.
doi: 10.1001/jamanetworkopen.2021.36128.

Efficacy and Safety Associated With Immune Checkpoint Inhibitors in Unresectable Hepatocellular Carcinoma: A Meta-analysis

Alexandre A Jácome  1 , Ana Carolina G Castro  1 , João Paulo S Vasconcelos  1 , Maria Helena C R Silva  1 , Marco Antônio O Lessa  2 , Eduardo D Moraes  2 , Aline C Andrade  1 , Frederico M T Lima  3 , João Paulo F Farias  3 , Roberto A Gil  3 , Gabriel Prolla  4 , Bernardo Garicochea  5
Affiliations
Meta-Analysis

Efficacy and Safety Associated With Immune Checkpoint Inhibitors in Unresectable Hepatocellular Carcinoma: A Meta-analysis

Alexandre A Jácome et al. JAMA Netw Open. .

Abstract

Importance: Immune checkpoint inhibitors (ICIs) have yielded conflicting results in hepatocellular carcinoma (HCC). The overall effect of ICIs compared with standard therapies in unresectable HCC requires more research.

Objective: To estimate the efficacy and safety associated with ICIs compared with standard therapies in patients with unresectable HCC.

Data sources: PubMed, Cochrane Library, Web of Science, Latin American and Caribbean Health Sciences Literature, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings were systematically searched. Reference lists from studies selected by electronic searching were manually searched to identify additional relevant studies. The search included literature published or presented from February 2010 to February 2020.

Study selection: From December 2019 to February 2020, independent reviewers evaluated each database, scanning the title, abstract, and keywords of every record retrieved. Full articles were further assessed if the information given suggested that the study was a randomized clinical trial (RCT) comparing ICIs vs standard therapies in the treatment of unresectable HCC.

Data extraction and synthesis: The full text of the resulting studies and extracted data were reviewed independently according to PRISMA guidelines. Summary hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were calculated by a random-effects model. The likelihood of ICIs being associated with overall response rate (ORR) and treatment-related adverse events (TRAEs) was expressed by odds ratios (ORs) using a random-effects model.

Main outcomes and measures: The main outcomes were OS, PFS, ORR, and TRAEs.

Results: Of 1836 studies yielded by the search, 3 were retained, totaling 1657 patients (985 treated with ICIs vs 672 receiving standard treatment). Two studies evaluated ICIs as monotherapy, and 1 study investigated the combination of ICIs with bevacizumab. Compared with standard therapies (sorafenib in first-line therapy or placebo in second-line therapy), ICIs were associated with significantly improved OS (HR, 0.75; 95% CI, 0.62-0.92; P = .006), PFS (HR, 0.74; 95% CI, 0.56-0.97; P = .03), and ORR (OR, 2.82; 95% CI 2.02-3.93; P < .001). The probability of grade 3 or 4 TRAEs was lower with ICIs than with sorafenib (OR, 0.44; 95% CI, 0.20-0.96; P = .04).

Conclusions and relevance: This meta-analysis found superior efficacy and safety associated with ICIs compared with standard therapies and highlights the survival benefit associated with the combination of antiangiogenic therapy with ICIs in first-line systemic therapy of unresectable HCC.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Jacome reported receiving grants from Bayer, personal fees from Roche, Amgen, Servier, Brisol Myers Squibb, Eli Lilly, Bayer, and IPSEN outside the submitted work. Dr Vasconcelos reported receiving personal fees from Roche, personal fees from MSD, Brisol Myers Squibb, and Merck outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Selection Flowchart
Figure 2.
Figure 2.. Assessment of Overall Survival
The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI); HR, hazard ratio; ICI, immune checkpoint inhibitor. Risks of bias are present (+) or absent (-), with A indicating random sequence generation (selection bias); B, allocation concealment (selection bias); C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment (selection bias); E, incomplete outcome data (attrition bias); F, Selective reporting (reporting bias); and G, other bias.
Figure 3.
Figure 3.. Assessment of Progression-Free Survival
The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI); HR, hazard ratio; ICI, immune checkpoint inhibitor. Risks of bias are present (+) or absent (-), with A indicating random sequence generation (selection bias); B, allocation concealment (selection bias); C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment (selection bias); E, incomplete outcome data (attrition bias); F, Selective reporting (reporting bias); and G, other bias.
Figure 4.
Figure 4.. Assessment of Overall Response Rate
The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI); ICI, immune checkpoint inhibitor; OR, odds ratio. Risks of bias are present (+) or absent (-), with A indicating random sequence generation (selection bias); B, allocation concealment (selection bias); C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment (selection bias); E, incomplete outcome data (attrition bias); F, Selective reporting (reporting bias); and G, other bias.
See this image and copyright information in PMC

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