Changes in immunoglobulin G levels upon initiation of immune checkpoint inhibitor treatment are associated with survival in patients with hepatocellular carcinoma

Background & aims Immunotherapy represents the new standard of care in systemic first-line treatment of hepatocellular carcinoma (HCC). Biomarkers that predict treatment response and survival remain an unmet clinical need.

Methods Patients with HCC treated with immune checkpoint inhibitors (ICI) between 10/2017 and 03/2022 were retrospectively evaluated. Immunoglobulin levels (IgG, IgM, IgA) were measured at baseline and six weeks after initiation of ICI treatment. Impact of relative changes on overall survival (OS), progression-free survival (PFS), and time to progression (TTP) were evaluated.

Results Seventy-two patients with HCC receiving ICI (mostly atezolizumab/bevacizumab n=54, 75%) were included (mean age: 68±12 years, cirrhosis: 72%, mean Child-Turcotte-Pugh (CTP) score: 7±2 points). Most patients had a preserved performance status (ECOG-PS-0, n=45, 63%), 25 (35%) showed macrovascular invasion, and 32 (44%) had extrahepatic spread. Baseline immunoglobulin values (median, IgG: 1395 mg/dL, IgM: 337 mg/dL, IgA: 89 mg/dL) were not different between responders and non-responders, and neither baseline nor follow-up immunoglobulin values correlated with OS, PFS, and TTP. However, the relative change in IgG (Δ-IgG) independently predicted OS in multivariable Cox regression analysis after adjusting for severity of liver disease, ECOG PS, baseline AFP and CRP as well as for Δ-IgA and Δ-IgM. Patients could be stratified into high (Δ-IgG≥+14%) vs. low (Δ-IgG<+14%) risk groups (median OS: 6.4 vs. 15.9 months; p=0.001; ▶Figure A). Importantly, Δ-IgG was also associated with PFS and TTP (▶Figure B, C) on adjusted multivariable Cox regression analyses.

Conclusion Our study proposes a higher increase of Δ-IgG upon ICI treatment as a negative prognostic marker in patients with HCC, independent of underlying liver disease severity. These results require independent validation.

Publication History

Article published online:
26 August 2022