Serum FGF21 as a predictor of response to atezolizumab and bevacizumab in HCC

Abstract

Background & aims: Fibroblast growth factor 21 (FGF21) is a crucial regulator of cell metabolism. Tumour-secreted FGF21 has shown immune-checkpoint factor functions, and high FGF21 levels are associated with a poor prognosis for patients. However, its prognostic value and impact on treatment response in patients with hepatocellular carcinoma (HCC) treated with immune-checkpoint inhibitors (ICIs) remain unclear. Thus, this study investigated the potential of high FGF21 levels as a prognostic marker and whether traditional ICI-based therapy can improve the prognosis of patients with high FGF21 levels.

Methods: In this retrospective multicentre study, patients with unresectable HCC who received atezolizumab/bevacizumab in the NORTE study group (n = 117) were classified into high (≥915 pg/ml; n = 29) and non-high (n = 88) FGF21 groups. For validation, we investigated patients treated with atezolizumab/bevacizumab in an independent cohort (n = 285). Overall survival, progression-free survival, and treatment response were compared between patients with and without high baseline FGF21 levels.

Results: The median overall survival (p <0.001) and progression-free survival (p = 0.045) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. Independent cohort analysis validated these results. In the overall cohort, the median progression-free survival (5.75 vs. 8.84 months; p = 0.027) and median overall survival (14.13 vs. 22.08 months; p <0.001) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. The durable response (≥6 months) + complete response rate was significantly decreased in the high FGF21 group (p = 0.045). No patient with a high FGF21 level achieved a complete response, whereas this was achieved in 4.1% (13/319) of patients with non-high FGF21 levels. Multivariate Cox regression analysis identified high baseline serum FGF21 as an independent poor prognostic factor for overall survival (hazard ratio 2.20, p <0.001).

Conclusions: Serum FGF21 may be a robust, non-invasive prognostic and treatment response marker for unresectable HCC treated with atezolizumab/bevacizumab.

Impact and implications: FGF21 has been reported to act as a secreted immune-checkpoint factor, and elevated levels of FGF21 are associated with a poor prognosis in patients with HCC. It is not fully understood whether ICIs can overcome the impact of high FGF21 levels on the shortened prognosis of patients with HCC. In this multicentre retrospective study, patients with HCC and high baseline levels of serum FGF21 who received atezolizumab/bevacizumab treatment exhibited a significantly shorter overall survival and shorter progression-free survival. These findings suggest serum FGF21 as a robust prognostic marker and an indicator of treatment response in unresectable HCC treated with ICI-based therapy. These findings could be crucial for the implementation of personalised treatment strategies for unresectable HCC. However, identifying optimal therapeutic options for patients with unresectable HCC and high serum FGF21 levels remains an urgent and critical clinical issue.

Keywords: Atezolizumab; Bevacizumab; FGF21; Hepatocellular Carcinoma; Immune-checkpoint inhibitor; Prognosis.

Graphical abstract

Fig. 1

OS and PFS of patients treated with atezolizumab and bevacizumab and stratified according to baseline serum FGF21 levels. (A,B) Discovery cohort. (A) OS: level of significance, p <0.001 (log-rank test); PFS, level of significance, p = 0.045 (log-rank test). (B) Patients were categorised using propensity scores (BCLC stage, Child-Pugh grade, sex, age, ALT, TNM stage, presence of Vp, and AFP levels). OS, level of significance: p = 0.025 (log-rank test); PFS, level of significance: p = 0.024 (log-rank test). (C,D) Validation cohort. (C) OS, level of significance: p = 0.003 (log-rank test); PFS, level of significance: p = 0.090 (generalised Wilcoxon test). (D) Patients were categorised using propensity scores (BCLC stage, Child-Pugh grade, sex, age, ALT, TNM stage, presence of Vp, and AFP levels). OS, level of significance: p = 0.029 (log-rank test); PFS, level of significance: p = 0.031 (generalised Wilcoxon test). AFP, alpha-fetoprotein; ALT, alanine aminotransferase; BCLC, Barcelona Clinic Liver Cancer; high FGF21, high baseline FGF21 levels; HR, hazard ratio; non-high FGF21, non-high baseline FGF21 levels; NR, not reached; (m)OS, (median) overall survival; (m)PFS, (median) progression-free survival.

Fig. 2

OS, PFS, and treatment response of patients treated with atezolizumab and bevacizumab and stratified according to baseline serum FGF21 levels in the whole cohort. (A) OS, level of significance: p <0.001 (log-rank test). (B) PFS, level of significance: p = 0.027 (generalised Wilcoxon test). (C,D) Patients with unresectable HCC treated with atezolizumab and bevacizumab were categorised using propensity scores, including BCLC stage, Child-Pugh grade, sex, age, ALT, TNM stage, presence of Vp, and AFP levels. (C) OS, level of significance: p = 0.002 (log-rank test). (D) PFS, level of significance: p = 0.028 (generalised Wilcoxon test). (E) ORR, DCR, durable rate, and CR rat, level of significance: p = 0.741, p = 0.282, p = 0.045, and p = 0.069, respectively (Fisher’s exact test). Durable is defined as durable response of PR or SD of >6 months, or CR. CR, complete response; DCR, disease control rate; high FGF21, high baseline FGF21 levels; HR, hazard ratio; non-high FGF21, non-high baseline FGF21 levels; ORR, objective response rate; (m)OS, (median) overall survival; (m)PFS, (median) progression-free survival; PR, partial response; SD, stable disease.

Fig. 3

Comparison of OS, PFS, and treatment response among patients treated with atezolizumab/bevacizumab, lenvatinib, or sorafenib, stratified according to baseline serum FGF21 levels. (A,B) Kaplan–Meier estimates of OS and PFS stratified by treatment regimen in patients with high baseline FGF21 levels (high FGF21). (A) OS, level of significance: p = 0.491 (log-rank test). (B) PFS, level of significance: p = 0.366 (log-rank test). (C,D) Kaplan–Meier estimates of OS and PFS stratified by treatment regimen in patients with non-high baseline FGF21 levels (non-high FGF21). (C) OS, level of significance: p = 0.013 (log-rank test). (D) PFS, level of significance: p <0.001 (log-rank test). (E) Comparison of CR rate among atezolizumab/bevacizumab, lenvatinib, or sorafenib in patients with high FGF21. Lenvatinib was the only treatment to achieve CR in four cases. (F) Changes in FGF21 levels from baseline to PD. Atezolizumab/bevacizumab, p <0.001; lenvatinib, p = 0.952. (Wilcoxon matched-pairs signed rank test). Atezo/Bev, atezolizumab/bevacizumab; CR, complete response; high FGF21, high baseline FGF21 levels; HR, hazard ratio; non-high FGF21, non-high baseline FGF21 levels; (m)OS, (median) overall survival; PD, progressive disease; (m)PFS, (median) progression-free survival.