Serum IGF-1 Scores and Clinical Outcomes in the Phase III IMbrave150 Study of Atezolizumab Plus Bevacizumab versus Sorafenib in Patients with Unresectable Hepatocellular Carcinoma

Abstract

Purpose Child-Turcotte-Pugh class A (CTP-A) in unresectable hepatocellular carcinoma (HCC) is the standard criterion for active therapy and clinical trial enrollment. We hypothesized that insulin-like growth factor-1 (IGF-1) derived scores may provide improved survival prediction over CTP classification. This study aimed to evaluate the potential prognostic and predictive effects of IGF-1 derived scores in the phase III IMbrave150 study. Patients and Methods Baseline and on-treatment serum IGF-1 levels from 371 patients were subjected to central analysis. Patients’ IGF-1 score (1/2/3) and IGF-CTP score (A/B/C) were determined based on pre-specified cutoffs. Outcomes were analyzed by baseline and by on-treatment changes of the IGF-1 and IGF-CTP scores within and between the two treatment arms. The interaction between these scores and outcomes was assessed using univariate and multivariate analyses. Results Baseline IGF-CTP score (A vs B/C) showed prognostic significance for OS in both the atezolizumab-bevacizumab (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.20–0.56; P <0.001) and sorafenib (HR, 0.32; 95% CI, 0.16–0.65; P =0.002) arms. Baseline IGF-1 score (1 vs 2/3) also showed prognostic significance for OS in both the atezolizumab-bevacizumab (HR, 0.33; 95% CI, 0.20–0.55; P <0.001) and sorafenib (HR, 0.48; 95% CI, 0.26–0.89; P =0.02) arms. HRs for PFS were consistent with those for OS. No significant predictive effects were observed for either score between the two arms. Kinetic analysis revealed that patients with increased IGF-1 score (1-> 2/3) at 3 weeks post treatment had shorter OS than patients with stable IGF-1 score of 1 in both the atezolizumab-bevacizumab (HR, 3.70; 95% CI, 1.56–8.77; P =0.003) and sorafenib (HR, 5.83; 95% CI, 1.88–18.12; P =0.0023) arms. Conclusion Baseline and kinetic change of IGF-CTP and IGF-1 scores are independent prognostic factors for patients with unresectable HCC treated with atezolizumab-bevacizumab or sorafenib. These novel scores may provide improved patient stratification in future HCC clinical trials. IMbrave150 ClincialTrials.gov number, NCT03434379.

Promising Novel Biomarkers for Hepatocellular Carcinoma: Diagnostic and Prognostic Insights

“… 109 A biomarker study from the IMbrave150 pool showed that high baseline IGF-1 level is associated with improved OS in both the atezolizumab–bevacizumab and sorafenib arms, and it was suggested as a prognostic but not predictive biomarker. 96 Also, patients with decreased IGF-1 during treatment showed poor OS compared to stable IGF-1 in both the combination and sorafenib arms, which suggests IGF-1 as a surrogate marker for survival for both treatments. Notably, relatively few patients had decreased IGF-1 (32 cases in atezolizumab–bevacizumab and 14 cases in sorafenib) during treatment, so interpretation from the findings should be done with caution.…”

“…Serum IGF-1 and AFP levels were suggested as surrogate and/or prognostic biomarkers by the exploratory studies from the IMbrave150 and GO30140 cohorts. 96 , 97 As the liver synthesizes the majority of IGF-1, IGF-1 has been proposed as a liver synthetic function marker. 109 A biomarker study from the IMbrave150 pool showed that high baseline IGF-1 level is associated with improved OS in both the atezolizumab–bevacizumab and sorafenib arms, and it was suggested as a prognostic but not predictive biomarker.…”

“…Notably, relatively few patients had decreased IGF-1 (32 cases in atezolizumab–bevacizumab and 14 cases in sorafenib) during treatment, so interpretation from the findings should be done with caution. 96 …”

Mechanisms of angiogenesis in tumour

“…The combination of antiangiogenic therapy and immunotherapy has demonstrated superior antitumour properties and significantly improved patient survival. In a phase III clinical trial of renal cell carcinoma, researchers found that the use of bevacizumab combined with the PD-1 inhibitor atezolizumab significantly improved the overall survival and progression-free survival rates of patients compared with sorafenib alone ( 174 ). Similarly, nivolumab (anti-PD-1 antibody) plus cabozantinib showed superior progression-free survival, overall survival, and objective response compared with sunitinib for the treatment of renal cell carcinoma ( 175 ).…”

Safety and Efficacy of Atezolizumab and Bevacizumab Combination as a First Line Treatment of Advanced Hepatocellular Carcinoma

“…Consequently, the novel combination of IGF-1 levels and Child-Pugh scores may help improve patient stratification in clinical practice. 68 …”