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.

Keywords:

• IGF-CTP score
• prognostic biomarker
• immunotherapy
• HCC

Data Sharing Statement

Serum IGF-1 data for the IMbrave150 trial will be deposited to the European Genome-Phenome Archive under accession number EGAS00001005519. Qualified researchers may request access to individual patient-level data through the clinical study data request platform at http://www.clinicalstudydatarequest.com. Further details on Roche’s criteria for eligible studies are available at https://clinicalstudydatarequest.com/StudySponsors/Study-Sponsors-Roche.aspx. For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see http://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm.

Acknowledgments

We are grateful for the participation and commitment of patients, families, and doctors in biomarker studies of the IMbrave150 trial. Without their contribution, this study would not have been possible. We thank Vincent E. Gaillard and Yifan Wang for helpful discussions and inputs on the manuscript. We also want to acknowledge Nancy Yang and Leona Ma for coordinating sample collection, assay implementation, and data transfer.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

A.O.K. has received honoraria from Bayer Health, Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, and Merck; has received consulting fees from Bayer Health, Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, and Merck; has received institutional research funding from Adaptimmune, Bayer/Onyx, Bristol Myers Squibb, Genentech, Hengrui Pharmaceutical, and Merck; and has received travel, accommodations, and other expense support from Bayer/Onyx, Bristol Myers Squibb, Exelixis, and Merck. Y.G. is an employee of Genentech and holds stock or other ownership interests in F. Hoffmann-La Roche. B.G.Y. has no conflicts of interest to disclose. A.R.A. and S.L. are employees of Genentech and hold stock or other ownership interests in F. Hoffmann-La Roche. E.H. has no conflicts of interest to disclose. H.C.T. has received honoraria from Roche, MSD Merck, Ipsen, and AstraZeneca. W.V. and Y.W. are employees of Genentech and hold stock or other ownership interests in F. Hoffmann-La Roche. The authors report no other conflicts of interest in this work.

Additional information

Funding

This study was funded by F. Hoffmann-La Roche/Genentech. Editorial support was provided by Jennifer Sollenberger of Health Interactions, funded by the sponsor.