Abstract
In recent years, the therapeutic landscape for patients with advanced/unresectable hepatocellular carcinoma (HCC) has become more complex, novel immunotherapy combinations have demonstrated their activity and represent a new standard of care, such as atezolizumab plus bevacizumab, or will soon be included in the treatment algorithm, such as durvalumab plus tremelimumab. For other combinations such as cabozantinib plus atezolizumab, a progression-free survival (PFS) benefit not associated with an improvement in overall survival (OS) was shown. However, tyrosine kinase inhibitors, including cabozantinib, still remain important therapeutic options in the management of patients with advanced HCC. In this field there is a lack of prognostic and predictive biomarkers and alpha-fetoprotein (AFP) remains the most widely used prognostic biomarker in clinical practice and the only predictive biomarker available only for ramucirumab. Cabozantinib inhibits receptor tyrosine kinases implicated in HCC progression, tumor immunosuppression, and resistance to antiangiogenic therapy, including VEGF receptors 1–3, MET, and the TAM family kinases TYRO3, AXL, and MER. Cabozantinib significantly improved OS and PFS compared to placebo in patients with previously treated advanced HCC in the phase 3 CELESTIAL trial. In the presented exploratory analyses, outcomes were evaluated according to baseline plasma biomarker levels and changes during treatment at week 4 or 8. Biomarkers chosen for the study included AFP, cabozantinib targets and their ligands, and other plasma proteins with prognostic significance in HCC. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at week 4 or 8 as continuous variables; multivariable analyses adjusted for clinical covariates were also performed. Finally, outcomes were also evaluated based on clinical factors as ALBI grade and adverse events. Several biomarkers or clinical factors at baseline or during treatment were identified as prognostic and associated with different OS and/or PFS. Low baseline levels of AFP, MET, HGF, GAS6, IL-8, ANG2, high levels of IGF-1, and ALBI grade 1 were identified as potential favorable prognostic biomarkers/factors in previously treated advanced HCC. However, hazard ratios for OS and PFS favored cabozantinib over placebo at low and high baseline levels for all biomarkers, and no baseline biomarkers predicted treatment benefit. Cabozantinib induced pharmacodynamic changes in several biomarkers, but these changes were not associated with OS or PFS, except for AFP response which correlated with improved OS and PFS. The occurrence of some adverse events during treatment has been associated with longer OS and PFS with cabozantinib. Future studies should explore both circulating and tumor biomarkers related to angiogenic signaling, inflammation, and immune-cell function, in order to identify prognostic and predictive biomarkers to guide clinical decision-making and improve outcomes for patients with advanced HCC.
Citation Format: Lorenza Rimassa. Prognostic and predictive biomarkers for cabozantinib in HCC [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA12.
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