Outcomes Based on Plasma Biomarkers for the Phase 3 CELESTIAL Trial of Cabozantinib versus Placebo in Advanced Hepatocellular Carcinoma

Liver Cancer

Baek-Yeol Ryoo¹  Lorenza Rimassa²  Evelyn Wang³  Paul McAdam⁴  Yi-Wah Chan⁴  Philippe Merle⁵  Jean-Frederic Blanc⁶  Ghassan K. Abou-Alfa⁷  Joong-Won Park⁸  Ann-Lii Cheng⁹  Tim Meyer^1,10  Ho Yeong Lim^1,11  Robin Kate Kelley^1,12  Anthony B. El-Khoueiry^1,13  Albert Tran^1,14 

[1] Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy;Exelixis, Inc., Alameda, CA, USA;Fios Genomics Ltd, Edinburgh, United Kingdom;Groupement Hospitalier Lyon Nord, Lyon, France;Hôpital Haut-Lévêque, CHU Bordeaux, Bordeaux, France;Memorial Sloan Kettering Cancer Center, New York, NY, USA;National Cancer Center, Goyang, Republic of Korea;National Taiwan University College of Medicine, Taipei, Taiwan;Royal Free Hospital and UCL Cancer Institute, London, United Kingdom;Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA;USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA;Université Côte d’Azur, Nice, France;

关键词: hepatocellular carcinoma;    plasma biomarkers;    prognostic factors;    cabozantinib;   

DOI  :  10.1159/000519867

来源: DOAJ

【 摘 要 】

Introduction: Cabozantinib, an inhibitor of MET, AXL, and VEGF receptors, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). In this exploratory analysis, outcomes were evaluated according to plasma biomarker levels. Methods: Baseline plasma levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, EPO, ANG2, IGF-1, VEGF-C, and c-KIT for 674/707 randomized patients; and Week 4 levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, and EPO for 614 patients. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at Week 4 as continuous variables; biomarkers were considered potentially prognostic if p < 0.05 and predictive if p < 0.05 for the interaction between treatment and the biomarker. Multivariable analyses adjusting for clinical covariates were also performed. Results: In the placebo group, high levels of MET, HGF, GAS6, IL-8, and ANG2 and low levels of IGF-1 were associated with shorter OS in univariate and multivariable analyses; these associations were also observed for MET, IL-8, and ANG2 in the cabozantinib group. Hazard ratios for OS and PFS favored cabozantinib over the placebo at low and high baseline levels for all biomarkers. No baseline biomarkers were predictive of a treatment benefit. Cabozantinib promoted pharmacodynamic changes in several biomarkers, including increases in VEGF-A, PlGF, AXL, and GAS6 levels and decreases in VEGFR2 and HGF levels; these changes were not associated with OS or PFS. Conclusion: Cabozantinib improved OS and PFS versus placebo at high and low baseline concentrations for all biomarkers analyzed. Low baseline levels of MET, HGF, GAS6, IL-8, and ANG2 and high levels of IGF-1 were identified as potential favorable prognostic biomarkers for survival in previously treated advanced HCC. Although cabozantinib promoted pharmacodynamic changes in several biomarkers, these changes were not associated with survival.

【 授权许可】

Unknown