Lorenza Rimassa1,2, Robin Kate Kelley3, Tim Meyer4, Baek-Yeol Ryoo5, Philippe Merle6, Joong-Won Park7, Jean-Frederic Blanc8, Ho Yeong Lim9, Albert Tran10,11,12, Yi-Wah Chan13, Paul McAdam13, Evelyn Wang14, Ann-Lii Cheng15, Anthony B El-Khoueiry16, Ghassan K Abou-Alfa17,18. 1. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy. 2. Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy. 3. UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA. 4. Royal Free Hospital and UCL Cancer Institute, London, United Kingdom. 5. Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 6. Groupement Hospitalier Lyon Nord, Lyon, France. 7. National Cancer Center, Goyang, Republic of Korea. 8. Hôpital Haut-Lévêque, CHU Bordeaux, Bordeaux, France. 9. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 10. Université Côte d'Azur, Nice, France. 11. CHU de Nice, Digestive Center, Nice, France. 12. INSERM, U1065, C3M, Team 8, Nice, France. 13. Fios Genomics Ltd, Edinburgh, United Kingdom. 14. Exelixis, Inc., Alameda, California, USA. 15. National Taiwan University College of Medicine, Taipei, Taiwan. 16. USC Norris Comprehensive Cancer Center, Los Angeles, California, USA. 17. Memorial Sloan Kettering Cancer Center, New York, New York, USA. 18. Weill Medical College at Cornell University, New York, New York, USA.
Abstract
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.
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.
Authors: Lorenza Rimassa; Eric Assenat; Markus Peck-Radosavljevic; Marc Pracht; Vittorina Zagonel; Philippe Mathurin; Elena Rota Caremoli; Camillo Porta; Bruno Daniele; Luigi Bolondi; Vincenzo Mazzaferro; William Harris; Nevena Damjanov; Davide Pastorelli; María Reig; Jennifer Knox; Francesca Negri; Jörg Trojan; Carlos López López; Nicola Personeni; Thomas Decaens; Marie Dupuy; Wolfgang Sieghart; Giovanni Abbadessa; Brian Schwartz; Maria Lamar; Terri Goldberg; Dale Shuster; Armando Santoro; Jordi Bruix Journal: Lancet Oncol Date: 2018-04-03 Impact factor: 41.316
Authors: Michael Teufel; Henrik Seidel; Karl Köchert; Gerold Meinhardt; Richard S Finn; Josep M Llovet; Jordi Bruix Journal: Gastroenterology Date: 2019-02-06 Impact factor: 22.682
Authors: Ghassan K Abou-Alfa; Tim Meyer; Ann-Lii Cheng; Anthony B El-Khoueiry; Lorenza Rimassa; Baek-Yeol Ryoo; Irfan Cicin; Philippe Merle; YenHsun Chen; Joong-Won Park; Jean-Frederic Blanc; Luigi Bolondi; Heinz-Josef Klümpen; Stephen L Chan; Vittorina Zagonel; Tiziana Pressiani; Min-Hee Ryu; Alan P Venook; Colin Hessel; Anne E Borgman-Hagey; Gisela Schwab; Robin K Kelley Journal: N Engl J Med Date: 2018-07-05 Impact factor: 91.245
Authors: L Zhou; X-D Liu; M Sun; X Zhang; P German; S Bai; Z Ding; N Tannir; C G Wood; S F Matin; J A Karam; P Tamboli; K Sircar; P Rao; E B Rankin; D A Laird; A G Hoang; C L Walker; A J Giaccia; E Jonasch Journal: Oncogene Date: 2015-09-14 Impact factor: 9.867
Authors: David J Pinato; Matthew W Brown; Sebastian Trousil; Eric O Aboagye; Jamie Beaumont; Hua Zhang; Helen M Coley; Francesco A Mauri; Rohini Sharma Journal: Br J Cancer Date: 2019-02-15 Impact factor: 7.640