4537 - Outcomes based on plasma biomarkers for the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in advanced hepatocellular carcinoma (aHCC)

Background

C inhibits tyrosine kinases implicated in HCC progression and resistance to antiangiogenic therapy, including VEGFR, MET, and AXL. In the phase 3 CELESTIAL trial (NCT01908426), C significantly improved overall survival (OS) and progression-free survival (PFS) vs P in previously treated aHCC (Abou-Alfa, NEJM 2018). Here, we evaluate outcomes based on plasma biomarkers in CELESTIAL.

Methods

707 patients (pts) were randomized 2:1 to receive C (60 mg qd) or P. Pts were Child-Pugh A and ECOG PS ≤ 1, must have received prior sorafenib, and could have received up to 2 prior systemic regimens for HCC. Plasma samples were collected at baseline and on treatment for 674 pts and analyzed by Luminex assay (Assay Gate) for MET, AXL, VEGFR2, c-KIT, HGF, GAS6, VEGF-A, VEGF-C, PlGF, ANG2, IL-8, IGF-1, and EPO. OS and PFS were evaluated for low and high baseline biomarker levels dichotomized at the median. Prognostic factors were identified by comparing high vs low biomarker levels within each treatment arm, using the criterion that the HR 95% CI does not include 1.0. Biomarkers were considered predictive if p ≤ 0.05 for the interaction between treatment and subgroup.

Results

For low and high levels of all 13 biomarkers analyzed, hazard ratios favored C over P for both OS (Table) and PFS (all C vs P HRs<0.55; not shown). Analyses comparing high vs low biomarker levels identified MET, HGF, GAS6, ANG2, IL-8, and IGF-1 as possible prognostic factors for OS in both treatment arms; VEGF-A in the P arm only; and AXL and EPO in the C arm only (Table). No baseline biomarkers were found to be predictive of an OS benefit with C (p interaction >0.05).Table:

678PD

Conclusions

C treatment was associated with improved OS and PFS vs P in previously treated aHCC irrespective of baseline biomarker levels. Low baseline levels of MET, HGF, GAS6, VEGF-A, ANG2, and IL-8 and high levels of IGF-1 were identified as potential prognostic biomarkers for longer OS with P.

Clinical trial identification

NCT01908426.

Editorial acknowledgement

David Markby, Exelixis Inc.

Legal entity responsible for the study

Exelixis Inc.

Funding

Exelixis Inc.

Disclosure

L. Rimassa: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): AbbVie; Honoraria (self): Gilead; Honoraria (self), Honoraria paid for lectures: Roche; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sirtex Medical; Advisory / Consultancy: Itafarmaco; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Research grant / Funding (institution): ArQule; Advisory / Consultancy: Baxter; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Amgen; Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Agios. R.K. Kelley: Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Agios; Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): QED; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Taiho. T. Meyer: Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): BTG; Advisory / Consultancy: Celgene; Advisory / Consultancy: MSD; Research grant / Funding (institution): Bayer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol Meyers Squibb; Advisory / Consultancy: Boehringer Ingelheim. P. Merle: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self): Eisai; Honoraria (self): BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self): Lilly; Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Onxeo. J. Park: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Advisory / Consultancy: Ono; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech. J. Blanc: Honoraria (self): Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Eisai. H.Y. Lim: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Eisai. A. Tran: Leadership role: Investigator. A.E. Borgman-Hagey: Shareholder / Stockholder / Stock options, Full / Part-time employment: Exelixis Inc. D.O. Clary: Shareholder / Stockholder / Stock options, Full / Part-time employment: Exelixis Inc. E. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Exelixis Inc. A. Cheng: Advisory / Consultancy: Bayer Schering Pharma; Honoraria (self): Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Honoraria (self): Merck Sharp Dohme; Honoraria (self): Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: IQVIA; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Nucleix Ltd; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Yakuhin, Ltd; Speaker Bureau / Expert testimony: Amgen Taiwan. A.B. El-Khoueiry: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: EMD Serono; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self): Novartis; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Research grant / Funding (self): Astex Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: CytomX Therapeutics. G.K. Abou-Alfa: Advisory / Consultancy: 3DMedcare; Advisory / Consultancy, Research grant / Funding (institution): Agios; Advisory / Consultancy: Alignmed; Advisory / Consultancy: Amgen; Advisory / Consultancy: Antengene; Advisory / Consultancy: Aptus; Advisory / Consultancy: Aslan; Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Beigene; Advisory / Consultancy: Bioline; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Boston Scientific; Advisory / Consultancy: Bridgebio; Advisory / Consultancy: Carsgen; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): Casi; Advisory / Consultancy: Cipla; Advisory / Consultancy: CytomX; Advisory / Consultancy: Daiichi; Advisory / Consultancy: Debio; Advisory / Consultancy: Delcath; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Genoscience; Advisory / Consultancy, Research grant / Funding (institution): Halozyme; Research grant / Funding (institution): Hengrui; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy: Inovio; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Jazz; Advisory / Consultancy: Jansen; Advisory / Consultancy: Kyowa Kirin; Advisory / Consultancy: LAM; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Loxo; Advisory / Consultancy: Merck; Advisory / Consultancy: Mina; Advisory / Consultancy: Novello; Research grant / Funding (institution): Mabvax; Research grant / Funding (institution): Novartis; Advisory / Consultancy: Onxeo; Research grant / Funding (institution): OncoQuest; Advisory / Consultancy: PCI Biotech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pieris; Research grant / Funding (institution): Polaris Puma; Advisory / Consultancy, Research grant / Funding (institution): QED; Research grant / Funding (institution): Roche; Advisory / Consultancy: Redhill; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Silenseed; Advisory / Consultancy: Sillajen; Advisory / Consultancy: Sobi; Advisory / Consultancy: Targovax; Advisory / Consultancy: Tekmira; Advisory / Consultancy: Twoxar; Advisory / Consultancy: Vicus; Advisory / Consultancy: Yakult; Advisory / Consultancy: Yiviva. All other authors have declared no conflicts of interest.