The FOXFIRE randomised studies [FOXFIRE, SIRFLOX and FOXFIRE-Global] were designed to evaluate SIRT using yttrium-90 resin microspheres + first-line chemotherapy for unresectable metastatic colorectal cancer (mCRC). All the studies had similar designs, allowing a prospective, combined overall survival (OS) analysis. KRAS mutations are associated with poor outcomes in mCRC. Here, we report the impact of KRAS mutation status and primary tumour site on OS.
Chemotherapy-naïve mCRC patients with liver metastases not suitable for curative resection/ablation were randomised (1:1) to Control arm (standard oxaliplatin-based chemotherapy ± a biologically targeted agent) or Test arm (chemotherapy ± biological + SIRT). Patients with primary tumours in situ or limited extra-hepatic metastases were included. The primary endpoint was OS.
1103 patients (Control n = 549; Test n = 554) were enrolled; median follow-up 43.3 months (m). There was no difference in OS between the treatment arms (pooled HR 1.04; 95% CI, 0.90‒1.19; p = 0.609) or PFS (HR 0.90; 95% CI, 0.79‒1.02; p = 0.108). 182 (16.5%) patients had a KRAS mutation (MT), 279 (25.3%) had wildtype (WT) status and 642 (58.2%) had unknown (UN) status. There was no evidence that OS differed between treatment arms in patients with an MT (HR 1.03; 95% CI, 0.74–1.43; p = 0.878), WT (HR 1.10; 95% CI, 0.83–1.46; p = 0.499), or UN KRAS status (HR 1.01; 95% CI, 0.85–1.21; p = 0.878). OS in both treatment arms was lower with MT KRAS status than WT or UN status Control v SIRT: MT 19.1m v 18.7m; WT 28.3m v 24.2m; UN 23.1m v 22.6m. OS time in patients with right-side primary tumours was significantly longer in the Test than in the Control arm (22.0m v 17.1m; p = 0.007), but there was no significant OS difference between treatment arms in left-side tumours (24.6 vs. 26.6 m p = 0.279).
KRAS mutation status does not appear to be a predictive factor for survival outcome following SIRT in mCRC. OS was significantly better with the addition of SIRT in right-side primary tumours. These data suggest that primary tumour site and not KRAS status may predict for potential treatment interaction with SIRT.
Clinical trial identification
FOXFIRE has ISRCTN Registry number ISRCTN83867919. SIRFLOX and FOXFIRE-Global are registered with ClinicalTrials.gov with registration numbers NCT00724503 and NCT01721954, respectively.
Legal entity responsible for the study
The University of Oxford, UK, Sirtex Medical Ltd (SIRFLOX and FOXFIRE-Global), Sydney, Australia
Sirtex Medical Ltd (SIRFLOX and FOXFIRE-Global) and The University of Oxford (FOXFIRE)
H. Wasan: Honoraria from Sirtex for consulting/advisory roles and giving presentations. R. Sharma: Research funding, honoraria, and consultancy fees from Sirtex Medical Ltd V. Heinemann: Honoraria from Amgen, Roche, Sanofi and Sirtex Medical Ltd for consulting roles, participation in advisory boards, and his institution has received study grants from Amgen, Merck, Roche, Sanofi and Sirtex Medical Ltd N. Sharma: Honoraria from Sirtex Medical Ltd. J. Ricke: Personal fees and grants from Sirtex Medical Ltd. M. Findlay: Grants from Sirtex Medical Ltd. P.S. Virdee: Grants from Cancer Research UK and grants and non-financial support from Sirtex Medical Ltd. S. Love, P. Dutton: Grants from Cancer Research UK and grants and non-financial support from Sirtex Medical Ltd. J. Moschandreas: Grants from Cancer Research UK and grants from and non-financial support from Sirtex Medical Ltd. V. Gebski: Compensation for participation in Advisory Committees from Sirtex Medical Ltd. A.M. Gray: Grants from Cancer Research UK. P. Gibbs: Honoraria from Sirtex for participation in advisory boards and for giving presentations. G. Van Hazel: Compensation for participation in Advisory Committees from Sirtex Medical. All other authors have declared no conflicts of interest.