Abstract 465P
Background
The CORRECT trial showed an overall survival (OS) benefit for regorafenib in mCRC pts who progressed after standard therapies. No predictive biomarker exists for regorafenib and treatment is often burdened by severe toxicity. We investigated the prognostic and predictive value of genetic variants selected based on previous associations with antiangiogenic treatment.
Methods
Genomic DNA from 507 pts (337 regorafenib, 170 placebo) was genotyped using a customized OncoArray (Illumina). 149 candidate SNPs representing 78 genes and 15 pathways were identified. Stratified multivariable Cox proportional hazards regression was used to jointly assess the predictive and prognostic effects, using a 2-df likelihood ratio test of the SNP effect and SNP*treatment interaction. SNPs were coded additively. False discovery rate (FDR) was controlled at Q = 0.1.
Results
A functional SNP, rs1056560, in the CRY1 gene in the clock pathway was significantly associated with OS (P < .001, Q = .06). Both prognostic and predictive effects (marginal SNP effect and SNP*treatment interaction) achieved nominal significance (P = .04 and P < .001, respectively). Significant OS benefit was found for pts with rs1056560 C allele variant treated with regorafenib: 6.5 vs 3.3 months with placebo for CC genotype carriers (N = 93, HR 0.48, 95%CI 0.30-0.78, P = .003) and 6.9 vs 5.4 months for CA genotype (N = 221, HR 0.62, 95%CI 0.45-0.85, P = .003). No treatment benefit was observed for the AA genotype (N = 174). No SNP achieved FDR significance for progression free survival, however, CRY1 rs1056560 was nominally significant for the 2-df test (P = .01) and the predictive effect (P = .007).
Conclusions
For the first time we identify a potential predictive biomarker for regorafenib in the CORRECT population. CRY1 is a negative regulator of the clock machinery, which modulates the circadian expression of key target genes, including VEGF. Growing interest is focusing on alterations of this pathway in cancer. Our finding helps better understand regorafenib response and may support alternative treatment choices based on CRY1 rs1056560 genotypes to optimize regorafenib benefit.
Clinical trial identification
NCT01103323.
Editorial acknowledgement
Legal entity responsible for the study
Bayer.
Funding
Bayer.
Disclosure
F. Battaglin: Travel/Accommodation/Expenses: Caris Life Sciences. A. Skubala: Full/Part-time employment: Chrestos Concept GmbH & Co. KG; Full/Part-time employment: Bayer. Y.A. Wang, K. Köchert, A. Schulz: Full/Part-time employment: Bayer. M. Teufel: Full/Part-time employment: Bayer; Full/Part-time employment: Boehringer Ingelheim. H.J. Lenz: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Serono; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: GlaxoSmithKline; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Isofol Medica. All other authors have declared no conflicts of interest.