Z Gastroenterol 2013; 51 - K62
DOI: 10.1055/s-0033-1352702

Mutational analysis of biomarker samples from the CORRECT study: Correlating mutation status with clinical response to regorafenib

A Stein 1, M Jeffers 2, E van Cutsem 3, AF Sobrero 4, S Siena 5, A Falcone 6, M Ychou 7, Y Humblet 8, O Bouche 9, L Mineur 10, C Barone 11, A Adenis 12, J Tabernero 13, T Yoshino 14, HJ Lenz 15, RM Goldberg 16, D Laurent 17, A Wagner 17, A Grothey 18
  • 1Hubertus Wald Tumorzentrum, II. Medizinische Klinik und Poliklinik, Hamburg, Germany
  • 2Bayer Healthcare Pharmaceuticals, Montville, United States
  • 3Leuven Cancer Institute, Leuven, Belgium
  • 4Ospedale San Martino, Genova, Italy
  • 5Ospedale Niguarda Ca' Granda, Milano, Italy
  • 6Universita di Pisa, Pisa, Italy
  • 7CRLC Val d'Aurelle, Montpellier, France
  • 8Saint-Luc University Hospital, Brussels, Belgium
  • 9University Hospital Robert Debre, Reims, France
  • 10Institut Sainte-Catherine, Avignon, France
  • 11Catholic University of Sacred Heart, Roma, Italy
  • 12Centre Oscar Lambret, Lille, France
  • 13Vall d'Hebron Institute of Oncology, Barcelona, Spain
  • 14National Cancer Center Hospital East, Kashiwa, Japan
  • 15USC Norris Comprehensive Cancer Center, Los Angeles, United States
  • 16Ohio State University, Columbus, United States
  • 17Bayer Healthcare Pharmaceuticals, Berlin, Germany
  • 18Mayo Clinic, Rochester, United States

Aims: In the CORRECT Ph3 trial, regorafenib demonstrated significant improvement in OS and PFS vs. placebo in subjects with metastatic colorectal cancer (mCRC) who had progressed on standard therapies. An exploratory biomarker substudy was conducted on samples collected from subjects enrolled in CORRECT.

Methods: DNA was isolated from archival tumor tissue and fresh baseline plasma samples that were available from 239 (31%) and 503 (66%) subjects enrolled in CORRECT, respectively. Mutations in KRAS, PIK3CA and BRAF were evaluated via BEAMing technology.

Results: Mutations were readily detected in DNA isolated from both tumor and plasma samples: KRAS: 59/69%; PIK3CA: 12/17% and BRAF: 1.5/3.4%. The frequency of KRAS mutation detected in tumor samples via BEAMing (59%) was identical to the frequency determined from pre-existing “historical” KRAS mutation data that was available from 96% of the subjects enrolled in the study. Concordance among the mutations detected via BEAMing in tumor vs. plasma was 76% (KRAS), 88% (PIK3CA), and 97% (BRAF). A subset of CRC which was found to be KRAS-wildtype in DNA from archival tumor, but KRAS-mutant in DNA from fresh plasma was identified and may represent subjects whose KRAS mutational status had changed during prior therapy. Correlative subgroup analyses demonstrated that regorafenib mediated a trend for clinical benefit vs. placebo in both KRAS wildtype and mutant subgroups identified by plasma BEAMing (OS: KRAS WT, HR: 0.67, 95% CI: 0.41 – 1.08; KRAS mutant, HR: 0.81, 95% CI: 0.61 – 1.09; interaction p = 0.561). Similar results were noted for PIK3CA WT/mutant subgroups (OS: WT, HR: 0.75, 95% CI: 0.57 – 0.99; mutant, HR: 0.84, 95% CI: 0.47 – 1.50; interaction p = 0.723). BRAF was not analysed due to the small number of BRAF-mutant samples.

Conclusions: The mutational analysis of DNA isolated from fresh plasma is feasible and robust using the BEAMing platform and may better represent the mutational status of the tumor(s) that a mCRC patient harbors at the time of enrollment than does the mutational analysis of archival primary tumor tissue. Regorafenib was associated with clinical benefit (vs. placebo) in all mutational subgroups evaluated.

Clinical trial information: NCT01103323.