PD-0002 - KRAS/NRAS and BRAF mutations in the 20050181 study of panitumumab + FOLFIRI for the 2nd-line treatment of metastatic colorectal cancer: Updated anal...

Date 27 June 2014
Event World GI 2014
Session Poster discussion session 1 – EGFR-targeted agents
Topics Anti-Cancer Agents & Biologic Therapy
Colon Cancer
Rectal Cancer
Presenter Marc Peeters
Citation Annals of Oncology (2014) 25 (suppl_2): ii5-ii13. 10.1093/annonc/mdu164
Authors K. Oliner1, A. Cervantes2, M. Ducreux3, Y. Hotko4, T. André5, E. Chan6, A. Strickland7, G. Wilson8, T. Ciuleanu9, L. Roman10, H. Yu11, A.S. Jung1, S. Patterson1
  • 1Amgen Inc., Thousand Oaks/US
  • 2Biomedical Research Institute Inclica, University of Valencia, Valencia/ES
  • 3Institut Gustave Roussy, Villejuif /FR
  • 4Uzhgorod National University, Uzhgorod/UA
  • 5Hopital Saint-Antoine, Paris/FR
  • 6Vanderbilt University Medical Center, Nashville/US
  • 7Monash Medical Center, East Bentleigh/AU
  • 8The Christie NHS Foundation Trust, Manchester/UK
  • 9Institutul Oncologic Prof. Dr. Ion Chiricuta and UMF Iuliu Hatieganu, Cluj-Napoca/RO
  • 10Leningrad Regional Oncology Dispensary, Saint Petersburg/RU
  • 11Amgen Inc., San Francisco/US

Abstract

Introduction

Previously, extended RAS analysis from the 20050181 study showed a trend towards improved overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) with panitumumab + FOLFIRI vs FOLFIRI alone in the wild-type (WT) RAS population vs the WT KRAS exon 2 population. Here we report updated RAS data and a new analysis by BRAF status.

Methods

The primary objective was to assess the treatment effect of panitumumab + FOLFIRI vs FOLFIRI on OS and PFS based on RAS/BRAF mutation status in the primary analysis population. Bidirectional Sanger sequencing was used to detect mutations in KRAS exons 3 and 4, NRAS exons 2, 3 and 4 and BRAF exon 15 in patients known to have WT KRAS exon 2 mCRC.

Results

Overall RAS/BRAF ascertainment rate was 85% (n = 1014/1186). 18% of WT KRAS exon 2 patient's tumours harboured additional RAS mutations (n = 107/597). The incidence of BRAF mutations was 8.3% (45/541). For patients with WT RAS mCRC, median OS was 16.2 vs 13.9 months for panitumumab + FOLFIRI (n = 208) vs FOLFIRI (n = 213); HR: 0.81 (95% confidence interval [CI]: 0.63-1.03); p = 0.08. Median PFS was 6.4 vs 4.6 months, respectively; HR: 0.70 (95% CI: 0.54-0.91); p = 0.007. No significant OS (HR: 0.91 [95% CI: 0.76-1.10]; p = 0.34) or PFS (HR: 0.86 [95% CI: 0.71-1.05]; p = 0.14) benefits were observed on addition of panitumumab to FOLFIRI in patients with mutant RAS (n = 593 overall). For patients with WT RAS/WT BRAF mCRC, median OS was 18.7 vs 15.4 months for panitumumab + FOLFIRI (n = 186) vs FOLFIRI (n = 190); HR: 0.83 (95% CI: 0.64-1.07); p = 0.15. Median PFS was 6.9 vs 5.5 months, respectively; HR: 0.68 (95% CI: 0.51-0.90); p = 0.006). Patients with WT RAS/mutant BRAF mCRC had reduced OS and PFS irrespective of treatment: panitumumab + FOLFIRI (n = 22) vs FOLFIRI (n = 23) median OS 4.7 vs 5.7 months, respectively; HR: 0.64 (95% CI: 0.32-1.28); p = 0.20. Median PFS 2.5 vs 1.8 months, respectively; HR: 0.69 (95% CI: 0.32-1.49); p = 0.34).

Conclusion

Improvements continued to be observed in the treatment effect of panitumumab + FOLFIRI vs FOLFIRI on OS and PFS in the WT RAS population vs WT KRAS exon 2 population in this update. Patients with mutant RAS mCRC are unlikely to benefit by the addition of panitumumab to FOLFIRI, similar to patients with mutant KRAS exon 2 mCRC. BRAF mutations appear to be associated with reduced OS among patients without RAS mutations, regardless of treatment arm. These findings support RAS testing to determine potentially appropriate mCRC patients for panitumumab treatment.