Introduction: Köhne et al. (Ann Oncol 2002;13:308–17) have previously reported that mCRC can be divided into three prognostic risk groups (high, medium and low risk) on the basis of four baseline clinical parameters: Eastern Cooperative Oncology Group (ECOG) performance status, white blood cell count, alkaline phosphatase, and number of metastatic sites. BRAF mutation is an additional negative prognostic marker in mCRC. In the first-line mCRC study, PRIME, panitumumab + FOLFOX4 significantly improved overall survival (OS) vs. FOLFOX4 alone in the overall RAS WT population. We retrospectively analysed survival outcomes in patients from the PRIME study categorised according to Köhne and BRAF prognostic risk.
Methods: PRIME, a randomised phase 3 open-label study of first-line panitumumab + FOLFOX4 vs FOLFOX4 (NCT00364013), enrolled adults with untreated mCRC and an ECOG performance status of 0–2. This post-hoc analysis, conducted when 80% of enrolled patients had died, includes patients with RAS WT tumours for whom a Köhne prognostic category could be established (n = 495). Progression-free survival (PFS) and OS were retrospectively analysed for RAS WT and RAS WT/BRAF WT populations in each Köhne category by the Kaplan–Meier method and presented as median (95% confidence interval [CI]) values. PFS and OS were also analysed in patients with BRAF mutant tumours. Hazard ratios (HRs) for PFS and OS in the panitumumab + FOLFOX4 arm vs. the FOLFOX4 alone arm were calculated using a Cox proportional hazards model.
Results: The overall RAS WT analysis included 97, 297 and 101 patients categorised as high, medium and low risk, respectively. Metastatic disease was confined to the liver in 85% of low-risk patients and ≤1% of medium and high-risk patients. At the time of analysis, the percentages of patients in each category who had died were 94%, 81% and 75%, respectively. In the RAS WT population, the OS HR favoured panitumumab + FOLFOX4 vs. FOLFOX4 alone overall (HR = 0.76 [95% CI: 0.63-0.93]) and in the high- (HR = 0.91 [95% CI: 0.60-1.39]), medium- (HR = 0.70 [95% CI: 0.55, 0.91]) and low-risk (HR = 0.76 [95% CI: 0.48-1.21]) groups. The OS difference was similar in the RAS WT/BRAF WT population (overall: HR = 0.78 [95% CI: 0.64-0.95]); data by risk group and BRAF status are shown in the table.
Conclusion: Köhne prognostic score allows accurate risk classification in RAS WT and RAS WT/BRAF WT mCRC, particularly with regard to OS. BRAF mutations are also a strong negative predictor of outcome, and such patients should be classified as high risk regardless of other clinical parameters. The HRs in this retrospective and exploratory analysis suggest that addition of panitumumab to FOLFOX4 may provide OS and PFS benefit in RAS WT and RAS WT/BRAF WT mCRC overall and across all risk categories vs FOLFOX4 alone.
