Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 and patients with other activating RAS mutations do not benefit from anti–epidermal growth factor receptor (EGFR) therapy and may in fact be harmed by it. In an analysis reported in The New England Journal of Medicine by Jean-Yves Douillard, MD, PhD, of Institut de Cancérologie de l’Ouest René Gauducheau, Nantes, France, and colleagues, it was found that the addition of panitumumab (Vectibix) to FOLFOX4 (oxaliplatin, fluorouracil, and leucovorin) in the PRIME trial was associated with improved progression-free and overall survival among patients with metastatic colorectal cancer who had no RAS mutations, and worse progression-free survival and overall survival in patients with any RAS mutations.1
The PRIME trial compared panitumumab/FOLFOX4 vs FOLFOX4 as first-line therapy in patients with metastatic colorectal cancer according to KRAS exon 2 status. At the time of the primary analysis (when 54% of patients had died), panitumumab/FOLFOX4 was associated with a significant improvement in median progression-free survival (9.6 vs 8.0 months, P = .02) and a nonsignificant improvement in median overall survival (23.9 vs 19.7 months, P = .07) among patients without KRAS mutations in exon 2. In an exploratory updated analysis (when 82% of patients had died), panitumu-
mab/FOLFOX4 was associated with a significant improvement in overall survival (23.8 vs 19.4 months, P = .03) among these patients.
In a prospectively planned retrospective analysis, the effects of panitumumab/FOLFOX4 vs FOLFOX4 were assessed among patients according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%.
Effect of RAS Mutation
A total of 512 patients had no RAS mutations. Among these patients, median progression-free survival was 10.1 months with panitumumab/FOLFOX4 (n = 259) vs 7.9 months with FOLFOX4 alone (n = 253; hazard ratio [HR] = 0.72, P = .004). Median overall survival was 26.0 vs 20.2 months (HR = 0.78, P = .04) at the time of primary analysis and 25.8 vs 20.2 months (HR = 0.77, P = .009) at the time of updated analysis among these patients.
Among 548 patients with any RAS mutations, panitumumab/FOLFOX4 (n = 272) was associated with significantly shorter progression-free survival (7.3 vs 8.7 months, HR = 1.31, P = .008) and overall survival at the time of primary analysis (15.6 vs 19.2 months, HR = 1.25, P = .03) and updated analysis (15.5 vs 18.7 months, HR = 1.21, P = .04) compared with FOLFOX4 alone (n = 276).
Among 108 patients with nonmutated KRAS exon 2 but other RAS mutations, there were no significant differences between panitumumab/FOLFOX4 patients (n = 51) and FOLFOX4 patients (n = 57) in progression-free survival (7.3 vs 8.0 months, HR = 1.28, P = .33), overall survival at the time of the primary analysis (17.1 vs 18.3 months, HR = 1.29, P = .31), or overall survival at the time of updated analysis (17.1 vs 17.8 months, HR = 1.39, P = .12).
Among 221 panitumumab/FOLFOX4 patients and 219 FOLFOX4 patients with KRAS mutations in exon 2, progression-free survival was 7.3 vs 8.8 months (HR = 1.29, P = .02), overall survival at primary analysis was 15.5 vs 19.3 months (HR = 1.24, P = .07), and overall survival at updated analysis was 15.5 vs 19.2 months (HR = 1.16, P = .16).
Effect of BRAF Mutation
BRAF mutation was an overall negative prognostic factor. Among 228 patients in the panitumumab/FOLFOX4 group and 218 in the FOLFOX4 group with no RAS or BRAF mutations, progression-free survival was 10.8 vs 9.2 months (HR = 0.68, P = .002) and overall survival was 28.3 vs 20.9 months (HR = 0.74, P = .02). However, there was no difference between groups in progression-free survival (6.1 vs 5.4 months, HR = 0.58, P = .12) or overall survival (10.5 vs 9.2 months, HR = 0.90, P = .76) among 24 panitumumab/FOLFOX4 patients and 29 FOLFOX4 patients with BRAF mutation but no RAS mutation.
Among 296 panitumumab/FOLFOX4 patients and 305 FOLFOX4 patients with BRAF or RAS mutations, progression-free survival was 7.3 vs 8.0 months (HR = 1.24, P = .03) and overall survival was 15.3 vs 18.0 months (HR = 1.21, P = .06). Among 75 panitumumab/FOLFOX4 patients and 86 FOLFOX4 patients with no KRAS mutation in exon 2 but other RAS or BRAF mutations, progression-free survival was 6.7 vs 7.3 months (HR = 1.05, P = .80) and overall survival was 14.5 vs 15.8 months (HR = 1.14, P = .51).
Adverse event rates in the two treatment groups according to presence or absence of RAS mutations were similar to those reported in the two treatment groups overall. Among panitumumab/FOLFOX4 patients and FOLFOX4 patients with no RAS mutations, rates of adverse events with a worst grade of 3, 4, and 5 were 57%, 28%, and 5% vs 50%, 20%, and 6%. Moreover, serious adverse events occurred in 43% of the panitumumab/FOLFOX4 group vs 37% of the FOLFOX4 alone group, and adverse events led to discontinuation of study treatment in 25% vs 16%.
Among panitumumab/FOLFOX4 patients and FOLFOX4 patients with any RAS mutations, rates of adverse events with a worst grade of 3, 4, and 5 were 57%, 24%, and 7% vs 53%, 20%, and 4%. Serious adverse events occurred in 45% vs 31% of the two groups, respectively, and adverse events led to discontinuation of study treatment in 22% vs 13%. No new safety signals were identified.
The investigators concluded:
…RAS mutations, in addition to KRAS exon 2 mutations, predict a lack of response to anti-EGFR therapy in patients with metastatic [colorectal cancer]. Panitumumab plus oxaliplatin-containing regimens have no value in patients with metastatic [colorectal cancer] and mutated RAS. The benefit-risk profile of panitumumab/FOLFOX4 was improved by excluding patients with mutated RAS metastatic [colorectal cancer] tumors. Pooled trials or metaanalyses of anti-EGFR therapy are needed to confirm these findings. ■
Disclosure: The study was funded by Amgen and others. For full disclosures of the study authors, visit www.nejm.org.
1. Douillard J-Y, Oliner KS, Siena S, et al: Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369:1023-1034, 2013.