Presence of RAS Mutations in Metastatic Colorectal Cancer Predictive of Negative Response to Panitumumab/FOLFOX4 Treatment
Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-EGFR therapy. However, other activating RAS mutations may predict poorer outcome with anti-EGFR therapy. 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, and colleagues, the addition of panitumumab (Vectibix) to FOLFOX4 (oxaliplatin, fluorouracil [5-FU], and leucovorin) in the PRIME trial was associated with improved progression-free survival and overall survival in patients with metastatic colorectal cancer without RAS mutations.
Study Details
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), panitumumab/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/FOFOX4 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
Among 512 patients without RAS mutations, 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.
A total of 108 patients with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival (7.3 vs 8.0 months, HR = 1.28, P = .33) and overall survival at the time of the primary analysis (17.1 vs 18.3 months, HR = 1.29, P =.31) and at the time of updated analysis (17.1 vs 17.8 months, HR = 1.39, P = .12) among 51 panitumumab/FOLFOX4 patients vs 57 FOLFOX4 patients. These results were consistent with those among patients with KRAS mutations in exon 2. Among all 548 patients with RAS mutations, progression-free survival was 7.3 vs 8.7 months (HR = 1.31, P = .008) and overall survival was 15.6 vs 19.2 months (HR = 1.25, P = .03) at the time of primary analysis and 15.5 vs 18.7 months (HR = 1.21, P = .04) at the time of updated analysis for 272 panitumumab/FOLFOX4 patients vs 276 FOLFOX4 patients.
Effect of BRAF Mutation
BRAF mutation was a 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), whereas 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 vs 29 FOLFOX4 patients with BRAF mutation but no RAS mutation.
No new safety signals were identified when treatment groups were considered according to presence or absence of RAS and BRAF mutations.
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 meta-analyses of anti-EGFR therapy are needed to confirm these findings.”
The study was funded by Amgen and others.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
