RAS Mutations Predict a Lack of Response in Patients with Metastatic Colorectal Cancer who Receive Panitumumab–FOLFOX4

Improvement in overall survival observed in patients without RAS mutations

Patients with metastatic colorectal cancer (mCRC) and 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 a prospectively planned retrospective biomarker analysis from the PRIME study, reported in The New England Journal of Medicine on 12 September 2013 by Dr Jean-Yves Douillard of Institut René Gauducheau, who is currently a Chair of the ESMO Educational Committee, and colleagues, the addition of panitumumab to FOLFOX4 regimen was associated with improved progression-free survival (PFS) and overall survival (OS) in patients without RAS mutations. RAS mutations predicted a lack of response to panitumumab/FOLFOX4.

The PRIME trial compared panitumumab/FOLFOX4 vs FOLFOX4 as first-line therapy in patients with mCRC according to KRAS exon 2 status. At the time of the primary analysis, panitumumab/FOLFOX4 was associated with a significant improvement in median PFS (9.6 vs. 8.0 months, p = 0.02) and statistically non-significant improvement in median OS (23.9 vs. 19.7 months, p = 0.07) 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 OS (23.8 vs. 19.4 months, p = 0.03) 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 additional biomarker: 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%.

Expended RAS mutation analysis

Among 512 patients without RAS mutations, median PFS was 10.1 months with panitumumab/FOLFOX4 (n = 259) vs. 7.9 months with FOLFOX4 alone (n = 253) (p = 0.004). Median OS was 26.0 vs. 20.2 months (p = 0.04) at the time of primary analysis and 25.8 vs. 20.2 months (p = 0.009) at the time of updated analysis among these patients.

A total of 108 patients with non-mutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior PFS (7.3 vs. 8.0 months, p = 0.33) and OS at the time of the primary analysis (17.1 vs. 18.3 months, p = 0.31) and at the time of updated analysis (17.1 vs. 17.8 months, p = 0.12) 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, PFS was 7.3 vs. 8.7 months (p = 0.008) and OS was 15.6 vs. 19.2 months (p = 0.03) at the time of primary analysis and 15.5 vs. 18.7 months (p = 0.04) at the time of updated analysis for 272 panitumumab/FOLFOX4 patients vs. 276 FOLFOX4 patients.

BRAF mutation analysis

Among 228 patients in the panitumumab/FOLFOX4 group and 218 in the FOLFOX4 group with no RAS or BRAF mutations, PFS was 10.8 vs. 9.2 months (p = 0.002) and OS was 28.3 vs. 20.9 months (p = 0.02), whereas there was no difference between groups in PFS (6.1 vs. 5.4 months) or OS (10.5 vs.9.2 months) 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 that RAS mutations, in addition to KRAS exon 2 mutations, predict a lack of response to anti-EGFR therapy in patients with mCRC. Panitumumab plus oxaliplatin-containing regimens have no value in patients with mCRC and mutated RAS. In patients with mCRC without RAS mutations, improvements in overall survival were observed with panitumumab–FOLFOX4 therapy. Pooled trials or meta-analyses of anti-EGFR therapy are needed to confirm the findings.

The study was funded by Amgen and supported by grants from the Royal Marsden Hospital and the Institute of Cancer Research, National Institute for Health Research, Biomedical Research Centre (to Dr. Cunningham), and Oncologia Ca' Granda Onlus Fondazione (to Dr. Siena).

Drs. Douillard and Oliner contributed equally to the article.

PRIME ClinicalTrials.gov number, NCT00364013.