<em>RAS</em> Status Matters in mCRC: Confirmed by Second-Line Data

February 25, 2014
Jason M. Broderick

Special Reports, Gastrointestinal Cancers (Issue 1), Volume 1, Issue 1

RAS mutations beyond KRAS exon 2 are negative predictive biomarkers for panitumumab in mCRC, according to an analysis of phase III, second-line data, which are consistent with previously reported data in first-line mCRC.

Marc Peeters, MD, PhD

RASmutations beyondKRASexon 2 are negative predictive biomarkers for the EGFR-inhibitor panitumumab (Vectibix) in metastatic colorectal cancer (mCRC), according to an analysis of phase III, second-line data, which are consistent with previously reported data in first-line mCRC. The combined results support the use of more comprehensiveRAStesting in determining the appropriate patient population for panitumumab.

“These results confirm that it isRASstatus that matters, not justKRAS, when determining if panitumumab could be beneficial,” lead author Marc Peeters, MD, PhD, said in a statement. Peeters, a professor of oncology at Antwerp University Hospital in Edegem, Belgium, presented the research at a presscast held ahead of the 2014 Gastrointestinal (GI) Cancers Symposium.

“ExpandedRAStesting should become the standard of care in order to best identify who will benefit from anti-EGFR therapy,” added presscast moderator Smitha Krishnamurthi, MD, medical oncologist and associate professor of Medicine at University Hospitals Case Medical Center and Case Western Reserve University.

In the primary analysis of the phase III 20050181 study (J Clin Oncol. 2010;28[31]:4706—4713), second-line panitumumab plus FOLFIRI was shown to significantly improve progression-free survival (PFS) versus FOLFIRI alone in patients with wild-type (WT)-KRASmCRC (5.9 months vs 3.9 months; hazard ratio [HR] = 0.73;P= .004), and also led to a non-statistically significant improvement in overall survival (OS; 14.5 months vs 12.5 months; HR = 0.85;P= .12). There was no benefit with panitumumab in patients withKRASmutations.

The prospective-retrospective 20050181 mutational analysis presented at the GI Symposium examined the impact of additionalRASmutations (KRAS and NRAS, exons 2, 3, and 4) on the efficacy of panitumumab. The researchers were able to determine the RAS status of 85% of the primary study population (1008/1186).

The WT-RASdata showed improvement in PFS and OS outcomes with panitumumab as compared with the WT-KRASdata from the primary analysis. In patients with WTRAS, PFS was 6.4 months in the panitumumab arm versus 4.4 months with chemotherapy alone (HR = 0.695;P= .006). OS was 16.2 months with panitumumab versus 13.9 months with chemotherapy alone. Adding panitumumab to chemotherapy did not result in a significant PFS or OS benefit in patients withRASmutations.

Further, the analysis found that 18% of WT-KRASexon 2 patients had otherRASmutations. Without additionalRAStesting, patients such as these are likely to receive panitumumab, which will not help them. “For patients with aRASmutation, these findings will spare them the costs and side effects of a treatment that will not improve their outcomes,” Peeters said.

The second-lineRASanalysis presented at the GI Symposium presscast corroborated similar research in the first-line mCRC setting from the phase III PRIME trial. In the primary study, combination treatment with panitumumab and FOLFOX4 chemotherapy significantly improved PFS (hazard ratio [HR] = 0.80;P= .02), with a trend toward improved OS, versus FOLFOX4 alone in patients with WT-KRASexon 2 tumors (Douillard et al.J Clin Oncol. 2010;28[31]:4697—4705). However, in patients with mutantKRAS, PFS and OS were worse in the panitumumab arm versus chemotherapy alone.

A recently published prospective-retrospective analysis of the PRIME study found that additionalRASmutations (KRASexon 3 or 4;NRASexon 2, 3, or 4) were also biomarkers for negative outcomes with panitumumab in mCRC (N Engl J Med. 2013; 369:1023—1034). In patients with WT-RAStumors (n = 512), PFS improved by 2.2 months (HR = 0.72;P= .004) and OS improved by 5.8 months (HR = 0.78;P= .04) with first-line panitumumab/FOLFOX4 versus FOLFOX4 alone. In patients with WT-KRASexon 2 who had otherRASmutations (n = 108), PFS and OS were inferior with panitumumab versus chemotherapy alone.

Peeters M, Oliner KS, Price TJ, et al. Analysis ofKRAS/NRAS