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ONCAlert | Upfront Therapy for mRCC

RAS Testing Before Panitumumab Use in mCRC Confirmed by Second-Line Data

Published Online: 4:33 PM, Wed January 15, 2014
Marc Peeters, MD, PhD

Marc Peeters, MD, PhD

RAS mutations beyond KRAS exon 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 comprehensive RAS testing in determining the appropriate patient population for panitumumab.

“These results confirm that it is RAS status that matters, not just KRAS, 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.

“Expanded RAS testing 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)-KRAS mCRC (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 with KRAS mutations.

The prospective-retrospective 20050181 mutational analysis presented at the GI Symposium examined the impact of additional RAS mutations (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-RAS data showed improvement in PFS and OS outcomes with panitumumab as compared with the WT-KRAS data from the primary analysis. In patients with WT RAS, 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 with RAS mutations.

Further, the analysis found that 18% of WT-KRAS exon 2 patients had other RAS mutations. Without additional RAS testing, patients such as these are likely to receive panitumumab, which will not help them. “For patients with a RAS mutation, these findings will spare them the costs and side effects of a treatment that will not improve their outcomes,” Peeters said.

The second-line RAS analysis 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-KRAS exon 2 tumors (Douillard et al. J Clin Oncol. 2010;28[31]:4697–4705). However, in patients with mutant KRAS, PFS and OS were worse in the panitumumab arm versus chemotherapy alone.

A recently published prospective-retrospective analysis of the PRIME study found that additional RAS mutations (KRAS exon 3 or 4; NRAS exon 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-RAS tumors (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-KRAS exon 2 who had other RAS mutations (n = 108), PFS and OS were inferior with panitumumab versus chemotherapy alone.

Peeters M, Oliner KS, Price TJ, et al. Analysis of KRAS/NRAS mutations in phase 3 study 20050181 of panitumumab (pmab) plus FOLFIRI versus FOLFIRI for second-line treatment (tx) of metastatic colorectal cancer (mCRC). Presented at: 2014 GI Cancers Symposium; January 16-18, 2013; San Francisco, CA. LBA387.

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