Marc Peeters, MD, PhD
An analysis of phase III, second-line data found that RAS mutations beyond KRAS exon 2 are negative predictive biomarkers for the EGFR-inhibitor panitumumab (Vectibix) in metastatic colorectal cancer (mCRC). These findings are consistent with previously reported data in first-line mCRC. Combined, the results support the use of more comprehensive RAS testing in determining the appropriate patient population for panitumumab. Abstract LBA387
“These results confirm that it is RAS status that matters, not just KRAS, when determining if panitumumab could be beneficial,” said lead author Marc Peeters, MD, PhD, a professor of Oncology at Antwerp University Hospital in Edegem, Belgium, in presenting the research as part of the 2014 Gastrointestinal (GI) Cancers Symposium held January 16-18, 2014, in San Francisco.
In the primary analysis of the phase III 20050181 study (J Clin Oncol. 2010;28:4706– 4713), second-line panitumumab plus FOLFIRI was shown to significantly improve progressionfree 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). However, 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 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 WTKRAS exon 2 patients had other RAS mutations. Without additional RAS testing, patients such as these will likely receive panitumumab, which would be ineffective. “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 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;28:4697–4705). 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.
As many oncology nurses may remember, initially we looked at epidermal growth factor receptor (EGFR) overexpression in order to determine whether a patient with metastatic colorectal cancer (mCRC) might benefit from the EGFR-targeted therapies (initially only cetuximab was available; later panitumumab became available). The prevailing thought at that time was that the more EGFR was overexpressed, the better the response to EGFR-targeted therapy would be. Unfortunately, this did not turn out to be the case.
Subsequent research revealed that it was not EGFR overexpression, but KRAS status which was important. Specifically, those patients who had a mutated KRAS would not respond to EGFR-targeted therapy and, in fact, could potentially have accelerated progression of their cancer. As approximately only 50% of colorectal tumors are not mutated, that is KRAS wild-type, this limits the therapy for KRAS-mutant patients, but was cause for much hope and excitement in the KRAS wild-type patients. And, we were not disappointed in about half of these patients. As predicted, their cancer responded extremely well to the EGFR therapy with diminution of their cancer and many were rendered NED (no evidence of disease). But, there was still a population of wild-type KRAS patients who did not respond to EGFR therapy and this was both puzzling and disappointing, both to the patients and to those of us who care for them.
This newly published prospective-retrospective analysis of the PRIME study has identified additional RAS mutations which are biomarkers for negative outcomes with panitumumab in mCRC. So what does this mean now? Rather than just KRAS testing, physicians will need to order RAS testing in order to identify if any of these particular mutations exist. Those patients would then not be candidates for EGFR therapy. This helps us understand why some patients did not respond to EGFR therapy, despite being KRAS wild-type. It is also helpful as there is no benefit to giving a patient a treatment which will not be effective. However, as there is no alternative therapy available at this time it is somewhat disheartening. We can hope that some of the therapies being looked at in clinical trials might turn out to be effective for these patients, and as oncology nurses we should strongly encourage our appropriate patients to enroll.