New data from a phase III clinical trial shows that patients with metastatic colorectal cancer (mCRC) tumours that contain RAS mutations beyond KRAS exon 2 are unlikely to benefit from the addition of panitumumab to second-line FOLFIRI chemotherapy.

Currently, doctors routinely test mCRC tumours for mutations in the KRAS gene at exon 2, which was previously shown to predict response to panitumumab treatment; however, the results of this study confirm the need to test for additional RAS mutations prior to administering panitumumab.

“By testing for RAS mutations, doctors will be able to better select among metastatic colorectal cancer patients and only recommend panitumumab treatment to those who are most likely to benefit,” said lead study author Marc Peeters, MD, PhD, a professor of oncology at Antwerp University Hospital in Edegem, Belgium.

“These results confirm that it is RAS status that matters, not just KRAS, when determining if panitumumab therapy could be beneficial. 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.”

Panitumumab is a fully human monoclonal antibody that blocks the epidermal growth factor receptor (EGFR), a protein known to promote the growth of colorectal cancer. Previous research has shown that EGFR inhibitors like panitumumab are not effective for colorectal tumours with mutations in the KRAS gene at exon 2, which occur in approximately 40 to 50 percent of mCRC patients.

More recent studies have identified additional genetic biomarkers in the RAS family of genes that predict clinical response to panitumumab, most notably mutations in KRAS and NRAS gene exons (segments of a gene that contain information for producing a protein). Collectively, these mutations are referred to as RAS mutations.

In the present study, tumour samples from patients treated as part of a large, phase III study that were already known to be unmutated at KRAS exon 2 were assessed for other RAS mutations, specifically in KRAS exons 3 and 4 and NRAS exons 2, 3 and 4. The results indicate that 18 percent of these patients harbored one or more RAS mutations and that these mutations predicted clinical response to panitumumab treatment.

Among patients receiving both panitumumab and chemotherapy, both median overall survival (OS) and progression-free survival (PFS) was improved for patients with wild-type (unmutated) RAS tumours compared to those with RAS mutations (median OS: 16.2 months vs. 11.8 months; median PFS: 6.4 months vs. 4.8 months). For patients in the mutated RAS group, the addition of panitumumab to FOLFIRI resulted in no significant survival differences over FOLFIRI alone (median OS: 11.8 months vs. 11.1 months; median PFS: 4.8 months vs. 4.0 months).

These findings support previously reported outcomes of panitumumab treatment based on RAS status in mCRC and provide the first published phase III data in a second-line setting. In addition, the results, combined with those of other trials, support the use of more comprehensive RAS testing to identify specific subgroups of patients for whom panitumumab and other anti-EGFR treatment is appropriate.

Source: ASCO