Updated CRYSTAL Data Support Effectiveness of Cetuximab (Erbitux) in Wild-Type KRAS Metastatic Colorectal Cancer

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At the 2010 Gastrointestinal Cancers Symposium, new data from the CRYSTAL (Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial identified gene mutations as a poor prognostic indicator in metastatic colorectal cancer (mCRC) but not predictive of response to therapy. The phase III CRYSTAL study included an intent-to-treat population of 1198 patients with epidermal growth factor receptor-expressing mCRC and has produced several notable, practice-changing findings.

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In this updated analysis of CRYSTAL data, presented by Eric Van Cutsem, MD, of University Hospital Gasthuisberg in Leuven, Belgium, researchers found that patients with wild-type tumors who had a mutation demonstrated worse survival outcomes compared with a similar subset of patients without a mutation. is a serine/ threonine kinase localized downstream of the pathway.

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Van Cutsem reported that investigators had now ascertained status for 1063 patients in the study and determined that 56% (n = 666) had wild-type . Of these 666 patients, status was evaluated for 625, with results showing that 566 had wild-type and 59 had mutant .

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Patients in the study were randomized to treatment with cetuximab (Erbitux) plus FOLFIRI or FOLFIRI alone. Looking at just those patients with wild-type , objective response rate (ORR) was nearly double for those in the combination arm, at 57.3% compared with 39.7% for those in the FOLFIRI-alone group. Patients in the combination arm also had longer progression-free survival (PFS), at 9.9 months compared with 8.4 months for the FOLFIRI-alone group. Overall survival (OS), another study endpoint, reached 23.5 months for those receiving cetuximab compared with 20 months for those treated only with FOLFIRI. This represented a 30.4% reduction in the risk of disease progression for patients receiving cetuximab. Response and survival outcomes were notably worse in both groups of patients with mutant , and more so for those in the combination arm (Table 1).

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Van Cutsem said that in patients with wild-type and wild-type tumors, findings were consistent with the wild-type KRAS group overall (Table 2). ORR was 61.0% in the combination arm compared with 42.6% in the FOLFIRI-only arm. OS for patients assigned to combination therapy was 25.1 months compared with 21.6 months for the FOLFIRI-only group. PFS for these patients was 10.9 months with cetuximab plus FOLFIRI compared with 8.8 months without cetuximab.

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In patients with wild-type who had mutations, however, Van Cutsem said there was no statistically significant difference in ORR, OS or PFS between the study arms. ORR was 19% with cetuximab plus FOLFIRI versus 15% with FOLFIRI alone. Median PFS was 8.0 months with the combination compared with 5.6 months with FOLFIRI alone, and median OS was 14.1 months in the combination arm versus 10.3 months for the FOLFIRI-only arm.

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“This analysis suggests mutation is a poor prognostic factor in first-line mCRC,” Van Cutsem said. He added that the population of wild-type/ mutant patients was too small for investigators to draw meaningful conclusions about whether mutations have any relationship to the efficacy of cetuximab. “ mutation status does not appear to be a strong biomarker for the addition of cetuximab to FOLFIRI,” said Van Cutsem, but he recommended the effect of mutations in mCRC be studied further.