Phase III trial of FOLFIRI or mFOLFOX6 with bevacizumab or cetuximab for patients with expanded RAS analyses in untreated metastatic adenocarcinoma of the colon or rectum

During ESMO 2014, results of the expanded RAS analysis in the CALGB/SWOG 80405 study were presented. Earlier this year, the study researchers presented the findings with the conclusion that FOLFIRI/cetuximab and mFOLFOX6/bevacizumab are equivalent in terms of overall survival (OS) in patients with previously untreated KRAS wild type (codons 12 and 13) metastatic colorectal cancer and that either regimen is appropriate as first-line treatment. The OS longer than 29 months and 8% of long-term survivors confirmed the progress in this setting. However, the oncology community expected that expanded RAS and other molecular and clinical analyses might identify subsets of patients who would get more or less benefit from specific regimens.

The original CALGB/SWOG 80405 study included unselected patients with metastatic colorectal cancer who received treatment according to physician-selected chemotherapy (FOLFIRI or mFOLFOX6) and who were randomised to cetuximab, bevacizumab or both (the third arm was subsequently closed). After 1,420 patients had been accrued, the study was amended as follows: only patients with wild type KRAS tumours (codon 12 and 13) were included. A total of 3,058 unselected patients was enrolled in the study and 2,334 KRAS wild type patients were randomised. The final number included 1,137 patients (333 pre-amend eligible retrospective KRAS test, and 804 post-amend).1

Expanded RAS was tested in all wild type RAS exon 2 using beaming technology including KRAS exon 3,4 and NRAS exon 2, 3 and 4 with a detection sensitivity of 0.01%. The primary endpoint was OS. In the expanded RAS wild type population, the median OS was pushed beyond 30 months. However, there was no significant difference between cetuximab and bevacizumab in combination with chemotherapy (32 months vs. 31.2 months) (see slides).1 In a separate analysis performed in f KRAS wild type patients undergoing surgery as a part of treatment strategy, which goal was to determine the characteristics and the long-term outcome of patients enrolled in the trial, investigators reported that 132 patients enrolled reached a stage of non-evidence of disease (NED) after chemotherapy and surgery. The median OS in these patients was 67.4 months when they were treated with chemotherapy and bevacizumab (N=50) and 64.1 months when treated with chemotherapy and cetuximab (N=82) (HR[95%CI]: 1.2 [0.6-2.2]; p = 0.55), Surprisingly, this analysis revealed that more patients on cetuximab went to surgery than patients on bevacizumab did. During the session, Dr Venook reported that patients were likelier to reach NED stage on cetuximab.2


1. Lenz H-J, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with expanded ras analyses in untreated metastatic adenocarcinoma of the colon or rectum. Presented at ESMO 2014; Abstract 501O.
2. Venook A, et al. CALGB/SWOG 80405: Analysis of patients undergoing surgery as part of treatment strategy. Presented at ESMO 2014; Abstract LBA10.

Speaker Heinz-Josef Lenz


Prof. Heinz-Josef Lenz, MD, PhD,
Division Of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, USA


See: Keyslides

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