Cetuximab with FOLFOX6, FOLFIRI demonstrated high response rates in advanced colorectal cancer

In patients with inoperable colorectal liver metastases, adding cetuximab to neoadjuvant chemotherapy with FOLFOX6 or FOLFIRI shrunk tumors and led to increased resectability or surgery.

From December 2004 to March 2008, researchers randomly assigned patients from 17 centers in Germany and Austria to cetuximab (Erbitux, Imclone) plus FOLFOX6 (group A; n=56) or to cetuximab plus FOLFIRI (group B; n=55).

Two patients assigned to the first group did not receive treatment, one patient from each group did not receive the first full dose, and one patient in the second treatment group had pulmonary embolism.

Data from this phase-2 trial were originally presented at the 2009 ASCO Gastrointestinal Symposium in January.

Sixty-two percent of patients showed objective tumor response (95% CI, 52-72). The difference between treatment groups did not reach statistical significance, with a difference of 11% (P=.023). Patients with KRAS wild-type tumors had higher tumor response (70%; 95% CI, 58-81) than patients with KRAS tumor mutations (41%; 95% CI, 22-61).

Additionally, tumor response was observed in 72% of patients whose tumors were wild-type for both KRAS and BRAF genes (95% CI, 59-82) vs. 40% of those whose tumors harbored a mutation in either gene (95% CI, 23-59). This difference reached statistical significance (P=.0030).

Overall, 34% (95% CI, 25-44) of patients had R0 resections; 46% had R0 or R1 resection and/or radiofrequency ablation. In review, 60% of tumors were judged as resectable after chemotherapy vs. 32% at baseline (P<.0001).

Seventy-two percent of patients had grade-3 or higher toxicity; the most common toxicities were skin toxicity and neutropenia.

Folprecht G. Lancet Oncol. 2009;doi:10.1016/S1470-2045(09)70330-4.

These findings suggest that adding cetuximab to either chemotherapy regimen may have increased the resectability rate for patients. The trial design did not include chemotherapy alone arms, so the added value of cetuximab is undetermined. Treatment with cetuximab in these patients appears to add some effective therapy that may make patients resectable. One interesting finding is that these patients were deemed unresectable at the outset as part of eligibility criteria. Yet, in a blinded independent retrospective review, about 30% of the patients were felt to be resectable. So, on one hand, the treatment effect of this study brings us the hope that in KRAS wild-type patients, cetuximab plus chemotherapy may make more patients resectable. But, it also raises the question that deeming who is resectable at the outset is in the eye of the beholder. So, this study emphasizes the need for more and more multidisciplinary therapy and the idea that one surgeon's unresectable is another surgeon's resectable. And these findings fit with other data sets that exist.

– Alan P. Venook, MD
HemOnc Today Editorial Board member