No gain from adding cetuximab to FOLFOX4 in patients with resected stage III colon cancer

PETACC8 study suggest a benefit in several patient subgroups

Final results of the PETACC8 Intergroup phase III trial showed that adding cetuximab to FOLFOX4 does not improve overall survival in patients with resected stage III colon cancer whose tumours express KRAS-wild type (-wt) and KRAS/BRAF-wt, but a certain benefit is observed in several subgroups of patients. The study results are reported by Dr Julien Taieb on behalf of the PETACC researchers at the Presidential Symposium of the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna.

Patients with colon cancer were randomised between 28 to 56 days following resection to receive either 12 biweekly cycles of FOLFOX4 alone (arm A) or together with weekly cetuximab (arm B) at 250 mg/m2 following the initial dose of 400 mg/m2. The primary endpoint was disease free survival (DFS).

The trial enrolled 2,559 patients from 340 sites in Europe. From those patients 1,602 were with KRAS-wt tumours; arm A had 811 patients and 791 patients were randomly assigned to arm B. BRAF status was determined in 1134 (71%) KRAS-wt patients. Analysis done at a median follow-up of approximately 40 months showed no difference between arms for either disease-free survival (DFS)  (HR 1.047; p = 0.66) or overall survival (OS) (HR 1.09; p = 0.55) in KRAS-wt patients.

No differences were observed in 984 KRAS/BRAF-wt patients in DFS (HR 0.985; p = 0.91) or OS (HR 0.98; p = 0.92). Poorer DFS outcomes were seen with cetuximab in 149 patients older than 70 years (HR 1.97; p = 0.051), in 666 females (HR 1.45; p = 0.03) and in 570 patients with right-sided colon cancer (HR 1.40; p = 0.04).

A trend towards better outcome was seen in patients with poor prognosis, high grade, T4N2 tumours, perforation/obstruction or VELI+ tumours and was significant in 146 patients who were staged as pT4N2 at diagnosis, HR 0.55; p = 0.01.

The authors concluded that adding cetuximab to FOLFOX4 did not improve disease-free survival in patients with colon cancer and therefore the primary endpoint was not met, but benefit was seen in patients with pT4N2 tumours. Patients who were elderly, female or had right-sided tumours had poorer outcomes with cetuximab and MSI analysis is ongoing to explore the interaction with poor outcome in these subgroups. There was almost 10 years long effort to perform this study. Dr Fortunato Ciardiello, who discussed the abstract data at the Presidential Symposium of the ESMO 2012, said that reasons for failure of that study might be in different biology of micrometastases in stage III colorectal cancer from the biology of macrometastases in stage IV disease. In addition, the backbone chemotherapy, FOLFOX namely, might not be the most appropriate  combination for cetuximab.

The study was initially presented at the ESMO 14th World Congress on Gastrointestinal Cancer in Barcelona, Spain (27 – 30 June 2012).