Adding cetuximab to adjuvant chemotherapy offers no benefit to patients with resected stage III colon cancer

Findings from the primary analysis of the randomized Phase 3, European intergroup PETACC8 trial, presented at ESMO 2012 by Dr Julien Taieb of the Georges Pompidou European Hospital, Paris, France, showed that the addition of cetuximab to standard adjuvant FOLFOX4 chemotherapy regimen offers no benefit to patients with resected stage III, KRAS wild-type (wt) colon cancer.

The rationale for this adjuvant study was based on previous finding that adding cetuximab to FOLFOX was beneficial in patients with metastatic KRAS wt colon cancer. However, PETACC8 is the second trial to test cetuximab in the adjuvant setting, with findings from the US N0147 trial (cetuximab + mFOLFOX6) also failing to show any benefit.

As large clinical trials are needed to show significant benefits with any adjuvant therapy for digestive tract cancers, several cooperative groups came together under the name of PETACC (Pan-European Trials in Alimentary Tract Cancer) to enable enrolment of a large number of patients. This consortium is composed of over a dozen European national and international co-operative groups. This major pan-European collaboration was launched to investigate whether cetuximab in combination with oxaliplatin-based chemotherapy (FOLFOX4) would reduce disease recurrence and prolong survival in fully resected stage III colon cancer after surgery. Scientists from the Fédération Francophone de Cancérologie Digestive (FFCD) led this intergroup trial in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC) and national groups involved in the PETACC structure.

In this PETACC8 trial, 1602 patients with KRAS wt, stage III, fully resected colon cancer were randomized 28–56 days following resection to 12 biweekly cycles of oxaliplatin 85 mg/m2 on day 1, with leucovorin 200 mg/m2 and 5-FU 400 mg/ m2 bolus IV followed by 5-FU 600 mg/m2 over 22 hours IV on days 1–2 (FOLFOX4), without (arm A) or with (arm B) weekly cetuximab 250 mg/m2 (loading dose 400 mg/m2). The primary endpoint was disease free survival (DFS), and secondary endpoints included overall survival, treatment compliance, safety and biological studies for evaluation of markers predictive for relapse and/ or treatment efficacy.

At the time of this interim analysis, the median follow-up was approximately 3.3 years. No difference was seen between the arms for DFS (HR 1.047; 95% CI: 0.853–1.286; p=0.6562) or overall survival (OS; HR 1.092; 95% CI: 0.813–1.466; p=0.5583) in KRAS wt patients (n=1602) or for DFS (HR 0.985; 95% CI: 0.755–1.284; p=0.9117) or OS (HR 0.981; 95% CI: 0.669–1.438; p=0.9236) in KRAS/BRAF wt patients (n=984).

Worse DFS was seen with cetuximab in patients aged >70 years (n=149, HR 1.97; 95% CI: 0.99– 3.93; p=0.051), in females (n=666; HR 1.45; 95% CI: 1.03–2.02; p=0.031) and patients with right-sided colon cancer (n=570; HR 1.40; 95%: CI: 1.01–1.94; p=0.043). Conversely, a trend towards a better outcome was seen in patients with poor prognosis tumours (i.e. those with high grade tumours [HR 0.76; 95% CI: 0.49– 1.16], T4 disease [HR 0.71; 95% CI: 0.50–1.02], or perforation/obstruction [HR 0.79; 95% CI: 0.53– 1.18]) and was significant in patients with pT4N2 at diagnosis (n=146; HR 0.555; 95% CI: 0.348– 0.885; p=0.0122).

Dr Taieb concluded that “The addition of cetuximab to FOLFOX4 offered no DFS or OS benefit to patients with resected, stage III, KRAS wt or KRAS and BRAF wt colon cancer.” He reasoned that “cetuximab may have a different form of activity in micrometastatic disease compared with that observed in stage IV disease” as a possible explanation for why cetuximab did not provide any additional benefit in this setting.