New-EPOC trial

Background

Phase 3 RCT. 257 patients with resectable or suboptimally resectable KRAS wild-type (codons 12, 13, 61) colorectal liver metastases. Tested whether adding cetuximab to perioperative chemotherapy improves progression-free survival.

Interventions and follow up

Arm A: Perioperative chemotherapy (FOLFOX, FOLFIRI if prior oxaliplatin, or CAPOX) + cetuximab (500 mg/m² Q2W, or 400 mg/m² load then 250 mg/m² weekly with CAPOX) surrounding hepatic resection
Arm B: Perioperative chemotherapy alone
Primary endpoint: Progression-free survival (PFS)
Median follow-up: 66.7 mo (IQR 58.0–77.5)

Results

mPFS: 22.2 mo (chemo alone, arm B) vs 15.5 mo (+cetuximab, arm A); HR 1.17, 95% CI 0.87–1.56, P=.304
OS: NR

Adverse events

Hematologic: Grade 3–4 neutropenia 15% (+cetuximab) vs 19% (chemo alone)
GI/skin: Grade 3–4 diarrhea ~10% each; oral mucositis 10% vs 2%; skin rash 16% vs 1%
Vascular: Thromboembolic events 8% vs 7%

Conclusions

Adding cetuximab to perioperative chemotherapy in operable KRAS wild-type colorectal liver metastases significantly shortened PFS and should not be used in this setting.

Key Limitations

Suboptimally resectable disease was included alongside clearly resectable cases. The detrimental effect of cetuximab in this setting remains biologically unexplained despite KRAS wild-type selection (RAS-extended testing was not used at trial design). Modest sample size limits subgroup interpretation.

Clinical Context

New-EPOC established that anti-EGFR therapy should not be added to perioperative chemotherapy for resectable colorectal liver metastases, contrasting with its benefit in left-sided RAS wild-type metastatic disease. ESMO guidance favors perioperative chemotherapy (e.g., FOLFOX) alone in this setting; EGFR antibodies are reserved for unresectable/conversion or palliative contexts.

References