Patients with KRAS exon 2 wild-type resectable colorectal liver metastases treated with cetuximab plus chemotherapy experienced shorter PFS than those treated with chemotherapy alone, according to an interim analysis of the EPOC trial.
“These results were unexpected,” John Primrose, MD, professor of surgery at the University of Southampton, said in a press release. “Our trial tested [the cetuximab and chemotherapy combination] in people who had cancer spread to the liver who were suitable for surgery from the outset … but for these patients, it seems to have an adverse effect. More research is needed to understand this surprising result.”
Patients with colorectal liver metastases who undergo surgery have an estimated 40% chance of surviving for 5 years. The addition of oxaliplatin and fluorouracil chemotherapy extends PFS, and the addition of cetuximab (Erbitux, Merck) extends OS in patients with advanced, KRAS exon 2 wild-type disease.
In the randomized, controlled EPOC trial, Primrose and colleagues evaluated outcomes of cetuximab plus standard chemotherapy in patients with resectable colorectal liver metastases.
The primary analysis included 236 patients. Researchers assigned 117 patients chemotherapy with oxaliplatin and fluorouracil or oxaliplatin and capecitabine. Patients who had received adjuvant oxaliplatin were eligible to receive IV irinotecan with fluorouracil instead of oxaliplatin.
The other 119 patients received chemotherapy plus cetuximab for 12 weeks before and 12 weeks after liver resection. Cetuximab was administered in one of two doses — either an IV dose of 500 mg/m2 every 2 weeks, or a loading dose of 400 mg/m2 followed by weekly infusion of 250 mg/m2 — depending on the nature of the chemotherapy regimen.
PFS served as the primary endpoint.
During a median follow-up of 20.7 months (95% CI, 17.9-25.6), 123 events occurred.
Results showed patients assigned cetuximab demonstrated significantly shorter median PFS than those assigned chemotherapy alone (14.1 months vs. 20.5 months; HR=1.48; 95% CI, 1.04-2.12).
Preoperatively, researchers reported higher rates of grade 3 or grade 4 peripheral neuropathy (4% vs. 1%) and low neutrophil count (11% vs. 4%) among patients assigned chemotherapy alone. Patients assigned to cetuximab experienced higher rates of preoperative grade 3 or grade 4 skin rash (15% vs. 1%), embolic events (6% vs. 4%), and nausea or vomiting (4% vs. 3%).
Postoperatively, researchers reported higher rates of grade 3 or grade 4 low neutrophil count (8% vs. 4%), peripheral neuropathy (4% vs. 2%), embolic events (3% vs. 2%) and skin rash (8% vs. 0%) among patients assigned cetuximab. Patients assigned chemotherapy alone experienced higher rates of postoperative grade 3 or grade 4 nausea or vomiting (4% vs. 2%).
Researchers reported four potential treatment-related deaths. Three occurred in the cetuximab arm (one due to pulmonary embolism, one due to interstitial lung disease, and one due to bronchopneumonia and pulmonary embolism). One patient assigned chemotherapy died due to heart failure.
“These are very important data,” Primrose said. “Our results demonstrate the importance of clinical trials to ensure patients with cancer receive the best of treatment for their condition.”
Disclosure: The researchers report advisory board roles with and honoraria/research funding from Amgen, AstraZeneca, Bayer, Celgene, Merck, Novartis, Roche and Sanofi-Aventis.