The first randomized phase 3 study specifically designed to determine if adding cetuximab to chemotherapy would render patients with initially unresectable KRAS wild-type colorectal liver metastases as surgical candidates has resulted in a significant increase of successful surgical rates, and a 10-month extension of  overall survival (OS).

The study, concluded in Shanghai, People’s Republic of China, and published online April 8th in the Journal of Clinical Oncology, also suggests that the combination of cetuximab plus chemotherapy improves tumor shrinkage and extends survival compared with chemotherapy alone, even for patients with inoperable liver metastases who cannot undergo surgery.1 Although about 50% of patients with colorectal cancer develop liver metastases during the course of the disease, currently, about 10% to 20% of patients are surgical candidates.

Lead author Jianmin Xu, MD, PhD, a surgeon at Zhongshan Hospital, Fudan University, in Shanghai, said the combination also improved quality of life. “While our study evaluated only Chinese patients, these findings may also be relevant for patients in North America and Europe,” he added.

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After resection of their primary tumors, Dr. Xu and colleagues randomly assigned patients with stage 4 colorectal cancer and metastases limited to the liver to chemotherapy—FOLFIRI (leucovorin, fluorouracil, and irinotecan) or mFOLFOX6 (leucovorin, fluorouracil, and oxaliplatin) alone (n=68) or plus cetuximab (n=70). The primary endpoint was the rate of patients converted to resection for liver metastases; tumor response and survival were secondary endpoints.

At a median 25 months of follow-up, 3-year OS for all patients was 30% and median survival, 24.4 months. The R0 resection rates for liver metastases was 25.7% (18 of 70 patients) in the cetuximab plus chemotherapy arm and 7.4% (five of 68 patients) in the chemotherapy-alone arm (P<0.01).

Patients in the cetuximab plus chemotherapy arm had improved objective response rates (57.1% vs. 29.4%; P<0.01), increased 3-year OS rate (41% vs. 18%; P=0.013), and prolonged median survival (30.9 vs. 21.0 months; P=0.013) compared with those who received chemotherapy alone.

In addition, those patients receiving the combination who had resection of liver metastases had a significantly improved median survival compared with those who did not undergo surgery (46.4 vs. 25.7 months; P<0.01). The addition of cetuximab did not appear to increase frequency or severity of known toxicities of the chemotherapy regimens and, as has previously been shown, higher-grade skin toxicities were associated with an improved overall response rate.

Gary K. Schwartz, MD, Chief of Memorial Sloan-Kettering Cancer Center’s Melanoma and Sarcoma Service in New York, NY, who also directs the Laboratory of New Drug Development, said he believes these results are translatable to an American population. “A definitive answer would require further studies,” he told

Dr. Schwartz noted that the 30.9- versus 21-month median survival is a “pretty impressive improvement,” adding that 25 years ago, median survival was 6 months. While targeted drugs are “making a difference in patients with this type of cancer,” the field is currently in a “holding pattern.”

“The next step is new drug discovery against new targets, and it depends on the basic biology of colon cancer,” he said. “The real next leap will be understanding, ‘what is the next druggable target in colon cancer and is there a drug to target that pathway, either alone or in combination?’ This represents a paradigm that is a model for us to pursue in drug development. Now we just have to pursue the next step. That’s where the research is going.”

Although frequency rates may be low, the overall impact can be quite large, since so many patients have tumor types with these underlying mutations. “Payers will have to support this approach” for “customized medicine,” Dr. Schwartz emphasized.

The American Society of Clinical Oncology recommends routine testing for KRAS gene alterations before giving anti-epidermal growth factor receptor (EGFR) therapy, because EGFR inhibitors, such as cetuximab, are ineffective against tumors with KRAS gene alterations.


1. Ye LC, Liu TS, Ren L, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013. DOI:10.1200/JCO.2012.44.8308. Available at: Accessed April 3, 2013.