Best First-line Treatment for Advanced Colorectal Cancer Remains Unclear 

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In patients with advanced colorectal cancer, it remains unclear which biologic agent added to standard chemotherapy is best, even after a head-to-head comparison of two commonly used agents.

In the phase III FIRE-3 trial, conducted by the German AIO CRC Study Group, the addition of cetuximab (Erbitux) provided about a 4-month increase in overall survival, compared to bevacizumab (Avastin), but the primary endpoint—overall response rate—was not improved, according to principal investigator Volker Heinemann, MD, PhD, Professor of Medical Oncology at the University of Munich in Germany. The study was presented at an oral session by Sebastian Stintzing, MD, who is currently a postdoctoral fellow at the University of Southern California/Norris Comprehensive Cancer Center.1

Study Rationale and Design

Dr. Heinemann explained the rationale at a press briefing. “So far, it’s unclear which targeted agent—cetuximab or bevacizumab—should be used preferentially first-line. This is important since the drugs have different mechanisms of action and side-effect profiles. FIRE-3 aims to determine the optimal choice.”

The study compared the efficacy of cetuximab vs bevacizumab when added to FOLFIRI (leucovorin, fluorouracil, irinotecan) in 592 patients with previously untreated wild-type KRAS metastatic colorectal cancer. Patients received FOLFIRI every 2 weeks plus cetuximab (400 mg/m2 on day 1, followed by 250 mg/m2 weekly) or FOLFIRI plus bevacizumab (5 mg/kg) every 2 weeks.

Median duration of treatment with all three study drugs was 4.8 months for the cetuximab combination and 5.3 months for the bevacizumab combination. The cetuximab arm received significantly fewer cycles than the bevacizumab arm (10 vs 12, P = .014). Patients were followed for a median of 33 and 39 months in the two groups, respectively.

Primary Endpoint Missed

In the intent-to-treat analysis, the study did not meet its primary endpoint of an improvement in objective response rate, which was 62% with FOLFIRI/cetuximab and 58% with FOLFIRI/bevacizumab (odds ratio = 1.18; P = .183). Similarly, median progression-free survival was comparable at 10.0 and 10.3 months, respectively (hazard ratio = 1.06; P = .547).

However, in the subgroup of 526 patients who were assessable for response—defined as having had three cycles of chemotherapy and one postbaseline CT scan—a statistically significant benefit emerged in the cetuximab arm, which had a response rate of 72.2% vs 63.1% in the bevacizumab arm (odds ratio = 1.52; P = .017).

“The objective response rate favored cetuximab but did not reach the level of significance within the intent-to-treat population. However, the response rate was significantly greater by 10% with cetuximab in the assessable patients. We believe this relates to the survival benefit we saw with cetuximab,” he said.

While not a primary endpoint, median overall survival was significantly longer with cetuximab, 28.7 months vs 25.0 months with bevacizumab (hazard ratio = .77; P = .017).

Deeper Tumor Shrinkage?

There are indications, according to Dr. Heinemann, that cetuximab-based therapy “causes deeper tumor shrinkage” than bevacizumab. “The difference in response rates in the assessable patients and the slightly higher rate of complete responses indicates there may be some truth to that,” he said.

Another explanation may be that the sequence of anti-EGFR directed followed by anti-VEGF-directed therapy may have a beneficial effect on outcome. Data regarding treatment sequence will be presented at a later meeting this year.

“Based on our findings, we believe a substantial gain in survival can be obtained when physicians offer cetuximab to patient with KRAS wild-type tumors,” Dr. Heinemann said. ■

Disclosure: Dr. Heinemann reported no potential conflicts of interest.


1. Heinemann V, von Weikersthal LF, Decker T, et al: Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). 2013 ASCO Annual Meeting. Abstract LBA3506. Presented June 1, 2013.

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