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Cetuximab plus FOLFIRI extended survival in metastatic colorectal cancer
CHICAGO — First-line treatment with cetuximab and FOLFIRI chemotherapy extended OS by nearly 4 months compared with bevacizumab plus FOLFIRI in patients with KRAS wild-type metastatic colorectal cancer, according to phase 3 study results presented at the ASCO Annual Meeting.
Cetuximab (Erbitux, Eli Lilly) and bevacizumab (Avastin, Genentech) are commonly used in combination with chemotherapy as initial treatment for metastatic colorectal cancer.
The researchers involved with the FIRE-3 study aimed to determine which approach is more effective for patients with non-mutated forms of the KRAS gene.
“We suspected that cetuximab would produce a better response, but we didn’t know this would translate into better survival,” Volker Heinemann, MD, PhD, a professor of medical oncology at the University of Munich in Germany, said in a press release.
Heinemann and colleagues randomly assigned 592 patients with wild-type KRAS metastatic colorectal cancer to first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus either cetuximab or bevacizumab.
The median duration of treatment was 4.7 months in the cetuximab arm and 5.3 months in the bevacizumab arm. Overall response rate served as the primary endpoint. Median follow-up was 2 years.
The overall response rate in 526 assessable patients was significantly higher among patients assigned to cetuximab (72.2% vs. 63.1%; P=.017).
Median PFS was similar between the two arms (10 months for the cetuximab arm vs. 10.3 months for the bevacizumab arm). However, researchers reported markedly longer OS among patients assigned to cetuximab (28.7 months vs. 25 months; HR=0.77; 95% CI, 0.62-0.95).
FOLFIRI is the standard chemotherapy regimen in Germany for patients with metastatic colorectal cancer. In the United States, patients often receive FOLFOX (folinic acid, 5-fluorouracil and oxaliplatin).
A study designed to compare the addition of cetuximab or bevacizumab to FOLFOX is under way, Heinemann said. Researchers also are trying to identify molecular markers that predict response to cetuximab or bevacizumab.
For more information:
Heinemann V. Abstract # LBA3506.Presented at: ASCO Annual Meeting; May 31-June 4, 2013; Chicago.
Disclosure: The researchers report research funding and honoraria from Merck and Roche.
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Three studies presented at ASCO suggest that an irinotecan-based backbone (FOLFIRI) remains preferred when considering combinations with biologics (VEGF or EGFR inhibitors) in metastatic colorectal cancer (mCRC). The EPOCH trial suggested harmful effects when adding cetuximab to FOLFOX vs. FOLFOX alone in resectable liver-only mCRC. FIRE3 and TRIBE showed very consistent results with FOLFIRI and bevacizumab, with superior survival compared with historical controls. Although TRIBE suggests that the triple drug regimen (FOLFOXIRI) may be superior when added to bevacizumab vs. the doublet, the absence of second-line data limits the interpretation of results.
FIRE3 suggested that the addition of cetuximab to FOLFIRI did not improve overall response rate — the primary endpoint — when compared with bevacizumab added to the same. Median PFS was the same, but OS was surprisingly superior in the cetuximab arm. Again the absence of second-line data presented limits the interpretation of this result, although we are being told more data regarding second-line data will be presented at ESMO World Congress on Gastrointestinal Cancer in early July. Essentially, FIRE 3 should be interpreted as evidence that the two biologics have equivalent activity when added to FOLFIRI in the first-line treatment of mCRC. I think we have now final confirmation that cetuximab should not be combined with FOLFOX, with four negative studies (COIN, NORDIC N0147 and EPOCH) and — in the case of EPOCH — potential harmful effects in KRAS wild-type mCRC patients.
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In patients who were on the prescribed treatment for only 5 months, the curves for OS didn’t separate until 24 months. It’s really interesting to see a survival curve like this. It’s unprecedented in colon cancer. It suggests that many different regimens contribute to OS, and it’s really not clear whether the first regimen is responsible for all of the benefit or if it’s the interplay of all of the different treatments. In addition, there’s the potential for heterogeneity between groups.
All patients in this study were KRAS wild type. KRAS wild type tells us patients have the potential to respond to cetuximab, but there’s no guarantee that they will. It’s likely there are other biomarkers that we don’t sufficiently understand that could affect whether patients responded to one regimen or the other. All in all, this is good news for patients with colorectal cancer. We’re extending survival beyond 2 years, and many patients are living much longer than that. The field has changed a great deal for the positive over the past 5 years, and we hope to see continuing changes.