In this issue of ONCOLOGY, Burtness reviews the use of monoclonal antibodies to the epidermal growth factor receptor (EGFR) in colorectal cancer. The review effectively summarizes the role of such agents in the continuum of colorectal cancer care. While these agents have proven efficacy in second- and third-line settings, our current body of knowledge does not completely answer whether these drugs should be used earlier in the care continuum, if we should be combining them with other targeted therapies, and how to predict their efficacy.
Cetuximab (Erbitux) was approved by the US Food and Drug Administration in 2003 based on the improved response rate (22.9% vs 10.8%) and time to progression (4.1 vs 1.5 months) with cetuximab plus irinotecan (Camptosar) vs cetuximab alone in patients whose disease had proven refractory to irinotecan. This study's design followed up on an earlier proof-of-principle study suggesting that part of cetuximab's efficacy was linked to overcoming tumor resistance to irinotecan.
Two large phase III studies presented in 2007 defined the role of cetuximab as monotherapy in the third-line setting (patients refractory to fluorouracil [5-FU], oxaliplatin [Eloxatin], and irinotecan) and in the second-line setting for metastatic colorectal cancer (ie, patients refractory to 5-FU and oxaliplatin but not previously treated with irinotecan). The third-line Canadian CO.17 study showed an overall survival benefit for cetuximab monotherapy compared with best supportive care (6.1 vs 4.6 months). Importantly, this study did not allow crossover for patients in the best supportive care group. By comparison, the third-line study of panitumumab (Vectibix) vs best supportive care did allow crossover at progression. This may explain the positive survival benefit in the cetuximab but not the panitumumab third-line study, despite almost identical progression-free survival and response rates.
The second-line Erbitux Plus Irinotecan in Colorectal Cancer (EPIC) trial, demonstrated a benefit for irinotecan plus cetuximab vs irinotecan alone in terms of progression-free survival (4 vs 2.6 months) and response rate (16% vs 4%). However, no benefit was seen for overall survival, the study's primary endpoint. Approximately half of the patients in the irinotecan-only group received cetuximab after progression, given the commercial availability of cetuximab. For these patients, the comparison in EPIC reflects concurrent vs sequential use of cetuximab rather than cetuximab vs no cetuximab. One explanation for the improvement in progression-free survival without improvement in overall survival in the EPIC study may be the benefit seen after crossover in the control group.
The role of cetuximab in the first-line setting was defined by the Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) study, which was presented in 2007. This study demonstrated a significantly improved progression-free survival (8.9 vs 8 months), the study's primary endpoint, and an increased response rate (46.9% vs 38.7%). The investigators found no difference in overall survival, which may be related to many factors, including the limited impact of cetuximab on progression and benefit from postprogression therapies.
Two studies of cetuximab in combination with chemotherapy plus bevacizumab (Avastin) in the first-line setting are currently ongoing: the Dutch study of capecitabine (Xeloda)/oxaliplatin/bevacizumab with or without cetuximab and the US Gastrointestinal Intergroup study of FOLFOX (5-FU, leucovorin, oxaliplatin) or FOLFIRI (5-FU, leucovorin, irinotecan) plus cetuximab, plus bevacizumab, or plus cetuximab and bevacizumab. Efficacy data from the Dutch study may be available in late 2007 or 2008; the GI Intergroup study is still actively accruing patients. Two ongoing studiesIntergroup N0147 and the Pan-European Trials in Adjuvant Colon Cancer (PETACC 8)are examining the role of cetuximab combined with chemotherapy in the adjuvant setting.
The role of panitumumab was defined in third-line metastatic colorectal cancer by the phase III comparison of panitumumab vs best supportive care. Panitumumab is a fully human IgG2 monoclonal antibody that binds EGFR and blocks EGFR signaling. Compared with best supportive care, patients treated with panitumumab had a longer progression-free survival (8 vs 7.3 weeks) and higher response rate (10% vs 0%). Overall survival was not increasedagain, possibly related to the availability of panitumumab at progression.
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2. Jonker DJ, Karapetis CS, Moore M, et al: Randomized phase III trial of cetuximab monotherapy plus best supportive care (BSC) versus BSC alone in patients with pretreated metastatic epidermal growth factor receptor (EGFR)-positive colorectal carcinoma: A trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and the Australasian Gastro-Intestinal Trials Group (AGITG). Presented at the AACR Annual Meeting. Los Angeles; Apr 14-18, 2007.
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10. Erbitux® (cetuximab) package insert. ImClone Systems Inc, New York, and Bristol-Myers Squibb Company, Princeton, NJ; March 2006.