Monoclonal antibodies to the epidermal growth factor receptor (EGFR) are among the promising novel targeted therapies being explored in colorectal cancer. Two such agents that inhibit EGFR signaling by interfering with ligand-binding are cetuximab (Erbitux) and panitumumab (Vectibix). This review will address the use of cetuximab and panitumumab in chemotherapy-refractory colorectal cancer as well as in front-line therapy for the disease, consider predictors of response and resistance, and outline comparisons between these agents.
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.
The role of panitumumab in first line metastatic colorectal cancer was addressed by the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study, which compared FOLFOX/bevacizumab with FOLFOX/bevacizumab plus panitumumab. At the time of its planned interim analysis, this study reported no benefit for progression-free survival, the study's primary endpoint. Of interest, this study also reported increased toxicity, particularly GI toxicities, and trends for inferior progression-free survival and overall survival. While previous pilot studies had shown significant toxicity for panitumumab when combined with IFL (irinotecan, 5-FU, leucovorin) or FOLFIRI chemotherapy, the amount of toxicity seen in PACCE was likely not anticipated and may have been significant enough to have complicated the efficacy endpoints. For this reason, panitumumab's use should be restricted to the third-line setting, where its safety and benefit have been firmly established. At this time, there is no evidence that supports using panitumumab in patients whose disease has progressed on cetuximab.
While the efficacy of cetuximab and panitumumab have been well documented, certain questions remain as to which patients will benefit most from them. Initially, studies were designed such that only patients with EGFR-positive tumors were eligible for enrollment.[1,6] However, the degree of EGFR expression has not been shown to correlate with clinical response. Several explanations might account for this lack of correlation, including limitations of EGFR immunohistochemical staining in archived paraffin, the limited correlation of receptor number with receptor activation and state, and the importance of other regulators of cellular proliferation and apoptosis that may mediate responsiveness to EGFR inhibition. Elegant gene-expression studies have suggested that sensitivity to cetuximab may be predicted by expression of the EGFR ligands amphiregulin and epiregulin as well as the absence of activating Ras mutations (which may confer proliferative and antiapoptotic signals that bypass EGFR).
Dermatologic complications of EGFR inhibitors have been well described, although optimal management strategies have not yet been developed. Interestingly, the presence of skin rash has been suggested as a potential predictor of benefit from EGFR inhibitors. Almost 90% of patients receiving cetuximab develop some degree of rash. Cunningham et al reported higher response rates with cetuximab in patients with skin reactions than in patients without a rash. Van Cutsem et al found similar results in patients who received panitumumab. The second- and third-line studies of cetuximab also demonstrated a correlation between rash and clinical benefit.
The reason for this correlation is not certain but may reflect pharmacokinetic variability or differential host sensitivity, such as EGFR promoter polymorphisms, which may also be conserved in the patient's tumor. The EVEREST pilot study (a cetuximab dose-escalation trial) in patients with metastatic colorectal cancer with no or slight skin reactions on cetuximab standard-dose treatment evaluated a dose escalation-to-rash strategy. The data revealed a modest benefit in response rate for dose escalation, but as noted by Burtness, the increased number of patients with a partial response was offset by the decreased number with stable disease. These data suggest that benefit may be improved by dose escalation in patients with tumors that have some intrinsic sensitivity to EGFR inhibition, but that escalation is unlikely to convert insensitive tumors into sensitive ones.
Infusion-related hypersensitivity reactions are a rare but important complication seen with EGFR inhibitors. Cetuximab, a chimeric monoclonal antibody, is more prone to infusion reactions than its fully humanized counterpart, panitumumab, but the drugs have not been compared head-to-head in terms of either toxicity or efficacy. Severe hypersensitivity reactions occur in up to 3% of patients receiving cetuximab and in less than 1% of patients receiving panitumumab.[9,10] Of note, anecdotal evidence supports a significantly higher incidence of cetuximab infusion reactions in the American Mid-South region than in other parts of the country. The pathophysiology behind these findings is unclear.
Several phase III studies that have been reported in the past year have now established the role of EGFR inhibitors in metastatic colorectal cancer. As appropriately noted in the review by Burtness, more answers to questions are forthcoming regarding when and how to optimally incorporate these drugs into the continuum of care for patients with metastatic colorectal cancer.
Yousuf Zafar, MD
Herbert I. Hurwitz, MD
Dr. Hurwitz is a consultant for and has received research support from Genetech, Roche, GlaxoSmithKline, AstraZeneca, Amgen, and Sanofi-Aventis.
1. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004.
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.
3. Van Cutsem E, Peeters M, Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658-1664, 2007.
4. Sobrero AF, Fehrenbacher L, Rivera F, et al: Randomized phase III trial of cetuximab plus irinotecan versus irinotecan alone for metastatic colorectal cancer in 1298 patients who have failed prior oxaliplatin-based therapy: The EPIC trial. Presented at the AACR Annual Meeting. Los Angeles; Apr 14-18, 2007.
5. Van Cutsem E, Nowacki M, Lang I, et al: Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial (abstract 4000). J Clin Oncol 25(18S):164s, 2007.
6. Saltz L, Rubin M, Hochster H, et al: Cetuximab plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer that expresses epidermal growth factor receptor (EGFR) (abstract 7). Proc Am Soc Clin Oncol 20:3a, 2001.
7. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulin and amphiregulin and K-RAS mutation status are associated with disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. In press.
8. Van Cutsem E, Humblet Y, Gelderblom H, et al: Cetuximab dose-escalation study in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic and efficacy data of a randomized study (abstract 237). Gastrointestinal Cancers Symposium. Orlando, Fla; Jan 19-21, 2007.
9. VectibixTM (panitumumab) package insert. Amgen Inc; Thousand Oaks, Calif; 2006.
10. ErbituxÂ® (cetuximab) package insert. ImClone Systems Inc, New York, and Bristol-Myers Squibb Company, Princeton, NJ; March 2006.