New Indication for Cetuximab plus FOLFIRI to Treat EGFR-positive, Wild-type KRAS Metastatic Colorectal Cancer

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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.


In July 2012, cetuximab (Erbitux) was approved for use in combination with FOLFIRI (irinotecan, fluorouracil [5-FU], leucovorin) for first-line treatment of patients with KRAS mutation–negative (wild-type), epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer as determined by FDA-approved tests.1,2 The Therascreen KRAS RGQ PCR Kit (by QIAGEN) was approved for use in determining KRAS mutation status concurrently with the cetuximab approval.

Cetuximab has several indications in squamous cell head and neck cancer. In EGFR-positive, wild-type KRAS metastatic colorectal cancer, cetuximab was already approved for use in combination with irinotecan in patients refractory to irinotecan-based chemotherapy and as single-agent treatment when irinotecan- or oxaliplatin-based chemotherapy has failed or in patients who were intolerant of irinotecan.

Approval of cetuximab was based on retrospective analyses of outcomes of cetuximab treatment in patients with EGFR-positive, wild-type KRAS metastatic colorectal cancer in the CRYSTAL trial and two supporting trials, CA225025 and OPUS. These analyses showed that the addition of cetuximab to chemotherapy or best supportive care resulted in improved overall survival, progression-free survival, and overall responses rates in the subset of patients with wild-type KRAS tumors, with potential harm or no benefit being observed in patients with KRAS mutant tumors.

In the open-label, randomized, controlled CRYSTAL trial, 1,217 patients with EGFR-positive tumors and no prior therapy for metastatic disease received FOLFIRI with or without cetuximab; the primary endpoint was progression-free survival. Retrospective evaluation for KRAS mutation status in 89% of the patients (1,079/1,217) showed that 676 (63%) had wild-type tumors and 403 (37%) had mutant tumors. Among patients with wild-type KRAS, the addition of cetuximab to FOLFIRI significantly improved median overall survival from 19.5 to 23.5 months (HR = 0.80, 95% CI = 0.67–0.94), as well as significantly improving median progression-free survival (9.5 vs 8.1 months, HR = 0.70, 95% CI = 0.57–0.86) and increasing overall response rate (57% vs 39%). Among patients with mutant KRAS, the addition of cetuximab resulted in no improvement in overall survival, progression-free survival, or overall response rate.

CA225025 was an open-label, randomized trial comparing cetuximab plus best supportive care vs best supportive care alone in 572 patients with previously treated EGFR-positive metastatic colorectal cancer; the primary outcome measure was overall survival. Tumor tissue was evaluable for KRAS mutation status in 79% of patients. Among patients with wild-type KRAS, cetuximab significantly increased median overall survival from 5.0 to 8.6 months (HR = 0.63, 95% CI = 0.47–0.84) and significantly increased progression-free survival from 1.9 to 3.8 months (HR = 0.42, 95% CI = 0.32–0.56). No improvement in overall survival, progression-free survival, or overall response rate was observed with cetuximab treatment among patients with mutant KRAS.

OPUS was an open-label, randomized, phase II study comparing cetuximab plus FOLFOX4 (5-FU, leucovorin, oxaliplatin) with FOLFOX4 alone as first-line treatment in 337 patients with EGFR-positive metastatic colorectal cancer; overall response rate was the primary outcome measure. Tumor tissue was evaluable for analysis of KRAS mutation status in 93% of patients. Among patients with wild-type KRAS, the addition of cetuximab improved overall response rate (57% vs 34%), median progression-free survival (8.3 vs 7.2 months, HR = 0.57, 95% CI = 0.38–0.86), and median overall survival (22.8 vs 18.5 months, HR = 0.86, 95% CI = 0.60–1.22). No improvement in overall survival, progression-free survival, or overall response rate was observed with the addition of cetuximab in patients with mutant KRAS.

How It Works

EGFR is constitutively expressed in normal epithelial tissues, and expression is also detected in many human cancers, including those of the head and neck, colon, and rectum. Cetuximab is a monoclonal antibody that binds specifically to EGFR on both normal and tumor cells, competitively inhibiting binding of EGF and other ligands, such as transforming growth factor-α. Cetuximab binding blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and VEGF (vascular endothelial growth factor). Signal transduction through EGFR results in activation of wild-type KRAS protein. However, in cells with activating KRAS somatic mutations, the mutant KRAS protein is continuously active and appears to act independent of EGFR regulation.

The QIAGEN Therascreen test is a real-time polymerase chain reaction assay that detects seven different mutations of the KRAS gene. Tumors are considered to be wild-type KRAS if they are negative for these mutations.

How It Is Given

Cetuximab is given in combination with FOLFIRI at a recommended initial dose of 400 mg/m2 as a 120-minute infusion and at a weekly dose of 250 mg/m2 (maximum infusion rate of 10 mg/min for both). Cetuximab infusion should occur 1 hour prior to FOLFIRI administration. Patients should be premedicated with an IV H1 antagonist (eg, diphenhydramine, 50 mg) 30 to 60 minutes prior to the first dose of cetuximab. For subsequent doses, premedication should be based on clinical judgment and the presence and severity of prior infusion reactions.

Infusion rate should be reduced by 50% for grade 1, 2, and nonserious grade 3 infusion reactions, and cetuximab should be immediately and permanently discontinued for serious infusion reactions. For each of the first three occurrences of severe acneiform rash, infusion should be delayed for 1 to 2 weeks. If there is no improvement by this time, cetuximab should be discontinued; if improvement occurs, cetuximab should be continued at 250 mg/m2 after the first occurrence, reduced to 200 mg/m2 and 150 mg/m2 after the second and third occurrences, respectively, and discontinued after the fourth occurrence.

Safety Profile

The frequency and nature of the adverse events, including adverse events typically associated with cetuximab (acneiform rash, infusion reactions, cardiac events, and hypomagnesemia) observed in CRYSTAL, CA225025, and OPUS in the wild-type KRAS population were consistent with the known adverse drug reaction profiles of cetuximab, chemotherapy agents, or the underlying disease. Among patients with wild-type KRAS, grade 3 or 4 adverse events that occurred more frequently among patients receiving cetuximab compared with FOLFIRI alone in the CRYSTAL trial included acne-like rash (18% vs < 1%), diarrhea (16% vs 10%), palmar-plantar erythrodysesthesia (4% vs < 1%), paronychia (4% vs 0%), and stomatitis (3% vs 0%).

Cetuximab carries a boxed warning for infusion reactions and for cardiopulmonary arrest/sudden death, the latter having been observed in patients with head and neck cancer receiving cetuximab combined with radiation therapy or platinum-based therapy including 5-FU. In addition, cetuximab carries warnings/precautions for pulmonary toxicity, dermatologic toxicity, and hypomagnesemia. ■


1. U.S. Food and Drug Administration: Cetuximab in combination with FOLFIRI/Therascreen. Available at Accessed July 24, 2012.

2. ERBITUX (cetuximab) injection prescribing information. ImClone LLC, a wholly owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company, July 2012. Available at Accessed July 24, 2012.