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    Colon Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Stage IV and Recurrent Colon Cancer Treatment



    Cetuximab is a partially humanized monoclonal antibody against the epidermal growth factor receptor (EGFR). Because cetuximab affects tyrosine kinase signaling at the surface of the cell membrane, tumors with mutations causing activation of the pathway downstream of the EGFR, such as KRAS mutations, are not sensitive to its effects. The addition of cetuximab to multiagent chemotherapy improves survival in patients with colon cancers that lack a KRAS mutation (i.e., KRAS wild type). Importantly, patients with mutant KRAS tumors may experience worse outcome when cetuximab is added to multiagent chemotherapy regimens containing bevacizumab.

    Evidence (cetuximab):

    1. For patients who have progressed on irinotecan-containing regimens, a randomized, phase II study was performed of either cetuximab or irinotecan and cetuximab.
      • The median TTP for patients receiving cetuximab was 1.5 months, and the median TTP for patients receiving irinotecan and cetuximab was 4.2 months.[73][Level of evidence: 1iiDiii]
      • On the basis of this study, cetuximab was approved for use in patients with metastatic colorectal cancer refractory to 5-FU and irinotecan.
    2. The Crystal Study (NCT00154102) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab.[74]
      • The addition of cetuximab was associated with an improved PFS (HR, 0.85; 95% CI, 0.72-0.99, P = .048) by a stratified log rank test), but not OS.[74][Level of Evidence: 1iiDii]
      • Retrospective studies of patients with metastatic colorectal cancer have suggested that responses to anti-EGFR antibody therapy are confined to patients with tumors that harbor wild types of KRAS (i.e., lack activating mutations at codon 12 or 13 of the KRAS gene).
      • A subset analysis evaluating efficacy vis a vis KRAS status was done in patients enrolled on the Crystal Study. There was a significant interaction for KRAS mutation status and treatment for tumor response (P = .03) but not for PFS (P = .07). Among patients with KRAS wild-type tumors, the HR favored the FOLFIRI/cetuximab group (HR, 0.68; 95% CI, 0.50-0.94).
    3. In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab.[75]
      • The median PFS was 9.4 months in the group receiving cetuximab and 10.7 months in the group not receiving cetuximab (P = .01).
      • In a subset analysis, cetuximab-treated patients with tumors bearing a mutated KRAS gene had significantly decreased PFS compared with cetuximab-treated patients with wild-type KRAS tumors (8.1 months vs. 10.5 months; P = .04).
      • Cetuximab-treated patients with mutated KRAS tumors had a significantly shorter PFS compared with patients with mutated KRAS tumors not receiving cetuximab (8.1 months vs. 12.5 months; P = .003) as well as OS (17.2 months vs. 24.9 months; P = .03).[75][Level of evidence: 1iiDiii]
    4. The Medical Research Council (MRC) (COIN [NCT00182715] trial) sought to answer the question of whether adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with first-line KRAS wild-type tumors was beneficial.[76,77]
      • In addition, the MRC sought to evaluate the effect of intermittent chemotherapy versus continuous chemotherapy. The 1,630 patients were randomly assigned to three treatment groups:
        • Arm A: fluoropyrimidine/oxaliplatin.
        • Arm B: fluoropyrimidine/oxaliplatin/cetuximab.
        • Arm C: intermittent fluoropyrimidine/oxaliplatin.
      • The comparisons between arms A and B and arms A and C were analyzed and published separately.[76,77]
      • In patients with KRAS wild-type tumors (arm A, n = 367; arm B, n = 362), OS did not differ between treatment groups (median survival, 17.9 months [interquartile range (IQR) 10.3-29.2] in the control group vs. 17.0 months [IQR, 9.4-30.1] in the cetuximab group; HR, 1.04; 95% CI, 0.87-1.23, P = .67). Similarly, there was no effect on PFS (8.6 months [IQR, 5.0-12.5] in the control group versus 8.6 months [IQR, 5.1-13.8] in the cetuximab group; HR, 0.96; 0.82-1.12, P = .60).[76,77][Level of evidence: 1iiA]
      • The reasons for lack of benefit in adding cetuximab are unclear. Subset analyses suggest that the use of capecitabine was associated with an inferior outcome, and the use of second-line therapy was less frequent in patients treated with cetuximab.
      • There was no difference between the continuously treated patients (arm A) and the intermittently treated patients (arm C). Median survival in the intent-to-treat population (n = 815 in both groups) was 15.8 months (IQR, 9.4-26.1) in arm A and 14.4 months (IQR, 8.0-24.7) in arm C (HR, 1.084; 80% CI, 1.008-1.165). In the per-protocol population, which included only those patients who were free from progression at 12 weeks and randomly assigned to continue treatment or go on a chemotherapy holiday (arm A, n = 467; arm C, n = 511), median survival was 19.6 months (IQR, 13.0-28.1) in arm A and 18.0 months (IQR, 12.1-29.3) in arm C (HR, 1.087; 95% CI, 0.986-1.198). The upper limits of CIs for HRs in both analyses were greater than the predefined noninferiority boundary. While intermittent chemotherapy was not deemed noninferior, there appeared to be clinically insignificant differences in patient outcomes.
    5. The OPUS study sought to evaluate the effect of adding cetuximab to first-line treatment with a FOLFOX regimen in an open-labeled, randomized, multicenter, phase II study of patients with EGFR-expressing metastatic colorectal cancer.[78]
      • In the trial, 344 patients were randomly assigned to receive FOLFOX-4 alone or FOLFOX-4 plus cetuximab. There was no statistically significant difference in response rate or PFS.
      • On subset analysis, patients with KRAS wild-type tumors were analyzed separately. In the KRAS wild-type tumor population, there was a statistically significant improvement in response rate (61% vs. 37%, P = .011) and PFS (7.7 months vs. 7.2 months, P = .0163).
      • On subset analysis, patients with KRAS mutant tumors receiving FOLFOX4-cetuximab had a statistically significant worse PFS than patients with KRAS mutant tumors receiving FOLFOX4 (5.5 months vs. 8.6 months, P = .0192).[78][Level of evidence: 1iiD]
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