Cetuximab

For patients who had disease progression while receiving irinotecan-containing regimens, a randomized phase II study was performed using either cetuximab or irinotecan and cetuximab.[75][Level of evidence C3]

For patients who had disease progression while receiving irinotecan-containing regimens, a randomized phase II study was performed using either cetuximab or irinotecan and cetuximab.[75][Level of evidence C3]

The median TTP for patients who received cetuximab was 1.5 months, compared with the median TTP of 4.2 months for patients who received irinotecan/cetuximab.[75][Level of evidence B1]

For patients who had disease progression while receiving irinotecan-containing regimens, a randomized phase II study was performed using either cetuximab or irinotecan and cetuximab.[75][Level of evidence C3]

Based on this study, cetuximab was approved for use in patients with metastatic colorectal cancer refractory to 5-FU and irinotecan.

The Crystal Study (EMR 62202-013 [NCT00154102]) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab.[76][Level of evidence B1]

The Crystal Study (EMR 62202-013 [NCT00154102]) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab.[76][Level of evidence B1]

The addition of cetuximab was associated with an improved PFS (HR, 0.85; 95% CI, 0.72–0.99; stratified log-rank P = .048) but not OS.

The Crystal Study (EMR 62202-013 [NCT00154102]) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab.[76][Level of evidence B1]

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 variants at codon 12 or 13 of the KRAS gene).

The Crystal Study (EMR 62202-013 [NCT00154102]) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab.[76][Level of evidence B1]

A subset analysis evaluating efficacy in relation to KRAS status was done in patients enrolled in the Crystal Study. There was a significant interaction for KRAS variant 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).

In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab.[77][Level of evidence B1]

In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab.[77][Level of evidence B1]

The median PFS was 9.4 months in the group who received cetuximab and 10.7 months in the group who did not receive cetuximab (P = .01).

In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab.[77][Level of evidence B1]

In a subset analysis, patients with tumors with KRAS variants who received cetuximab had significantly decreased PFS compared with patients with wild-type KRAS tumors who received cetuximab (8.1 months vs. 10.5 months; P = .04).

In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab.[77][Level of evidence B1]

Among patients with KRAS-altered tumors, PFS was significantly shorter in those who received cetuximab than those did not receive cetuximab (8.1 months vs. 12.5 months; P = .003). OS was also significantly shorter (17.2 months vs. 24.9 months, respectively; P = .03).

The Medical Research Council (MRC) COIN trial (NCT00182715) sought to determine if adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with KRAS wild-type tumors was beneficial.[78,79] 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:The comparisons between arms A and B and arms A and C were analyzed and published separately.[78,79]

The Medical Research Council (MRC) COIN trial (NCT00182715) sought to determine if adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with KRAS wild-type tumors was beneficial.[78,79] 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:The comparisons between arms A and B and arms A and C were analyzed and published separately.[78,79]

Arm A: fluoropyrimidine/oxaliplatin.

The Medical Research Council (MRC) COIN trial (NCT00182715) sought to determine if adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with KRAS wild-type tumors was beneficial.[78,79] 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:The comparisons between arms A and B and arms A and C were analyzed and published separately.[78,79]

Arm B: fluoropyrimidine/oxaliplatin/cetuximab.

The Medical Research Council (MRC) COIN trial (NCT00182715) sought to determine if adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with KRAS wild-type tumors was beneficial.[78,79] 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:The comparisons between arms A and B and arms A and C were analyzed and published separately.[78,79]

Arm C: intermittent fluoropyrimidine/oxaliplatin.

The Medical Research Council (MRC) COIN trial (NCT00182715) sought to determine if adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with KRAS wild-type tumors was beneficial.[78,79] 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:The comparisons between arms A and B and arms A and C were analyzed and published separately.[78,79]

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; 95% CI, 0.82–1.12; P = .60).[78,79][Level of evidence A1]

The Medical Research Council (MRC) COIN trial (NCT00182715) sought to determine if adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with KRAS wild-type tumors was beneficial.[78,79] 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:The comparisons between arms A and B and arms A and C were analyzed and published separately.[78,79]

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.

The Medical Research Council (MRC) COIN trial (NCT00182715) sought to determine if adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with KRAS wild-type tumors was beneficial.[78,79] 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:The comparisons between arms A and B and arms A and C were analyzed and published separately.[78,79]

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 Medical Research Council (MRC) COIN trial (NCT00182715) sought to determine if adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with KRAS wild-type tumors was beneficial.[78,79] 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:The comparisons between arms A and B and arms A and C were analyzed and published separately.[78,79]

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.

The OPUS study sought to evaluate the effect of adding cetuximab to first-line treatment with a FOLFOX regimen in an open-label, randomized, multicenter, phase II study of patients with EGFR-expressing metastatic colorectal cancer.[80]

The OPUS study sought to evaluate the effect of adding cetuximab to first-line treatment with a FOLFOX regimen in an open-label, randomized, multicenter, phase II study of patients with EGFR-expressing metastatic colorectal cancer.[80]

In the trial, 344 patients were randomly assigned to receive FOLFOX-4 alone or FOLFOX-4/cetuximab. There was no statistically significant difference in response rate or PFS.

The OPUS study sought to evaluate the effect of adding cetuximab to first-line treatment with a FOLFOX regimen in an open-label, randomized, multicenter, phase II study of patients with EGFR-expressing metastatic colorectal cancer.[80]

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).

The OPUS study sought to evaluate the effect of adding cetuximab to first-line treatment with a FOLFOX regimen in an open-label, randomized, multicenter, phase II study of patients with EGFR-expressing metastatic colorectal cancer.[80]

On subset analysis among patients with KRAS-altered tumors, those who received FOLFOX-4/cetuximab had a statistically significant worse PFS than patients who received FOLFOX-4 alone (5.5 months vs. 8.6 months; P = .0192).[80][Level of evidence B1]