Similarly, the addition of panitumumab to a regimen of FOLFOX/bevacizumab resulted in a worse PFS and worse toxicity compared with a regimen of FOLFOX/bevacizumab alone in patients not selected for KRAS mutation in metastatic rectal cancer (11.4 months vs. 10.0 months, HR, 1.27; 95% CI, 1.06–1.52).[Level of evidence: 1iiDiii]
In another study (NCT00339183 ), patients with metastatic colorectal cancer who had already received a fluoropyrimidine regimen were randomly assigned to either FOLFIRI or FOLFIRI plus panitumumab. In a post hoc analysis, patients with KRAS wild-type tumors experienced a statistically significant PFS advantage (HR, 0.73; 95% CI, 0.59–0.90; P = .004, stratified log-rank).[Level of evidence: 1iiDiii] Median PFS was 5.9 months (95% CI, 5.5 months–6.7 months) for panitumumab-FOLFIRI and 3.9 months (95% CI, 3.7 months–5.3 months) for FOLFIRI alone. OS was not significantly different. Patients with mutant KRAS tumors experienced no benefit from the addition of panitumumab.
The Medical Research Council (MRC) (UKM-MRC-COIN-CR10 [NCT00182715] or COIN 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.[64,65] 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.[64,65]
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 vs. 8.6 months [IQR, 5.1–13.8] in the cetuximab group; HR, 0.96; 0.82–1.12, P = .60).[64,65][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 in patients treated with cetuximab.