Stage IV and Recurrent Colon Cancer
Importantly, patients with mutant KRAS tumors may experience worse outcome when cetuximab is added to multiagent chemotherapy regimens containing bevacizumab. In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab. 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).[Level of evidence: 1iiDiii]
Panitumumab is a fully humanized antibody against the EGFR. In a phase III trial, patients with chemotherapy refractory colorectal cancer were randomly assigned to panitumumab or best supportive care. Patients receiving panitumumab experienced an improved PFS (8 weeks vs. 7.3 weeks, HR = 0.54; 95% CI, 0.44-0.66; P <.0001).[Level of evidence: 1iiDiii] There was no difference in OS, which was thought to be the result of 76% of patients on best supportive care crossing over to panitumumab. The FDA-approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.
In the PRIME (NCT00364013) study, 1,183 patients were randomly assigned to FOLFOX4 with or without panitumumab as first-line therapy for metastatic colorectal cancer. The study was amended to enlarge the sample size to address patients with the KRAS wild-type tumors and patients with mutant KRAS tumors separately. For patients with KRAS wild-type tumors, a statistically significant improvement in PFS was observed in those who received panitumumab-FOLFOX4 compared with those who received only FOLFOX4 (HR = 0.80; 95% CI, 0.66-0.97; P = .02, stratified log-rank test).[Level of evidence: 1iiDiii] Median PFS was 9.6 months (95% CI, 9.2 months-11.1 months) for patients who received panitumumab-FOLFOX4 and 8.0 months (95% CI, 7.5 months-9.3 months) for patients who received FOLFOX4. OS was not significantly different between the groups (HR = 0.83; 95% CI, 0.67-1.02; P = .072). For patients with mutant KRAS tumors, there was worse PFS with the addition of panitumumab (HR = 1.29; 95% CI, 1.04-1.62; P = .02, stratified log-rank test). Median PFS was 7.3 months (95% CI, 6.3 months-8.0 months) for panitumumab-FOLFOX4 and 8.8 months (95% CI, 7.7 months-9.4 months) for FOLFOX4 alone.
Similarly, the addition of panitumumab to a regimen of FOLFOX/bevacizumab resulted in a worse PFS and worse toxicity compared to a regimen of FOLFOX/bevacizumab alone in patients not selected for KRAS mutation in metastatic colon cancer (11.4 months vs. 10.0 months, HR = 1.27; 95% CI, 1.06-1.52).[Level of evidence: 1iiDiii]