In the Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME [20050203 or 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 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.