The primary endpoint was PFS, which was not significantly different among the three arms: 7.9 months versus 8.3 months versus 7.3 months with FLOX, FLOX-cetuximab, and “stop/go” FLOX-cetuximab, respectively. Overall response rates were also not significantly different between the three arms (41% vs 49% vs 47%), and OS was similarly unchanged in the three groups (20.4 months vs 19.7 months vs 20.3 months). In the 60% of patients without KRAS mutations, there was still no significant benefit seen for the addition of cetuximab: in comparing arm A (FLOX alone) versus arm B (FLOX + cetuximab), the response rate was 47% versus 46%, PFS was 8.7 versus 7.9 months (P = 0.66), and OS was 22.0 months versus 20.1 months (P = 0.66). Given that this trial used an unconventional chemotherapy regimen, the reason for the failure of the study to produce positive results is unclear.
Panitumumab
Panitumumab is a fully human IgG2 EGFR monoclonal antibody. Like cetuximab, it targets the extracellular domain of the EGFR and blocks downstream signaling, leading to antitumor effects.26 Because it is fully humanized, panitumumab does not have the same risk of hypersensitivity reactions seen with the chimeric antibody cetuximab. This may be especially important in some areas of the southeastern United States, where reactions to cetuximab occur at a higher frequency than has been reported in clinical trials.27 Panitumumab was approved for monotherapy of relapsed/refractory metastatic colorectal cancer by the FDA in September 2006. As with cetuximab, its use is now specified to tumors harboring wild-type KRAS.
Panitumumab is a fully human IgG2 EGFR monoclonal antibody. Like cetuximab, it targets the extracellular domain of the EGFR and blocks downstream signaling, leading to antitumor effects.26 Because it is fully humanized, panitumumab does not have the same risk of hypersensitivity reactions seen with the chimeric antibody cetuximab. This may be especially important in some areas of the southeastern United States, where reactions to cetuximab occur at a higher frequency than has been reported in clinical trials.27 Panitumumab was approved for monotherapy of relapsed/refractory metastatic colorectal cancer by the FDA in September 2006. As with cetuximab, its use is now specified to tumors harboring wild-type KRAS.
Initial phase I data in patients with metastatic colorectal cancer treated with panitumumab showed a 13% response rate.28 In phase II studies in relapsed and refractory metastatic disease, panitumumab (6 mg/kg every 2 weeks or 2.5 mg/kg every week) showed activity, with objective responses in 3%–13% and stable disease in 21%–33% of patients with EGFR immunostaining. 12,29,30
A large randomized phase III study was conducted in 463 patients whose disease had progressed after prior therapies including 5-FU, irinotecan, and oxaliplatin (Table 1).31 Patients were randomized to receive either panitumumab (6 mg/kg every 2 weeks) and best supportive care (BSC) or BSC alone, and crossover was allowed from the control arm to panitumumab upon disease progression. The primary endpoint was PFS, which was 8 weeks for the panitumumab-treated patients versus 7.3 weeks in the BSC-alone group (HR = 0.54; P < 0.001). Similar to the phase II data, partial responses were seen in 10% of patients receiving panitumumab (versus none in the control group), and stable disease was seen in an additional 27% of panitumumab-treated patients. No significant improvement was seen in OS, which may have been due to the fact that 76% of patients in the BSC group crossed over to receive panitumumab at the time of disease progression.
KRAS testing was performed retrospectively. In KRAS wild-type patients, the median PFS was 12.3 weeks with panitumumab versus 7.3 weeks for BSC (HR = 0.45; P < 0.0001; Table 1), whereas in KRAS-mutant patients, the median PFS was 7.4 weeks with panitumumab and 7.3 weeks with BSC (HR = 0.99).32 The partial response rate with panitumumab was 17% in KRAS wild-type patients and 0% in KRAS-mutant patients.
Panitumumab has now been tested in phase III trials in both first-line and second-line settings. Peeters et al randomized 1,186 patients with metastatic disease to receive second-line therapy with FOLFIRI with or without panitumumab (Table 1).33 As part of their first-line regimen, 19% of patients had received bevacizumab, and 67% had received oxaliplatin. After enrollment but prior to data analysis, the PFS and OS endpoints were changed to incorporate stratification for KRAS status. In the KRAS wild-type population, PFS was 5.9 months with the addition of panitumumab and 3.9 months for FOLFIRI alone (HR = 0.73; P = 0.004), and there was a trend toward improvement in OS (14.5 months vs 12.5 months; HR = 0.85; P = 0.12). No benefit was seen in KRAS-mutant patients treated with panitumumab.
In the first-line setting, the PRIME study randomized 1,183 previously untreated patients to receive first-line FOLFOX4 with or without panitumumab (Table 2).34 As in the second-line trial, PFS and OS endpoints of the trial were changed prior to any efficacy analysis to specify KRAS wild-type patients. In this group, the median PFS was improved with panitumumab (9.6 months vs 8.0 months; HR = 0.80; P = 0.02). OS favored the panitumumab group (23.9 months vs 19.7 months), but this was not statistically significant (HR = 0.83; P = 0.07). In the KRAS-mutant patients, the addition of panitumumab was harmful, with de¬creases in PFS and OS compared with FOLFOX4 alone.