PATIENTS AND METHODS: We used a two-stage study design to treat patients with
panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until
disease progression, death, inability to tolerate
panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-
cetuximab and anti-
panitumumab antibodies.
RESULTS: We treated twenty patients for a median of two cycles (range 1-4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months.
Panitumumab was well tolerated. Thirteen patients (65%) had grade 1-2 dry skin or
rash, and three patients had treatment-related grade 3 toxicities (one each with
hyperglycemia,
hyperbilirubinemia, and
hypokalemia). No patients had detectable anti-
cetuximab antibodies at any time point; one patient developed anti-
panitumumab antibodies.
CONCLUSIONS:
Panitumumab has minimal benefit in patients with KRAS wild-type metastatic
colorectal cancer that has progressed on prior
cetuximab. Discussion Both
cetuximab and
panitumumab competitively inhibit
ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with
cytotoxic agents.
Cetuximab is a chimeric antibody with approximately 30% murine
protein, while
panitumumab is a fully human
monoclonal antibody. Correspondingly, rates of severe
hypersensitivity reactions are somewhat increased with
cetuximab (3%) compared to
panitumumab (1%). However, the potential efficacy of
panitumumab in patients who have developed
disease progression on
cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic
colorectal cancer patients with
cetuximab and
irinotecan followed by
panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to
panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to
cetuximab and
irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anti-
cetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective
disease progression on
cetuximab or for whom
cetuximab-containing regimens may have been ceased due to toxicity in the absence of
disease progression. In both circumstances,
retreatment with
panitumumab may be expected to demonstrate some degree of clinical activity. In our study,
disease progression after at least 4 weeks of
cetuximab documented radiographically or by increased
carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on
cetuximab. While it remains possible that a small subset of patients may benefit from
panitumumab after progression on
cetuximab, our results suggest that this approach should not be adopted until predictive
biomarkers for
panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on
cetuximab should be enrolled in trials of novel agents.