Overexpression of epidermal growth factor receptor (EGFR) is seen in many human malignancies, including colorectal cancer.
The cellular pathways that are triggered by EGFR activation are involved in cell growth and proliferation.
Thus, inhibiting EGFR by blocking the binding of ligand to the receptor can inhibit these tumor-promoting pathways.
Monoclonal antibodies to EGFR (such as cetuximab) have already shown clinical utility.
Panitumumab is the first fully-humanized IgG2 antibody to enter clinical trials. It is manufactured in mice that carry human immunoglobulin genes, and has a high affinity for EGFR.
Phase I studies have found that panitumumab is very well tolerated, with dose-dependent acne-like rash being the most common side effect.
Phase II studies have established a recommended dose of 2.5 mg/kg given intravenously once every week.
Investigation of panitumumab together with chemotherapy drugs such as irinitecan and paclitaxel has shown that these are safe and feasible therapeutic combinations.
A phase II trial of panitumumab monotherapy in 148 patients with colorectal cancer who previously received chemotherapy found an overall response rate of 9%, with stable disease in 29%. Almost all patients (95%) developed skin reactions, but very few had grade 3 toxicity. Other toxicities included diarrhea, fatigue, nausea, and stomatitis.
Another phase II trial looked at first-line treatment with panitumumab and IFL (bolus 5-FU and irinotecan) in 19 patients and panitumumab and FOLFIRI (infusional 5-FU and irinotecan) in 24 patients with colorectal cancer. In the IFL group, 47% of patients responded and 32% had stable disease. Median progression-free survival was 8.2 months; median overall survival was 16.4 months. Most common side effects were skin toxicity and diarrhea. Efficacy data from the FOLFIRI group are not yet available, but diarrhea occurred less often than in the IFL arm.
At present, there are phase II studies underway testing the efficacy of panitumumab in patients who have disease progression after irinotecan- or oxaliplatin-based therapy. These phase II studies will look at both pts with tumors that have high EGFR and low/no EGFR expression.
In terms of phase III studies, there are ongoing randomized trials evaluating panitumumab vs. placebo in the second-line setting, and chemotherapy + bevacizumab (Avastin) with or without panitumumab in the first-line setting.
The forthcoming results of these studies will be very valuable in the advancement of therapies for advanced colorectal cancer.