|Julia Draznin Maltzman, MD|
|The Abramson Cancer Center of the University of Pennsylvania|
On Feb 12th, 2004, the US Food and Drug Administration (FDA) approved a new monoclonal antibody called Cetuximab (Erbitux, formally known as C225, ImClone Systems and Bristol-Myers Squibb Company) for second line treatment of refractory colon cancer.
Cetuximab is a chimeric monoclonal antibody (Mab) specific for the epidermal growth factor receptor (EGFR). EGFR's are receptors that span the cell membrane with ends protruding into both the outside and the inside of the cell. The part of the receptor that is found on the outside of the cell is called the extracellular domain and the end inside the cell is called the intracellular domain. Receptors are proteins that function to transmit signals from the outside of the cell to the cell nucleus found in the heart of the cell. A variety of proteins found in the blood stream may pass by the extracellular domain of the receptor, some may recognize it, and a smaller fraction will bind to it. Binding to the receptor initiates a variety of signals within the cell by way of the intracellular domain, including those commanding cell division, growth, and differentiation. These signals are transmitted only in the event that the receptor is activated by the appropriate protein. If something interferes with the binding, these signals will not be transmitted and the cell will not divide or grow. Over-expression of EGFR on the surface of many solid tumor cancer cells is very common. Studies have shown that increased expression of this receptor correlates with a poor prognosis and decreased survival.
Cetuximab is a man-made antibody that is specific for the EGFR. Cetuximab binds to the EGFR and thereby interferes with the normal, physiologic binding and cellular signaling pathways are interrupted. Put in a different way, by binding to the EGFR, Cetuximab does not allow the natural blood born protein to bind to the receptor and to transmit its signals for growth, cell division, and differentiation. When these signals are absent, the cell stops growing and will eventually die. Some believe that by overexpressing EGFR on their surface, tumors get multiple signals to grow and divide and therefore grow at a much faster rate than normal healthy tissue. Cetuximab blocks this growth signal and thereby kills the cancer cells.
Chimeric monoclonal antibodies
Monoclonal antibodies are antibodies made in large quantities in a laboratory that are all targeted at the same specific target. Chimeric refers to the fact that the antibody produced is a hybrid between a human and a mouse antibody. By using another species such as a mouse, laboratory researchers are able to produce multiple copies of a particular antibody. Since there is a possibility that a human will react to a mouse antibody, the mouse portion is minimized by hybridizing it to a human antibody.
The efficacy of Cetuximab has been investigated in several clinical trials with various solid tumor malignancies. One large trial was a phase II study of metastatic colon cancer in which 120 patients were treated with either irinotecan (Camptosar, CPT-11) or irinotecan in combination with Cetuximab. The addition of the antibody increased tumor response in 22.5% of patients. Although this trial was encouraging, lack of scientific rigor to the trial prevented the drug from gaining approval by the FDA in 2001. One year later, for ASCO 2002 another Cetuximab trial in heavily pretreated advanced colorectal cancer patients was presented. A 10.5% partial response rate was reported. However, this trial was small with only 57 patients. Two subsequent phase III randomized controlled trials corrected these shortcomings. One trial looked at Cetuximab with a platin compound (cisplatin or carboplatin) in head and neck cancer and the other examined Cetuximab alone or in combination with irinotecan in colorectal cancer.
The pivotal colorectal trial was presented at the 2003 ASCO. This was a multi-center trial with 326 advanced colon cancer patients refractory to irinotecan. The end-point examined was the objective response rate of Cetuximab as single agent or in combination with irinotecan in patients progressing on irinotecan based therapy. Secondary end-points included time to progression, survival time, and drug safety. Patients were randomized in a 2:1 ratio to receive Cetuximab weekly plus irinotecan or Cetuximab alone. An independent review committee, composed of three radiologists and one oncologist, were invited to determine disease response for all participants. A 22.9% partial response rate was seen in the combination arm and a 10.8% partial response rate was noted in the monotherapy arm. These response rates, initially, may seem low, however, these patients were heavily pretreated and their options were limited. Disease stabilization was noted in over half (55.5%) of the participant in the combination arm and 32.4% of the participants in the monotherapy arm. Time to progression was 4.1 month in the combination arm and 1.5 months in the single agent Cetuximab group. All of these results were highly statistically significant. Furthermore, there was a slight survival benefit that was noted using the combination therapy.
The authors concluded that Cetuximab demonstrated significant clinical activity in patients with advanced, heavily pre-treated colorectal cancer. All end-points examined - objective response rate, disease control, and time to tumor progression were better in the combination group than in the single agent Cetuximab arm. Cetuximab was well tolerated by all patients. Finally, the authors touted Cetuximab for offering a new and very promising treatment option for patients with metastatic colorectal cancer.
Cetuximab gained FDA approval for use in combination with irinotecan in the treatment of patient's with metastatic colorectal cancer who are refractory to irinotecan based regimens as well as for use as single agent in the treatment of metastatic colorectal cancer for patient who are intolerant to irinotecan.
Cetuximab appears to be well tolerated. An acne-like rash was the most common drug related toxicity (12%) that was noted in these trials. Rarely, patients develop an allergic reaction to the drug. If the reaction were to occur, it will usually happen with the first infusion.
Cetuximab is currently under investigation in clinical trials to evaluate the effectiveness in colon, lung, pancreas, breast, and head and neck cancers.