David A. Karnofsky Memorial Award and Lecture: Targeting the EGF Receptor for Cancer Therapy

John Mendelsohn, MD
University of Texas, MD Anderson Cancer Center
Houston, TX, USA


Several epidermal growth factor receptor inhibitors are under regulatory review in the United States. In phase I, II and III investigations these agents show promise against a variety of advanced cancers as single agents and in combination with chemotherapy. Future research will seek to optimize combination therapy, as well as, look at these agents in earlier stage disease.

Researchers have produced a number of antibodies that interfere with the epidermal growth factor receptor (EGFR). They have also produced a number of tyrosine kinase inhibitors that act internally on the receptor. All these agents seek to stop the signal transduction EGFR initiates after activation.

One of these agents is monoclonal antibody 225 (C225), which Dr. Mendelsohn and colleagues described in 1983. Among other properties, C225 binds with EGFR and inhibits activation of receptor tyrosine kinase. This was probably the first example of a targeted therapy against an oncogene product.

The U.S. Food and Drug Administration is currently reviewing data on this and two other anti-EGFR tyrosine kinase inhibitors, ZD1839 (Iressa®) and OSI-774 (TarcevaTM).

EGFR inhibition attacks many acquired capabilities of cancer cells. This includes the ability to produce their own growth factors, evade apoptosis, sustain angiogenesis and metastasize.

Multiple animal studies supporting the hypothesis that EGFR inhibition can augment anti-tumor effects of conventional chemotherapy or radiation.

As shown in the following slide, both paclitaxel and ZD1839 reduce tumor volume somewhat in colon cancer xenografts, but the combination produces very small tumors.

One study showed that refractory head and neck cancer patients had partial or complete responses to C225 plus cisplatin, including several patients who had previously failed cisplatin. A phase II study involving 63 patients who failed to respond to cisplatin-based chemotherapy alone. About 25% showed a response.

A phase II trial of ZD1839 as a single agent in non-small cell lung cancer had a 19% overall response rate. Responding patients showed improvement in symptoms. Subsequently, investigators conducted a 1,000-patient randomized phase III trial of ZD1839 as first-line therapy in non-small cell lung cancer. Results will be forthcoming.

A phase II trial of OSI-774 as a single agent in previously treated non-small cell lung cancer reported 2% complete response and 11% partial response. The median survival was 37 weeks and 1-year survival was 48%.

C225 has been studied in colorectal cancer. The study included 120 colorectal cancer patients who had progressed on irinotecan. Patients received irinotecan as combination therapy with C225. There was a 22.5% partial response rate and 7% had stable disease.

A trial at this meeting reports an 11% response for C225 used as a single agent in patients who progressed on irinotecan.

In 21 trials of C225 including 813 patients, the most common grade 3-4 toxicities were an acne-like rash (16%) and asthenia (9%).

A number of important challenges lie ahead. In an attempt to optimize chemotherapy results, dozens of trials with a C225, ZD1839 and OSI-774 are underway.

Some trials are examining the use of these agents in early stage disease. Finally, researchers hope to eventually be able to pre-select or predict which tumors will respond to EGFR inhibitors.


Reporter: Andrew Bowser