A Clinician’s Perspective on ASCO 2001: Going After the Epidermal Growth Factor Receptor

Among the most exciting new anticancer products presented at the 2001 ASCO meeting were new drugs that block the epidermal growth factor receptor (EGFR). About 30% to 90% of carcinomas express high levels of EGFR. These include, among others, head and neck cancer, lung cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, and bladder cancer.

New smart antibodies and small molecules target these receptors and trigger intracellular mechanisms that block their function. The function of EGFR is to activate a pathway leading to uncontrolled tumor growth. Preclinical studies indicate that blocking this pathway can result in cancer cell death as well as potentiation of the anticancer effects of chemotherapy and/or irradiation.

So What Are These Antibodies and Smart Molecules?

Monoclonal Antibodies

First, and further along in the clinical testing arena, is C225 (cetuximab, made by Imclone), a monoclonal antibody that binds to extracellular EGFR. In abstract #7 of the 2001 ASCO Proceedings, Dr. Leonard Saltz from Memorial Sloan-Kettering Cancer Center working with Cancer Care Associates in Florida, the group at New York University, and our Pacific Shores Medical Group in Long Beach, as well as others, presented results on cetuximab plus irinotecan (Camptosar) in patients with progressive, refractory, colorectal carcinoma.

We treated 120 patients with metastatic colorectal cancer, refractory to previous chemotherapy with both fluorouracil (5-FU) and leucovorin as well as irinotecan, whose tumors tested positive for EGFR. Importantly, 72% of the tumors tested were positive for EGFR.

Complete and partial responses were seen in 22.5% of patients with a median duration of 6 months, and an additional 9% of patients had stabilization of disease. (The results were important because patients not expected to respond to any therapy achieved significant and durable control of their cancers.) Based on these encouraging results in refractory patients, a front- line chemotherapy program in combination with cetuximab in advanced and previously untreated colorectal cancer is planned.

In abstract #895, the group from M.D. Anderson together with other centers reported on the use of cisplatin (Platinol) and cetuximab in patients with recurrent head and neck cancer that was not responding to previous cisplatin chemotherapy. Specifically they reported on 38 patients whose disease was stable after 6 weeks of platinum therapy. Twenty-one percent of patients had objective responses, and 22% had disease stabilization. The study is ongoing.

In abstract #518, again a group from M.D. Anderson and others reported on the use of cetuximab in combination with gemcitabine (Gemzar) in patients with advanced pancreatic cancer. Patients with pancreatic cancer who had not received prior chemotherapy received gemcitabine and cetuximab. Eighty-nine patients were treated, and 12% had a partial response, 39% had stable disease or a minor response. The median time to progression was about 3 months.

During the scientific symposia session, an ongoing study was also mentioned where primary radiation therapy is being compared with radiotherapy and cetuximab in patients with head and neck cancer. The study protocol calls for 416 patients to be entered into this trial, which is past the 50% level of accrual at present.

Side effects of cetuximab include a folliculitis/rash, which occurred in up to half of the patients, generally of mild degree. About 2% of patients had allergic reactions. For the most part, cetuximab is well tolerated. We are currently participating in a study of cetuximab in head and neck cancer. We are also hopeful that the drug will be approved for use in the near future.

Smart Small Molecules

Smart small molecules can also be utilized to block the EGFR pathway. These molecules actually work inside the cell by blocking EGFR tyrosine kinase. These molecules are very selective and specifically bind and block EGFR-associated tyrosine kinase, thus inhibiting the EGFR pathway. This is associated with cancer cell suppression and death. Two such compounds are currently under intensive study. One is ZD1839 (Iressa) and the other one is OSI-774 (Tarceva).

ZD1839 (Iressa)

ZD1839 (Iressa made by AstraZeneca Pharmaceuticals) is an oral selective inhibitor of EGFR. Preliminary trials show single-agent activity in some patients with refractory lung cancer, and studies are ongoing. Dr. Lisa Hammond and others, in abstract #544, presented a study of Iressa in combination with 5-FU and leucovorin in advanced colorectal cancer. Multiple dose schedules were tested in order to determine an appropriate dose and schedule. Side effects reported included rash, diarrhea, mucositis, and neutropenia. Responses were reported and the trial is ongoing.

In abstract #1301 Dr. Vincent Miller and others presented a pilot trial of Iressa in combination with carboplatin (Paraplatin) and paclitaxel (Taxol) in patients with previously untreated non-small-cell lung cancer. Different doses and schedules of administration were tested. The drug was well tolerated, and only one dose-limiting grade 3 skin rash toxicity was reported. The preliminary results were encouraging, with 7 of 25 patients having a partial response. A phase III trial comparing carboplatin and paclitaxel with and without Iressa (placebo-controlled) is in progress.

A Japanese study presented in abstract #1292 by Dr. Shunichi Negoro, tested single-agent Iressa in patients with a variety of tumor types. Response was seen in some patients, even though they had had extensive prior chemotherapy.

A very exciting study was presented in abstract #8 by Dr. Stacey Moulder showing that Iressa inhibits HER-2-overexpressing mammary cancer cells. Interestingly, this effect was augmented by the presence of the HER-2 antibody trastuzumab (Herceptin). Because of these findings, it is proposed that a study be conducted in breast cancer patients with a combination of Iressa and trastuzumab. This phase II study has been approved and is expected to be initiated very soon. In this particular study, patients who have breast cancer that is HER-2 positive will receive a combination of trastuzumab and Iressa.

OSI-774 (Tarceva)

Another very interesting small smart molecule is OSI-774 (Tarceva, Pfizer-Genentech). Again, Tarceva is a blocker of tyrosine kinase. In this sense, this is a similar drug to Iressa and it is being tested very intensively.

In abstract #6, Dr. Neil Senzer, presented the results of a phase II evaluation of OSI-774 in patients with squamous cell carcinoma of the head and neck. A dose of 150 mg/d continuously was used. The main side effect was skin rash. The rash was severe about 8% of the time and responded to reduction in the dose. Thirteen percent of patients had a partial response and 29% had stabilization of the disease.

Additional studies demonstrate that OSI-774 is active in a variety of tumor types, and studies of the agent are ongoing.

Summary

In summary, blocking the epidermal growth factor receptor (EGFR) can lead to cancer cell death as well as potentiation of the antitumor effects of chemotherapy and/or radiation therapy. Studies are showing that the majority of patients with head and neck cancer, lung cancer, pancreatic cancer, and colon cancer actually have in their tumors overexpression of EGFR, and are candidates for treatment.

A significant percentage of patients with ovarian, breast, bladder, prostate, gastric and other cancers also overexpress EGFR. C225 (cetuximab) is a monoclonal antibody that blocks EGFR. It is given IV once a week.

The addition of cetuximab to chemotherapy and/or radiation therapy induced responses or stabilization in one third of patients with colon cancer as shown by preliminary results. The median duration of response so far seems to be about 6 months, but some patients have ongoing responses exceeding 1 year.

It is hoped that by using cetuximab in combination with chemotherapy and/or radiation therapy earlier on in the disease course, we can induce more durable remissions and perhaps improve the chances of cure of some cancers.

Iressa is an oral agent that targets EGFR tyrosine kinase and therefore is easy to administer. While the antibody (cetuximab) has to be given by vein, Iressa is given orally. Preliminary results also indicate that Iressa is effective in a variety of tumor types that overexpress EGFR, and it also seems to be synergistic with chemotherapy. We are currently testing Iressa in lung cancer.

OSI-774 (Tarceva) is also an oral tyrosine kinase inhibitor and is active in a variety of tumor types. We are about to start trials of Tarceva in breast and lung cancer.

Only additional studies in time will tell us whether there are advantages of these compounds over each other and whether they could even be used in combination.

Either way, targeted therapy is here to stay and offers a novel, hopeful, and more specific approach to cancer management. The presentations on these new compounds made the 2001 ASCO meeting one of the most promising and exciting we have ever attended.