Anti-Epidermal Growth Factor Antibody May Extend Survival in Pancreatic Cancer

SAN FRANCISCO—In an effort to extend the activity of gemcitabine (Gemzar) against pancreatic cancer, researchers have paired an investigational chimeric monoclonal antibody, IMC-C225 (cetuximab) with the standard chemotherapy. IMC-C225 selectively binds to epidermal growth factor receptor (EGFR).

How IMC-C225 Works

Growth factors EGF and TGF-alpha bind to EGF receptor (EGFR) and activate the EGFR pathway, which is involved in tumor growth, repair, angiogenenesis, and metastases. IMC-C225 binds to EGFR and blocks the ability of these growth factors to signal the tumor cell. IMC-C225 leads to the internalization of EGFR, preventing future receptor activation.

The phase II trial, involving 40 patients, produced a 1-year overall survival rate of 32.5% and an increase in time to progression from 2 months for historical controls to almost 4 months.

James Abbruzzese, MD, chairman, Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, reported the results at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 518).

"This work explores the value of targeting specific molecules and proteins intimately associated with the growth of pancreatic cancer cells," Dr. Abbruzzese said. "In this case, we looked at targeting EGFR, known to be important in pancreatic cancer growth." Of the 54 patients screened for the study, more than 90% tested positive for EGFR expression, a condition for acceptance into the trial.

Compared with historical controls receiving gemcitabine alone, combining IMC-C225 and gemcitabine more than doubled the response rate, from 6% to 13%, Dr. Abbruzzese said. At the 1-year point, 32.5% of patients were still alive with this combined treatment, compared with 18% to 20% of historical control patients receiving gemcitabine alone.

The most common adverse reactions reported during the study were nausea, fatigue, and an acne-like rash.

"It looks promising at this point," Dr. Abbruzzese said. "But we have to confirm it in a larger randomized study." He said that a larger study is under discussion with the sponsoring company, ImClone Systems Incorporated. "There’s no written protocol yet," he said, "but we have discussed how it would be designed and who would be involved. I’m hoping this will move along quickly so that we have a study ready to go by the third or fourth quarter of this year."

Dr. Abbruzzese noted that he and his colleagues did not see any evidence that patients who express more EGFR are more likely to respond. "It turns out that in pancreatic cancer, about 95% of patients express the target anyway, so whether one needs to test for it in the larger trial is an issue people have talked about. But it may simply be that we didn’t have enough patients to address that question. I think it’s still an open issue."

Colon Cancer Study

In a phase II study of 120 patients with advanced refractory colorectal cancer, IMC-C225 plus irinotecan (Camp-tosar) produced a 22.5% response rate. Partial responses were seen in 27 patients, and an additional 9 patients (7.5%) had stable disease, reported Leonard Saltz, MD, of Memorial Sloan-Kettering Cancer Center (ASCO abstract 7). The median duration of response at the time of the ASCO meeting was 186 days.

Patients in the study were resistant to both irinotecan and fluorouracil, and had tumors that tested positive for EGFR. In fact, of 400 patients screened for the study, approximately 72% were positive for EGFR, Dr. Saltz said.

Patients received a 400 mg/m² loading dose of IMC-C225, followed by 250 mg/m² weekly, plus irinotecan at the patient’s previous dose and schedule.

Dr. Saltz said that a large-scale, randomized, multicenter phase III trial will test IMC-C225 in combination with other chemotherapy drugs as part of a first-line treatment for advanced-stage colorectal cancer.

Head and Neck Cancer

IMC-C225 also shows promise in patients with refractory head and neck cancer. In ASCO abstract 895, Roy Herbst, MD, PhD, of M.D. Anderson Cancer Center, reported response rates of 23% in 63 patients with stable or progressive head and neck cancer who received IMC-C225 in combination with cisplatin (Platinol).

The study enrolled 96 patients with squamous cell carcinoma of the head and neck. Of these patients, 22 responded to initial chemotherapy with a combination that included cisplatin, and 11 dropped out of the study. The remaining patients (41 with stable disease and 22 with progressive disease) received IMC-C225. In the first group, there was one complete response and nine partial responses, with a median duration of 24 weeks. The second group had 5 partial responses, with a median duration of 12 weeks.