Some Activity for Gefitinib in Heavily Pretreated Breast Cancer

February 1, 2003

SAN ANTONIO-In the first phase II trial of gefitinib (Iressa, also known as ZD1839) in breast cancer, the agent showed limited activity in patients with heavily pretreated metastatic breast cancer, according to a report presented at the 25th Annual San Antonio Breast Cancer Symposium (abstract 20).

SAN ANTONIO—In the first phase II trial of gefitinib (Iressa, also known as ZD1839) in breast cancer, the agent showed limited activity in patients with heavily pretreated metastatic breast cancer, according to a report presented at the 25th Annual San Antonio Breast Cancer Symposium (abstract 20).

But the novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor appeared to have some benefit in a subset of patients, and it provided significant relief of bone pain in additional patients, according to Kathy S. Albain, MD, professor of medicine, Division of Hematology/Oncology, Loyola University Health System.

Describing the rationale for using gefitinib in breast cancer, Dr. Albain noted that activation of the EGFR pathway occurs via multiple mechanisms that result in phosphorylation of its intracellular tyrosine kinase domain. This triggers the downstream signaling mediators that lead to breast cancer proliferation, inhibition of apoptosis, secretion of growth factors, angiogenesis, and decreased sensitivity to treatment. As a result, she said, tyrosine kinase is believed to be an important target for breast cancer therapy.

Gefitinib is a potent small molecule inhibitor of EGFR tyrosine kinase. Preclinical research has shown that gefitinib inhibits the growth of breast cancer cell lines in human breast xenograft models, and a few patients with end-stage breast cancer have achieved stable disease in early phase I trials.

Eligible patients in the current multi-center phase II, open-label trial had measurable metastatic breast cancer that was actively progressing. They were fully ambulatory, with an adequate laboratory profile. No upper or lower limit was placed on prior chemotherapy or hormonal therapy, and paraffin-embedded tumor had to be available.

Patients began treatment with 500 mg/d of gefitinib. Treatment was continued until disease progression or prohibitive toxicity, and response was evaluated every 2 months. Dose interruptions of up to 14 days were allowed for adverse events, with dose reductions to 250 mg if needed.

The study enrolled 63 patients, with a median age of 52 years (range, 34 to 81); 43% had estrogen-receptor-positive tumors; 27% had HER-2 3+ tumors by immunohistochemistry; and 79% had visceral disease.

Patients were heavily pretreated: 30% had received three to four chemotherapy regimens for metastatic disease, and 19% had received five or more; 54% had undergone hormonal therapy, and 36% had received trastuzumab (Herceptin). The majority had also received prior adjuvant chemotherapy, with or without hormonal therapy.

Dr. Albain reported that gefitinib treatment is ongoing in two patients. Therapy was stopped in 54 patients as a result of tumor progression. Four patients dropped out because of adverse events, three of which were drug related (gastrointestinal toxicity in two patients and anxiety in one). Three patients withdrew for miscellaneous reasons.

"ZD1839 was generally well-tolerated," Dr. Albain said. "Short treatment interruptions for a median of 5 days (range, 1 to 18 days) ameliorated toxicity. Only four patients required a dose reduction to 250 mg."

Sixteen patients (25%) experienced a grade 3-4 toxicity, primarily grade 3 diarrhea, nausea, vomiting, or rash. Twenty-eight patients (44%) developed an acneiform rash, of which four were grade 3-4. There was no pulmonary toxicity.

The treatment resulted in one partial response and two prolonged stabiliza-tions (at least 6 months), for a clinical benefit rate of 4.8% (95% CI, 0% to 12%). Six other patients had stable disease for up to 6 months, for a total of nine patients (14.3%) with a partial response or stable disease. Of these patients, two had HER-2-positive disease, and five had hormone-receptor-positive tumors.

The duration of benefit for the patient with the partial response was 5 months. One patient had stable disease for 1 to 2 months, two patients for 2 to 3 months, and five patients for 4 to 7+ months. Treatment continued beyond the first assessment at 2 months in 28 patients (44%). Ten percent of the patients continued on treatment for 4 to 6 months, and 5% continued for 6 to 8+ months.

Median progression-free survival was 57 days (range, 16 to 205+ days), and was clustered at the week 8 evaluation point. The median survival was 144 days.

Bone Pain

Although the study was not prospectively designed to assess quality-of-life measures, several patients reported improvement in bone pain.

"Twelve patients were entered onto study with bone pain," Dr. Albain said. "Five, or 42%, noted marked relief of bone pain. Several stopped all scheduled narcotic medications. In fact, two patients remained on ZD1839 despite objective progression of disease because of major palliation of pain."

In conclusion, Dr. Albain said that gefitinib was generally well tolerated at the 500 mg/d dose, with a toxicity profile similar to what has been observed in single-agent trials of gefitinib in advanced lung cancer.

Although objective evidence of activity using a rigid definition was low, she noted that, a "not insignificant" subset of patients may have derived benefit: 14.3% had a partial response or stable disease, 15% remained on treatment for 4 to 8+ months, and additional patients had major relief of bone pain despite objective progression. Dr. Albain emphasized that all patients were actively progressing, most with extensive prior treatment. "Collectively, these findings support additional study of this novel agent in breast cancer, but in different settings," she concluded. "Results of molecular analyses under way will be used to inform the design of future studies that might address, for example, minimal bulk disease, patients in complete or partial response after other standard systemic therapy, and those with bone-dominant disease/pain."

The study was conducted at Loyola University, Chicago; Baylor College of Medicine; Northwestern University Medical Center; University of Michigan; University of Texas Health Science Center at San Antonio; Memorial Sloan-Kettering Cancer Center; M.D. Anderson Cancer Center, and the University of California, San Francisco.