Targeting EGFR Shown Effective

Iressa offers hope for nonsmall cell lung cancer patients

The "first of a new generation of target-specific anticancer agents" shows promise against nonsmall cell lung cancer (NSCLC) by zeroing in on the so-called epidermal growth factor receptor (EGFR), whose action causes malignant cells to spread and multiply. The product of recent research focusing on anticancer agents that target only malignant tissue and exhibit diminished toxicity, gefitinib (Iressa) hurdled trials with "remarkable and encouraging" results, according to British medical oncologist Michael Cullen.

    Cullen, the United Kingdom representative to the European Society of Medical Oncology, presided over the Philippine launch of Iressa in a symposium during the annual convention of the Philippine Society of Medical Oncologists in October. An epidermal growth factor receptor tyrosine kinase inhibitor, Iressa was approved for local use by the Bureau of Food and Drugs on September 23.

    Cullen said one of the latest studies on cancer zeroed in on EGFR, a transmembrane glycoprotein that when activated initiates cellular proliferation and maturation. While these processes are needed by normal cells to grow and function, they are also responsible for tumor growth and progression. EGFR enhances resistance to chemotherapy and inhibits apoptosis, giving malignant cells survival advantage. It also endows tumor cells the ability for invasion, metastasis, and angiogenesis.

    Noting that EGFR "is abundant or over-expressed in tumor cells" in up to 80 percent of NSCLC cases, Cullen said that it is associated with poor prognosis, disease progression, decreased survival, diminished response to therapy, and resistance to chemotherapeutic agents.

    Cullen said the understanding of the physiologic process of EGFR activation led researchers to the discovery of specific antagonists that can interfere with the cell cycle, and later to the development of Iressa. A synthetic, orally active anilino-quinazoline, Iressa was shown in laboratory experiments to have a potent activity against tumor cells with varying levels of EGFR expression. Synergistic activity was also documented in vitro when Iressa was combined with chemotherapy and radiotherapy.

    Phase one trials "showed quite remarkable responses," said Cullen. In four open-label, multicenter, dose-escalation studies, objective responses were noted in 252 heavily pretreated patients with various solid malignancies, particularly in 100 patients with advanced NSCLC. Response to therapy was documented at dose ranges of 150 to 700 mg/day. Patients reported symptom control, particularly reduction in pain and dyspnea.

    Two large-scale multicenter, randomized, double-blind, parallel group phase two trials called the Iressa Dose Evaluation in Advanced Lung cancer (IDEAL) evaluated the drug's response, efficacy, and tolerability profile as a single agent in patients with histologically or cytologically confirmed stage-three or four NSCLC.

    In the IDEAL 1 trial, the complete and partial response rate was 18.4 percent for the 250 mg/day and 19.0 percent for the 500 mg/day. On the other hand, disease control rate for patients in the IDEAL 2 trial who already had disease progression before treatment showed response rates of 54.4 percent and 51.4 percent for the 250 mg/day and 500 mg/day doses respectively (see Figure).

    Around 40 percent of patients on the 250 mg/day regimen reported a two-point improvement in lung cancer symptom lasting for four weeks or more while 37 percent of patients on the 500 mg/day regimen reported significant improvement.

    "The benefit occurs quite quickly and often before any objective improvement on [CT] scanning or X-rays [is seen]," said Cullen, noting that "seven out of 10 patients had symptom improvement within the first eight days of treatment." Also, 96 percent of patients achieved partial response with symptom improvement.

    The Functional Assessment of Cancer Therapy-Lung cancer (FACT-L) instrument was used to assess improvement in quality of life (QOL), defined as a two-point-improvement for four weeks. Among patients who had a complete and partial response, there was a 92-percent QOL improvement in the 250 mg/day group vis-à-vis 80 percent in the 500 mg/day group. For patients who had stable disease, 61 percent of those on the 250 mg/day regimen and 45 percent of those in the 500 mg/day regimen reported improved QOL.

    Based on the results, Cullen concluded that "patients who received prior platinum chemotherapy achieved clinically meaningful anti-tumor activity and quick symptom relief with very favorable safety profile when given Iressa 250 mg/day."

    Currently Iressa is indicated for patients with locally advanced or metastatic NSCLC who have failed one or more chemotherapy regimens because of disease progression or intolerable adverse events, as well as those not fit for chemothe-rapy. Lucio Victor Jr.