WHAT THIS STUDY ADDS:

• Gefitinib can alleviate symptoms and induce tumor regression in patients with NSCLC that has persisted despite multiple courses of chemotherapy.

NEW YORK CITY—Few options other than supportive care have been available for patients with non–small cell lung cancer (NSCLC) when several courses of chemotherapy have failed to halt their disease. However, a recent phase II trial suggests that the epidermal growth factor receptor (EGFR) inhibitor gefitinib is likely to be useful in this situation.[1]

“Our trial showed rapid symptom improvement and tumor regression in NSCLC patients treated with gefitinib,” said lead investigator Mark G. Kris, MD. “Although this was just a phase II trial, the results have generated a lot of excitement because gefitinib is the first new lung cancer therapy to come along in nearly 20 years,” added Dr. Kris, Chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City.

MECHANISM OF ACTION

Gefitinib, which is taken orally, prevents cancer cell proliferation by blocking EGFR tyrosine kinases; apoptosis follows and the tumor begins to regress. Dr. Kris’ team had hypothesized that the drug might be effective in NSCLC, because EGFR is overexpressed in many of these tumors.

The group’s six-month, randomized, double-blind, multicenter trial compared 250- and 500-mg daily doses of gefitinib for stage IIIB or IV NSCLC. Participants had previously undergone at least two courses of chemotherapy with a carboplatin/docetaxel combination or cisplatin; nearly 60% had received three or more courses of chemotherapy before the study. One blinded dose reduction, from 250 to 100 mg or from 500 to 250 mg, was permitted during the trial.

Of the 221 patients initially enrolled, five were excluded after randomization because they never received the study drug.

RAPID TREATMENT EFFECT

During their last course of chemotherapy before the trial, 79% of study participants had evidence of disease progression. Eighteen percent had had intolerable side effects from chemotherapy, mainly peripheral neuropathy.

During the gefitinib trial, NSCLC symptom improvement occurred in 43% of the 250-mg group and in 35% of the 500-mg group. Most of the patients experienced symptomatic relief within three weeks—often, within one week.

A partial radiographic response to treatment (defined as a greater than 50% decrease in tumor size) occurred in 12% of the 250-mg group and in 9% of the 500-mg group. The median duration of this response was seven months and six months, respectively.

An improvement in symptoms was seen in 96% of the patients with partial responses, 73% of those with stable disease (no partial response but no progression), and 17% of those with disease progression. Symptomatic relief and partial radiographic responses were both more commonly found in the patients with adenocarcinoma than in those with other histologic types of NSCLC.

Projected median survival was seven months for the 250-mg group and six months for the 500-mg group. The two groups’ respective one-year survival rates were estimated to be 27% and 24%.

The adverse effects of gefitinib were generally mild, manageable, and noncumulative, Dr. Kris and his colleagues found. Skin toxicity (rash, acne, dry skin, or pruritus) and diarrhea were the most common side effects, occurring in the majority of patients in both groups; however, both of these adverse effects occurred more frequently in the 500-mg group than in those receiving the lower dose. Gefitinib was also occasionally associated with self-limited eye redness or itchiness and nausea or vomiting. Most of gefitinib’s adverse effects were reversible with drug cessation or symptomatic treatment.

There were no cases of gefitinib-related interstitial lung disease (ILD), and a statistical analysis suggested that the highest incidence that might have been seen was 1.7%. That is lower than the ILD incidence observed with many chemotherapeutic agents, pointed out the investigators.

Because the 250-mg dose produced symptom and radiographic improvement comparable to that obtained with the 500-mg dose yet was linked with fewer adverse reactions, Dr. Kris and his colleagues recommend the 250-mg dose of gefitinib.

Does gefitinib improve survival in NSCLC, and how does it compare to other treatments for the disease? “Those are questions for other clinical trials,” said Dr. Kris. “Our trial did not address them.”

—Timothy Begany

Reference
1. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non–small cell lung cancer. JAMA. 2003;290:2149-2158.

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