GEFITINIB SUPERIOR TO CHEMOTHERAPY FOR LUNG CANCER PATIENTS WITH EGFR MUTATIONS

June 25, 2010 — Gefitinib (Iressa) used as first-line therapy in patients with advanced nonsmall-cell lung cancer (NSCLC) and epidermal growth-factor receptor (EGFR) mutations might improve progression-free survival, according to a study published in the June 24 issue of the New England Journal of Medicine.

In this subgroup of patients with NSCLC, those who received gefitinib had significantly longer median progression-free survival than the group receiving standard chemotherapy (10.8 vs 5.4 months; hazard ratio, 0.30).

The Japanese researchers also report that patients in the gefitinib group experienced a significantly higher rate of complete response than the standard chemotherapy group (73.7% vs 30.7%).

The results of this study add to the growing evidence that NSCLC patients with EGFR mutations might be more likely to derive benefit from gefitinib than from conventional chemotherapy, the researchers conclude.

Previous Results Show Efficacy

As previously reported by Medscape Oncology, 3 trials conducted in Asian populations have reported a similar finding of gefitinib efficacy in patients with lung cancer and EGRF mutations. Similar findings have been reported for erlotinib (Tarceva) by Spanish researchers.

Thus far, IPASS (IRESSA Pan-Asia Study) is the largest of these studies, and was conducted in 87 centers in Asia and involved 1217 patients with advanced NSCLC. The results of IPASS were presented at the 2009 annual meeting of the American Society of Clinical Oncology (ASCO), and at that time Richard L. Schilsky, MD, former president of ASCO and professor of medicine at the University of Chicago in Illinois, noted that the study affirmed much of what had been reported in smaller trials in the previous several years.

He pointed out that "we now need to think about nonsmall-cell lung cancer as at least 2 distinct types of cancer."

However, in an interview with Medscape Oncology, David Gandara, MD, professor of medicine at the University of California Davis, cautioned that the findings of IPASS should not be taken out of context. "The trial was done in Asia, entirely in those with adenocarcinoma, 94% of whom were never smokers, and 80% of whom were female," he said, adding that this is "not a typical lung cancer population — especially in the United States."

He noted that only 15% of American lung cancer patients have an EGFR mutation, and that IPASS results need to be interpreted with caution in the United States.

Current Results Can Be Extrapolated

Despite the fact that the latest study was conducted in Japan, corresponding author Akira Inoue, MD, PhD, from the Tohoku University Hospital in Sendai, Japan, feels that the results can be extrapolated to other populations.

"As the Spanish group reported in a small study, even in the Western population patients with EGFR-mutated NSCLC similarly benefit from gefitinib or erlotinib," he told Medscape Oncology.

Even if the number of lung cancer patients with EGFR mutations is low in the American population, Dr. Inoue noted that "15% of lung cancer patients is still larger than the number of patients with ovarian cancer; this is not a minor population."

"I have heard that second-line chemotherapy is generally performed in 60% to 70% of NSCLC patients in the United States," he said. "If so, I recommend first-line EGFR-TKI [tyrosine kinase inhibitor] therapy so as not to miss this most effective treatment for EGFR-mutated NSCLC patients."

Gefitinib Results Superior

The current study was conducted in 230 patients from 43 centers in Japan, all of whom had advanced NSCLC harboring sensitive EGFR mutations and were treatment naïve. Dr. Inoue and colleagues randomized the cohort to receive either gefitinib (260 mg daily) or standard chemotherapy, consisting of paclitaxel (200 mg/m2) and carboplatin (area under curve, 6).

The authors conducted a preplanned interim analysis 4 months after the 200th patient was enrolled (May 2009). Because it showed a significant difference in progression-free survival between the 2 treatment groups (P < .001), the independent data and safety monitoring committee recommended termination of the study, and it was halted immediately.

The median follow-up time was 527 days (range, 30 to 1261 days). Progression-free survival was significantly longer in the gefitinib group than in the chemotherapy group in both the interim and final analysis of the study.

The 1-year rate of progression-free survival was 42.1% in the gefitinib group and 3.2% in the chemotherapy group. The 2-year rates of progression-free survival were also superior for patients who received gefitinib (8.4% vs 0.0%).

The authors conducted a subgroup analysis that showed that women had significantly longer progression-free survival than men (median, 6.5 vs 6.0 months; hazard ratio for death or disease progression, 0.68; 95% confidence interval, 0.51 - 0.92; P = .01).

The median overall survival was also better for the gefitinib group, although there was no significant difference between the 2 groups (30.5 vs 23.6 months). Patient sex and clinical stage did not have a significant effect on overall survival, and the time to an ECOG performance status score of 3 or more did not differ significantly between the 2 groups.

Dr. Inoue noted that it is not surprising that overall survival did not differ between the 2 groups because most patients receiving first-line chemotherapy received gefitinib as their second-line treatment.

"The important thing is to use EGFR-TKI for EGFR-mutated NSCLC," he emphasized.

Improved Safety Profile

The incidence of severe (grade 3 or higher) toxic effects were significantly higher among patients receiving chemotherapy than among those receiving gefitinib (71.7% vs 41.2%; P < .001). The most common adverse events observed in the gefitinib group were rash and elevated levels of liver enzymes (aspartate aminotransferase and alanine aminotransferase); in the chemotherapy group, they were appetite loss, neutropenia, anemia, and sensory neuropathy.

Among patients receiving gefitinib, there were 6 cases of interstitial lung disease (5.3%) in the gefitinib group; 3 cases were severe and 1 of the 3 was fatal.

The study showed that gefitinib results in progression-free survival "that is twice as long as that obtained with . . . carboplatin–paclitaxel in patients with mutated-EGFR nonsmall-cell lung cancer, with a tolerable toxicity profile, including less hematologic toxicity and neurotoxicity than is seen with chemotherapy," write the authors.

"EGFR-TKI should be at least one of the standard therapies for advanced NSCLC with EGFR mutations, not only in Japan but also in Western countries, as the ASCO and [National Comprehensive Cancer Network] guidelines have already mentioned," Dr. Inoue said.

The study was funded by grants-in-aid from the Japan Society for Promotion of Science and the Japanese Foundation for the Multidisciplinary Treatment of Cancer, and a grant from the Tokyo Cooperative Oncology Group. Several of the study authors disclosed relevant financial relationships, as noted in the paper.

N Engl J Med. 2010;362:2380-2388. Abstract