EGFR Mutations Give Survival Benefit in Lung Cancer

Roxanne Nelson

October 18, 2010

October 18, 2010 (Milan, Italy) — Patients with epidermal growth-factor receptor (EGFR) mutation-positive nonsmall-cell lung cancer (NSCLC) might have a survival advantage over those with EGFR mutation-negative disease.

Final data from the Iressa Pan-Asia Study (IPASS) showed improved overall survival in patients with EGFR mutation-positive NSCLC, whether they receive treatment with gefitinib (Iressa) or carboplatin/paclitaxel chemotherapy.

The data were presented here at the 35th European Society for Medical Oncology (ESMO) Congress.

However, in contrast to earlier findings, overall survival was similar in patients treated with gefitinib and those treated with carboplatin/paclitaxel. Even though preliminary results demonstrated a significant improvement in progression-free survival in patients treated with gefitinib, this did not translate into an overall survival advantage.

Dr. Chih-Hsin James Yang

According to mature IPASS data, median overall survival for patients receiving gefitinib was 18.8 months, compared with 17.4 months for those receiving doublet chemotherapy (hazard ratio [HR], 0.90, 95% confidence interval [CI], 0.79 - 1.02; P = .11).

"It wasn't statistically significant — there wasn't any difference in overall survival time," said study author Chih-Hsin James Yang, MD, PhD, director of the Cancer Research Center, College of Medicine, National Taiwan University, in Taipei.

But the mature overall survival data clearly demonstrate that patients with EGFR mutation-positive tumors had better outcomes than those with EGFR mutation-negative tumors, regardless of the first-line treatment they received, Dr. Yang said.

The median overall survival for patients with EGFR mutation-positive NSCLC who received gefitinib was 21.6 months, compared with 21.9 months for those who received combination chemotherapy (HR, 1.002; 95% CI, 0.756 - 1.328; P = .990).

The median overall survival for patients with EGFR mutation-negative tumors was only 11.2 months for patients receiving gefitinib, compared with 12.7 months for those receiving combination chemotherapy (HR, 1.181; 95% CI, 0.857 - 1.628; P = .309).

Contrast With Earlier Data

Early results of the IPASS trial were first presented at the 2008 ESMO Congress and, as reported by Medscape Medical News at that time, showed superiority for gefitinib in progression-free survival. This was particularly true for patients with EGFR mutations, compared with those without mutations (objective response rate, 71.2% vs 1.1%).

Progression-free survival was significantly longer with gefitinib than with chemotherapy in patients with EGFR mutations (HR, 0.48; P < .0001), but chemotherapy produced a better response in patients with EGFR mutations than in those without them (47.3% vs 23.5%).

Gefitinib is currently licensed in the United States for use in the treatment of patients with locally advanced or metastatic NSCLC whose disease has progressed after first-line chemotherapy. Last year, gefitinib was approved by the European Commission for the treatment of adults with locally advanced or metastatic NSCLC with activating mutations of EGFR tyrosine kinase across all lines of therapy.

Several noncomparative studies have demonstrated that EGFR tyrosine kinase inhibitors have superior effectiveness in certain populations, Dr. Yang noted. "We know that gefitinib has activity in patients of East Asian origin with adenocarcinoma histology who have never smoked or who smoked very little."

Patients with these characteristics appear to have a higher incidence of EGFR mutations. "We hypothesized that a clinically selected group of patients with these characteristics treated with an EGFR tyrosine kinase inhibitor as first-line therapy would have efficacy as least as good as carboplatin/paclitaxel, with benefits in tolerability and quality of life," he explained.

High Degree of Crossover

In the IPASS study, Dr. Yang and colleagues from Taiwan, China, Thailand, and Japan randomized 1217 chemotherapy-naïve patients with advanced NSCLC (adenocarcinoma) to either gefitinib (250 mg/day) or carboplatin (AUC 5 or 6) plus paclitaxel (200 mg/m2), and conducted a preplanned evaluation of the secondary end point of overall survival.

There was a high percentage of crossover in the cohort, which Dr. Yang believes might be the reason for the lack of significant difference between the treatment groups. In the gefitinib group, 60% of patients received subsequent combination chemotherapy, whereas in the chemotherapy group, 51% received subsequent gefitinib or erlotinib treatment. Only 31% of patients in the gefitinib group and 38% in the carboplatin/paclitaxel group did not receive further treatment.

"The crossing over may have diluted the overall survival outcome," he said.

These data reinforce the need for EGFR mutation testing as a standard part of the treatment of NSCLC, Dr. Yang said, adding that "it is important to consider very carefully when choosing a first-line treatment for advanced nonsmall-cell lung cancer, as many patients in clinical practice will not receive further active treatments."

Patients receiving chemotherapy reported a higher incidence of nausea and vomiting, alopecia, and neurotoxicity; those receiving gefitinib reported more rash/acne, diarrhea, and dry skin.

Reasons for First-Line Gefitinib

Jean-Charles Soria, MD, PhD, pointed out that it is not the sequence of therapy that makes a difference in patients with EGFR mutations.

But it is useful, nonetheless, to test for EGFR mutations, explained Dr. Soria, professor of medicine and medical oncology at the Paris University XI, France, and discussant of the paper. "Front-line gefitinib in these patients can be advocated for several reasons," he said.

Compared with chemotherapy, gefitinib offers a better quality of life, oral availability of the drug, similar symptom-improvement rates, a more favorable tolerability profile, and even a higher chance of efficacy later in the course of the disease, he said.

The study was sponsored by AstraZeneca. Dr. Yang reports receiving honoraria and/or doing advisory board work for AstraZeneca, Pfizer, Roche, Merck Serono, Bayer, MSD, and Boehringer Ingelheim. Several of his coauthors report relationships with AstraZeneca, Boehringer Ingelheim, Merck Serono, Chugai Pharmaceutical Co., Daiichi Sankyo Co., Eli Lilly, Eisai, Bristol-Myers Squibb, Takeda, and Pfizer.

35th European Society for Medical Oncology (ESMO) Congress: Abstract LBA2. Presented October 11, 2010.

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