CHCIAGO, Nov. 17 -- For carefully selected Asian patients with non-small-cell lung cancer, the tyrosine kinase inhibitor gefitinib (Iressa) significantly improved progression-free survival compared with the standard carboplatin (Paraplatin) and paclitaxel (Taxol), researchers reported here.
The phase III IRESSA-Pan Asia Study (IPASS) included patients who were chemotherapy naÃ¯ve, were never smokers or light smokers with a good performance status, an adenocarcinoma histology and Stage IIIb/IV non-small-cell lung cancer. The patients were selected from centers in China, Singapore, Japan, Thailand, Malaysia, Indonesia, the Philippines and Taiwan.
The researchers assigned 609 patients to gefitinib at 250 mg/day and 609 patients were offered carboplatin at a dose of 5 or 6 area under the curve with paclitaxel at 200 mg/m2. The aim of the study was to show that gefitinib was non-inferior to the chemotherapy regimen, but Tony Mok, M.D., of the Chinese University of Hong Kong, found that patients taking gefitinib had superior outcomes.
After 12 months, 25.6% of patients on gefitinib had achieved progression-free survival compared with 18.3% of patients on carboplatin-paclitaxel, a highly significant superiority (P<0.0001), Dr. Mok reported at the Chicago Multidisciplinary Symposium on Thoracic Oncology, co-sponsored by the American Society for Therapeutic Radiology and Oncology, the American Society of Clinical Oncology, the International Association for the Study of Lung Cancer (IASLC), and the University of Chicago.
"This means there is a 25% reduction of the risk of progression with gefitinib during the study period," he said. He noted that for the first five or six months, treatment with chemotherapy appeared better, but then patients on gefitinib seemed to reverse the trend and gefitinib patients continued to have less progression than chemotherapy patients out to beyond a year.
"Epidermal growth factor receptor mutation status was a strong predictive biomarker for the effect of gefitinib compared to carboplatin-paclitaxel," said Dr. Mok at a press briefing. About 71.2% of mutation positive patients responded to treatment with gefitinib compared with 47.3% of the patients on the combination chemotherapy. On the other hand, just 1.1% of mutation-negative patients responded to gefitinib compared with 23.5% of mutation negative patients taking the combination.
"We had thought that the EFGR gene was the target for treatment, but as we learned further, the mutated receptor gene was the more specific target," Dr. Mok said. The mutation is found most often in patients with Asian ethnicity. "We have seen from many studies that patients with the mutation have much better survival so we attempted to select patients for treatment with the tyrosine kinase inhibitors."
Patients were on gefitinib for an average of 6.4 months compared with 3.4 months for the chemotherapy-treated patients. The patients were about 57 years old and 79% were women. Ninety-four percent had never smoked; those that had smoked used tobacco for about 11 to 14 years, and their mean time since quitting was greater than 20 years. About half the patients in the study, sponsored by AstraZeneca, were Chinese; another 20% were Japanese.
Among the other findings:
- About 43% of patients responded to gefitinib compared with 32% of patients on chemotherapy (P=0.0001).
- Greater numbers of patients on chemotherapy had neutropenia, leukopenia, anemia, and thrombocytopenia. An acne-like rash was more common with gefitinib, as was diarrhea.
- Gefitinib patients fared significantly better on the Functional Assessment of Cancer Therapy-Lung (P=0.0148) and the Trial Outcomes Index (P<0.0001) quality of life and disease symptom measurements, but was not statistically superior compared with chemotherapy in the Lung Cancer Subscale of the index (P=0.3037).
- There were no differences in overall survival.
"This study also established that EGFR mutation is a very potent predictor of who will respond to gefitinib," Dr. Mok said.
"Clinical features are not enough to determine who should get this pill and who shouldn't," said Paul A. Bunn, Jr., M.D., executive director of the IASLC. "In the United States it is not routine at the moment to get the tumor tissue. This is a paradigm shift. Tumor tissue should be obtained and analyzed on all patients to determine their treatment."
He noted that gefitinib is not approved for this use in the United States, and he asked rhetorically, "Why isn't it?"
|Dr. Mok disclosed financial associations with AstraZeneca; Roche; Pfizer; Eli Lilly, and a co-author disclosed relationships with AstraZeneca; Chugai; Takeda; Merck Serono. Dr. Bunn disclosed relationships with Bristol-Myers Squibb/Imclone, OSI, Genentech, Roche, AstraZeneca and Eli Lilly.|
Primary source: Multidisciplinary Symposium on Thoracic Oncology
Mok T, et al "Gefitinib (g) vs. carboplatin/paclitaxel (c/p) in clinically selected chemonaÃ¯ve patients (pts) with advanced non-small-cell lung cancer (nsclc) in Asia (ipass): Randomized, open-label, phase III study" CTS 2008, p. 100.