The seminal IPASS study by Tony Mok, MD, and colleagues demonstrated moderate efficacy for gefitinib(Drug information on gefitinib) (Iressa) in advanced non–small–cell lung cancer patients, most notably in patients with predictive factors, including adenocarcinoma histology, no history of smoking, and Asian ethnicity (N Engl J Med 361:947–957, 2009).
Now researchers from Japan have taken gefitinib one step further, showing that as a single agent, gefitinib significantly delayed disease progression in patients with EGFR mutations, making it a reasonable choice as first–line treatment for advanced NSCLC.
"This is the first phase–III study for advanced NSCLC patients selected [prospectively] by sensitive EGFR mutations, and it demonstrates the superiority of gefitinib against carboplatin(Drug information on carboplatin)/paclitaxel in terms of progression–free survival in the first line," said Akira Inoue, MD, who is from the Tohoku University Hospital in Sendai and led the NEJ002 study. The evidence confirms the novel antitumor effects seen in earlier NEJ001 study results and supports this approach, Dr. Inoue added (J Clin Oncol 27:1394–1400, 2009).
The NEJ002 study planned to randomize 320 treatment–naïve patients to gefitinib (250 mg/d) or chemotherapy with paclitaxel(Drug information on paclitaxel) (200 mg/m2) and carboplatin (AUC 6) in a 21–day cycle. A planned interim analysis in May 2009 revealed a significant benefit for gefitinib, and the study stopped accrual at 230 patients. The current data are based on the full analysis of the first 200 patients (ECCO/ESMO 2009 abstract 9LBA).
Progression–free survival, the primary endpoint, was doubled with single–agent gefitinib. Median PFS was 10.4 months with gefitinib vs 5.5 months with chemotherapy (P < .001), Dr. Inoue reported (see Table).
Overall response rate was also significantly higher with gefitinib (74%) than with chemotherapy (29%; P < .001), including a 4% rate of complete response with the single agent. Outcomes were analyzed according to the type of EGFR mutation (deletion or L858R), and no differences were observed in the mutation subsets, whether treated with gefitinib or chemotherapy, he said.
In spite of heavy crossover to the opposite arm after completion of first–line treatment, a survival trend was observed for gefitinib. The rate of crossover was 73% after gefitinib and 94% after chemotherapy. In the intent–to–treat analysis, median survival with gefitinib was 28 months vs 23.6 months with chemotherapy (P = .354), with two–year survival rates of 61% vs 45%, Dr. Inoue reported.
Nonhematological toxicity profiles differed between the arms. Gefitinib was more commonly associated with elevated liver enzymes, diarrhea, rash, and pneumonitis. The chemotherapy doublet was more likely to produce constipation, appetite loss, fatigue, alopecia, neuropathy, and arthralgia.
"In terms of the risk/benefit balance, gefitinib should be considered the standard first–line treatment for advanced NSCLC with sensitive EGFR mutations," he concluded.
Additionally, Dr. Inoue called for global routine testing of EGFR mutation status as an "essential step in guiding the decisions for NSCLC treatment."
Results are impressive, but questions remain
Data from the Japanese NEJ002 study may turn out to be better than IPASS results, said Dr. Johnson, a professor of medicine at Harvard Medical School and the Dana–Farber Cancer Institute in Boston.
"Unlike IPASS, patients were prospectively selected for having an EGFR mutation, and the hazard ratio favoring gefitinib was 0.357 (P < .001)," he said. "Furthermore, there was a trend for a survival benefit, even after extensive crossover. So we now know that patients on gefitinib have a survival time that is at least as good as—if not better than—they have with standard chemotherapy, though follow–up time is short and about half the patients in this study are still alive."
The IPASS trial demonstrated a longer PFS in advanced NSCLC patients with EGFR mutations, which was retrospectively determined. More importantly, the IPASS study showed patients who were given gefitinib and had a wild type EGFR had a worse outcome than if they had been treated with paclitaxel/carboplatin.
"Therefore, if you use clinical criteria to select patients for [a randomized trial], you are potentially doing harm to the subjects with wild type EGFR if they are treated with gefitinib," he said. "While we await survival data from IPASS, the PFS hazard ratio of 0.357 (P < .001) in the NEJ002 study is impressive, signifying a close to 50% reduction in progression with single–agent gefitinib given to patients with EGFR mutations."
"The unresolved issue is this: Would we see the same outcomes if patients were treated first with chemotherapy, followed by gefitinib second–line?" he said. "The other issue is the cost of gefitinib, which is a good bit higher in the U.S. than it is in Japan. Also, the cost of identifying patients with mutations is higher, since the yield is lower than in the Japanese population. These will be considerations as we learn how to apply these data clinically."
Dr. Johnson holds a patent on an EGFR mutation assay.