GEFITINIB FOR NSCLC

August 20, 2009 (San Francisco, California) — Two large studies on the oral agent gefitinib (Iressa, AstraZeneca) affirm its use as a treatment in select lung cancer patients with mutations of epidermal growth-factor receptor (EGFR) — particularly female Asian patients with advanced nonsmall-cell lung (NSCLC) adenocarcinoma who have never smoked or who have smoked very little. The findings were presented here at the 13th World Conference on Lung Cancer (WCLC), organized by the International Association for the Study of Lung Cancer. But whether or not the results of these studies will have an impact on lung cancer patients in the United States is open to debate, say experts.

Results from 1 of the studies, the Iressa Pan-Asia Study (IPASS), conducted in 87 centers in Asia, were announced in late 2008 at the European Society for Medical Oncology Congress, as reported by Medscape Oncology. The IPASS randomized phase 3 trial involved 1217 patients with advanced NSCLC with adenocarcinoma histology who had never smoked or who had smoked very little. In these chemotherapy-naïve patients, gefitinib was compared with the standard regimen of carboplatin and paclitaxel. Although overall survival did not differ between the 2 groups, progression-free survival at 1 year was superior in the gefitinib group (25% vs 7%; hazard ratio [HR], 0.74; P < .0001).

Importance of EGFR Mutation

The IPAAS study also found that patients with the EGFR mutation fared better with gefitinib than those without (overall response rate, 71.2% vs 1.1%). In new results announced at the WCLC meeting, researchers took their analysis a step further and looked at response rates in those with different types of EGFR mutations — exon 19 deletions, exon 21 L858R deletions, and exon 20 T790M deletions.

"We've demonstrated previously that the presence of the EGFR mutation is vital for the success of the drug," said Tony Mok, MD, lead author and professor of clinical oncology at the Chinese University of Hong Kong. "Targeted therapy is much better than chemotherapy as long as there is a target. Now we have details on the target," he added.

Information on EGFR status was available for about a third of the trial participants (n = 437), and among those, a high percentage — 60% — were EGFR positive. Further analysis of those receiving gefitinib revealed that those with an exon 19 deletion fared better than those with an exon 21 deletion. In patients with an exon 19 deletion, progression-free survival HR was 0.38 (gefitinib:carboplatin plus paclitaxel), but in those with an exon 21 deletion, it was 0.55. Also, patients receiving gefitinib with an exon 19 deletion had a better overall response rate (85% vs 43.2%) than those receiving chemotherapy. "That's the highest response rate ever documented with gefitinib," Dr. Mok noted.

In patients with an exon 21 deletion, the overall response rate was 60.9% in the gefitinib group and 53.2% in the chemotherapy group.

"Overall, there's a benefit for gefitinib with both exon 19 and 21 [deletions], but there's a greater benefit with the exon 19 deletion," Dr. Mok said. Also, the researchers reported that 3 of 5 patients with an exon 20 T790M deletion experienced partial responses to gefitinib. It was previously reported that this mutation is resistant to EGFR tyrosine kinase inhibitors.

"This is an extraordinarily helpful trial because we can now learn more about lung cancer biology. But at the same time, it can't 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," noted David Gandara, MD, WCLC program chair and professor of medicine at the University of California-Davis, in an interview with Medscape Oncology. "This is not a typical lung cancer population — especially in the United States." Dr. Gandara noted that that only 15% of American lung cancer patients have an EGFR mutation, and the results of the IPASS trial should be interpreted with caution in the United States.

Gefitinib is currently approved in the United States only for those who have previously benefited from the drug, and whether it should be used here in advanced lung cancer patients with EGFR mutations is controversial, Dr. Gandara said. The drug is licensed for use elsewhere, such as in China, Japan, and the European Union.

Second Trial is Complementary

In another phase 3 randomized clinical trial reported here at the WCLC meeting, the First-SIGNAL study, oral gefitinib failed to show a benefit in terms of overall survival, although it improved progression-free survival. This Korean trial involved 313 NSCLC patients with adenocarcinoma who had never smoked and who had stage IIIB or IV lung cancer; nearly 89% of the patients were female. Patients were randomized to gefitinib or standard chemotherapy with gemcitabine and cisplatin.

Overall survival was similar in both groups, although progression-free survival at 1 year was superior in the gefitinib group than in the chemotherapy group (20.3% vs 5.0%). The objective response rate was also significantly better in the gefitinib group (53.5% vs 45.3%; odds ratio, 1.385; P = .1533). Patients in the gefitinib group showed improved quality of life compared with those in the chemotherapy group, although there were 2 grade 5 interstitial lung disease events in the gefitinib group.

In nearly a third of the patients in this trial, EGFR mutation status was known (n = 96), and the subgroup of patients who were EGFR positive did dramatically better when treated with gefitinib than those who were negative for the mutation. Overall survival was 30.6 months in EGFR-positive patients and 18.4 months in EGFR-negative patients (HR, 0.845; P = .643), and median progression-free survival was 8.4 months and 2.1 months, respectively (HR, 0.394; P = .0006). Overall response rate was also dramatically better among EGFR-positive than among EGFR-negative patients (84.6% vs 25.9%).

"EGFR mutation status is a strong predictive marker for overall response and progression-free survival. Because of its high overall response rate and better toxicity, gefitinib is a good therapy for these Asian nonsmokers," said lead researcher Jin S. Lee, MD, from the National Cancer Center Korea in Goyang.

The First-SIGNAL trial is complementary and very similar to IPASS, Dr. Gandara remarked. "It's valuable in that it gives us more assurance that the results of IPASS are reproducible," he said.

Need to Consider Molecular Markers

"Both these trials point out that we need to be looking at molecular markers in lung cancer patients, rather than just clinical parameters," said Heather Wakelee, MD, assistant professor of medicine and codirector of the Thoracic Oncology Program at Stanford University in California, and a member of the organizing committee for the WCLC, in an interview with Medscape Oncology. "Hopefully, in 5 years, we'll be able to test every patient for their mutation status and pick the best treatment based on those results," she said.

She noted that even in these 2 trials where the patient populations were very similar — most patients were Asian, female, never smokers with adenocarcinoma — there were clear differences in treatment response based on the presence and type of EGFR mutation. "Molecular analysis is clearly the future of lung cancer treatment," she said.

The IPASS study and First-SIGNAL studies were sponsored by AstraZeneca. Dr. Gandara is a consultant for Response Genetics, Sanofi-Aventis, Bayer, AstraZeneca, Lilly Oncology, Amgen, Genentech, Bristol-Myers Squibb, and Pfizer; and has received research support from Lilly, Bristol-Myers Squibb, Genentech, Pfizer, and Abbott Oncology. Dr. Mok is a consultant to Roche, AstraZeneca, Merck Serono, Eisai, and Pfizer. Dr. Lee and Dr. Wakelee have disclosed no relevant financial relationships.

13th World Conference on Lung Cancer: Abstracts PRS.4 and B9.5. Presented August 1 and 3, 2009