EGFR Inhibitor Effective as Salvage Therapy for NSCLC

MIAMI BEACH—Drugs that block epidermal growth factor receptor (EGFR) tyrosine kinase activity may represent a new option for patients whose non-small-cell lung cancer (NSCLC) has progressed despite standard chemotherapy, Jose Baselga, MD, reported at the Molecular Targets and Cancer Therapeutics meeting (abstract 630A).

The meeting was sponsored by the American Association for Cancer Research, National Cancer Institute, and European Organization for Research and Treatment of Cancer.

Dr. Baselga, of Vall D’Hebron University Hospital, Barcelona, Spain, reported phase II data from a multicenter, international, randomized, double-blind, parallel-group study of two different dosages of the investigational EGFR tyrosine kinase inhibitor ZD-1839 (Iressa) as salvage monotherapy for patients with advanced NSCLC.

"Early on in the phase I trials of ZD1839, we saw some responses in various tumor types including NSCLC. Since there are few options for these patients, we proceeded to the phase II trial," Dr. Baselga said.

The investigators enrolled 210 patients with advanced NSCLC whose disease had progressed despite one or two chemotherapy regimens. The study objectives were to evaluate the objective tumor response rate and the safety profiles of two doses of ZD1839.

Secondary objectives included estimating disease-related symptom improvement using the 7-item lung cancer subscale from the FACT-L questionnaire and to estimate disease control rates, defined as responses plus stable disease. Patients were not selected by tumor EGFR status.

Patients were randomized to receive oral ZD1839 at 250 mg or 500 mg once daily. Tumors were assessed every 4 weeks after the start of treatment for the first 4 months, then every 8 weeks. Of 210 patients enrolled, 208 were evaluable for response, with a minimum follow-up of 4 months.

Response Rates

"Our findings were that ZD1839 was quite active. The overall response rate was 18.7%, and 52.9% of patients had clinical benefit, defined as stable disease or response," Dr. Baselga said. Median progression-free survival was 84 days, and 34% of patients remained without progression after 4 months of treatment.

This tumor effect was accompanied by overall disease-related symptom improvement in 38.7% of patients. The median time to improvement in symptoms was 8 days.

Importantly, Dr. Baselga noted, there was an improvement in quality of life with the improvement in symptoms. "The quality-of-life measures included breathing, chest pain, appetite, and energy levels, and the improvement we observed was very dramatic and occurred early on in treatment," he said.

Response rates were identical for the two dose levels of ZD1839, but patients on the higher dose were more likely to have grade 3-4 adverse events (50.9% vs 32%). These were primarily grade 3 diarrhea, seen in 8.5% of patients on 500 mg/d vs 1% of patients on 250 mg/d, and grade 3-4 rash (6.6% vs 1%).

"Our conclusion is that ZD1839 is active as second-line or third-line therapy for NSCLC. It does improve quality of life. It does improve symptoms, and it is well tolerated," Dr. Baselga said.

Evaluating EGFR Status

The investigators are currently doing a subgroup analysis of the effect of EGFR status. "The majority of NSCLC tumors express EGFR. In the laboratory, ZD1839 produces very good responses independent of the level of EGFR expression. The receptor has to be there, but whether it has to be overexpressed for the drug to be effective is not yet known," Dr. Baselga said.

Studies with ZD1839 as with other EGFR-directed agents would benefit from the development of validated, standardized methods for measuring EGFR expression, which presently do not exist, he said.

Ongoing Phase III Trials

Ongoing phase III trials in NSCLC are comparing standard chemotherapy with or without ZD1839. Dr. Baselga’s data suggest that a head-to-head comparison of standard chemotherapy against ZD1839 might be useful, but he said that no such trial is yet on the drawing board.

The phase II trial included investigators in Spain, Japan, the Netherlands, France, Belgium, Australia, South Africa, the United States, and Britain. It was supported by AstraZeneca, which is developing ZD1839.