FDA Approves Gefitinib for Patients with EGFR-Positive Advanced NSCLC

Richard Pazdur, MD

Richard Pazdur, MD

Certain subgroups of patients with advanced non—small cell lung cancer (NSCLC) have a new frontline treatment option following the FDA’s approval July 13 of gefitinib (Iressa).

The new approval applies to patients who have metastatic, EGFR-positive NSCLC with an exon 19 deletion or exon 21 (L858R) substitution. The FDA also approved the therascreen EGFR RGQ PCR Kit along with the targeted therapy as a companion diagnostic test.

FDA’s decision was based on the single-arm, phase IV IFUM trial in which gefitinib had an overall response rate (ORR) of 50% in 106 treatment-naïve patients with EGFR-positive NSCLC. Participants in that multicenter, open-label study, received 250 mg of gefitinib daily until disease progression or unacceptable toxicity.

The primary ORR endpoint was measured by both the investigators and an independent review panel. The panel reported a clinical response in half of the patients, with a median duration of response (DOR) of 6 months. The investigator-determined ORR and DOR were higher at 70% and 8.3 months, respectively.

“Iressa offers another effective first-line therapy option for selected lung cancer patients. This approval provides further support for a highly targeted approach to treating cancer,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Additionally, the approval was supported by subset data from 186 EGFR-positive patients enrolled in the open-label IPASS trial. In this study, the median progression-free survival was 10.9 months with 250 mg once-daily gefitinib (n = 88) versus 7.4 months in patients (n = 98) receiving ≤6 cycles of carboplatin/paclitaxel. The ORR for the gefitinib arm was 67% compared with 41% with chemotherapy.

The safety of gefitinib was evaluated in 1129 patients enrolled in a double-blind, placebo controlled trial (N = 1692). The most common all-grade adverse events (AEs) were skin reactions, increased AST and ALT levels, proteinuria, and diarrhea. The most frequently reported grade 3/4 AEs included proteinuria, diarrhea, increased ALT and AST levels, decreased appetite, and skin reactions. AE-related treatment discontinuations were reported for about 5% of patients.

A separate review was conducted to evaluate serious and uncommon adverse drug reactions with gefitinib. The analysis included 2462 patients with NSCLC who received single-agent gefitinib in three randomized clinical trials. Significant adverse reactions included interstitial lung disease (1.3% of patients), fatal hepatotoxicity (0.04%), and grade 3 ocular disorders (0.1%).

The FDA initially granted gefitinib an accelerated approval in 2003 for patients with advanced NSCLC whose disease progressed following platinum doublet chemotherapy and docetaxel. However, the drug was subsequently voluntarily withdrawn from the market after the drug's benefit was not validated in confirmatory trials.

AstraZeneca, the drug’s manufacturer, is examining combination regimens with gefitinib in lung cancer, including a study evaluating the EGFR inhibitor in combination with the anti¬—PD-L1 agent durvalumab (MEDI4736).