Gefitinib (Iressa) FDA Approved in Patients With EGFR-Positive NSCLC

Richard Pazdur, MD

Richard Pazdur, MD

Gefitinib (Iressa) was recently approved by the FDA for the frontline treatment of patients who have metastatic,EGFR-positive non­—small cell lung cancer (NSCLC) with an exon 19 deletion or exon 21 (L858R) substitution. The therascreenEGFR RGQ PCR Kit was approved along with the targeted therapy as a companion diagnostic test.

The approval is based on the single-arm, phase IV IFUM trial in which gefitinib had an overall response rate (ORR) of 50% (95% CI, 0.41-0.59) in 106 treatment-naïve patients with EGFR-positive NSCLC.

“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.

In the multicenter, open-label pivotal study, patients 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 six months. The investigator-determined ORR and DOR were higher, at 70% (95% CI, 0.61-0.78) and 8.3 months, respectively.  

The approval was also supported by subset data from 186EGFR-positive patients enrolled in the open-label IPASS trial which involved 1217 patients with metastatic NSCLC and adenocarcinoma histology. Patients in the trial were randomized in a 1:1 ratio to 250 mg once daily or ≤6 cycles of carboplatin and paclitaxel. In the subset, 88 patients received gefitinib and 98 patients received chemotherapy. 

An independent panel determined that gefitinib reduced the risk of disease progression by 46%, with a median progression-free survival of 10.9 months versus 7.4 months with carboplatin/paclitaxel (HR = 0.54; 95% CI, 0.38-0.79). The ORR for the gefitinib arm was 67% (95% CI, 0.56-0.77) compared with 41% (95% CI, 0.31-0.51) with chemotherapy. DOR was 9.6 versus 5.5 months, respectively. 

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.

Commenting on the approval, Antoine Yver, head of Oncology, Global Medicines Development at AstraZeneca, the company that manufactures gefitinib, said, “The approval of IRESSA provides physicians and patients in the United States with a new choice of first-line treatment for metastatic non-small cell lung cancer. AstraZeneca is at the forefront of research into targeted therapies for EGFR mutated lung cancer and is committed to improving the outlook for patients at all stages of the disease.”

AstraZeneca is also 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).