The U.S. Food and Drug Administration has approved Iressa (gefitinib) for the frontline treatment of patients with metastatic non-small cell lung cancer that is positive for EGFR and has one of two additional mutations.
A drug for the treatment of certain non-small cell lung cancers, previously approved for use after chemotherapy, has been given the green light as a frontline treatment for the same conditions.
The U.S. Food and Drug Administration (FDA) has approved Iressa (gefitinib) for the frontline treatment of patients with metastatic non-small cell lung cancer (NSCLC) that is positive for EGFR, or the epidermal growth factor receptor, and has one of two additional mutations: an exon 19 deletion or an exon 21 (L858R) substitution. A companion diagnostic test to help determine which patients will benefit from the targeted therapy — the therascreen EGFR RGQ PCR Kit — was approved simultaneously.
Iressa works by binding to the EGFR that sits on the outsides of some cells, preventing the cells from multiplying.
In 2003, the FDA granted Iressa an accelerated approval for the treatment of patients with advanced NSCLC whose disease had progressed following platinum doublet chemotherapy and docetaxel. However, the drug was then voluntarily withdrawn from the market by its developer after its benefit was not validated in confirmatory trials.
The latest approval is based on the single-arm, phase 4 IFUM trial, in which Iressa demonstrated an overall response rate (ORR) of 50 percent 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, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
In the multicenter, open-label study, patients received 250 mg of Iressa daily until disease progression or unacceptable toxicity. ORR, the primary endpoint of the trial, 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 percent and 8.3 months, respectively.
The approval was also supported by subset data from 186 EGFR-positive patients enrolled in the open-label IPASS trial, which involved 1,217 patients with metastatic NSCLC and adenocarcinoma histology. Patients in the trial were randomized in a 1:1 ratio to either Iressa or a combination of carboplatin and paclitaxel. In the subset, 88 patients received Iressa and 98 patients received chemotherapy.
An independent panel determined that Iressa reduced the risk of disease progression by 46 percent, with a median progression-free survival of 10.9 months versus 7.4 months with carboplatin/paclitaxel. The ORR for the Iressa arm was 67 percent compared with 41 percent with chemotherapy. DOR was 9.6 versus 5.5 months, respectively.
The safety of Iressa was evaluated in 1,129 patients enrolled in a double-blind, placebo controlled trial; in all, that trial included 1,692 people. The most common side effects of any severity were skin reactions; increased levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which can signal liver injury; proteinuria, or elevated protein levels in the urine, which can be a sign of kidney damage; and diarrhea. The most frequently reported severe side effects included proteinuria, diarrhea, increased ALT and AST levels, skin reactions and decreased appetite. Side effect-related treatment discontinuations were reported for about 5 percent of patients.
A separate review was conducted to evaluate serious and uncommon adverse drug reactions with Iressa. The analysis included 2,462 patients with NSCLC who received single-agent Iressa in three randomized clinical trials. Significant adverse reactions included interstitial lung disease, or scarring of the lung tissue (1.3 percent of patients), fatal hepatotoxicity (0.04 percent) and grade 3 ocular disorders (0.1 percent).
Commenting on the approval, Antoine Yver, head of Oncology, Global Medicines Development at AstraZeneca, the company that manufactures Iressa, 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 Iressa in lung cancer, including a study evaluating the EGFR inhibitor in combination with an immunotherapy, the anti¬—PD-L1 agent durvalumab (MEDI4736).