Ten years after the FDA restricted marketing of AstraZeneca's gefitinib (Iressa), the agency has approved the drug as first-line treatment for metastatic non–small cell lung cancer with exon 19 deletions or exon 21 L858R substitutions, along with a companion diagnostic kit.

Ten years after the FDA restricted marketing of AstraZeneca's gefitinib (Iressa) for metastatic non–small cell lung cancer (NSCLC), the agency has approved the drug for a subset of NSCLC patients whose tumors have the most common EGFR mutations. The move adds a third option to the arsenal of targeted treatments for this patient population.

A tyrosine kinase inhibitor (TKI), gefitinib was approved for first-line treatment of metastatic NSCLC with exon 19 deletions or exon 21 L858R substitutions, along with a companion diagnostic kit, Therascreen EGFR RGQ PCR (Qiagen). The approval was based on a single-arm study of 106 patients with EGFR-mutated metastatic NSCLC in which about 50% of patients showed tumor shrinkage lasting an average of 6 months (Br J Cancer 2014;110:55–62). The FDA also considered a retrospective analysis in which gefitinib improved progression-free survival compared with chemotherapy (J Clin Oncol 2011;29:2866–74).

Gefitinib received accelerated approval as a third-line treatment for NSCLC in 2003, but a subsequent confirmatory trial failed to show significant survival benefit, leading the FDA to restrict its use in 2005 to patients already benefiting from treatment.

Although some patients responded to gefitinib during the trial that led to its 2003 approval, researchers did not know why until they uncovered the role of EGFR mutations in lung cancer a few years later. By then, the confirmatory-trial design couldn't be altered, says Lecia V. Sequist, MD, MPH, a medical oncologist at Massachusetts General Hospital in Boston, MA, who led some of the first trials demonstrating gefitinib's effectiveness.

“Gefitinib is a textbook example of how much oncology has changed over the past decade,” says Sequist. “The trial to follow up and get full approval of gefitinib wasn't designed with smart selection of patients based on mutations.”

Since then, two other EGFR TKIs have been approved for NSCLC: erlotinib (Tarceva; Genentech) and afatinib (Gilotrif; Boehringer Ingelheim). The availability of these treatments may have reduced the urgency to reintroduce gefitinib in the United States even though it has been used extensively in Asia and Europe, says Thomas Lynch, MD, director of the Yale Cancer Center in New Haven, CT.

Oncologists have had little guidance on the relative effectiveness of gefitinib, erlotinib, and afatinib, and whether they might elicit different responses in patients with exon 19 deletions versus those with exon 21 L858R substitutions, says Sequist. Ongoing head-to-head trials may offer answers, including a phase IIb trial comparing afatinib with gefitinib as first-line therapy.

Clinicians are also monitoring current trials of emerging third-generation therapies, says Lynch, including rociletinib (Clovis) and AZD9291 (AstraZeneca), which are designed to selectively target mutant EGFR. Both drugs have proven effective as first-line treatments for patients with activating EGFR mutations and as second-line treatments for patients who develop T790M resistance mutations.

“The real story is what's coming next and whether these new drugs will have greater activity and fewer side effects,” says Lynch. “How do we sequence them with older drugs? Should we start with a first-generation drug and move to a newer drug or start with the newer drug? These are compelling questions.”

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