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A new targeted therapy, afatinib (Gilotrif, Boehringer Ingelheim), has been approved by the US Food and Drug Administration (FDA) for use in the treatment of metastatic nonsmall-cell lung cancer (NSCLC) that tests positive for epidermal growth-factor receptor mutations (EGFRm+). A companion diagnostic test, the Therascreen EGFR PCR Kit(from Qiagen), has been approved at the same time.

About 10% to 15% of NSCLC is EGFRm+ in Western populations, although the incidence of the mutation is higher in Asian populations.

Two other targeted drugs for use in the treatment of EGFRm+ NSCLC — erlotinib (Tarceva) and gefitinib (Iressa) — are already available in most countries worldwide, but there is a notable exception — gefitinib is not available in the United States.

"Today's approvals further illustrate how a greater understanding of the underlying molecular pathways of a disease can lead to the development of targeted treatments,," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research, in a press statement.

Afatinib is also awaiting approval in Europe.

In a clever strategy that has been laying the groundwork for product marketing, Boehringer Ingelheim has been conducting a "Let's Test Initiative," which aims to educate healthcare professionals about the critical role of biomarker testing in NSCLC.

The FDA emphasized the testing in their press statement released today. "The approval of companion diagnostic tests and drugs are important developments in oncology, as they help us bring safe and effective treatments to patients who need them," said Alberto Gutierrez, PhD, director of the FDA Office of In Vitro Diagnostics and Radiological Health.

"Most Robust" Clinical Trial

The approval of afatinib was based on the international LUX-Lung 3 study, which has been described as the "most robust phase 3 trial in EGFRm+ lung-cancer patients." This study involved 345 patients with stage 3/4 lung adenocarcinoma that had tested positive for EGFR mutations who had not previously received chemotherapy.

They all received treatment with pemetrexed plus cisplatin and were randomized to have afatinib or placebo added to their chemotherapy. Median progression-free survival was better with afatinib than with placebo (11.1 vs 6.9 months; hazard ratio, 0.58;  = .0004).

Discussing the LUX-Lung 3 results at a meeting last year, Baohui Han, MD, from the Chest Hospital at Shanghai Jiao Tong University in China, noted that disease control was better with afatinib than with chemotherapy in this trial.

The results are comparable to what has already been seen with other targeted agents in this patient population, he said, referring to erlotinib in the European Randomised Trial of Tarceva vs Chemotherapy (EURTAC) and gefitinib in the Iressa Pan-Asia Study (IPASS). With afatinib, disease control is comparable to and might be even better than the other targeted agents, and the adverse-effect profile appears to be a "little less worse," he noted.

Tony Mok, MD, professor of clinical oncology at the Chinese University of Hong Kong, cautioned such cross-trial comparisons are problematic. "But the figures speak for themselves," he told Medscape Medical News. In selected patient populations with EGFRm+ NSCLC, progression-free survival with afatinib in the LUX-Lung trial was 11.6 months, with erlotinib in EURTAC it was 9.2 months, and with gefitinib in IPASS it was 9.5 months.

Dr. Mok noted that in IPASS, which he headed, trial participants were selected on a clinical basis and EGFR testing was carried out retrospectively; however, the 9.5 months of progression-free survival with gefitinib comes from the large subgroup of patients who tested positive for an EGFR mutation. The other 2 studies were conducted in selected patient populations with the EGFR mutation.

He emphasized that the only true way to compare the drugs is a head-to-head study, and such a trial is under way. LUX-Lung 7 is comparing afatinib with gefitinib in EGFRm+ NSCLC and is already half done, he said. The results should be available in about 2 years.

According to the FDA, common adverse effects of afatinib include diarrhea, skin breakouts that resemble acne, dry skin, pruritus, inflammation of the mouth, paronychia, decreased appetite, decreased weight, cystitis, nose bleed, runny nose, fever, eye inflammation, and hypokalemia. Serious adverse effects include diarrhea that can result in kidney failure, severe dehydration, severe rash, lung inflammation, and liver toxicity.

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