Afatinib Could Be First-Line Option in EGFR-Mutated NSCLC

Megan Brooks

July 09, 2013

The human epidermal growth-factor receptor (EGFR) inhibitor afatinib (Boehringer Ingelheim), which is under priority review at the US Food and Drug Administration (FDA), could be considered a first-line option for patients with metastatic nonsmall-cell lung cancer (NSCLC) who have an EGFR mutation, say LUX-Lung 3 investigators.

In that study, progression-free survival was better with afatinib than with the standard best-in-class chemotherapy of cisplatin and pemetrexed. In addition, clinically meaningful improvements in response rate and lung cancer symptoms were better with afatinib.

The evidence for afatinib in EGFR-mutant NSCLC is "very robust," lead investigator James Chih-Hsin Yang, MD, PhD, director of the Cancer Research Center at National Taiwan University in Taipei, told Medscape Medical News.

The FDA is expected to make a decision this summer on the approval of afatinib.

The LUX-Lung 3 study results, published online July 1 in the Journal of Clinical Oncology, were originally presented at the 2012 annual meeting of the Chinese Society of Clinical Oncology, as reported by Medscape Medical News.

Afatinib is an irreversible inhibitor of the ErbB receptor family, and has been described as the first of a new generation of tyrosine kinase inhibitors (TKIs). It has been shown to maintain activity against EGFR mutations that have become resistant to the 2 reversible TKIs currently used to treat EGFR-mutated NSCLC — erlotinib (Tarceva, Genentech/Astellas) and gefitinib (Iressa, AstraZeneca).

After positive results in phase 2 testing, the LUX-Lung 3 global randomized open-label phase 3 study enrolled 345 patients with advanced NSCLC who carried the EGFR (ErbB1) mutation. Patients were randomized in a 2:1 ratio to receive afatinib 40 mg daily or standard chemotherapy with cisplatin 75 mg/m² and pemetrexed 500 mg/m² intravenously every 21 days for up to 6 cycles.

Afatinib significantly improved response rates and disease control, compared with standard chemotherapy.

Median progression-free survival — the primary end point — was significantly longer with afatinib than with chemotherapy (11.1 vs 6.9 months; hazard ratio [HR], 0.58; P = .0004).

The difference in progression-free survival was even greater in the large subgroup of patients who had the 2 most common EGFR mutations (exon 19 deletion and L858R). "Median progression-free survival in the 90% of study patients with these common EGFR mutations who were treated with afatinib has reached 13.6 months, the longest of all previous studies with the same patient population," Dr. Yang reported.

At the time of the analysis, no difference in overall survival between treatment groups was apparent, the investigators note.

In the afatinib group, the most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis; in the chemotherapy group, they were nausea, fatigue, and decreased appetite. Patient-reported outcomes "favored afatinib, with better control of cough, dyspnea, and pain," the investigators say.

Better Than First-Generation TKIs?

The LUX-Lung 3 study is the largest prospective randomized trial to date of patients with advanced-stage NSCLC who carry the EGFR mutation, and the first study to compare first-line EGFR-targeted TKI therapy with the best-in-class chemotherapy regimen, according to the investigators.

Will afatinib change clinical practice if it is approved? Dr. Yang did not say directly, but he noted that "gefitinib, erlotinib, and afatinib have similar efficacy and side-effect profiles." He explained that no clinical trial looking at efficacy and adverse events has compared afatinib with either erlotinib or gefitinib. "However, the afatinib efficacy in the LUX-Lung 3 study is the best among all previous gefitinib and erlotinib studies of this kind that have been independently reviewed," he added.

The LUX-Lung 3 team thinks afatinib "could be considered a standard option" in patients with metastatic lung cancer with EGFR mutations.

It is not possible to say if afatinib is better.

As expected, progression-free survival was better with afatinib than with chemotherapy, said Fred R. Hirsch, MD, PhD, from the University of Colorado Cancer Center in Aurora, who has been involved in clinical/translational research in lung cancer for 25 years but wasn't involved in the LUX-Lung 3 study.

That afatinib also showed symptomatic improvement is "a good thing," he told Medscape Medical News.

"However, based on the results from this study, it is not possible to say if afatinib is better than the first-generation EGFR TKIs," Dr. Hirsch noted.

Although these results might lead to the first-line use of afatinib in patients with an EGFR mutation in clinical practice, "the challenge is how to increase the cure rate. I believe that only a combination of new agents can significantly increase the cure rate, and we need to learn how to combine the molecular targeted agents," said Dr. Hirsch.

This study was funded by Boehringer Ingelheim, the manufacturer of afatinib. Dr. Yang reports serving as a consultant or advisor and receiving honoraria from Boehringer Ingelheim. A complete list of author disclosures is listed in the publication. Dr. Hirsch has disclosed no relevant financial relationships.

J Clin Oncol. Published online July 1, 2013. Abstract

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