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Gilotrif (Afatinib) Extends Overall Survival in Phase III Lung Cancer Trial

Treatment provides survival benefit compared with chemotherapy

Overall survival (OS) results have been published in The Lancet from two independent phase III clinical trials (LUX-Lung 3 and LUX-Lung 6) in epidermal growth factor receptor (EGFR) mutation-positive patients with metastatic non–small-cell lung cancer (NSCLC). In each study, patients whose tumors had the most common EGFR mutation (deletion in exon 19 [Del19]) lived more than 1 year longer when treated with first-line Gilotrif (afatinib, Boehringer Ingelheim) compared with those receiving standard chemotherapy.

Afatinib is an oral, once-daily kinase inhibitor that is designed to irreversibly bind and inhibit the following receptors: EGFR (ErbB1), HER2 (ErbB2), and ErbB4. It is the first EGFR inhibitor to demonstrate an OS benefit compared with chemotherapy in the first-line treatment of NSCLC patients with EGFR mutation.

Results from the two phase III trials showed similar OS in the afatinib and chemotherapy arms in the overall NSCLC EGFR mutation-positive population (LUX-Lung 3: median OS, 28.2 vs. 28.2 months, respectively; hazard ratio [HR], 0.88; P = 0.39; LUX-Lung 6: median OS, 23.1 vs. 23.5 months; HR, 0.93; P = 0.61). However, a pronounced benefit was observed in patients with the Del19 mutation.

Both studies demonstrated a reduction in the risk of death with first-line afatinib compared with chemotherapy in patients whose tumors had the Del19 mutation. That translated into a survival benefit of more than 1 year compared with chemotherapy (LUX-Lung 3: median OS, 33.3 vs. 21.1 months, respectively; HR, 0.54; P = 0.0015; LUX-Lung 6: median OS, 31.4 vs. 18.4 months; HR, 0.64; P = 0.0229).

This effect was not observed in patients whose tumors had L858R mutations, as OS did not differ significantly between treatment arms in each trial (LUX-Lung 3: HR, 1.30; P = 0.29; LUX-Lung 6: HR, 1.22; P = 0.34).

LUX-Lung 3 (global) and LUX-Lung-6 (Asian), two of the largest trials in patients with NSCLC, had similar designs, with the exception of the platinum-based chemotherapy comparator regimen: pemetrexed/cisplatin in LUX-Lung 3 and gemcitabine/cisplatin in LUX-Lung 6. Both studies met the primary endpoint of progression-free survival for patients whose tumors had common EGFR mutations receiving first-line afatinib. The most common adverse events (grade-3 and -4) associated with afatinib in comparison with chemotherapy included rash/acne, diarrhea, paronychia, and stomatitis/mucositis.

​Treatment-naïve patients with stage-IIIB/IV lung adenocarcinoma and confirmed EGFR mutations in the tumor were enrolled in LUX-Lung 3 (N = 345; recruited globally) and LUX-Lung 6 (N = 364; recruited in China, Korea, and Thailand). The patients were randomly assigned to receive oral afatinib (40 mg/day) or up to six cycles of intravenous pemetrexed/cisplatin (LUX-Lung 3) or gemcitabine/cisplatin (LUX-Lung 6) at standard doses.

In some people, genetic mutations lead to constant activation of the EGFR protein, which is associated with uncontrolled cell division and the development and progression of NSCLC. Among patients diagnosed with NSCLC (the most common form of lung cancer), it is estimated that between 10% and 15% of Caucasians and approximately 40% of Asians have either Del19 or L858R mutations, which occur in 90% of cases of NSCLC.

Gilotrif (afatinib) is indicated for the first-line treatment of patients with metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. The safety and efficacy of afatinib have not been established in patients whose tumors have other EGFR mutations.

Source: Boehringer Ingelheim; January 12, 2015.

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