Afatinib (also known as Gilotrif and Giotrif) is an anti-cancer drug developed by Boehringer-Ingelheim for the treatment of non-small cell lung cancer (NSCLC), the most common type of lung cancer that accounts for 80-85 percent of all lung cancer cases.

There are several subtypes of NSCLC. At present, the treatment options for patients with advanced disease remain limited and rely heavily on chemotherapy. Several targeted treatments allowing better outcome and reduced side effects were developed in recent years. Afatinib is one of the newest drugs from this class, the others include Iressa (gefitinib) and Tarceva (erlotinib).

How afatinib works

Afatinib acts as an irreversible inhibitor of the receptor tyrosine kinases EGRF and HER2. Various mutations in the genes encoding for these proteins were shown to be linked to cancer development. Inhibition of mutated proteins may result in slowing disease progression. Research has shown that inhibitors of EGRF and HER2 can be effective in the treatment of various cancers, including lung cancer and breast cancer. In NSCLC, afatinib showed a positive effect in patients with certain mutations in the EGRF gene, namely a deletion in a region of the gene called exon 19, or a letter change in another region called exon 21, as detected by a specifically developed test approved by the U.S. Food and Drug Administration (FDA).

Afatinib in clinical trials

The results of a Phase IIb/III randomized clinical trial (the LUX-Lung 1 trial, NCT00656136) comparing afatinib with placebo in patients with stage IIIb/IV adenocarcinoma (advanced metastatic NSCLC) were published in 2012. Although the overall survival was not statistically different between the two groups (10.8 months in patients who took afatinib and 12 months in those who took placebo), the progression-free survival was better in patients who took afatinib (3.3 months), compared to those who took placebo (1.1 months).

Another study published in February 2015 analyzed the effect of afatinib as a first-line therapy on overall survival in patients with EGRF mutation-positive lung adenocarcinoma (stage IIIb or IV) in comparison with patients receiving chemotherapy (pemetrexed-cisplatin — the LUX-Lung 3 trial — NCT00949650, or gemcitabine-cisplatin — the LUX-Lung 6 trial — NCT01121393). The overall survival in patients with the EGRF exon 19 deletion mutation was significantly longer in patients who took afatinib compared to those who took pemetrexed-cisplatin (33.3 months versus  21.1 months), and those who took afatinib compared to those who took gemcitabine-cisplatin (31.4 months versus 18.4 months). No such effect was observed in patients with other mutations in the EGRF gene.

Another randomized trial (the LUX-Lung 5 trial, NCT01085136) compared the effect of afatinib plus Taxol (paxitacel) with a single-agent chemotherapy in patients with relapsed/drug-resistant disease. The results demonstrated improved progression-free survival in patients who took aflatinib plus Taxol compared to those who took a single-agent chemotherapy (5.6 months versus 2.8 months). However, no improvements in overall survival were recorded. Researchers concluded that treatment with afatinib can benefit patients who developed resistance to erlotinib/gefitinib.

A Phase IIb open-label, randomized, controlled trial (the LUX-Lung 7 trial, NCT01466660) compared the effects of afatinib with the effects of Iressa as a first-line therapy in EGRF mutation positive stage IIIb/IV patients with NSCLC. The findings demonstrated that afatinib has better effects in terms of progression-free survival and time-to-treatment failure. Similarly, the superiority of afatinib over Tarceva in terms of overall survival and progression-free survival in patients with squamous cell carcinoma (a type of NSCLC) was demonstrated by the preliminary results of the ongoing LUX-Lung 8 trial, NCT01523587.

Based on the results of these clinical trials, afatinib was approved by the FDA in 2013 for the treatment of metastatic NSCLC with exon 19 deletions, or exon 21 substitution in the EGRF gene. The drug also was approved for the treatment of squamous cell carcinoma of the lungs in 2016.

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