Cell Proliferation

Afatinib is a second-generation potent EGFR-TKI that covalently binds to all homo and heterodimers form by the members of the HER family, such as EGFR, HER2, ErbB3, and ErbB4. In both cell-free kinase and cell proliferation assays, afatinib shows much better inhibitory activity on EGFR harboring L858R/T790M mutations compared to first-generation EGFR-TKIs.

Research shows that the activity of afatinib on the T790M mutation was lower than that; hence on single sensitizing mutations such as L858R or E19del; but it remain within a range that indicate similar effectiveness. In addition, afatinib reduce tumor volume by approximately half in transgenic mice with L858R/T790M mutation-driven cancer.

Acquired resistance to first-generation

Although afatinib was expect to overcome acquire resistance to first-generation EGFR-TKI; so it fail to show an overall survival (OS) benefit over placebo in patients with advance EGFR-mutant lung cancer following previous EGFR-TKI therapy . This discordance with pre clinical data might explaine by amplification of T790M.

The irreversible EGFR-TKIs were initially effective in vitro and in vivo against EGFR mutant tumors; so containing T790M; hence while resistance arose when T790M was amplify over time. The efficacy of afatinib on T790M seems to be dependent on the T790M allele frequency; so not just positivity of T790M. This implies that the clinical activity of afatinib could also vary according to the T790M allele frequency.

The improvement of progression-free survival (PFS), tumor response rate; also disease relate symptoms in the LUX-Lung 1 clinical trial despite no OS benefit could be understood in a similar context. Therefore, they assume that afatinib may reduce the rate or delay the time of T790M acquisition during first-line EGFR-TKI therapy; so because the T790M amplification that decreases afatinib efficacy probably occurs in the later phase.

Skin problems and less drug

Accordingly, retrospective studies reveal that the T790M acquisition by afatinib (20.0%) was lower than that by gefitinib (52.8%) or erlotinib (44.6%). However, this is controversial due to contradictory reports showing that the frequency; hence of T790M at the time of progression was not different according to the type of EGFR-TKIs.

One limitation of our study is the small number of patients in the afatinib group. Afatinib has more side effects than gefitinib which affect the clinician’s choice of EGFR-TKIs. There is a tendency to favor gefitinib in female patients who are more concern about skin problems and less drug tolerability in real-world practice, which seems to be the reason why more female patients are include in the gefitinib group.

EGFR mutations are more common in female patients; also therefore the number of patients treate with afatinib came to be relatively small. it was evident that direct comparison despite uneven baseline characteristics; so between two groups might cause bias analysis, so the process of PS matching was needed. However, due to the small size of the afatinib group; so even with a 1:3 ratio assigne to gefitinib; so approximately 66% of the gefitinib data was discarded.
This led to significantly less statistical power in our analysis. To overcome this issue, more patients need to be enroll in the afatinib group in the following investigations. In conclusion, afatinib has the inhibitory effect on the growth of the lung cancer cells with low T790M frequency. However, it could not be translate into the clinical efficacy to lower the rate or delay the time of T790M acquisition.