Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7)

關於LUX-Lung 7 一點點小小的心得：

1. Response rate 70% v.s. 56% (Afa v.s. Gef) 在這樣的情況下ASP8273和AZD9291的Phase III 第一線對上Erlotinib和Gefitinib要用多少sample size才能claim non-inferiority? (感覺要燒超多錢......) 但可以想見的是safety profile和病人的QoL 一定會比第一代和第二代的EGFR-TKI好很多。

2. 一開始的試驗設計primary endpoint是要看PFS和Disease control in 12 months，後來又加上了time-to-treatment failure 和 overall survival，disease control改成secondary endpoint。或許是考量到臨床上會有treatment beyond progression，才加上time-to-treatment failure ?

3. Phase IIb, randomized controlled, open-label study. 沒有hypothesis下的p value不知道代表著什麼樣的意義，應該只有HR 有參考價值吧。

Questions that I have.....

1. My understanding of statistically significant is based on a pre-defined hypothesis. We calculated the sample sizes according to the power of the design to answer the hypothesis. How can we have no hypothesis and claim statistically significant ? 

2. I knew that we could calculate sample size according to the estimated response rate. Regarding to FLAURA study or any first-line 3rd-G TKI v.s. 1st-G TKI study, how could we estimate the sample sizes by response rate since the difference of these two agents are quite small ? Can we do that by the difference of PFS or PFS rate at any given time point, for example, PF rate at 18 months or 24 months ? 

3. I am not sure about the anti-tumor activity of afatinib in acquired resistance, eg. T790M. In Lux-Lung 4, there is only 8.2% of response rate in patients failed one or two TKI and more than 80% of them received afatinib in less than 4 weeks after previous TKIs. But, we did not know much about the resistance profile at that time. Recently, NTUH published a paper about the resistance profile after afatinib treatment. It showed no big difference comparing to get or erlo. 

I tend to believe that afatinib have better potency to treat EGFRmu tumor.