LUX-Lung 7 Comments and replies. Afatinib v.s. Gefitinib

這一期Lancet Oncology有三篇Commentary討論LUX-Lung 7，節錄一些有趣的觀點:
先複習一下這個study, Afatinib v.s. Gefitinib, NO HYPOTHESIS.

Three co-primary endpoints: PFS, OS, Time-to-treatment failure

1. 沒有overall survival的data。這篇文章應該要報出所有的primary endpoints才合理。Time-to-treatment-failure Afatinib (13.7 months) v.s. Gefitinb (11.5 months)但是兩個PFS是很相近的，表示Afatinib有比較多的treatment beyond progression，主文中應該要指出progression site, metastatic numbers, and volumetric burden應該可以提供一些有意義的訊息。

2. Afatinib和gefitinib看起來沒什麼差異，除非有更大的study可以證明兩者progression之後的resistance profile有差異，不然其實first line要用誰根本就沒差，並且有提到台大吳醫師和施醫師做的post-afatinib的resistance mechanism的paper! 如果post afatinib最常見的mutation不是T790M，那這樣病人就無法使用Osimertinib，這對病人並不太好。

3. 也許afatinib irreversible binding的特徵有使他的效果變得更強，主文中也有提到maximum percentage change in the sum of target lesion，但是並沒有去探討它和預後的關係，或許這種"depth of response"和預後會有關，在rheumatoid arthritis的治療也有提到deep remission的概念，或許未來在EGFR-TKI的治療上可以再去探討這種deep response的概念，或許跟prognosis關聯。

沒提到的事情(個人淺見):
1. 這個Study沒有hypothesis，如果沒有Hypothesis，那我們要怎麼去討論difference和significance呢?

2. Osimertinib是有可能往First-line 發展的，這對現有的First-Generation TKI 會有什麼影響? Trial應該怎麼設計才能回答目前這些問題。

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.

進擊的妥復克Afatinib

Afatinib for lung cancer: let there be light?

隨著LUX-lung 3 和LUX-lung 6的發表，afatinib在first-line先後打敗了Pem+Cis和Gem+Cis， 在有exon19 or L858R的病人當中，PFS 分別為 13.6 months和11.1 months．Afatinib在有EGFR common mutation的病人，於第一線的治療比常規化療還好，看起來似乎也有比gefitinib或Erlotinib好的機會．文中作者提出幾點afatinib的臨床試驗尚未回答的問題：

1. 對uncommon mutation的病人是否有效？

臺大楊P在WCLC提出在LUX-Lung series中afatinib 對uncommon mutation的病人效果還不錯
G719X PFS 13.8 months, L861Q 8.2 months，但是在LUX-Lung 6的subgroup analysis看起來無差別，uncommon mutation是否第一線仍該考慮chemotherapy ?

2. non-Asian 的病人是否也一樣有效？

LUX-Lung 6是做在亞洲，non-Asian的病人只有在LUX-lung 3中有61個．

3. Gefitinib, erlotinib, afatinib, 到底該選誰呢(dochi?) 

這三個藥物的toxicity profile都不太一樣，而且彼此head-to-head的study結果也還沒出來，也無法知道選誰比較好．