Mutation | Frequency | Drug activity | References |
Exon 19 deletions# | 45% | Sensitive to first generation TKI | Costa et al. [13], 2007 |
L858R | 40% | Rosell et al. [14], 2009 | |
Maemondo et al. [15], 2010 | |||
Mitsudomi et al. [16], 2010 | |||
Mok et al. [17], 2009 | |||
Zhou et al. [18], 2011 | |||
Sequist et al. [19], 2013 | |||
In frame insertions exon 19 | 2% | Sensitive to first generation TKI | He et al. [20], 2012 |
G719X (A/C/S) | 2–3% | Sensitive to first generation TKI | Watanabe et al. [21], 2014 |
Possibly shorter response time | |||
L861 Q | 2% | Sensitive to first generation TKI | De Pas et al. [22], 2011 |
Pao and Chmielecki [23], 2010 | |||
L861 R | Rare | Resistance? | De Pas et al. [22], 2011 |
Exon 20 in frame insertions | 2%; up to 10% in some series | Resistance to first generation TKI | Pao and Chmielecki [23], 2010 |
Some - A763_Y764insFQEA - are sensitive to TKI | Oxnard et al. [24], 2013 | ||
Arcila et al. [25], 2013 | |||
Yasuda et al. [26], 2012 | |||
Yasuda et al. [27], 2013 | |||
T790M | ∼50% in progressing patients under TKI Rare in untreated patients | Resistance if secondary to treatment Negative impact on response rate and survival: may sometimes respond to first generation TKI | Sun et al. [28], 2013 Yu et al. [29], 2014 Ding et al. [30], 2014 |
D761Y | Rare | Uncertain significance, possible partial resistance | Balak et al. [31], 2006 |
L747 P/S | Rare | Uncertain significance, possible partial resistance | van der Wekken et al. [32], 2012 |
Costa et al. [33], 2007 | |||
Costa et al. [34], 2008 | |||
S768I | Rare | Resistance to first generation TKI? | Shigematsu et al. [35], 2005 |
Sensitive to afatinib? | De Pas et al. [22], 2011 | ||
May occur in association with other mutations | J.C. Yang and co-workers, personal communication | ||
E709 A/V | Rare | Resistance? | Shigematsu et al. [35], 2005 |
Occur in association with other activating mutations | |||
H870R | Rare | Resistance? | De Pas et al. [22], 2011 |
Occur with other mutations | |||
Shorten response time | |||
Other mutations: S720F, I715S, L862V, S784F | Rare | Unknown | Shigematsu et al. [35], 2005 |
De Pas et al. [22], 2011 | |||
Tsao et al. [36], 2005 | |||
Ludovini et al. [37], 2008 | |||
Compound mutations | Frequency unknown; few data exist and are mainly based on case reports |
#:There are several variants of exon 19 in frame deletions, some of them not encompassing the LRE region. Response to therapy may be different according to mutation type [38].