Table 1. Off-target resistance mechanisms and treatment options in ALK-positive NSCLC.

Off-target resistance mechanism	Treatment option	Literature
EGFR activation	Dual blockade of ALK and EGFR	Miyawaki, et al. 2017 [31] Tani, et al. 2016 [32]
HER activation	Dual blockade of ALK and EGFR	Tanizaki, et al. 2012 [33] Wilson, et al. 2015 [34]
KIT amplification	-	Katayama, et al. 2012 [35]
MET amplification	Dual blockade of ALK and MET	Dagogo-Jack, et al. 2020 [36]
MEK reactivation	Dual blockade of ALK and MEK	Hrustanovic, et al. 2015 [37] Shrestha, et al. 2020 [38]
PIK3CA mutations	-	Gainor, et al. 2016 [11] Crystal, et al. 2014 [39]
IGF-1R activation	Dual blockade of ALK and IGF-1R	Lovly, et al. 2014 [40]
SRC activation	Dual blockade of ALK and SRC	Crystal, et al. 2014 [39] Yoshida, et al. 2017 [41]
TP53 mutation	-	Gainor, et al. 2016 [11]
KRAS mutations (excluding G12C)	-	Doebele, et al. 2012 [20] Pailler, et al. 2019 [14]
KRAS G12C mutation	Sotorasib	McCoach, et al. 2018 [42] Hong, et al. 2020 [43]
RET fusion	Selpercatinib	Drilon, et al. 2020 [44] McCoach, et al. 2018 [42]