Biomedical Engineering Reference
In-Depth Information
20 months compared with 16 months for the wild-type cohort [40].
The results were not statistically significant as it was not powered to
detect a difference in overall survival. In addition, the analysis was
limited by the retrospective design of the study, the short duration
of follow-up, the small number of events, the demographics of the 2
cohorts and the number and type of therapies received. For instance,
41% of the
-positive patients went on to participate in
a clinical trial with an ALK inhibitor, which likely influenced the
outcome of this cohort [40]. In another retrospective study of surgical
outcomes in China, a similar improved trend in overall survival was
seen in the
EML4-ALK
EML4-ALK
-positive cohort (
n
= 12) compared with the
-negative
cohort had a median overall survival of 50.5 months, whereas the
EML4-ALK
EML4-ALK
-negative cohort (
n
= 91) [35]. The
EML4-ALK
-positive cohort did not have enough events to determine
the median survival [35]. Given the limited data available, it is still
unclear what the prognostic implications are for those with
ALK
rearranged NSCLC. Further retrospective and prospective analyses
will need to be performed.
16.5.1
Preclinical ALK Targeted Therapies in NSCLC
Several compounds have been shown to inhibit the kinase activity
of ALK thereby suppressing the growth of cells expressing the
NPM-ALK fusion protein commonly seen in ALCL. With the initial
groundbreaking discovery of the
EML4-ALK
translocation in NSCLC,
Soda
hinted that these same compounds may also be used to
inhibit the
et al.
fusion protein in NSCLC. Initial preclinical
studies with the NPM-ALK inhibitors, WHI-P154 and NVP-TAE684,
were shown to be effective in the regression of established tumors,
both
EML4-ALK
and in mouse xenografts [9, 54, 55]. Another small
molecule TKI targeting MET (mesenchymal epithelial transition
growth factor), a member of the IR family of TKs, showed antitumor
effects on cell and tumor models of NPM-ALK driven ALCL at
nanomolar concentrations [54, 55]. Based on these findings, this
oral ATP-competitive dual ALK/MET inhibitor, PF-2341066 (better
known as crizotinib) became the first ALK inhibitor to date to
undergo clinical trial testing for safety and efficacy in patients with
ALK-rearranged NSCLC.
in vitro
