The anaplastic lymphoma kinase (ALK) is a
receptor tyrosine kinase that is aberrant in a variety of malignancies. For
example, activating missense mutations
within full length ALK are found in a subset of neuroblastomas (Chen et al. 2008;
George et al. 2008;
al. 2008; Mosse et al. 2008). By contrast, ALK
fusions are found in anaplastic large cell lymphoma (e.g., NPM-ALK; Morris et al. 1994),
colorectal cancer (Lin
et al. 2009; Lipson et al. 2012), inflammatory
myofibroblastic tumor (IMT; Lawrence et al. 2000) non-small
cell lung cancer (NSCLC; Choi et al. 2008; Koivunen et al. 2008;
Rikova et al. 2007;
al. 2007; Takeuchi et al. 2009), and ovarian cancer
(Ren et al. 2012).
All ALK fusions contain the entire ALK tyrosine kinase domain. To date, those tested
biologically possess oncogenic activity in vitro and in vivo (Choi et al. 2008;
Morris et al. 1994;
al. 2007; Takeuchi et al. 2009). ALK fusions and
copy number gains have been observed in renal cell carcinoma (Debelenko et al.
2011; Sukov et
al. 2012). Finally, ALK copy number and protein expression aberrations have also
been observed in rhabdomyosarcoma (van Gaal et al. 2012).
The various N-terminal fusion partners promote dimerization
and therefore constitutive kinase activity
(for review, see Mosse,
Wood, and Maris 2009). Signaling downstream of ALK fusions results in
activation of cellular pathways known to be involved in cell growth and cell proliferation
Figure 1. Schematic representation of ALK
fusions. "X" represents the various fusion partners that have been described. Dimerization of the ALK fusion mediated
by the fusion partner ("X"), results in constitutive activation of the ALK tyrosine kinase. ALK signaling results in
pro-growth and anti-apoptosis.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. ALK. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
ALK in Non-Small Cell Lung Cancer (NSCLC)
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2014. ALK in Non-Small Cell Lung
Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/alk/
(Updated September 29).
Last Updated: September 29, 2014
ALK Fusions in Non-Small Cell Lung Cancer
|Location of mutation
||Chromosomal rearrangements involving the ALK gene on 2p23
|Frequency of ALK fusions in NSCLC
and Ramalingam 2012)
|Implications for Targeted Therapeutics
|Response to ALK TKIs
||Confers increased sensitivity
|Response to HSP90 inhibitors
||Confers increased sensitivity
|Response to EGFR TKIs
||Confers decreased sensitivity
|Response to anti-EGFR antibodies
||Unknown at this time
In an initial phase I trial, patients whose tumors harbored an ALK fusion displayed
a 60.8% radiographic objective response rate to the dual ALK/MET tyrosine kinase inhibitor (TKI), crizotinib (Camidge et al. 2012).
Median progression-free survival (PFS) was demonstrated to be 9.7 months, and the
probability of PFS at six months was estimated to be 87.9%. An international phase III trial
randomizing patients with advanced lung cancer harboring ALK fusions to crizotinib
vs. standard chemotherapy (docetaxel or pemetrexed) after disease progression on first-line
treatment confirmed significant PFS benefit with crizotinib in this patient population (7.7
months versus 3.0 months with chemotherapy; Shaw et al.
2013a). Several novel ALK-inhibitors are currently in clinical trials (Camidge et
al. 2013a; Camidge
et al. 2013b; Gadgeel
et al. 2013; Seto
et al. 2013; Shaw et al. 2013b).
In a large phase I trial, 180 ALK-fusion positive NSCLC patients demonstrated a 60%
response rate when treated with the second-generation ALK-inhibitor ceritinib (Kim et al.
2014). The response rate was 55.4% in a 121-patient cohort previously treated with
crizotinib, and 69.5% in a 59-patient cohort that was treatment-naïve (Kim et al.
Retrospective studies have evaluated activity of pemetrexed in ALK-fusion positive
NSCLC cohorts compared with other molecular subtypes (KRAS, EGFR). A small
retrospective study demonstrated that patients with ALK-fusion positive NSCLC
have improved response rates and progression-free survival when treated with either
pemetrexed monotherapy or combination therapy compared with KRAS-mutated,
EGFR-mutated, or KRAS/EGFR/ALK wild type
cohorts (Camidge et
al. 2011). In contrast, a subsequent larger restrospective analysis has
reported a shorter time to progression and lower response rate in ALK-fusion
positive NSCLC (Scagliotti et al. 2012). Whether ALK-fusion
positive NSCLC is more sensitive to pemetrexed than an unselected NSCLC cohort is still a
topic for investigation.
In addition, in a phase II non-randomized study of the heat shock protein 90 (HSP-90) inhibitor, IPI-504, in patients with
advanced lung cancer who previously progressed on EGFR TKI therapy, tumors from 3 patients
were retrospectively found to have ALK rearrangements. Two of these patients had
partial response while a third had prolonged stable disease (7.2 months, 24% decrease in
tumor size; Sequist et
al. 2010). In a phase II study of the HSP-90 inhibitor, ganetespib, 7 out
of 8 crizotinib-naïve ALK-fusion positive NSCLC patients experienced a partial
response (4 patients) or stable disease (3 patients), with an estimated median progression-free
survival interval of 8.1 months (Socinski et al. 2013).
In the vast majority of cases, ALK rearrangements are non-overlapping with other
oncogenic mutations found in NSCLC (e.g.,
EGFR mutations, KRAS mutations, etc.; Inamura et al. 2009;
al. 2010; Shinmura et al. 2008; Wong et al. 2009).
||Study Type / Phase
||Line of Treatment
||Mutation Status / Group
||# pts in study
|First-Generation ALK TKI (Crizotinib)
et al. 2013a
||Phase III (PROFILE 1007)
Kim et al. 2012
||Phase II (PROFILE 1005)
|Camidge et al. 2012
||Phase I (PROFILE 1001)
|Second-Generation ALK TKIs (Brigatinib, CH5424802, LDK378)
|Seto et al.
||46 (phase II)
|Gadgeel et al.
||≥ 2nd (failed crizotinib)
ALK+ NSCLC with prior crizotinib
||37 (evaluable N=30)
|Kim et al. 2016;
||Phase II (ALTA)
||brigatinib (90 mg qd)
|brigatinib (90 mg for 7d followed by 180 mg qd)
al. 2014; Shaw et al. 2013b
||Phase I (ASCEND-1)
||180 (evaluable N=66)
ALK+ crizotinib pretreated subgroup
ALK+ crizotinib naïve subgroup
|HSP-90 Inhibitors (retaspimycin, ganetespib)
|Sequist et al. 2010
ALK+ NSCLC subgroup
ALK+ NSCLC crizotinib naïve subgroup
NOTE: PFS = progression-free survival; PR = partial response; OS = overall survival; SD =
stable disease; TTP = time to progression.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2017. ALK Fusions in Non-Small
Cell Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/alk/66/
(Updated May 2).
Last Updated: May 2, 2017
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