• What is ALK?
  • ALK in Lung Cancer
  • ALK Fusions
  • Clinical Trials

ALK

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; Janoueix-Lerosey et 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; Soda et 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; Soda et 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).

alk.png

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.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. ALK. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/alk/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

ALK in Non-Small Cell Lung Cancer (NSCLC)

Approximately 3–7% of lung tumors harbor ALK fusions (Koivunen et al. 2008; Kwak et al. 2010; Shinmura et al. 2008; Soda et al. 2007; Takeuchi et al. 2008; Wong et al. 2009). ALK fusions are more commonly found in light smokers (< 10 pack years) and/or never-smokers (Inamura et al. 2009Koivunen et al. 2008; Kwak et al. 2010; Soda et al. 2007; Wong et al. 2009). ALK fusions are also associated with younger age (Inamura et al. 2009; Kwak et al. 2010; Wong et al. 2009) and adenocarcinomas with acinar histology (Inamura et al. 2009; Wong et al. 2009) or signet-ring cells (Kwak et al. 2010). Clinically, the presence of EML4-ALK fusions is associated with EGFR tyrosine kinase inhibitor (TKI) resistance (Shaw et al. 2009).

Multiple different ALK rearrangements have been described in NSCLC. The majority of these ALK fusion variants are comprised of portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the ALK gene. At least nine different EML4-ALK fusion variants have been identified in NSCLC (Figure 1; Choi et al. 2008; Horn and Pao 2009; Koivunen et al. 2008; Soda et al. 2007; Takeuchi et al. 2008; Takeuchi et al. 2009; Wong et al. 2009). In addition, non-EML4 fusion partners have also been identified, including KIF5B-ALK (Takeuchi et al. 2009) and TFG-ALK (Rikova et al. 2007). Clinically, the presence of an ALK rearrangement is detected by fluorescence in situ hybridization (FISH) with an ALK break apart probe. FISH testing is not able to discern which particular ALK fusion is found in a clinical sample.

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; Kwak et al. 2010; Shinmura et al. 2008; Wong et al. 2009).

alk-fusions.png

Figure 1.
Schematic of ALK fusions found in lung cancer.

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

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

Properties
Location of mutation Chromosomal rearrangements involving the ALK gene on 2p23
Frequency of ALK fusions in NSCLC 3–7% (Pillai 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. 2014).

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; Kwak et al. 2010; Shinmura et al. 2008; Wong et al. 2009).

ALK Fusions
Reference Study Type / Phase Line of Treatment Treatment Agent Mutation Status / Group # pts in study Response Rate PFS (months) OS (months)
First-Generation ALK TKI (Crizotinib)
Shaw et al. 2013a Phase III (PROFILE 1007) 2nd pemetrexed ALK+ NSCLC 99   4.2  
2nd crizotinib ALK+ NSCLC 173 65% 7.7  
Kim et al. 2012 Phase II (PROFILE 1005) ≥ 2nd crizotinib ALK+ NSCLC 261 60% 8.1  
Camidge et al. 2012 Phase I (PROFILE 1001) ≥ 1st crizotinib ALK+ NSCLC 143 60.8% 9.7  
Second-Generation ALK TKIs (Brigatinib, CH5424802, LDK378)
Seto et al. 2013 Phase I/II ≥ 1st CH5424802 (RO5424802) ALK+ NSCLC 46 (phase II) 93.5%    
Gadgeel et al. 2013 Phase I ≥ 2nd (failed crizotinib) CH5424802 (RO5424802) ALK+ NSCLC with prior crizotinib 37 (evaluable N=30) 48%    
Kim et al. 2016; Phase II (ALTA) ≥ 2nd brigatinib (90 mg qd) ALK+ NSCLC 112 46% 8.8 (DoR)  
brigatinib (90 mg for 7d followed by 180 mg qd) ALK+ NSCLC 110 54% 11.1 (DoR)  
Kim et al. 2014; Shaw et al. 2013b Phase I (ASCEND-1) ≥ 1st ceritinib (LDK378) ALK+ NSCLC 180 (evaluable N=66) 60% 7  
ALK+ crizotinib pretreated subgroup 121 55% 6.9  
ALK+ crizotinib naïve subgroup 59 70%    
HSP-90 Inhibitors (retaspimycin, ganetespib)
Sequist et al. 2010 Phase II ≥ 2nd retaspimycin (IPI-504) ALK+ NSCLC subgroup 3 67%    
Socinski et al. 2013 Phase II ≥ 2nd ganetespib ALK+ NSCLC crizotinib naïve subgroup 8 50% 8.1  
​NOTE: PFS = progression-free survival; PR = partial response; OS = overall survival; SD = stable disease; TTP = time to progression.

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Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

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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