ALK

  • Anaplastic lymphoma kinase proto-oncogene (ALK)
  • Gene Location: chromosome 2 (2p23)

ALK Biology

  • The ALK gene, located on chromosome 2p23, encodes a receptor tyrosine kinase belonging to the insulin receptor superfamily.1
  • Expression of ALK occurs in a variety of tissue types with the greatest expression seen in the brain.2
  • ALK is implicated in the activation of multiple signaling pathways, such as MAPK, PI3K/AKT, JAK/STAT, and mTOR, which influence cellular growth, transformation, and resistance to apoptosis.1,3-5

Etiology and Epidemiology

  • In non-small cell lung cancer (NSCLC), ALK rearrangements can lead to hyperactivation of ALK-mediated signaling, thereby leading to cancer development.
  • The first ALK rearrangement, involving an EML4-ALK gene fusion, was identified in 2007.5
  • Subsequently, over 20 different ALK fusion protein partners have been identified.6
  • ALK rearrangements are present in approximately 2% to 8% of NSCLC, primarily occurring in adenocarcinomas, women, individuals who are never- or light smokers, and a high frequency of brain metastases at diagnosis.7
  • Compared to chemotherapy, use of the first-generation ALK TKI crizotinib demonstrated superior activity with improved overall response rates (ORRs) and progression-free survival.4,7,8 However, the limited blood brain barrier penetration of crizotinib posed a challenge given the frequent occurrence of brain metastases in this patient population. This led to the development of newer ALK TKIs (eg, ceritinib, alectinib, brigatinib, lorlatinib) with greater efficacy and blood brain barrier penetration, whereby these agents have replaced crizotinib as first-line treatment for ALK-rearranged NSCLC.4,7,8
  • Despite demonstrated ORRs of up to 80%, resistance to ALK TKIs evolves.7 This includes on-target alterations (eg, ALK mutations/gene amplification), off-target bypass signaling pathways changes, such as EGFR, MET alterations or histological transformation to small cell lung cancer.4,8

ALK Testing

When to Test9:

  • All patients with advanced or metastatic lung adenocarcinoma should undergo broad molecular profiling at diagnosis.
  • Broad molecular profiling should also be considered for those with advanced or metastatic lung squamous cell carcinoma at diagnosis.
  • In early-stage disease, testing at diagnosis should include assessment of PD-L1, EGFR, and ALK.

Available Testing Methods:

  • Four primary methods for ALK testing are available: Fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), reverse transcriptase‐PCR (RT‐PCR), and next-generation sequencing (NGS).12
  • IHC allows for quick prescreening and may be applicable in certain scenarios. FDA-approved testing exists for both FISH and IHC methods. Although FISH has historically been the most widely used method for ALK testing, the use of NGS-based methods is rapidly increasing, particularly RNA-based NGS testing given the superiority in fusion detection.13

Guideline Recommendations for Testing:

  • The National Comprehensive Cancer Network (NCCN) NSCLC Panel recommends testing for ALK rearrangements in patients with metastatic nonsquamous NSCLC based on data showing the efficacy of alectinib, brigatinib, ceritinib, crizotinib, or lorlatinib for ALK rearrangements and on FDA approvals.9
  • ALK testing may also be considered for patients with squamous cell NSCLC, as ALK rearrangements also occur in this subtype, albeit less frequently than in nonsquamous NSCLC.10,11
  • In its 2023 update (Version 1), [TMT2] the NCCN recommends testing for ALK rearrangements, alongside EGFR mutations, in eligible patients with resectable early-stage NSCLC (stages IB–IIIA, stage IIIB [only T3,N2]) to determine optimal neoadjuvant and adjuvant approaches, due to the potential intrinsic resistance to immunotherapy.9

ALK Targeted Therapy

Approved Agents:

  • The US Food & Drug Administration (FDA) has approved 5 oral ALK inhibitors (crizotinib, approved in 2011; ceritinib, 2014; alectinib, 2015; brigatinib, 2017; and lorlatinib, 2018) for treating ALK-positive metastatic NSCLC.14-18

Alectinib14

  • FDA-Approved Indication:
    • Adjuvant treatment in adult patients following tumor resection of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) (tumors ≥ 4 cm or node positive) as detected by an FDAapproved test.
    • The treatment of adult patients with ALK-positive metastatic NSCLC as detected by an FDA-approved test.
  • Mechanism of Action:
    • Alectinib is a tyrosine kinase inhibitor that targets ALK and RET.
    • In nonclinical studies, alectinib inhibited ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins STAT3 and AKT, and decreased tumor cell viability in multiple cell lines harboring ALK fusions, amplifications, or activating mutations.
    • Alectinib in vitro and in vivo activity against multiple mutant forms of the ALK enzyme, including some mutations identified in NSCLC tumors in patients who have progressed on crizotinib.
    • In mouse models implanted with tumors carrying ALK fusions, administration of alectinib resulted in antitumor activity and prolonged survival, including in mouse models implanted intracranially with ALK-driven tumor cell lines.
  • Drug Information:
  • Patient Resources:

Brigatinib15

  • FDA-Approved Indication:
    • The treatment of adult patients with ALK-positive, metastatic non–small cell lung cancer (NSCLC) as detected by an FDA-approved test.
  • Mechanism of Action:
    • Brigatinib is a tyrosine kinase inhibitor (TKI) with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations.
    • Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays.
    • At clinically achievable concentrations (≤500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y.
    • Brigatinib exhibited in vivo antitumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib.
  • Drug Information:
  • Patient Resources:

Ceritinib16

  • FDA-Approved Indication:
    • The treatment of patients with metastatic non–small cell lung cancer (NSCLC) whose tumors are ALK-positive as detected by an FDA-approved test.
  • Mechanism of Action:
    • Ceritinib is a kinase inhibitor.
    • Targets of ceritinib inhibition identified in either biochemical or cellular assays at clinically relevant concentrations include ALK, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1. Among these, ceritinib is most active against ALK.
    • Ceritinib inhibited autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells in in vitro and in vivo assays.
  • Drug Information:
  • Patient Resources:

Crizotinib17

  • FDA-Approved Indication:
    • The treatment of metastatic non-small cell lung cancer (NSCLC) whose tumors are ALK- or ROS1-positive as detected by an FDA-approved test.
  • Mechanism of Action:
    • Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, HGFR, c-Met, ROS1, and RON.
    • Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins.
    • The formation of ALK fusion proteins results in activation and dysregulation of the gene's expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins.
  • Drug Information:
  • Patient Resources:

Ensartinib19

  • FDA-Approved Indication:
    • The treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) who have not previously received an ALK-inhibitor.
  • Mechanism of Action:
    • Ensartinib is a kinase inhibitor of anaplastic lymphoma kinase (ALK) and inhibits other kinases including MET and ROS1.
    • In vitro, ensartinib inhibited phosphorylation of ALK and its downstream signaling proteins AKT, ERK, and S6, thereby blocking ALK-mediated signaling pathways and inhibiting proliferation in cell lines harboring ALK fusions and mutations.
    • In vivo, ensartinib showed anti-tumor activity in a mouse xenograft model of human NSCLC harboring an ALK fusion.
  • Drug Information:
  • Patient Resources:

Lorlatinib18

  • FDA-Approved Indication:
    • The treatment of patients with ALK-positive, metastatic non–small cell lung cancer (NSCLC) whose disease has progressed on:
      • crizotinib and at least one other ALK inhibitor for metastatic disease; or
      • alectinib as the first ALK inhibitor therapy for metastatic disease; or
      • ceritinib as the first ALK inhibitor therapy for metastatic disease.
    • This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
  • Mechanism of Action:
    • Lorlatinib is a kinase inhibitor with in vitro activity against ALK and ROS1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK.
    • Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors.
    • Lorlatinib also demonstrated anti-tumor activity and prolonged survival in mice implanted intracranially with EML4-ALK-driven tumor cell lines.
  • Drug Information:
  • Patient Resources:

References

  1. Della Corte CM, Viscardi G, Di Liello R. et al. Role and targeting of anaplastic lymphoma kinase in cancer. Mol Cancer. 2018;17(1):30.doi:10.1186/s12943-018-0776-2
  2. The Human Protein Atlas. ALK. Accessed March 22, 2024. https://www.proteinatlas.org/ENSG00000171094-ALK/tissue
  3. Stoica GE, Kuo A, Powers C, et al. Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. J Biol Chem. 2002;277(39):35990-35998. doi:10.1074/jbc.M205749200
  4. Peng L, Zhu L, Sun Y, et al. Targeting ALK rearrangements in NSCLC: current state of the art. Front Oncol.2022;12:863461. doi:10.3389/fonc.2022.863461
  5. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561-566. doi:10.1038/nature05945
  6. Hallberg B, Palmer RH. The role of the ALK receptor in cancer biology. Ann Oncol. 2016;suppl 3:iii4-iii15. doi:10.1093/annonc/mdw301
  7. Schmid S, Cheng S, Chotai S, et al. Real-world treatment sequencing, toxicities, health utilities, and survival outcomes in patients with advanced ALK-rearranged non-small-cell lung cancer. Clin Lung Cancer. 2023;24(1):40-50. doi:10.1016/j.cllc.2022.09.007
  8. Chazan G, Solomon BJ. Optimal first-line treatment for metastatic ALK+ non-small cell lung cancer—a narrative review. Transl Lung Cancer Res. 2023;12(2):369-378. doi:10.21037/tlcr-22-656
  9. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, NSCLC, v3.2024. Accessed March 22, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  10. Lam VK, Tran HT, Banks KC, et al. Targeted tissue and cell-free tumor DNA sequencing of advanced lung squamous-cell carcinoma reveals clinically significant prevalence of actionable alterations. Clin Lung Cancer. 2019;20(1):30-36 e33. doi:10.1016/j.cllc.2018.08.020
  11. Sands JM, Nguyen T, Shivdasani P, et al. Next-generation sequencing informs diagnosis and identifies unexpected therapeutic targets in lung squamous cell carcinomas.Lung Cancer. 2020;140:35-41. doi:10.1016/j.lungcan.2019.12.005
  12. Du X, Shao Y, Qin HF, Tai YH, Gao HJ. ALK-rearrangement in non-small-cell lung cancer (NSCLC). Thorac Cancer. 2018;9(4):423-430. doi:10.1111/1759-7714.12613
  13. Lin Hm, Wu Y, Tin T, et al. Real-world ALK testing trends in patients with advanced non-small cell lung cancer in the United States. Clin Lung Cancer. 2023;24(1):E39-E49. doi:10.1016/j.cllc.2022.09.010
  14. Alecensa (alectinib). Prescribing information. Genentech, Inc,; 2024. Accessed December 2, 2024. https://www.gene.com/download/pdf/alecensa_prescribing.pdf
  15. Alunbrig (brigatinib). Prescribing information. Takeda Pharmaceuticals America, Inc; 2024. Accessed December 12, 2024. https://www.alunbrig.com/sites/default/files/2022-10/prescribing-information.pdf
  16. Zykadia (ceritinib). Prescribing information. Novartis Pharmaceuticals Corporation; 2021. Accessed December 12, 2024. https://www.novartis.com/us-en/sites/novartis_us/files/zykadia.pdf 
  17. Xalkori (crizotinib). Prescribing information. Pfizer Inc; 2023. Accessed December 12, 2024. https://labeling.pfizer.com/ShowLabeling.aspx?id=676
  18. Lorbrena (lorlatinib). Prescribing information. Pfizer Inc; April 2023. https://labeling.pfizer.com/ShowLabeling.aspx?id=11140
  19. Ensacova (ensartinib). Prescribing information. Xcovery Holdings, Inc., 2024. Accessed April 30, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218171s000lbl.pdf

Additional Reading

Kerr K. ALK in lung cancer ESMO biomarker factsheet. ESMO. Updated August 2, 2015. Accessed March 22, 2024. https://oncologypro.esmo.org/education-library/factsheets-on-biomarkers/alk-in-lung-cancer

Kim H, Chung JH. Overview of clinicopathologic features of ALK-rearranged lung adenocarcinoma and current diagnostic testing for ALK rearrangement. Transl Lung Cancer Res. 2015;4(2):149-155. doi:10.3978/j.issn.2218-6751.2014.12.02

Rosas G, Ruiz R, Araujo JM, Pinto JA, Mas L. ALK rearrangements: Biology, detection and opportunities of therapy in non-small cell lung cancer. Crit Rev Oncol Hematol. 2019;136:48-55. doi:10.1016/j.critrevonc.2019.02.006

Cognigni V, Pecci F, Lupi A, et al. The landscape of ALK-rearranged non-small cell lung cancer: a comprehensive review of clinicopathologic, genomic characteristics, and therapeutic perspectives. Cancers (Basel). 2022;14(19):4765. doi:10.3390/cancers14194765

Clavé S, Jackson JB, Salido M, et al. Comprehensive NGS profiling to enable detection of ALK gene rearrangements and MET amplifications in non-small cell lung cancer. Front Oncol. 2023;13:1225646. doi:10.3389/fonc.2023.1225646