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 Test: 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.9
  • 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.

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
  • Mechanism of Action: Each of these approved agents functions as an inhibitor of tyrosine kinase receptors and exhibits activity against ALK. However, they differ somewhat in their activity across various tyrosine kinases. Ceritinib specifically targets ROS1 and ALK, while alectinib primarily inhibits RET and ALK.14,16 Other ALK inhibitors have broader inhibitory activity: crizotinib targets ALK, c-MET, ROS1, and RON tyrosine kinase receptors; brigatinib targets ALK, ROS1, FLT-3, as well as certain EGFR deletions and point mutations; and lorlatinib demonstrates activity against ALK and ROS1, along with TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK.15,17,18

Learn more about Alectinib >

Learn more about Brigantinib >

Learn more about Ceritinib >

Learn more about Crizotinib >

Learn more about Lorlatinib >

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). Package insert. Genentech, Inc; September 2021.
  15. ALUNBRIG (brigatinib). Package insert. Takeda Pharmaceuticals America, Inc; February 2022.
  16. ZYKADIA (ceritinib). Package insert. Novartis Pharmaceuticals Corporation; October 2021.
  17. XALKORI (crizotinib). Package insert. Pfizer Inc; September 2023.
  18. LORBRENA (lorlatinib). Package insert. Pfizer Inc; April 2023.

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