Among cancer types, lung cancer is the most frequently diagnosed, having accounted for 11.4% of the estimated 19.3 million new cancer cases globally in 2020. Lung cancer is also the leading cause of cancer-related death, representing 18% of almost 10 million deaths (Figure 1).1 These statistics are consistent with those reported by the Centers for Disease Control and Prevention in the United States, where lung cancer has the third highest incidence and the highest rate of cancer-related death.2

Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers and represents a significant percentage of new cases and deaths.3 An acquired chromosome mutation is found in approximately 5% of NSCLC, resulting in fusion between the anaplastic lymphoma kinase (ALK) gene and various fusion partners.4 The most common fusion partner is the echinoderm microtubule-associated protein-like 4 (EML4) gene; the EML4-ALK variant is therefore the most common ALK-positive NSCLC.4 An increased risk of central nervous system (CNS) metastasis is common in the EML4-ALK NSCLC variant.3 Among patients with this variant, 50% to 60% develop brain metastases, and metastatic CNS disease is present at diagnosis among approximately 20% to 30% of patients.3,5

The approval of tyrosine kinase inhibitors (TKIs) transformed the treatment landscape for advanced metastatic ALK-positive NSCLC from an eminently chemotherapy-based approach to a targeted approach. However, treatment resistance due to the development of secondary ALK mutations and disease progression, particularly brain metastasis, is challenging to manage and requires appropriate selection and sequencing of TKI therapies. A practical approach to the treatment of ALK-positive NSCLC is presented in this article.

Start with genetic testing to confirm an ALK mutation

EML4-ALK transformation and treatment resistance arises from a genetic mutation and, as such, can be diagnosed through genetic testing. These tests include tissue- or plasma-based cell-free DNA techniques or liquid biopsy; blood tests for carcinoembryonic antigen, which is absent or present at a low level in people with an ALK mutation; and imaging of the lung.6,7

Current consensus is that all patients with advanced-stage adenocarcinoma be tested for ALK and other treatable genetic mutations, regardless of sex, race, smoking history, or other risk factors.8 Other experts recommend that all patients who have been diagnosed with NSCLC undergo genetic testing. Furthermore, patients who required genetic analysis at the time of initial diagnosis should be considered for liquid biopsy rather than tissue biopsy, particularly if tissue is challenging to obtain, a delay in diagnosis is expected, or a contraindication to biopsy exists.5

Genetic testing methodologies for use in NSCLC include fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), reverse transcription-polymerase chain reaction, and next-generation sequencing.4,8

  • FISH is the gold standard for detecting ALK rearrangements and is often used to validate other ALK mutation tests; however, this methodology cannot be used to distinguish among the various ALK fusion partners.4
  • The rationale for IHC is that in contrast to NSCLC with rearranged ALK, in which ALK is expressed at a modest level, NSCLC tissue without the ALK mutation does not express a detectable level of ALK. Therefore, ALK antibodies can reliably detect ALK-positive NSCLC. Although IHC is less costly, faster, and requires less expertise than FISH, it can be less reliable because, in some cases, in the same patient, IHC yields a negative result for ALK while FISH returns a positive result. Most laboratories recommend initial IHC and confirmation by FISH.4
  • Adding next-generation sequencing to these techniques can overcome limitations of multiple single-gene tests and identify ALK-acquired resistance mutations outside of gene fusions.

Liquid biopsy is minimally invasive and provides a rapid, highly specific diagnosis of ALK mutations.9 The International Association for the Study of Lung Cancer states that a positive diagnosis of ALK rearrangement by liquid biopsy is sufficient to initiate ALK-targeted therapy.10 According to McCusker and colleagues,5 if AKL-positive NSCLC progression is suspected during treatment with a first-generation or second-generation TKI, liquid biopsy is selected over tissue biopsy to diagnose resistance mechanisms due to the high specificity of plasma cell-free DNA for detecting ALK mutations.

TKI options for treating ALK-positive NSCLC

Approval of the first-generation TKI, crizotinib, in 201111 radically changed the treatment landscape and outcomes for patients with ALK-positive NSCLC. Crizotinib is an orally available small molecule that can penetrate the blood-brain barrier and is effective in patients with malignancy that has metastasized to the brain. A comparative study of crizotinib and chemotherapy demonstrated drastically improved progression-free survival (PFS) and a higher objective response rate with crizotinib.4 Crizotinib is approved as a first-line treatment for ALK-positive NSCLC based on the PROFILE 1014 study ( Identifier: NCT01154140), which demonstrated its superior efficacy and survival advantage compared with platinum-based chemotherapy.12,13

Treatment resistance from mutations in the ALK gene is a significant challenge with TKI therapies; indeed, resistance to crizotinib generally occurs within 2 years after initiating treatment. Second- and third-generation TKIs have been developed to overcome resistance. Ceritinib,14 alectinib,15 and brigatinib16 are second-generation TKIs effective against ALK-positive NSCLC that is resistant to crizotinib. Ceritinib and alectinib, approved in 2015, and brigatinib, approved in 2017, are all indicated for use in the first-line setting. A third-generation TKI, lorlatinib, was approved in March 2021 and is also indicated for use in the first-line treatment of ALK-positive metastatic NSCLC.17,18

ALK mutations are not the same; neither are TKIs

Fusion of the ALK gene with various partner proteins is a characteristic feature of NSCLC. The most common fusion partner is the EML4 protein, of which more than 15 variants have been identified, including the most common:

  • Variant 1 (breakpoint at exon 13 [43% of patient cases]);
  • Variant 2 (breakpoint at exon 20 [6% of cases]); and
  • Variant 3a/b (breakpoint at exon 6a/b [40% of cases]).

Data from retrospective analyses suggest that the response to TKIs and the potential to develop resistance differ among ALK-EML4 fusion variants9,20; however, confirmatory evidence from randomized clinical trials has been lacking. Several trials have provided a head-to-head comparison of alectinib and crizotinib (the latter regarded as the first-line standard of care for ALK-positive NSCLC). The ALEX trial ( Identifier: NCT02075840) was a phase 3 study in previously untreated patients with advanced ALK-positive NSCLC with a mix of EML4 variants 1, 2, and 3a/b, who were randomly assigned to receive alectinib 600 mg twice daily or crizotinib 250 mg twice daily.21 Alectinib was found to have longer PFS and lower toxicity than crizotinib and showed activity against CNS disease.

Subanalysis of the ALEX trial found that the presence of EML4 variants 1, 2, and 3a/b did not affect PFS, objective response rate, or duration of response.22 Moreover, the ALEX trial confirmed the earlier finding that alectinib provides superior PFS compared with crizotinib in untreated ALK-positive NSCLC, regardless of the EML4-ALK variant.22 Similar results were seen in the interim and final analyses of the J-ALEX trial, a phase 3 randomized study that compared alectinib to crizotinib in ALK inhibitor-naive Japanese patients with ALK-positive NSCLC (Table).23

Most patients with NSCLC eventually experience progression, and metastasis to the brain is challenging to treat, particularly with treatment resistance. Patients with CNS involvement have worsening prognosis and quality of life.24 With the availability of 5 TKIs indicated for use in the first-line setting, decision-making on treatment selection and strategy can be challenging. Despite development of resistance, crizotinib remains the first-line treatment of choice in several regions of the world.

In the United States, alectinib and ceritinib are the first-line treatments of choice for advanced ALK-positive NSCLC, particularly in patients with brain metastases. The head-to-head comparative ALEX trial found that alectinib was superior to crizotinib in overall response rate, PFS, and toxicity profile.25 Although ceritinib demonstrated superior efficacy over standard-of-care platinum-based chemotherapy, its toxicity profile is greater than that of chemotherapy, which might limit its clinical use.26

Ceritinib adverse effects
Ceritinib adverse effects
Ceritinib adverse effects commonly reported include diarrhea, nausea, abdominal pain, vomiting, and fatigue.

Alectinib is a highly selective ALK inhibitor effective against a broad spectrum of ALK mutations. Studies supporting its efficacy in patients with brain metastases, including patients who have experienced progression with crizotinib, have been reviewed by Tomasini and colleagues.3 The superior efficacy and safety of alectinib compared with crizotinib demonstrated in several randomized, head-to-head trials presents alectinib as the new standard of care for the first-line treatment of ALK-positive NSCLC and in patients resistant to crizotinib.3 Indeed, guidelines from the National Comprehensive Cancer Network (NCCN) recommend alectinib over crizotinib, ceritinib, and brigatinib as the treatment of choice for patients with ALK rearrangement.27 McCusker and colleagues identified alectinib as the first-line TKI of choice for ALK-positive NSCLC based on its PFS advantage, cumulative reduction in incidence of brain metastasis, and favorable toxicity profile.5

Alectinib adverse effects
Alectinib adverse effects
Alectinib adverse effects commonly reported include fatigue, constipation, edema, myalgia, and anemia.

A practical approach to treating resistant ALK-positive CNS-metastasized NSCLC

Despite an initial response to crizotinib, most patients with advanced NSCLC experience progression in 1 or 2 years due to treatment resistance. Prevailing evidence suggests that most crizotinib-resistant tumors are still driven by ALK and are sensitive to subsequent TKI therapy, provided that ALK mutations are detectable in plasma or tissue.29 Resistance to TKI therapy raises the question of a subsequent treatment choice for ongoing disease management.

In the setting of CNS progression, a TKI with adequate CNS penetration is essential. Among patients for whom crizotinib fails, the drug has a low cerebrospinal fluid-to-plasma concentration ratio and is associated with a high rate of CNS metastasis. CNS penetration increases with second- and third-generation TKIs (Table28); according to McCusker and colleagues, this penetration might be advantageous in delaying radiotherapy in patients with asymptomatic CNS disease.

With close monitoring, patients with mildly symptomatic CNS disease can be considered for treatment with a second-generation TKI. Patients with symptomatic CNS disease should receive an appropriate TKI in addition to local-regional treatment (stereotactic radiosurgery, whole-brain radiation therapy, or both) based on the number and dimensions of lesions.5 NCCN guidelines provide a comprehensive treatment algorithm for ALK-positive NSCLC.27 A treatment algorithm for ALK-rearranged advanced NSCLC based on available data from which NCCN, European Society of Medical Oncology, and Associazione Italiana di Oncologia Medica (Italian Association of Medical Oncology) guidelines were developed is shown in Figure 2.24

Some patients experience disease progression in the absence of a detectable ALK mutation, which is indicative of TKI treatment failure. For them, treatment options are limited, although platinum-based chemotherapy remains a valid treatment option.5 For Gristina and colleagues,24 lorlatinib, a third-generation ALK-TKI, is the treatment of choice upon progression in a patient taking a second-generation ALK inhibitor, due to the absence of putative mutations. Evidence suggests that, even in ALK-positive patients not presenting with a resistance point mutation, an overall response rate of 32% and median PFS of 5.5 months might be attained with lorlatinib.

Although investigational immunotherapy combined with chemotherapy has been evaluated, the efficacy of this combination in progressive disease, in the absence of a detectable ALK mutation, is inconclusive.


  1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660
  2. Centers for Disease Control and Prevention. Leading cancer cases and deaths, all races/ethnicities, male and female, 2017. Published online June 2020. Accessed June 5, 2021.
  3. Tomasini P, Egea J, Souquet-Bressand M, Greillier L, Barlesi F. Alectinib in the treatment of ALK-positive metastatic non-small cell lung cancer: clinical trial evidence and experience with a focus on brain metastases. Ther Adv Respir Dis. 2019;13:1753466619831906. doi:10.1177/1753466619831906
  4. Golding B, Luu A, Jones R, Viloria-Petit AM. The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC). Mol Cancer. 2018;17(1):52. doi:10.1186/s12943-018-0810-4
  5. McCusker MG, Russo A, Scilla KA, Mehra R, Rolfo C. How I treat ALK-positive non-small cell lung cancer. ESMO Open. 2019;4(Suppl 2):e000524. doi:10.1136/esmoopen-2019-000524
  6. Miao Y, Zhu S, Li H, et al. Comparison of clinical and radiological characteristics between anaplastic lymphoma kinase rearrangement and epidermal growth factor receptor mutation in treatment naïve advanced lung adenocarcinomaJ Thorac Dis. 2017;9(10):3927-3937. doi: 10.21037/jtd.2017.08.134
  7. Mendoza DP, Lin JJ, Rooney MM, et al. Imaging features and metastatic patterns of advanced ALK-rearranged non-small cell lung cancerAJR Am J Roentgenol. 2020;214(4):766-774. doi:10.2214/AJR.19.21982
  8. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Mol Diagn. 2018;20(2):129-159. doi:10.1016/j.jmoldx.2017.11.004
  9. Leighl NB, Page RD, Raymond VM, et al. Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non-small cell lung cancer. Clin Cancer Res. 2019;25(15):4691-4700. doi:10.1158/1078-0432.CCR-19-0624
  10. Rolfo C, Mack PC, Scagliotti GV, et al. Liquid biopsy for advanced non-small cell lung cancer (NSCLC): a statement paper from the IASLC. J Thorac Oncol. 2018;13(9):1248-1268. doi:10.1016/j.jtho.2018.05.030
  11. Xalkori. Prescribing information. Pfizer; 2021. Accessed June 5, 2021.
  12. Solomon BJ, Mok T, Kim D-W, et al; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167-2177. doi:10.1056/NEJMoa1408440
  13. Solomon BJ, Kim D-W, Wu Y-L, et al. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer. J Clin Oncol. 2018;36(22):2251-2258. doi:10.1200/JCO.2017.77.4794
  14. Zykadia. Prescribing information. Novartis; 2019. Accessed June 5, 2021.
  15. Alecensa. Prescribing information. Genentech; 2021. Accessed June 5, 2021.
  16. Alunbrig. Prescribing information. Takeda; 2020. Accessed June 5, 2021.
  17. Lorbrena. Prescribing information. Pfizer. Accessed June 5, 2021.
  18. U.S. FDA expands approval of Pfizer’s Lorbrena® as first line treatment for ALK-positive metastatic lung cancer. Press release. Pfizer; March 3, 2021. Accessed June 5, 2021.
  19. Lin JJ, Zhu VW, Yoda S, et al. Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK positive lung cancer. J Clin Oncol. 2018;36(12):1199-1206. doi:10.1200/JCO.2017.76.2294
  20. Yoshida T, Oya Y, Tanaka K, et al. Differential crizotinib response duration among ALK fusion variants in ALK-positive non-small-cell lung cancer. J Clin Oncol. 2016;34(28):3383-3389. doi:10.1200/JCO.2015.65.8732
  21. Peters S, Camidge DR, Shaw AT, et al; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377(9):829-838. doi:10.1056/NEJMoa1704795
  22. Camidge DR, Dziadziuszko R, Peters S, et al. Updated efficacy and safety data and impact of the EML4-ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non-small cell lung cancer in the global phase III ALEX study. J Thorac Oncol. 2019;14(7):1233-1243. doi:10.1016/j.jtho.2019.03.007
  23. Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017;390(10089):29-39. doi:10.1016/S0140-6736(17)30565-2
  24. Gristina V, La Mantia M, Iacono F, Galvano A, Russo A, Bazan V. The emerging therapeutic landscape of ALK inhibitors in non-small cell lung cancer. Pharmaceuticals (Basel). 2020;13(12):474. doi:10.3390/ph13120474
  25. Gadgeel S, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018;29(11):2214-2222. doi:10.1093/annonc/mdy405
  26. Soria J-C, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917-929. doi:10.1016/S0140-6736(17)30123-X
  27. Non-small cell lung cancer: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Version 3.2020; February 11, 2020. Accessed June 5, 2021.
  28. Singh A, Chen H. Optimal care for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer: a review on the role and utility of ALK inhibitors. Cancer Manag Res. 2020;12:6615-6628. doi:10.2147/CMAR.S260274
  29. Shaw AT, Solomon BJ, Besse B, et al. ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer. J Clin Oncol. 2019;37(16):1370-1379. doi:10.1200/JCO.18.02236

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Reviewed June 2021