Speaker's Highlight

• Don Sin University of British Columbia, St. Paul Hospital (Canada)
  Kenneth R. Chapman Toronto General Hospital Research Institute (Canada)
• Parameswaran Nair McMaster University (Canada)
  Carolyn Calfee UCSF (U.S.A.)
• Gregory P. Downey University of Colorado School of Medicine (U.S.A.)
  David A. Schwartz University of Colorado School of Medicine (U.S.A.)
• Neil Schluger Tuberculosis Control Branch, California Department of Public Health (U.S.A.)
  Nick Kim Critical Care & Sleep Medicine, University of California San Diego (U.S.A.)
• Nicola Hananiah Baylor College of Medicine (U.S.A.)
  Jae-Joon Yim Seoul National University College of Medicine (Republic of Korea)
• Koichiro Asano Tokai University School of Medicine (Japan)
  Diahn-Warng Perng Taipei Veterans General Hospital (Taiwan)
• Konstantinos Kostikas University of Ioannina (Greece)
  Karin Klooster University Medical Center Groningen (Kingdom of the Netherlands)

• Advances in Targeted Therapy for ALK-Positive Lung Cancer

  ALK-positive lung cancer is a distinct molecular subtype of non-small cell lung cancer (NSCLC), most often identified in people with adenocarcinoma and a history of little or no tobacco exposure. Although it represents a minority of lung cancers, its biology has transformed precision oncology. A rearrangement involving the anaplastic lymphoma kinase gene can produce a continuously active signaling protein that drives tumor growth.

  The development of ALK tyrosine kinase inhibitors (TKIs) has substantially improved response rates, symptom control, and survival. Treatment decisions now depend on the quality of molecular testing, the distribution of disease, the risk of central nervous system involvement, previous therapies, and the mechanisms that may cause resistance.

  These advances are closely aligned with the respiratory medicine focus of the APSR 2022 congress, where clinicians and researchers examined emerging evidence across thoracic oncology and related healthcare fields. Understanding the changing treatment sequence is essential for multidisciplinary teams caring for patients with advanced disease.

  Molecular Biology And Diagnostic Testing

  ALK rearrangements are usually detected through fluorescence in situ hybridization, immunohistochemistry, reverse-transcription polymerase chain reaction, or next-generation sequencing (NGS). NGS is increasingly valuable because it can identify ALK fusions alongside other actionable genomic alterations using limited tissue or, in selected cases, circulating tumor DNA.

  Testing should be performed before systemic treatment begins whenever advanced nonsquamous NSCLC is diagnosed. A comprehensive molecular panel helps prevent the use of therapies that are less effective for oncogene-driven tumors. When tissue is scarce, plasma-based testing can provide a rapid result, although a negative liquid biopsy may need confirmation with tissue analysis.

  Choosing Initial Targeted Therapy

  First-generation crizotinib established the clinical value of ALK inhibition, but newer agents have improved durability and intracranial activity. Alectinib, brigatinib, and lorlatinib are commonly considered in the first-line setting, with the choice shaped by efficacy, adverse-effect profiles, comorbidities, drug interactions, and access.

  Alectinib has demonstrated strong systemic and central nervous system control and is widely used as an initial option. Brigatinib is another potent inhibitor, while lorlatinib has particularly broad activity against several resistance mutations and penetrates the brain effectively. The best regimen is selected through shared decision-making rather than by response rate alone.

  Central Nervous System Control

  Brain metastases are common in ALK-rearranged NSCLC, and the nervous system can become a sanctuary site when an earlier TKI has limited blood-brain barrier penetration. Modern ALK inhibitors have changed this pattern by producing meaningful intracranial responses and delaying progression in patients with measurable brain lesions.

  Baseline brain magnetic resonance imaging is important even when neurological symptoms are absent. Patients receiving a CNS-active inhibitor still require clinical surveillance and periodic imaging based on disease status. Local treatments such as stereotactic radiosurgery remain useful for selected lesions, particularly when there is symptomatic, bulky, or rapidly progressive intracranial disease.

  Comparing ALK Inhibitors

  Clinical trials do not always compare every treatment option directly, and individual tolerability can differ considerably. The following overview summarizes practical distinctions rather than prescribing a universal sequence.

  Therapy	Key clinical strength	Important monitoring considerations
  Crizotinib	Established efficacy and broad clinical experience	Visual effects, gastrointestinal symptoms, liver toxicity, and weaker CNS control
  Alectinib	Durable systemic and intracranial activity	Liver enzymes, muscle symptoms, weight gain, bradycardia
  Brigatinib	Potent activity with CNS efficacy	Early pulmonary events, hypertension, creatine kinase, liver and pancreatic enzymes
  Lorlatinib	Strong CNS penetration and activity against several resistance mutations	Lipids, cognitive or mood changes, neuropathy, edema, and drug interactions

  Treatment selection should account for the patient’s baseline neurological status and other medical conditions. For example, a history of severe dyslipidemia, arrhythmia, pulmonary disease, or cognitive impairment may influence the risk-benefit discussion. Regular monitoring allows clinicians to manage toxicity without unnecessarily discontinuing an effective drug.

  Understanding Acquired Resistance

  Progression during ALK-targeted treatment may result from an ALK kinase-domain mutation, activation of an alternative signaling pathway, inadequate drug exposure, or disease that has evolved outside the original molecular profile. A repeat biopsy or plasma NGS can help identify the mechanism, although a negative plasma result does not exclude a targetable alteration.

  Lorlatinib can be particularly useful after failure of earlier next-generation inhibitors when a susceptible ALK mutation is present. However, resistance may be heterogeneous, with different lesions carrying different molecular features. Local ablative therapy may control isolated progression while the current TKI is continued, whereas widespread progression usually requires a change in systemic therapy.

  Careful interpretation is essential because radiographic progression does not always mean that every tumor focus has become resistant. Oligoprogression, treatment interruptions, drug interactions, and poor adherence should be assessed before abandoning a regimen. The broader respiratory oncology community also recognizes the importance of distinguishing infection from malignancy progression; related diagnostic complexity is discussed in non-tuberculous mycobacteria insights.

  Integrating Chemotherapy And Supportive Care

  When targeted options are exhausted or resistance is not adequately controlled, platinum-based chemotherapy, commonly combined with pemetrexed in nonsquamous NSCLC, remains an important treatment approach. Immunotherapy has a more limited role as a single agent in ALK-positive disease, particularly when effective targeted therapies have not yet been fully used.

  Supportive care should begin at diagnosis and continue throughout treatment. Symptom management, smoking cessation support, vaccination, exercise guidance, nutritional assessment, and psychological care can preserve quality of life. Bone metastases may require antiresorptive therapy, while painful or unstable lesions may benefit from radiotherapy or orthopedic intervention.

  Practical Priorities For Clinical Teams

  A coordinated approach helps ensure that molecular results, imaging, toxicity data, and patient preferences are considered together. Pulmonologists, medical oncologists, radiologists, pathologists, pharmacists, nurses, and palliative-care specialists each contribute to treatment continuity.

  Useful priorities include:

  • Confirm an ALK rearrangement with validated molecular testing before starting systemic therapy whenever feasible.
  • Obtain baseline brain imaging and select an inhibitor with appropriate CNS activity.
  • Review medications, cardiovascular risks, liver function, lipid levels, and neurological symptoms before treatment.
  • Investigate progression with tissue or plasma profiling when the result could change therapy.
  • Use multidisciplinary review for oligoprogression, brain metastases, radiation decisions, and supportive care.

  The pace of progress in ALK-positive lung cancer shows how molecular diagnosis can reshape the entire care pathway. Continued research is focused on newer resistance-directed inhibitors, combination strategies, minimal residual disease monitoring, and treatment approaches that preserve quality of life over many lines of therapy.

  Clinicians and researchers can follow the respiratory oncology discussions, congress resources, and emerging evidence associated with APSR and KATRD to support informed, patient-centered care for people living with ALK-rearranged lung cancer.

  Richard Russell Nuffield Department of Clinical Medicine, University of Oxford (United Kingdom)
• Mona Bafadhel King’s College London (United Kingdom)
  David Jackson Guy’s and St Thomas’ Hospital, King’s College London (United Kingdom)
• James Chalmers University of Dundee (United Kingdom)
  David Price University of Aberdeen (United Kingdom)