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Updated: Jun 16, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Targeting ALK receptors in non-small cell lung cancer: what is the road ahead?
Paolo Maione1, Valentina Palma2, Giuseppina Pucillo2
1Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy.
Introduction:
Anaplastic lymphoma kinase (ALK) gene-rearrangements are identified in about 3-5% of non-small cell lung cancers (NSCLC), and ALK-rearranged NSCLC is to be considered an oncogene-addicted cancer with peculiar clinical characteristics.
Areas Covered:
Several ALK inhibitors have been studied and approved for use in the treatment of advanced ALK-rearranged NSCLC with reported superiority in terms of efficacy and safety profile compared with chemotherapy. Second- and third-generation ALK inhibitors (alectinib, brigatinib, and lorlatinib) offer to NSCLC patients a clinically meaningful prolongment of survival with a very good quality of life profile. However, resistances to these agents always occur, with less satisfying options for second-line treatments. Direct comparisons among these agents are not available, and the choice among brigatinib, alectinib, and lorlatinib as first-line treatment remains challenging. Very recently, alectinib has been demonstrated to improve efficacy outcomes compared with chemotherapy also in resected stage IB-IIIA ALK-rearranged NSCLC, extending the clinical benefit offered by ALK inhibitors also to the adjuvant setting.
Expert Opinion:
Future development of ALK inhibitors in NSCLC treatment includes the search for optimal management of acquired resistance to first-line treatments and the extension of use of ALK inhibitors also to neoadjuvant and preferably to perioperative setting.
Insights
Anaplastic lymphoma kinase (ALK) inhibitors significantly improve survival for non-small cell lung cancer (NSCLC) patients, even in early stages. However, acquired resistance necessitates ongoing research into optimal treatment strategies and future applications.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Anaplastic lymphoma kinase (ALK) gene rearrangements occur in 3-5% of non-small cell lung cancers (NSCLC).
- ALK-rearranged NSCLC is an oncogene-addicted malignancy with distinct clinical features.
- ALK inhibitors represent a targeted therapy approach for advanced NSCLC.
Purpose of the Study:
- To review the efficacy and safety of ALK inhibitors in advanced ALK-rearranged NSCLC.
- To discuss the challenges in managing acquired resistance to ALK inhibitors.
- To explore future directions for ALK inhibitor therapy in NSCLC, including adjuvant and perioperative settings.
Main Methods:
- Review of clinical trial data and published literature on ALK inhibitors.
- Analysis of treatment outcomes, including survival, quality of life, and resistance patterns.
- Discussion of emerging therapeutic strategies and clinical trial designs.
Main Results:
- Second- and third-generation ALK inhibitors (alectinib, brigatinib, lorlatinib) demonstrate superior efficacy and safety over chemotherapy in advanced ALK-rearranged NSCLC.
- These agents prolong survival and maintain a good quality of life.
- Alectinib has shown improved outcomes in resected early-stage NSCLC, supporting its use in the adjuvant setting.
Conclusions:
- ALK inhibitors are highly effective for advanced and early-stage ALK-rearranged NSCLC.
- Acquired resistance remains a significant challenge, requiring development of novel treatment strategies.
- Future research should focus on optimizing resistance management and expanding ALK inhibitor use to neoadjuvant and perioperative settings.
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