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Review
. 2025 Jun 21;26(13):5969.
doi: 10.3390/ijms26135969.

Refining Criteria for Choosing the First-Line Treatment for Real-World Patients with Advanced ALK-Rearranged NSCLC

Edyta Maria Urbanska  1 , Peter Rindom Koffeldt  2 , Morten Grauslund  2 , Linea Cecilie Melchior  2 , Jens Benn Sørensen  1   3 , Eric Santoni-Rugiu  2   3
Affiliations
Review

Refining Criteria for Choosing the First-Line Treatment for Real-World Patients with Advanced ALK-Rearranged NSCLC

Edyta Maria Urbanska et al. Int J Mol Sci. .

Abstract

Choosing the optimal first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangements can be challenging in daily practice. Although clinical trials with next-generation ALK-tyrosine kinase inhibitors (TKIs) have played a key role in evaluating their efficacy and safety, which patients benefit from a specific ALK-TKI may still be questioned. The methodological inconsistencies in these trials, which led to the inclusion of different patient populations, appear to have been inadequately addressed. ALK-rearranged NSCLC is a heterogeneous disease, and co-existing molecular alterations may affect the outcome. The questions explored in these trials appear insufficient to support a personalized approach to the first-line treatment, while defining long-term responders and early progressors would be clinically useful. This narrative review presents several considerations from oncologists' and pathologists' perspectives. We propose defining favorable and unfavorable features, such as histology, type of ALK fusion, co-existing molecular alterations, plasma circulating tumor DNA (ctDNA, performance status, and brain metastases, to help identify patients with lower and higher risk of progression. Consequently, the most potent ALK-TKI to date, Lorlatinib, may be considered as the first-line treatment for high-risk patients with unfavorable features, while sequencing of ALK-TKIs may be appropriate for low-risk patients with favorable features. Although ALK signal inhibition is critical in this disease, it may not be sufficient for clinical control due to de novo co-alterations. A more personalized approach to first-line therapy requires consideration of risk factors for each patient.

Keywords: ALK rearrangement; IHC/FISH/NGS; de novo co-alterations; first-line ALK-TKI; intrinsic resistance.

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Conflict of interest statement

E.M.U. received research grants from AstraZeneca and Merck; speaker fees from Amgen, Janssen, and MSD; travel support related to participation in an international scientific meeting from AstraZeneca, MSD, and Roche; payment for participation in the Advisory Board from AstraZeneca and Pfizer. P.R.K. received grants from Sanofi and Takeda. M.G. received research funding from Merck and speaker honoraria from Pfizer. L.C.M. received speaker honoraria from Merck, Takeda, and Pfizer. J.B.S. received honoraria for lectures and advisory boards from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and Takeda, as well as research grants from Roche and Pfizer. E.S.-R. received honoraria for lectures and advisory boards from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and Takeda, as well as research grants from Pfizer, Roche, and Sanofi.

Figures

Figure 1
Figure 1
Discordances among current diagnostic methods (FISH, IHC, DNA-NGS, RNA-NGS) that result in poor outcomes. NA: non-applicable, indicates lack of analysis in the citated studies. References for row 1 [9,10,11,12,16,17,18,21,22]. References for row 2 [9,10,11,12,17,19,20,21,22,26]. References for row 3 [17,23,24].
Figure 2
Figure 2
Proposed personalized approach for choosing the first-line treatment for patients with low, uncertain, and high risk of progression based on the clinical, histological, and molecular features illustrated in detail in Table 1.
See this image and copyright information in PMC

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