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Emerging therapeutics and evolving assessment criteria for intracranial metastases in patients with oncogene-driven non-small-cell lung cancer

Nature Reviews Clinical Oncology volume 20, pages 716–732 (2023)Cite this article

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Abstract

The improved survival outcomes of patients with non-small-cell lung cancer (NSCLC), largely owing to the improved control of systemic disease provided by immune-checkpoint inhibitors and novel targeted therapies, have highlighted the challenges posed by central nervous system (CNS) metastases as a devastating yet common complication, with up to 50% of patients developing such lesions during the course of the disease. Early-generation tyrosine-kinase inhibitors (TKIs) often provide robust systemic disease control in patients with oncogene-driven NSCLCs, although these agents are usually unable to accumulate to therapeutically relevant concentrations in the CNS owing to an inability to cross the blood–brain barrier. However, the past few years have seen a paradigm shift with the emergence of several novel or later-generation TKIs with improved CNS penetrance. Such agents have promising levels of activity against brain metastases, as demonstrated by data from preclinical and clinical studies. In this Review, we describe current preclinical and clinical evidence of the intracranial activity of TKIs targeting various oncogenic drivers in patients with NSCLC, with a focus on newer agents with enhanced CNS penetration, leptomeningeal disease and the need for intrathecal treatment options. We also discuss evolving assessment criteria and regulatory considerations for future clinical investigations.

Key points

  • Central nervous system (CNS) metastasis and leptomeningeal disease are clinical challenges in the treatment of patients with advanced-stage non-small-cell lung cancers (NSCLCs) that are often associated with inferior outcomes.

  • Targeted therapies have improved the outcomes of several molecularly defined subgroups of patients with oncogene-driven NSCLCs, although certain small-molecule inhibitors confer only limited levels of CNS benefit, often owing to an inability to cross the blood–brain barrier.

  • Preclinical evaluations of Kpuu  (the unbound drug partition coefficient) are commonly used to assess the CNS penetrance of novel agents during drug development.

  • Several newer tyrosine-kinase inhibitors have improved CNS efficacy, including osimertinib in EGFR-mutant NSCLCs and alectinib and lorlatinib in ALK-rearranged NSCLCs, with many others in clinical development.

  • Response Assessment in Neuro-Oncology criteria for response assessment in patients with brain or leptomeningeal metastases are different from RECIST, and future clinical trials should incorporate those criteria into the study design.

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Fig. 1: Schematic illustration of the blood–brain barrier and blood–tumour barrier.
Fig. 2: Radiographic appearance and intrathecal administration strategies for patients with leptomeningeal disease.

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Acknowledgements

X.L. is supported by the Damon Runyon Foundation and V Foundation for Cancer Research. J.V.H. is supported by NIH R50CA265307, 5R01CA247975 and R01CA234183. K.C. is supported by NIH T32 CA009666. J.Z. is supported by the Cancer Prevention and Research Institute of Texas Multi-Investigator Research Award grant (RP160668), the NIH (NCI) R01CA234629-01 and 5U01CA256780.

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  1. Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Kelsey Pan & Kyle Concannon

  2. Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jing Li

  3. Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jianjun Zhang, John V. Heymach & Xiuning Le

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K.P. and X.L. wrote the manuscript. All authors researched data for the manuscript, made a substantial contribution to discussions of content and edited and/or reviewed the manuscript before submission.

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J.Z. has acted as a consultant and/or adviser of AstraZeneca, Bristol Myers Squibb, GenePlus, Innovent, Johnson & Johnson and Novartis, and has received research grants from Johnson & Johnson, Merck and Novartis. J.V.H. has acted as an adviser of AstraZeneca, Boehringer Ingelheim, BrightPath Biotherapeutics, Bristol Myers Squibb, Catalyst Biotech, EMD Serono, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Guardant Health, Hengrui Pharmaceutical, Janssen, Kairos Ventures, Leads Biolabs, Lilly, Mirati Therapeutics, Nexus Health Systems, Novartis, Pneuma Respiratory, Roche, Sanofi/Aventis, Spectrum Pharmaceuticals and Takeda, has received research funding from AstraZeneca, GlaxoSmithKline and Spectrum, is included in a licensing agreement between Spectrum and MD Anderson Cancer Center regarding intellectual property relating to treatments targeting of EGFR and HER2 exon 20 mutations, and declares stock and other ownership interests in Bio-Tree Consulting and Cardinal Spine. X.L. has acted as a consultant and/or adviser of Abbvie, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Eli Lilly, EMD Serono (Merck KGaA), Hengrui Therapeutics, Janssen, Novartis, Sensei Biotherapeutics and Spectrum Pharmaceutics, and has received research funding from Boehringer Ingelheim, Eli Lilly, EMD Serono and Regeneron. The other authors declare no competing interests.

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Pan, K., Concannon, K., Li, J. et al. Emerging therapeutics and evolving assessment criteria for intracranial metastases in patients with oncogene-driven non-small-cell lung cancer. Nat Rev Clin Oncol 20, 716–732 (2023). https://doi.org/10.1038/s41571-023-00808-4

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