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Critique of phase II agents for non-small cell lung cancer: what is our clinical need and which agents have potential?

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Expert opinion on investigational drugs 📖 저널 OA 3.8% 2022: 0/2 OA 2025: 0/6 OA 2026: 1/16 OA 2022~2026 2026 Vol.35(3) p. 239-251
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Spagnuolo A, Spagnoletti I, Nuccio E, Gridelli C

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[INTRODUCTION] Phase II studies provide signals that guide therapeutic development for advanced NSCLC.

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APA Spagnuolo A, Spagnoletti I, et al. (2026). Critique of phase II agents for non-small cell lung cancer: what is our clinical need and which agents have potential?. Expert opinion on investigational drugs, 35(3), 239-251. https://doi.org/10.1080/13543784.2026.2636928
MLA Spagnuolo A, et al.. "Critique of phase II agents for non-small cell lung cancer: what is our clinical need and which agents have potential?." Expert opinion on investigational drugs, vol. 35, no. 3, 2026, pp. 239-251.
PMID 41797519 ↗

Abstract

[INTRODUCTION] Phase II studies provide signals that guide therapeutic development for advanced NSCLC. This is particularly important for certain categories of patients, such as those who have already undergone immunotherapy and those with oncogene-addicted disease. However, promising results in phase II often do not translate into equally positive outcomes in phase III and the reason may be related to assay variability, sample heterogeneity, inadequate comparators or optimistic endpoints.

[AREAS COVERED] This paper provides an overview of treatments for advanced NSCLC and identifies settings where phase II evidence plays a decisive role: post-PD-(L)1/-chemotherapy, post-TKIs, frail patients or patients with brain disease. It also analyzes the reasons behind the failure of phase II success in phase III and proposes what makes a robust signal in phase II, while recognizing the limitations of surrogate endpoints. We take stock of the therapeutic classes that are gaining the most ground and provide a critical assessment of ongoing clinical programs.

[EXPERT OPINION] At present, a convincing phase II trial in NSCLC is possibly randomized, guided by biomarkers detected by standardized tests, with durable systemic and cerebral activity, inclusion of PROs, and is already in alignment with confirmatory study design and regulatory endpoints.

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