⁶⁸Ga-NK224 PET/CT Reveals Intra- and Intertumoral Heterogeneity of PD-L1 in Non-Small Cell Lung Cancer.

Authors

Liang Zhao, Hui Zhou, Lingyu Yu, Dan Ruan, Zhenyu Wu, Yin Li, Yaqing Dai, Jiancheng Li, Long Sun, Hua Wu, Yanjun Mi, Haojun Chen

Published in

Radiology. Volume 320. Issue 2. Pages e260372.

Abstract

Background Programmed death ligand 1 (PD-L1) expression assessed via immunohistochemical analysis of single-site biopsies is standard for guiding immunotherapy in non-small cell lung cancer (NSCLC). However, this approach fails to capture intra- and intertumoral heterogeneity. Purpose To investigate whether gallium 68 (⁶⁸Ga) NK224 PET/CT enables whole-body assessment of PD-L1 expression and heterogeneity in NSCLC and whether lesion-specific treatment response is associated with PET-defined PD-L1 uptake. Materials and Methods In this prospective study conducted from December 2023 to July 2025, participants with newly diagnosed or recurrent or metastatic NSCLC underwent ⁶⁸Ga-NK224 PET/CT and PD-L1 immunohistochemical analysis. Tumor uptake of ⁶⁸Ga-NK224 was quantified using maximum standardized uptake value (SUV_max) from biopsy-plane regions of interest (ROIs) and whole-lesion ROIs. PD-L1 tumor proportion score (TPS) was the reference standard. Intratumoral heterogeneity was assessed using the normalized range of SUV_max, and intertumoral heterogeneity was evaluated using the SUV_max coefficient of variation across lesions. Results This study included 48 participants (median age, 68 years [IQR, 59-75 years]; 31 men). Across 52 lesions, ⁶⁸Ga-NK224 uptake differed among PD-L1 TPS categories (P < .001), and biopsy-plane SUV_max correlated strongly with TPS (Spearman ρ = 0.80; P < .001). Receiver operating characteristic analysis identified an optimal SUV_max cutoff of 5.6 for discriminating tumors with high PD-L1 expression. Among 12 participants classified as PD-L1 negative via immunohistochemical analysis, five had one or more lesions with SUV_max above the cutoff (15 of 68 lesions). Intratumoral heterogeneity was substantially higher when assessed using whole-lesion ROIs (median normalized range, 1.0) versus biopsy-plane ROIs (median normalized range, 0.4) (P < .001). Intertumoral heterogeneity within individual participants was pronounced (median SUV_max coefficient of variation, 23.6% [IQR, 17.9%-36.7%]). In participants receiving immunotherapy (24 lesions), lesions with partial or complete response (shrinkage ≥30%; median shrinkage, 47.5%) showed greater ⁶⁸Ga-NK224 uptake than lesions with progressive or stable disease (shrinkage <30%; median shrinkage, 7.4%) (median SUV_max, 5.9 vs 1.9; P = .01). Conclusion ⁶⁸Ga-NK224 PET/CT enabled whole-body assessment of PD-L1 heterogeneity in NSCLC and revealed lesion-level heterogeneity not captured through biopsy, and uptake was associated with immunotherapy response. Clinical trial registration no. NCT06754345 © The Author(s) 2026. Published by the Radiological Society of North America under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Lopci in this issue.

PMID:
42610817
Bibliographic data and abstract were imported from PubMed on 18 Aug 2026.

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