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Clinical Trial
. 2025 Jun;132(10):913-921.
doi: 10.1038/s41416-025-02991-w. Epub 2025 Apr 5.

PD-L1 imaging with [99mTc]NM-01 SPECT/CT is associated with metabolic response to pembrolizumab with/without chemotherapy in advanced lung cancer

Daniel Johnathan Hughes  1   2   3 , Gitasha Chand  1   4 , Jessica Johnson  5 , Ronan Tegala  5 , Damion Bailey  5 , Kathryn Adamson  5 , Scott Edmonds  5 , Levente K Meszaros  4 , Amelia Elizabeth Broomfield Moore  1 , Thubeena Manickavasagar  1   3   6 , Susan Ndagire  7 , Spyridon Gennatas  3 , Alexandros Georgiou  3   8 , Sharmistha Ghosh  3 , Debra Josephs  3   8 , Eleni Karapanagiotou  3   8 , Emma McLean  9 , Hong Hoi Ting  4 , James Spicer  3   8 , Vicky Goh  1   6 , Gary J R Cook  10   11
Affiliations
Clinical Trial

PD-L1 imaging with [99mTc]NM-01 SPECT/CT is associated with metabolic response to pembrolizumab with/without chemotherapy in advanced lung cancer

Daniel Johnathan Hughes et al. Br J Cancer. 2025 Jun.

Abstract

Background: Programmed death-ligand 1 (PD-L1) immunohistochemistry is a predictive biomarker for anti-PD-(L)1 therapy in non-small cell lung cancer (NSCLC). It is not a reliable predictor of clinical benefit with non-invasive imaging providing a potential solution. We present the PECan study, the aim of which to assess the relationship of [99mTc]-labeled anti-PD-L1 single-domain antibody (NM-01) single-photon emission computed tomography (SPECT)/CT with metabolic response to anti-PD-(L)1.

Methods: PD-L1 tumour proportion score (TPS) measured using SP263 assay. [99mTc]NM-01 SPECT/CT and [18F]FDG PET/CT performed before and 9-weeks following pembrolizumab with/without chemotherapy in patients with advanced NSCLC. Tumor (T) to blood pool (BP) maximum region of interest (ROImax) measurements performed in primary and metastatic lesions using SPECT/CT images.

Results: Fifteen patients were included (median age 63 years, 9 male). Intertumoural heterogeneity evident in 10(67%) patients. Mean [99mTc]NM-01 T:BP demonstrated moderate correlation with PD-L1 TPS (r = 0.45, p < 0.05). Depth of [18F]FDG PET/CT metabolic response at 9-weeks (n = 13), correlated strongly with baseline [99mTc]NM-01 T:BP (r = -0.73, p < 0.05), but only moderately with PD-L1 TPS (r = -0.46, p = 0.06).

Conclusion: [99mTc]NM-01 SPECT/CT allows non-invasive quantification of PD-L1 in primary tumour and metastases in NSCLC. [99mTc]NM-01 uptake moderately correlates with PD-L1 immunohistochemistry, determines heterogeneity, and is associated with early metabolic response to anti-PD-1 pembrolizumab.

Clinical trials registration: PD-L1 Expression in Cancer (PECan) study (NCT04436406), registered 18 June 2020 https://clinicaltrials.gov/ct2/show/NCT04436406.

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Conflict of interest statement

Competing interests: DJH has received honoraria/speaker fees from Bristol Myers Squibb, Pfizer and Servier, transport/accommodation grants from Bristol Myers Squibb, Pfizer, Servier, Roche and Nanomab Technology (UK) Limited, research funding via institute from Nanomab, and is an executive committee member of the Association of Cancer Physicians (UK). GCh served as an executive director for Nanomab Technology (UK) Limited. JJ has no relevant conflicts of interest. RT has no relevant conflicts of interest. DB has received honoraria/speaker fees from Takeda, Roche, and Pfizer. KA has no relevant conflicts of interest. SE has no relevant conflicts of interest. LKM is a former employee and shareholder of Nanomab, provides consultancy for Nanomab Technology (UK) Limited and is an employee and shareholder of Radiopharm Theranostics Limited. AEBM has received research support via institution from and provided consultancy for Nanomab Technology (UK) Limited. TM has no relevant conflicts of interest. SN has no relevant conflicts of interest. SG has received honoraria/speaker fees from Astrazeneca, Amgen and Chugai, and travel/accommodation grants from Roche. AG has received honoraria/speaker fees from Merck, Amgen, Astrazeneca and Takeda, and travel/accommodation grants from Takeda. SGh has no relevant conflicts of interest. DJ has no relevant conflicts of interest. EK has received honoraria/speaker fees from Takeda, Roche, Pfizer, Janssen and Merck, Sharp &Dohme (MSD), travel/accommodation grants from MSD, has received research funding via institute from MSD and GlaxoSmithKline (GSK), and has participated in advisory board(s) with Amgen and MSD. EM has no relevant conflicts of interest. HT is a non-executive director of Nanomab Technology (UK) Limited. JS has no relevant conflicts of interest. VG has no relevant conflicts of interest. GJRC has received research support via institution from Nanomab Technology (UK) Limited, Theragnostics, Serac Healthcare, and provides consultancy for GE Healthcare, Nanomab Technology, Amgen, Blue Earth Diagnostics and Full-Life Technologies. Ethics approval and consent to participate: The study was performed in accordance with the ethical standards as laid down in the Declaration of Helsinki (1964) and its later amendments. The study underwent ethics review and was approved by a UK Research Ethics Committee (UK IRAS reference 256684). All patients provided written informed consent. Consent for publication: Written informed consent to participate and publication was required for this study as per UK Research Ethics Committee and Health Research Authority (IRAS reference 256684).

Figures

Fig. 1
Fig. 1. [99mTc]NM-01 uptake in NSCLC demonstrates intertumoural heterogeneity.
Baseline attenuation corrected and fused axial [18F]FDG PET/CT (left) and [99mTc]NM-01 SPECT/CT (right) images (a–d) in a 63 year old male with PD-L1 positive metastatic NSCLC (PD-L1 TPS 100%, biopsy from station 2 R lymph node). a [18F]FDG PET/CT showing 2 R node with SUVmax 25.2 (white arrow) and T5 vertebra metastasis SUVmax 14.3 (pink arrow). b [99mTc]NM-01 SPECT/CT with 2 R node T:BP of 3.88 (white arrow) and T5 vertebra metastasis T:BP 6.08 (pink arrow). c [18F]FDG PET/CT showing subcarinal node metastasis with SUVmax 29.9 (white arrow) and left hilar primary lesion SUVmax 29.6 (pink arrow). d [99mTc]NM-01 SPECT/CT with subcarinal node metastasis with T:BP of 2.38 (white arrow) and left hilar primary lesion with T:BP of 3.07. e Interlesional heterogeneity of baseline [99mTc]NM-01 T:BP within individual patients according to lesion location and size (mm), as determined with baseline CT imaging. f Bar chart showing the difference (%) between the [99mTc]NM-01 T:BP of both the maximum (dark green) and minimum (light green) metastases from the primary tumour in all patients, with a ± 25% difference between the primary and at least one metastasis in 100% (n = 15) patients, and ± 50% difference in 67% (n = 10).
Fig. 2
Fig. 2. Baseline [99mTc]NM-01 uptake correlates with PD-L1 immunohistochemistry.
a Matched to histology site mean [99mTc]NM-01 T:BP moderately correlates with PD-L1 TPS measured by immunohistochemistry (n = 15; r = 0.45, p < 0.05*). b Primary tumour [99mTc]NM-01 T:BP (non-matched) demonstrated weak correlation with PD-L1 TPS (n = 15; r = 0.30, p = 0.14).
Fig. 3
Fig. 3. [99mTc]NM-01 is associated with early metabolic response to anti-PD-1 therapy.
a Waterfall plot of 9-week [18F]FDG SUVmax % change, with EORTC ± 25% indicated with dashed horizontal lines, and patients according to treatment, as anti-PD-1 alone (IO only; maroon) or combined with chemotherapy (chemo-IO; dark blue). b Higher baseline mean [99mTc]NM-01 T:BP (i.e. PD-L1 expression) correlates with mean [18F]FDG SUVmax % change (response) (r = −0.73; p = 0.003*). c mean baseline [99mTc]NM-01 T:BP according to 9-week EORTC defined response (n = 10; median 3.31; lower quartile 2.29, upper quartile 3.83; pink) vs non-response (n = 3; median 1.92; lower quartile 1.87, upper quartile 2.28; blue), Mann Whitney U-test p < 0.05*. d [99mTc]NM-01 T:BP % change is significantly different in responders (n = 39; median −39.84; lower quartile −64.13, upper quartile 5.07; pink) vs non-responders (n = 19; median −0.67; lower quartile −17.92, upper quartile 79.37; blue), Mann Whitney U-test p = 0.002*. e Individual lesion [18F]FDG SUVmax % change from 0 to 9 weeks demonstrates weak correlation with [99mTc]NM-01 T:BP % change (r = 0.33; p = 0.006*). f Individual lesions (n = 63) [99mTc]NM-01 T:BP displayed according to response (pink) and non-response (blue), demonstrating higher [99mTc]NM-01 T:BP is associated with response status. For all boxplots, the horizontal line within the boxplot indicates the median, with the lower edge representing the lower quartile, and upper edge the upper quartile. Whiskers represent the minimum and maximum values.
Fig. 4
Fig. 4. Changes in [99mTc]NM-01 uptake may be associated with metabolic response.
Maximum intensity projection images of (a) baseline and (b) 9-weeks [18F]FDG PET/CT and (c) baseline and (d) 9-weeks [99mTc]NM-01 SPECT/CT in a 64 year old male with PD-L1 positive (PD-L1 TPS 80%; from stations 4 R, 4 L and 7 thoracic lymph nodes) metastatic NSCLC and dissociated metabolic response at 9-weeks following single agent anti-PD-1 pembrolizumab. For example, a subcarinal (station 7) node metastasis responds to treatment, with a baseline (a) [18F]FDG SUVmax of 9.1 and (c) [99mTc]NM-01 T:BP of 4.81, and 9-weeks (b) SUVmax 3.4 and (d) [99mTc]NM-01 T:BP of 1.41 (pink arrows). However, a left supraclavicular fossa node does not respond to treatment, with a baseline (a) [18F]FDG SUVmax of 8.5 and (c) [99mTc]NM-01 T:BP of 2.08, and 9-weeks (b) SUVmax 12.2 and (d) [99mTc]NM-01 T:BP of 2.74 (blue arrows).
See this image and copyright information in PMC

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