[<sup>18</sup>F]FDG-PET/CT's change in total lesion glycolysis can accurately identify early response upon neoadjuvant immunotherapy prior to curative-intent surgery in cutaneous squamous cell carcinoma; MATISSE trial.

Breukers, Sabine E; Crommelin, Robert D; Smit, Laura A; de Boer, Jan Paul; Navran, Arash; van Houdt, Winan J; de Bree, Remco; Devriese, Lot A et al. · Eur J Nucl Med Mol Imaging · 2026

rct · Level II

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Abstract

Ultra-short immunotherapy may spare cutaneous squamous cell carcinoma (CSCC) patients from mutilating surgery, but early identification of (non-)response is needed to safely guide treatment adaptation. This study evaluated the feasibility of sequential [<sup>18</sup>F]FDG-PET/CT (FDG-PET) as a response biomarker in resectable CSCC patients. In the MATISSE, a randomized phase-II trial, 50 CSCC patients received two courses of neoadjuvant nivolumab (weeks 0 and 2) with or without low-dose ipilimumab (week 0) before surgery (week 4). FDG-PET scans were obtained pre-treatment and shortly prior to surgery to assess the change (Δ) in maximum standardized uptake value (SUV<sub>max)</sub>, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) at the primary tumour and largest (= index) lymph node metastasis (ILN). ΔMTV<sub>50%/4.0</sub> and ΔTLG<sub>50%/4.0</sub> were calculated using thresholds of 50% SUV<sub>max</sub> and SUV ≥ 4.0. In 42 evaluable patients, 31 (74%) patients showed major or partial responses to immunotherapy. EORTC-criteria underestimated response but accurately identified non-responders (70% sensitivity, 100% specificity). In 28 primary tumours and 22 ILNs, a significant reduction in median SUV<sub>max</sub>, MTV<sub>50%</sub>, MTV<sub>4.0</sub>, TLG<sub>50%</sub>, and TLG<sub>4.0</sub> was observed in responders versus non-responders (overall, p ≤ 0.004, and p ≤ 0.03, respectively). ΔTLG<sub>50%</sub> and ΔTLG<sub>4.0</sub> correlated strongly with response (primary: 92% and 96% accuracy; ILN: 91% and 89% accuracy). Quantitative FDG-PET-response assessment allows early identification of (non-)responders upon neoadjuvant immunotherapy prior to surgery in locoregionally advanced CSCC patients. Early changes in FDG-PET's TLG can support future trials aiming at safe de-escalation of current standard of care surgery with or without adjuvant radiotherapy. EudraCT 2020-001074-30. Registered 9 March 2020, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-001074-30.

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