[18F]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

Purpose: 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 [18F]FDG-PET/CT (FDG-PET) as a response biomarker in resectable CSCC patients. Methods: 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 (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) at the primary tumour and largest (= index) lymph node metastasis (ILN). ΔMTV50%/4.0 and ΔTLG50%/4.0 were calculated using thresholds of 50% SUVmax and SUV ≥ 4.0. Results: 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 SUVmax, MTV50%, MTV4.0, TLG50%, and TLG4.0 was observed in responders versus non-responders (overall, p ≤ 0.004, and p ≤ 0.03, respectively). ΔTLG50% and ΔTLG4.0 correlated strongly with response (primary: 92% and 96% accuracy; ILN: 91% and 89% accuracy). Conclusions: 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. Trial registration: EudraCT 2020–001074-30. Registered 9 March 2020, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-001074-30