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Background Evaluation of tumor volume change and [18F]Fluoro-2-deoxy-2-D-glucose (FDG) uptake using whole-body PET/CT are frequently used to evaluate treatment response with immune checkpoint inhibitors (ICIs) in patients with advanced stage melanoma. We previously reported that early circulating tumor DNA (ctDNA) dynamics after ICI initiation appears to be a candidate biomarker to predict treatment response. 1 We hypothesize that early FDG-PET/CT uptake dynamics will offer similar predictive capabilities. Our study explores both early FDG-PET/CT parameters and multi-stages of ctDNA dynamics as predictors of treatment efficacy in ICI-treated patients with advanced melanoma.Methods A prospective study was conducted for patients with unresectable stage III/IV melanoma who underwent personalized, tumor-informed ctDNA analysis (Natera) and whole-body FDG-PET/CT imaging at baseline and at 3-4 weeks after ICI initiation. Serial ctDNA levels were assessed every 3-4 weeks during treatment. Assessed FDG-PET/CT parameters included: largest target lesion (TaL) volume, TaL SUVmax, TaL SUVmax-to-liver mean ratio, total lesion (ToL) SUVmax, ToL SUVmax-to-liver mean ratio, and ToL SUVmean. Cox proportional hazard models were used to assess associations between each biomarker change from baseline and 6-month progression free survival (PFS) outcome.Results 16 patients were enrolled and evaluable. Median baseline total number of metastatic lesions per patient was 4. Primary sites of melanoma included: cutaneous (11/16), unknown (2/16), uveal (2/16), mucosal (1/16). Disease stages included: M1d (2/16), M1c (5/16), M1b (4/16), M1a (3/16), III (2/16). ICI regimens included: ipilimumab/nivolumab (8/16), nivolumab/relatlimab (7/16), pembrolizumab (1/16). ctDNA change from baseline to 3–4 weeks was not significantly associated with 6-month PFS (HR 0.998, 95% CI 0.993–1.003, p=0.408 for continuous change), but ctDNA change at 6–8 weeks demonstrated significant association with 6-month PFS (HR 0.995, 0.991–0.999, p=0.022). Early (3-4 weeks) change of FDG-PET/CT imaging parameters showed stronger predictive signals for PFS. Early decrease in TaL SUVmax-to-liver ratio was strongly associated with 6-month PFS (HR 0.355, 95% CI 0.168-0.753, p=0.007 for continuous change; HR 0.038, 0.004–0.361, p=0.004 for categorical decrease). Other significant predictors for 6-month PFS included: TaL SUVmax, ToL SUVmax, and ToL SUVmax-to-liver mean ratio ( table 1).Conclusions Early changes in several FDG-PET/CT parameters, particularly SUVmax-to-liver ratio, may be better predictors of PFS than ctDNA dynamics after 3-4 weeks of ICI initiation. Notably, ctDNA dynamics at 6-8 weeks appears to have a strong predictive utility for 6-month PFS. Larger cohorts are needed to optimize the predictability of early ctDNA dynamics and changes in FDG-PET/CT parameters to predict treatment efficacy and long-term progression risk.Trial Registration NCT06199713Reference Ma VT, Park Y, Patel JD, Harris MS, Mannino MC, Schehr J, Birbrair A, Zhao SG, Lang JM. Early circulating tumor DNA (ctDNA) changes during treatment with immune checkpoint inhibitor (ICI) may predict clinical outcomes in advanced stage melanoma/skin cancer patients (pts). Abstract poster: 2024 American Society of Clinical Oncology (ASCO) Breakthrough Annual Meeting in Yokohama, Japan. doi: 10.1200/JCO.2024.42.23_suppl.225Ethics Approval The study protocol (2023-1089) is approved by the University of Wisconsin institutional ethical guidelines and complies with the guidelines of the institutional review board.Abstract 90 Table 1Predictors of 6-month progression free survival (PFS)