MRI-derived tumor burden and growth rate as translational biomarkers: Head-to-head comparison with RECIST and ctDNA in tebentafusp-treated metastatic uveal melanoma.

Abstract

e21584 Background: Tebentafusp improves survival in metastatic uveal melanoma (mUM), yet RECIST v1.1 responses are uncommon and may not reflect clinical benefit. We evaluated whether early, on-treatment liver MRI volumetric and kinetic biomarkers better predict overall survival (OS) than baseline imaging, ctDNA dynamics, and RECIST. Methods: We retrospectively included 88 consecutive HLA-A*02:01+ mUM patients treated with tebentafusp (2018–2022) with baseline and month-3 (M3 ±1 month) liver MRI. All measurable liver metastases (≥ 5 mm) were segmented to derive total tumor volume at baseline (TTV 1 ) and month 3 (TTV 2 ). Tumor growth rate between scans was computed assuming exponential growth (TGR 3m , %/month). Plasma ctDNA (ddPCR; GNAQ/GNA11/SF3B1) was assessed at baseline and M3 when available (n=68). Associations with OS were tested using Cox models; prognostic discrimination was evaluated using Harrell’s C-index with bootstrap resampling. A three-tier MRI risk score combined median cutoffs for TTV 2 and TGR 3m . Results: Median age was 59 years; median follow-up was 43.5 months. Median TTV 1 was 8.4 cm³ (IQR 1.7–83.8), TTV 2 14.6 cm³ (IQR 2.4–124.6), and TGR 3m 17.5%/month (IQR 5.2–31.7). Inter-reader reproducibility was high (ICC: 0.84 for TTV1, 0.88 for TTV2, 0.90 for TGR 3m ). In multivariable analysis, higher TTV 2 and TGR 3m were independently associated with shorter OS (HR per doubling of TTV₂ = 1.25 ; 95% CI 1.15–1.35; HR per +10%/month TGR 3m , 1.17; 95% CI 1.07–1.28; both P < 0.001), while baseline tumor burden and RECIST response were not retained. The MRI risk score separated three OS strata (log-rank P < 0.001) with median OS not reached (low risk), 34.6 months (intermediate), and 11.3 months (high risk). Prognostic performance favored the MRI score (C-index 0.79; 95% CI 0.71–0.86), outperforming ctDNA-based models (C-index 0.73; P = 0.01) and RECIST response (C-index 0.65; P < 0.001). Conclusions: Early, on-treatment liver MRI biomarkers, month-3 tumor burden (TTV 2 ) and growth rate (TGR 3m ), provide strong, independent prognostic information under tebentafusp and outperform ctDNA kinetics and RECIST. These metrics support MRI-based risk stratification at 3 months as a practical decision tool to guide monitoring and therapeutic adaptation in mUM.