Metabolic Parameters on Baseline and Early [18F]FDG PET/CT as a Predictive Biomarker for Resistance to BRAF/MEK Inhibition in Advanced Cutaneous BRAFV600-mutated Melanoma

Background: [ ¹⁸ F]FDG PET/CT plays a crucial role in evaluating cancer patients and assessing treatment response, including in BRAF-mutated melanoma. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have emerged as promising alternatives to standardized uptake value (SUV)-based measures for tumor assessment. This study evaluates the predictive value of SUVpeak, MTV, and TLG in predicting progression-free survival (PFS) in advanced BRAF-mutated melanoma treated with BRAF/MEK inhibitors. Results: Seventy-five patients with metastatic melanoma were enrolled in a multi-center trial and treated with vemurafenib/cobimetinib. [ ¹⁸ F]FDG-PET/CT scans were performed at baseline, week-2, and week-7. Imaging analysis included SUVpeak, MTV, and TLG of summed metastases, as well as percentage changes over time (∆). Baseline median PET-parameters were SUVpeak 12.59 (range 3.13-50.59), MTV 159mL (range 0-1897 mL), and TLG 1013 (range 1-13162). MTV had the highest predictive performance for risk of progression (AUC _{T=6 months} =0.714). Patients with TLG below the median had significantly prolonged PFS (15.4 vs. 8.5 months, P=0.024). MTV above optimal cutoff (45.3 mL) was associated with an increased risk of progression/death, even after adjusting for LDH, ECOG status, and metastatic sites (HR=2.97, 95% CI 1.17-7.52, P=0.022). At week-7, ∆SUVpeak% was predictive (median ∆SUVpeak%: 64); PFS was 5.0 months (95% CI: 4.3-NA) for patients below the median versus 14.7 months (95% CI: 9.2-20.2) for those above or with non-quantifiable scans (P=0.0002). Median ∆MTV was 95.5% at week-2 and 97.6% at week-7, with significant PFS differences at both time points (week-2: P=0.020, week-7: P<0.001). TLG mirrored MTV. Patients with MTV increases at week-7 after an initial response at week-2 had a median PFS of 5.3 vs. 12.6 months for those with stable or declining MTV (P=0.0023). Conclusion: This study supports the use of MTV and TLG as robust predictive markers for PFS in advanced melanoma treated with BRAF/MEK-inhibitors. Monitoring early PET parameters changes can provide valuable insights into therapeutic response and disease progression. Trial Registration Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.