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.

Abstract

BACKGROUND

[¹⁸F]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. [¹⁸F]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). Baseline MTV was the strongest predictor (AUC_{T=6 months}=0.714), while early changes in MTV, TLG, and especially week-7 ΔSUVpeak% showed similar or improved performance (P = 0.017 vs. baseline SUVpeak). 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-2, ∆SUVpeak% was not predictive in a multivariable analysis, but became predictive at week-7 (median ∆SUVpeak%: 64), with a more than three-fold hazard of progression for patients with ∆SUVpeak% below 64% (P = 0.0014); 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). As expected, 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). Intra-patient metabolic heterogeneity was also associated with outcome, with early reductions in SUVpeak variation between lesions correlating with better PFS.

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.