Poor diagnostic performance of the melanin-binding tracer [18F]MEL050 in human melanoma indicates biological heterogeneity

Purpose Malignant melanoma is a highly lethal malignancy typically characterized by the expression of melanin, which is an attractive diagnostic and therapeutic target in these cancers because it is expressed in few other tissues. Following preclinical evaluation of the melanin-targeting PET tracer, [ ¹⁸ F]-6-fluoro- N-[2-(diethylamino)ethyl] pyridine-3-carboxamide (MEL050), we sought to evaluate this agent in patients with melanoma. Method A phase I clinical trial was performed in ten patients with metastatic melanoma. Safety, dosimetry and diagnostic performance of intravenously administered MEL050 were evaluated. Based on results from this trial, we further assessed the prevalence and prognostic significance of loss of melanin expression in two historical patient cohorts for which there was matching histological and clinical outcome data. Results Across the trial cohort, no adverse safety signals resulted from MEL050 administration. The whole-body effective dose was 0.0163 mSV/MBq for an adult male and 0.0206 mSV/MBq for an adult female. The human biodistribution was favorable with low uptake in organs at high risk of metastatic spread, including the brain. Of metastatic sites identified as melanoma on FDG PET/CT, only 31/65 (48%) were positive on MEL050 PET. Four FDG + MEL050 + metastases were resected from three patients and found to be melanotic by histological examination, whereas five FDG + MEL050- metastases from two patients were amelanotic. In historical cohorts, amelanosis was more common in metastatic than primary disease (45% versus 20%) and the presence of melanin within sentinel lymph node metastases was associated with worse disease-free (HR 2.3 95% CI 1.3–4.3, p = 0.002) and disease-specific survivals (HR 3.6, 95% CI 1.4–9.7,p = 0.009) in stage III disease, compared with amelanotic sentinel lymph node metastases. Conclusion Our results warrant caution in the use of melanin-targeted agents for diagnosis and therapy of melanoma but further assessment of their utility as prognostic or predictive imaging biomarkers is required.