Targeted therapy and immunotherapy response assessment with F-18 FLT PET in melanoma brain metastasis (MBM)

Objectives: F-18 FLT PET - a cell proliferation biomarker - has the advantage of negligible parenchymal brain uptake compared with the commonly used F-18 FDG PET and may be particularly feasible for treatment monitoring in patients with brain metastasis. This pilot study seeks to explore the utility of F-18 FLT PET for early treatment monitoring in patients with MBM who are undergoing targeted therapy or immunotherapy.

Methods: Patients with newly diagnosed MBM selected for targeted therapy (dabrafenib, trametinib) or immunotherapy (ipilimumab, nivolumab) were eligible. Enrolled subjects underwent baseline and follow-up PET scan performed at least one month after therapy initiation on a hybrid PET/MRI scanner (5 mCi F-18 FLT, Biograph mMR, Siemens); Dixon MR sequence was used for attenuation correction; co-registered pre- and post-Gd MR images were correlated with PET images. Interval change in lesion maximum SUV and greatest lesion diameter was quantified between baseline and follow-up PET as well as MRI.

Results: Five subjects underwent the baseline F-18 FLT PET study; however, only two subjects returned for follow-up scan for whom the therapy response is being analyzed in this report. Subject #1 was a 55-year-old man who received targeted therapy with the combination of a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib). Multiple cerebral lesions demonstrated variable mild to intense FLT uptake at baseline PET, which showed a 30-77% decrease in metabolic activity at one-month follow-up (Figure 1). Compared to PET findings, the size reduction on MRI was lower ranging from 5%-55%, and the degree of contrast enhancement remained unchanged. There was no evidence of new metastasis on both PET and MRI. The patient maintained to have stable disease for 6 months, consistent with the partial response seen on FLT PET. Unfortunately, he then developed seizure and was found to have progressive brain metastasis, which required a change in treatment. Additional treatments with Cyberknife radiosurgery and therapy with ipilimumab and pembrolizumab were attempted, but he died 13 months after the initiation of targeted therapy. Subject #2 was a 36-year-old man who received immunotherapy with the combination of a PD1 inhibitor (nivolumab) and an anti-CTLA4 antibody (ipilimumab). Multiple larger cerebral metastases showed intense FLT uptake at baseline and demonstrated a mixed response at one-month follow-up with most lesions decreasing up to 76% in SUV, but a few lesions increased up to 75% in SUV. Many larger lesions showed no significant change in size or contrast enhancement on MRI. The therapy was switched over to dabrafenib and trametinib which led to a partial response intra-cranially and extra-cranially based on brain MRI and FDG PET/CT. The patient is still alive 16 months following therapy initiation.

Conclusion: PET/MR imaging with F-18 FLT has promise for early treatment response assessment in patients with MBM who are undergoing targeted therapy or immunotherapy. More studies are required to further characterize the metabolic change and to be able to define appropriate PET response criteria. Research Support: U.S Department of Energy, Grant # DE SC0008833 $$graphic_9633D4BC-C773-443B-A4E6-66CA005EFA15$$