Pharmacodynamic study using FLT PET/CT in patients with renal cell cancer and other solid malignancies treated with sunitinib malate

Abstract

Purpose: To characterize proliferative changes in tumors during the sunitinib malate exposure/withdrawal using 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) imaging.

Patients and methods: Patients with advanced solid malignancies and no prior anti-VEGF exposure were enrolled. All patients had metastatic lesions amenable to FLT PET/CT imaging. Sunitinib was initiated at the standard dose of 50 mg p.o. daily either on a 4/2 or 2/1 schedule. FLT PET/CT scans were obtained at baseline, during sunitinib exposure, and after sunitinib withdrawal within cycle #1 of therapy. VEGF levels and sunitinib pharmacokinetic (PK) data were assessed at the same time points.

Results: Sixteen patients (8 patients on 4/2 schedule and 8 patients on 2/1 schedule) completed all three planned FLT PET/CT scans and were evaluable for pharmacodynamic imaging evaluation. During sunitinib withdrawal (change from scans 2 to 3), median FLT PET standardized uptake value (SUV(mean)) increased +15% (range: -14% to 277%; P = 0.047) for the 4/2 schedule and +19% (range: -5.3% to 200%; P = 0.047) for the 2/1 schedule. Sunitinib PK and VEGF ligand levels increased during sunitinib exposure and returned toward baseline during the treatment withdrawal.

Conclusions: The increase of cellular proliferation during sunitinib withdrawal in patients with renal cell carcinoma and other solid malignancies is consistent with a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI) withdrawal flare. Univariate and multivariate analysis suggest that plasma VEGF is associated with this flare, with an exploratory analysis implying that patients who experience less clinical benefit have a larger withdrawal flare. This might suggest that patients with a robust compensatory response to VEGFR TKI therapy experience early "angiogenic escape."

Figure 1

Schema of pharmacodynamic and pharmacokinetics time points. Patients were administered sunitinib 50 mg daily on the intermittently dosed 4/2 schedule (top) or 2/1 schedule (bottom). FLT PET/CT images were performed at baseline, peak sunitinib exposure, and during sunitinib withdrawal as indicated by the wide arrows. FLT, ¹⁸F-Fluorothymidine. PET, positron emission tomography. CT, computed tomography. VEGF, vascular endothelial growth factor. PK, pharmacokinetics. w, week.

Figure 2

Examples of the tumor flare phenomenon on FLT PET/CT in various tumor types. ccRCC, clear cell renal cell carcinoma. SCLC, small cell lung cancer. SUV, standardized uptake value.

Figure 3

Pharmacokinetic and pharmacodynamic parameters at time points throughout the sunitinib cycle. ccRCC, clear cell renal cell carcinoma. Thin dotted lines show individual patients results.

Figure 4

Figures 4a and b: Change in SUV_mean and SUV_max (normalized to baseline) by clinical benefit group. Note that the 4/2 and 2/1 schedules are combined so that the abscissa is scaled to sunitinib exposure (and scan time points) instead of time. CB, clinical benefit. NCB, no clinical benefit. ccRCC, clear cell renal cell carcinoma.

Figure 4

Figures 4a and b: Change in SUV_mean and SUV_max (normalized to baseline) by clinical benefit group. Note that the 4/2 and 2/1 schedules are combined so that the abscissa is scaled to sunitinib exposure (and scan time points) instead of time. CB, clinical benefit. NCB, no clinical benefit. ccRCC, clear cell renal cell carcinoma.