Characterization of proliferative rebound during drug holiday by FLT-PET imaging in patients treated with sunitinib (SU).

Abstract

3094 Background: SU is a TKI of VEGFR, PDGFR and c-Kit. Increase in pain at sites of known metastasis during VEGFR TKI withdrawal has been reported. We hypothesized that this withdrawal flare is caused by increased tumor proliferation. The PET radiotracer [18F]-FLT accumulates in cells with high thymidine kinase-1 activity, indicating areas of cell proliferation. We characterized the proliferative properties of the withdrawal flare using FLT-PET and assessed it as a marker of clinical benefit (CB). Methods: Pts with advanced solid cancers and no prior anti-VEGF therapy were enrolled. All pts had metastatic lesions amenable to PET/CT imaging. For Part A, SU was given at 50 mg PO qd } 4 wks, followed by a 2 wk break (6 wk cycles); FLT-PET scans were obtained at baseline, wk 4 (on SU), and wk 6 (off SU). For Part B, SU was given at 50 mg PO qd × 2 wks, followed by a 1 wk break (6 wk cycles); FLT-PET scans were obtained at baseline, wk 2 (on SU), and wk 3 (off SU). Disease assessments by CT were repeated every 2 cycles. Changes in SUV were calculated and RECIST status determined. CB was defined as progression of disease at > 6 mos. Results: Of 25 pts enrolled (A: 14, B: 11), complete, analyzed sets of FLT-PET scans are available for 8 in Part A (5 renal, 1 prostate, 1 small cell lung, 1 thymus) and 5 in Part B (2 renal, 1 esophagus, 1 liver, 1 sarcoma). A relative increase in SUV (off SU) was observed in 6 pts on A from wk 4 to 6 (mean ΔSUVpeak +65%, range -25 to +250%) and 1 pt on B from wk 2 to 3 (+15%). On A, relative increase in proliferation after SU withdrawal (wk 4 to 6) was lower in the CB (3 renal, 1 small cell lung, 1 prostate) vs. no CB group (mean ΔSUVpeak +35 vs. +105%; p = NS). No such difference was seen in Part B (wk 2 to 3). Conclusions: On Part A, a proliferative increase in target lesions after SU withdrawal was observed in 75% of pts with varying tumor types; there was also a trend toward correlation of lower withdrawal flare with CB from SU. Significant proliferative rebound was not seen on Part B, likely due to the relatively long t1/2 of SU and/or failure to reach steady-state levels. Ongoing work is assessing pharmacodynamic changes on FLT-PET with a more potent VEGFR TKI (axitinib), with the future goal of exploiting the flare to enhance chemotherapy response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer