Dosimetry of [Lu]Lu-DOTATATE in Patients with Advanced Midgut Neuroendocrine Tumors: Results from a Substudy of the Phase III NETTER-1 Trial.

This substudy of the phase III NETTER-1 trial evaluated [Lu]Lu-DOTATATE (hereafter Lu-DOTATATE) for advanced midgut neuroendocrine tumors and aimed to assess dosimetry of a standard 4-cycle protocol and any potential relationship to toxicity. Change in tumor size by absorbed dose was an exploratory endpoint. Patients with locally advanced or metastatic, well-differentiated, midgut neuroendocrine tumors were enrolled in this substudy between August 2013 and January 2016. Patients were scheduled to receive 4 infusions of 7.4 GBq of Lu-DOTATATE for a cumulative injected activity of 29.6 GBq. After a Lu-DOTATATE infusion, whole-body planar images (4-6 time points for up to 7 d) and SPECT/CT images (at 24 and/or 48 h) were acquired, and absorbed and time-integrated activity coefficients were calculated to derive dosimetry. Blood and urine samples were used to determine the blood clearance and activity elimination rate. Tumor absorbed dose was derived using a sphere model, interpolating Lu dose factors on the basis of each lesion mass. Tumor size was assessed by measuring the longest and perpendicular dimensions on CT at measured time points. Dosimetric assessments were evaluated in 20 patients. Organ dosimetry showed substantial interpatient variability. The predicted mean cumulative absorbed doses to kidneys and bone marrow were 19.4 (SD, 8.7) and 1.0 (SD, 0.8) Gy, respectively. Three patients had kidney doses between 28 and 33 Gy; 2 had grade 1 increased serum creatinine, and 1 showed no evidence of renal toxicity (up to 5 y of follow-up). Hematologic toxicity was primarily mild or moderate (grade 1-2) with no increase over time or association with cumulative absorbed dose. Tumor kinetics in 65 lesions demonstrated stable activity over time. Inter- and intrapatient variability was observed, and the median cumulative absorbed dose was 134 Gy (range, 7-2,218 Gy). Acknowledging the limitations of the imaging methods used and tumor volume assessments, we found no correlation between the best tumor size reduction and the absorbed dose, though most tumors (90%) shrank over the 72-wk study period. The dosimetry data support the findings that the standard treatment regimen with Lu-DOTATATE that includes personalized adjustments according to acute toxicity assessments is well tolerated and manageable.