Analysis of Somatostatin Receptor Imaging Modalities and the Relationship Between Tumor Uptake and Treatment Response to [177Lu]Lu-DOTA-TATE in Patients from the Randomized Phase 3 NETTER-2 study

Introduction: The Phase 3 NETTER-2 study (NCT03972488) demonstrated significant improvement in progression-free survival and objective response rate (ORR) with [¹⁷⁷Lu]Lu-DOTA-TATE (hereafter ¹⁷⁷Lu-DOTATATE) given as first-line treatment in patients with advanced, well-differentiated high Grade 2 (G2) and G3 gastroenteropancreatic neuroendocrine tumors (GEP-NETs) as compared with high dose octreotide. Eligible patients had somatostatin receptor (SSTR) positive lesions with a tumor uptake score (based on a visual semi-quantitative scale) of 3 (greater than observed liver uptake but lower than spleen) or 4 (greater than spleen). This sub-analysis of NETTER-2 investigated the different somatostatin receptor imaging (SRI) modalities used to assess SSTR uptake at enrollment, the congruence of local versus central assessment and the relationship between treatment response and baseline SSTR uptake score.

Methods: The NETTER-2 study enrolled patients with newly diagnosed SSTR-positive well-differentiated high G2 or G3 (Ki67 ≥10% and ≤55%) GEP-NETs. Any SRI modality could be used for assessment of eligibility, with SSTR uptake first evaluated locally for eligibility and then reassessed centrally by independent blinded review. Participants were randomized (2:1) to receive 4 cycles of ¹⁷⁷Lu-DOTATATE (4 × 7.4 GBq at 8-weekly intervals [Q8W]) plus 30 mg octreotide long-acting repeatable (LAR) Q8W during ¹⁷⁷Lu-DOTATATE treatment then Q4W (¹⁷⁷Lu-DOTATATE group) or 60 mg octreotide LAR Q4W (control group). Analyses included comparisons of local and central highest SSTR tumor uptake scores at baseline for all patients, the highest and mean maximum standardized uptake value (SUVmax) across all lesions per patient for different SRI methods, and local and central assessment of uptake versus tumor response to ¹⁷⁷Lu-DOTATATE treatment.

Results: Final analysis consisted of 226 patients randomized into the study across 38 sites in 9 countries. PET/CT with [⁶⁸Ga]-DOTATOC or [⁶⁸Ga]-DOTATATE was used at screening in 90.3% of patients. Central re-assessment of SSTR tumor uptake score at baseline showed high congruence with local results, with 97% of patients being confirmed as having a tumor uptake score of 3 or 4. Assessment of SSTR SUVmax, per central review, showed that SUVmax was generally consistent between the two predominantly used Ga68 SRIs. A median (interquartile range) SSTR SUVmax of 28.2 (17.4, 47.0) was observed with [⁶⁸Ga]-DOTATOC PET/CT (n=127) compared with 28.6 (19.4, 41.2) for [⁶⁸Ga]-DOTATATE PET/CT (n=64). Results from the NETTER-2 primary analysis showed that ORR was 43.0% (95% CI: 35.0, 51.3) in the ¹⁷⁷Lu-DOTATATE arm compared with 9.3% (95% CI: 3.8, 18.3) in the control arm; stratified odds ratio 7.81 (95% CI: 3.32, 18.4; p<0.0001). In the ¹⁷⁷Lu-DOTATATE arm, the ORR in patients with a tumor uptake score of 3 and 4 SSTR tumor uptake was 45.8% (95% CI: 25.6, 67.2) and 42.3% (95% CI: 33.4, 51.5), respectively per central review at baseline and 37.5% (95% CI: 24.9, 51.5) and 46.3% (95% CI: 36.0, 56.8), respectively per local review at baseline.

Conclusions: Assessment of SSTR expression was generally consistent between local and central analysis and regardless of the local choice of imaging methodology ([⁶⁸Ga]-DOTATOC or [⁶⁸Ga]-DOTATATE). Response rates to ¹⁷⁷Lu-DOTATATE for patients with grade 3 vs. grade 4 SSTR uptake at baseline (regardless of local or central review) showed no substantial differences. Currently employed SRI methods therefore appear highly suitable for patient selection for ¹⁷⁷Lu-DOTATATE treatment.