Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE in patients with midgut neuroendocrine tumors.

Abstract

4112 Background: As demonstrated in the primary analysis of the phase 3 NETTER-1 trial, 177Lu-DOTATATE significantly prolonged progression-free survival (PFS) versus high-dose long-acting octreotide, with a HR of 0.18 (95% CI: 0.11, 0.29; p < 0.0001), in patients with advanced, progressive, well-differentiated, somatostatin receptor-positive midgut neuroendocrine tumors (NETs). Here we report final overall survival (OS) for NETTER-1. Methods: In this international open-label trial, eligible patients were randomized to receive either four cycles of 177Lu-DOTATATE 7.4 GBq (200 mCi) every 8 ± 1 weeks plus long-acting octreotide 30 mg or high-dose long-acting octreotide 60 mg every 4 weeks (control arm), both on top of best supportive care. After disease progression on randomized treatment or completion of an 18-month treatment period, patients in both arms entered long-term follow-up and could receive further anti-cancer treatment as recommended by their physicians. The primary endpoint was PFS per RECIST 1.1 and OS was a key secondary endpoint. Primary intention-to-treat analysis of OS was prespecified to take place after 158 deaths or 5 years after the last patient was randomized, whichever occurred first. Results: Of 231 randomized patients, 101/117 (86.3%) in the 177Lu-DOTATATE arm and 99/114 (86.8%) in the control arm entered long-term follow-up. Final analysis occurred 5 years after the last patient was randomized, following 142 deaths, with a median follow-up of more than 76 months. During long-term follow-up, 41/114 (36%) of patients in the control arm received subsequent radioligand therapy (“cross-over”), the majority (22.8%) within 24 months. Median OS was 48.0 months (95% CI: 37.4, 55.2) in the 177Lu-DOTATATE arm and 36.3 months (95% CI: 25.9, 51.7) in the control arm. HR was 0.84 (95% CI: 0.60, 1.17) with p = 0.30 (unstratified 2-sided log-rank test). A total of 2/112 (1.8%) 177Lu-DOTATATE treated patients in the study developed myelodysplastic syndrome (MDS). No new cases of MDS or acute leukemia were reported in the long-term follow-up. Overall, no new safety signals emerged during long-term follow-up. Conclusions: Median OS was 48.0 months in the 177Lu-DOTATATE arm of the NETTER-1 trial and 36.3 months in the control arm. This difference was not statistically significant, potentially impacted by a high rate (36%) of cross-over of patients in the control arm to radioligand therapy after progression. In overall conclusion, the NETTER-1 study demonstrated that 177Lu-DOTATATE yielded a clinically and statistically significant improvement in PFS as a primary endpoint (HR: 0.18, p < 0.0001) as well as a clinically meaningful trend towards improvement in median OS of 11.7 months. No new safety signals emerged during the 5-year long-term follow-up. Clinical trial information: NCT01578239.

Treatment of Neuroendocrine Neoplasms with Radiolabeled Peptides—Where Are We Now

“…In addition, 200 patients entered long-term follow up and could receive further anti-cancer treatment as needed, which showed a clinically meaningful improvement in median overall survival in the 177 Lu-DOTATATE group of 48 months compared to 36.3 months in the octreotide LAR group. Whilst this was not a statistically significant result, this may have been influenced by a high rate (36%) of cross-over of patients from the octreotide LAR group to the PRRT group [76]. Reassuringly, no new safety concerns were revealed during this long-term follow-up period.…”

Combination Therapies with PRRT

“…Recent analysis showed clinically improved median OS of 48 vs. 36 months compared to the control arm. However, the difference was not statistically significant between both groups, probably because of the high rate of cross-over-treatment in the study (36%) [73]. A debatable point of the NETTER-1 study is whether the effect of PRRT has been potentiated by SSA.…”

Radiolabeled Somatostatin Analogues for Diagnosis and Treatment of Neuroendocrine Tumors

“…Although the results of the final analysis of the NETTER-1 study indicate that PRRT is safe and effective, and rarely causes serious toxicity [ 155 ], there is evidence that dosimetric evaluation can play an important role—especially in patients with risk factors for renal or hematological toxicity, or those presenting with comorbidities [ 63 , 120 , 121 ]. Moreover, several studies have shown that additional PRRT cycles (salvage therapy setting) or re-treatments can be safely performed following dosimetric estimations [ 156 , 157 , 158 , 159 ].…”