First-line 177Lu-DOTATATE treatment is effective across NET grades and locations

Previously, the results of the phase III study NETTER-2 have shown that first-line treatment with the radioligand [¹⁷⁷Lu]Lu-DOTA-TATE (hereafter ¹⁷⁷Lu-DOTATATE) significantly increases the progression-free survival (PFS) and objective response rate (ORR) in patients with advanced, well-differentiated, high grade 2 and 3, gastroenteropancreatic neuroendocrine tumors (GEP-NETs), compared to high dose octreotide.¹ During ESMO GI 2024, dr. Simron Singh presented a preplanned subgroup analysis of the NETTER-2 study, which examined the efficacy of ¹⁷⁷Lu-DOTATATE by NET grade and origin.²

Study design

This phase III, international, randomised study enrolled patients aged ≥15 years with grade 2 or 3 somatostatin receptor positive (SSTR⁺) GEP-NETs. No prior treatment with PRRT or systemic therapy was allowed. Patients were randomised to receive 4 cycles of ¹⁷⁷Lu-DOTATATE plus 30 mg of long-acting release octreotide (Q8W during ¹⁷⁷Lu-DOTATATE treatment, Q4W after ¹⁷⁷Lu-DOTATATE treatment) or 60 mg long-acting release octreotide (Q4W). The primary endpoint was the PFS, and key secondary endpoints included the ORR, time to response (TTR) and duration of response (DOR), which were centrally assessed according to RECIST 1.1. For analysis purposes, patients were stratified by NET grade (2 or 3) and NET origin (pancreas or small intestine).

Results

A total of 226 patients were randomised: 151 were assigned to the ¹⁷⁷Lu-DOTATATE arm and 75 to the control arm. All subgroups displayed a clinical benefit in favour of ¹⁷⁷Lu-DOTATATE with regards to PFS and ORR. For patients with a grade 2 NET, the median PFS was 29.0 months with ¹⁷⁷Lu-DOTATATE treatment, versus 13.8 months with high-dose octreotide (HR [95% CI]: 0.306 [0.176-0.530]). Patients with a grade 3 NET had a median PFS of 22.2 months when treated with ¹⁷⁷Lu-DOTATATE, compared to 5.6 months when treated with high-dose octreotide (HR [95% CI]: 0.266 [0.145-0.489]). Patients with NETs originating from the pancreas had a median PFS of 19.4 months in case of ¹⁷⁷Lu-DOTATATE treatment and 8.5 months with high-dose octreotide treatment (HR [95% CI]: 0.336 [0.200-0.562]). For patients with NETs originating from the small intestine, these values were 29.0 and 8.4 months, respectively (HR [95% CI]: 0.305 [0.126-0.738]). The ORR was similar for patients with grade 2 or 3 NET (grade 2: 40.4%; grade 3: 48.1%), but differed based on the NET origin (pancreatic: 51.2%; small intestine: 26.7%). The TTR was evaluated among the 65 patients that had achieved a partial or complete response to ¹⁷⁷Lu-DOTATATE, and was similar across all 4 subgroups, with a value of approximately 5.8 months in all groups. The median DOR was 24.9 months (95% CI: 23.3-NE) for grade 2 NETs, 19.3 months (95% CI: 17.8-NE) for grade 3 NETs, 18.4 months (95% CI: 11.3-23.3) for pancreatic NETs and could not be estimated for NETs originating from the small intestine (95% CI: 24.9-NE).

Conclusions

In conclusion, this subgroup analysis of the phase III study NETTER-2 has shown that the previously reported efficacy of first-line ¹⁷⁷Lu-DOTATATE therapy is consistent across different NET grades and locations of origin. As a result, dr. Singh proposes that ¹⁷⁷Lu-DOTATATE should be considered as the standard of care for patients with advanced, well-differentiated grade 2 or 3 SSTR⁺ GEP-NET.

References

1. Singh S, Halperin DM, Myrehaug S, et al. [177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study. J Clin Oncol 2024;42(Number 3_suppl):LBA588.
2. Singh S, et al. First-line efficacy of [177Lu]Lu-DOTA-TATE in patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors by tumor grade and primary origin: Subgroup analysis of the phase III NETTER-2 study. Presented at ESMO GI 2024; Abstract 211MO.