Lutetium Lu 177 Dotatate Maintains PFS, ORR Benefits Across Subgroups in SSTR+ GEP-NETs

Simron Singh, MD, MPH

First-line treatment with lutetium Lu 177 dotatate (Lutathera) in combination with octreotide improved progression-free survival (PFS) and overall response rates (ORR) regardless of tumor grade and primary origin in patients with advanced, grade 2 and grade 3, well-differentiated, somatostatin receptor (SSTR)–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), according to findings from a subgroup analysis of the phase 3 NETTER-2 trial (NCT03972488).¹

Findings presented at the 2024 ESMO Gastrointestinal Cancers Congress showed that patients with grade 2 treated with lutetium Lu 177 dotatate experienced a median PFS of 29.0 vs 13.8 months for those with grade 2 disease treated with octreotide (n = 48; HR, 0.306; 95% CI, 0.176-0.530). In patients with grade 3 disease in the experimental arm (n = 52), the median PFS was 22.2 months vs 5.6 months for the control arm (n = 27; HR, 0.266; 95% CI, 0.145-0.489).

Patients with pancreatic NETs had a median PFS of 19.4 months when treated with lutetium Lu 177 dotatate (n = 82) vs a median PFS of 8.5 months with octreotide (n = 41; HR, 0.336; 95% CI, 0.200-0.562). Similarly, patients with small intestine NETs had a median PFS of 29.0 months in the lutetium Lu 177 dotatate arm (n = 45) vs 8.4 months in the octreotide arm (n = 21; HR, 0.305; 95% CI, 0.126-0.738).

"For PFS and ORR, a clinical benefit in favor of lutetium Lu 177 dotatate vs high-dose octreotide was evident across all subgroups [grade 2, grade 3, pancreatic, and small intestine NETs]," presenting study author Simron Singh, MD, MPH, of the Odette Cancer Centre, Sunnybrook Health Sciences Centre, in Toronto, Ontario, Canada, stated in the presentation of data.

At the 2024 Gastrointestinal Cancers Symposium, Singh presented findings from the primary analysis of the randomized trial, showing that the radiolabeled somatostatin analog significantly improved PFS over high-dose octreotide in the overall patient population (HR, 0.276; 95% CI, 0.182-0.418; P < .0001).²

Notably, findings from the pivotal phase 3 NETTER-1 trial (NCT01578239) led to the FDA approval of lutetium Lu 177 dotatate for patients with SSTR-positive GEP-NETs in 2018.³ The agent was also approved for the treatment of pediatric patients 12 years of age and older with SSTR-positive GEP-NETs, including foregut, midgut, and hindgut neuroendocrine tumors, in April 2023.⁴

NETTER-2 investigated the first-line efficacy of lutetium Lu 177 dotatate in patients 15 years of age or older with advanced, well-differentiated, SSTR-positive, grade 2 or grade 3 GEP-NETs with Ki67 scores ranging from at least 10% no more than 55%. A diagnosis made within the last 6 months prior to enrollment was required, and prior peptide receptor radionuclide therapy or systemic therapy was not allowed.¹

Investigators randomly assigned 226 patients in a 2:1 ratio to 2 treatment groups: the lutetium Lu 177 dotatate group and the high-dose octreotide group. In the former group, patients were treated with lutetium Lu 177 dotatate at 7.4 GBq (200 mCi) plus long-acting repeatable (LAR) octreotide at 30 mg every 8 weeks for 4 cycles before octreotide was continued once every 4 weeks. In the latter group, patients were given high-dose LAR octreotide at doses of 60 mg once every 4 weeks.

In the optional treatment extension phase, patients who experienced disease progression in the lutetium Lu 177 dotatate arm were able to be retreated with the agent at the original dosing level once every 8 weeks for 2 to 4 cycles. Contrarily, patients receiving high-dose octreotide were eligible to crossover to lutetium Lu 177 dotatate plus octreotide at the original dosing and cycles. In the follow-up phase, patients had a follow-up visit once every 6 months for 2 years.

The primary end point of the trial was PFS, with ORR serving as a key secondary end point.

“When we look at the treatment arms, they were fairly well balanced between the 2 groups,” Singh shared.

Across all patients in both groups, the primary tumor site was pancreas (54.5%), small intestine (29.2%), or other (16.4%). Notably, 65% of patients had a grade 2 disease with a median Ki67 of 13.0 (range, 10-20). Thirty-five percent of patients had grade 3 disease with a median Ki67 of 30.0 (range, 21-50).

Tumor origin by grade included grade 2 and grade 3 pancreas (33.6%; 20.8%), grade 2 and grade 3 small intestine (21.2%; 8.0%), and grade 2 and grade 3 other cancers (10.2%; 6.2%).

Additional data showed that the ORR with the investigative drug was maintained irrespective of NET origin or grade. In NETs grades 2 and 3 patients treated with lutetium Lu 177 dotatate had an ORR of 40.4% (95% CI, 30.7%-50.7%) and 48.1% (95% CI, 34.0%-62.4%), respectively, compared with respective ORRs of 10.4% (95% CI, 3.5%-22.7%) and 7.4% (95% CI, 0.9%-24.3%) with the control agent. In NETs originating in the pancreas and the small intestine, treatment with the investigative agent led to ORRs of 51.2% (95% CI, 39.9%-62.4%) and 26.7% (95% CI, 14.6%-41.9%) compared with ORRs of 12.2% (95% CI, 4.1%-26.2%) and 4.8% (95% CI, 0.1%-23.8%) with octreotide.

Notably, time to response with lutetium Lu 177 dotatate was similar across all subgroups with median time to responses at 5.73 months (range, 3.4-22.5), 5.82 months (3.7-13.8), 5.85 months (3.4-22.5), and 5.78 months (3.9-12.7) in patients with NETS grade 2 and 3 tumors and NETS originating in the pancreas or small intestine, respectively.

“Of course, these responses aren’t meaningful unless we have a prolonged duration. [However], between the grade 2 and grade 3 [groups], we saw a [median] duration of [response (DOR)] of 24.9 months and 19.3 months, respectively. When we look at the pancreas [group], we saw a [median] DOR of 18.4 months. We weren't able to calculate [DOR] for the small intestine group, but [there was] generally a long DOR for these patients,” Singh reported of the prolonged responses across subgroups.

References

1. Singh S, Halperin D, Myrehaug 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: 2024 ESMO Gastrointestinal Cancers Congress; June 26-29, 2024; Munich, Germany. Abstract 211MO.
2. Singh S, Halperin D, 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(suppl 3):LBA588. doi:10.1200/JCO.2024.42.3_suppl.LBA588
3. FDA approves lutetium Lu 177 dotatate for treatment of GEP-NETS. FDA. January 26, 2018. Accessed June 26, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lutetium-lu-177-dotatate-treatment-gep-nets
4. FDA approves lutetium Lu 177 dotatate for pediatric patients 12 years and older with GEP-NETS. FDA. April 23, 2024. Accessed June 26, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lutetium-lu-177-dotatate-pediatric-patients-12-years-and-older-gep-nets