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SAN FRANCISCO -- Adding a radioligand to standard therapy almost tripled median progression-free survival (PFS) in untreated high-grade gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a randomized trial showed.

Median PFS increased from 8.5 months with high-dose octreotide to 22.8 months with ¹⁷⁷Lu-Dotatate (Lutathera) plus standard-dose octreotide. The objective response rate improved from 9.3% to 43.0%, and benefits were observed across all prespecified subgroups.

Quality of life and rates of treatment-related adverse events (TRAEs) were similar between the two groups, reported Simron Singh, MD, of the University of Toronto, at the Gastrointestinal Cancers Symposium.

" is the first randomized trial to evaluate a radioligand therapy in first line for any metastatic solid tumor," said Singh. "NETTER-2 met its primary endpoint, reducing the risk of progression or death by 72%. The response rate observed with lutetium dotatate was among the highest observed in neuroendocrine tumors to date. The safety findings were consistent with the known safety profile for 177-lutetium dotatate. No new safety concerns have emerged in this patient population.

"These data have practice-changing implications and support consideration of first-line use of lutetium dotatate in high-grade 2 and grade 3, well-differentiated, gastroenteropancreatic neuroendocrine tumors."

NETTER-2 provided a much-needed answer to the question of how to treat high-grade 2 and grade 3 GEP-NETs, which make up about 6% of all GEP-NETS.

"Until now, we had no idea of the effects of any of our approved therapies for this group," said invited discussant Jordan Berlin, MD, of Vanderbilt University Medical Center in Nashville, Tennessee. "Standard of care is undefined for newly diagnosed high-grade 2 and grade 3 GEP-NETs."

The results showed a difference favoring ¹⁷⁷Lu-Dotatate so great "that you could drive a truck between the two [Kaplan-Meier] curves. They met the primary endpoints and the other endpoints," Berlin continued. "Neither treatment was particularly toxic, but it's still early, and we don't know what the long-term hematologic malignancies will be."

He noted that "we don't know anything about survival, and I'm sure somebody will say, 'Oh, crossover design will probably make it so there's not usually a different overall survival.' Well, in the real world there is crossover, so overall survival is still important."

The trial added to the "spectacular" results of NETTER-1, which established ¹⁷⁷Lu-Dotatate as standard of care for previously treated, well-differentiated midgut primary tumors, said Berlin. The results showed a 79% reduction in the hazard for progression or death and a 60% reduction in the survival hazard. About a third of the tumors were grade 2 and the rest were grade 1.

No standard of care existed for high-grade 2 or grade 3 GEP-NETs, providing a rationale for evaluating the radioligand in that setting. Enrollment was limited to advanced, somatostatin receptor-positive (SSTR+), grade 2 or three GEP-NETs, associated with Ki67 ≥10% and ≤55%.

Investigators in NETTER-2 randomized 226 patients 2:1 to ¹⁷⁷Lu-Dotatate plus standard-dose octreotide or to high-dose octreotide. The primary endpoint was PFS.

The results showed more than a 72% reduction in the hazard for disease progression or death in favor of the radioligand (95% CI 0.182-0.418, P<0.0001). The benefit was consistent irrespective of age, sex, race, tumor grade, tumor origin (pancreas, intestine, all non-pancreas), or SSTR uptake.

Eight patients in the ¹⁷⁷Lu-Dotatate group achieved complete responses versus none with high-dose octreotide, and 37.7% had partial responses versus 9.3% for the control arm. An additional 47.7% of patients had stable disease with ¹⁷⁷Lu-Dotatate, as did 56.0% of patients in the control group. Among responding patients, the median duration of response was 23.3 months with the radioligand versus 7.0 months for high-dose octreotide.

Time to deterioration of quality of life, a secondary endpoint, was similar between the two groups. No new or unexpected TRAEs occurred with ¹⁷⁷Lu-Dotatate, and rates of grade ≥3 TRAEs were 16% with ¹⁷⁷Lu-Dotatate and 4% with octreotide. The most common all-grade AEs in the radioligand arm were nausea (27.2%), diarrhea (25.9%), and abdominal pain (17.7%). Grade ≥3 AEs in the experimental arm included decreased lymphocyte count (5.4%), increased gamma-glutamyl transferase (4.8%), and small bowel obstruction (2.7%). One secondary hematologic malignancy occurred in the ¹⁷⁷Lu-Dotatate group.

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