Adding the radioligand lutetium-177 dotatate (Lu-177 dotatate) to standard therapy almost tripled the median progression-free survival in patients with untreated, high-grade, gastroenteropancreatic neuroendocrine tumors in the randomized phase III NETTER-2 study, researchers reported at the 2024 ASCO Gastrointestinal Cancers Symposium.¹

Median progression-free survival increased from 8.5 months with high-dose octreotide to 22.8 months with Lu-177 dotatate plus standard-dose octreotide. The objective response rate improved from 9.3% to 43.0%, and benefits were observed across all prespecified subgroups, according to Simron Singh, MD, MPH, FRCPC, of the University of Toronto.

Simron Singh, MD, MPH, FRCPC

“NETTER-2 is the first randomized trial to evaluate a radioligand therapy in the first line for any metastatic solid tumor. NETTER-2 met its primary endpoint, reducing the risk of disease progression or death by 72%,” said Dr. Singh. “Unprecedented response rates were observed, and time to deterioration in quality of life remained similar -between the arms. These data have practice-changing implications and support consideration of the first-line use of lutetium dotatate earlier within the disease course of grade 2 and grade 2 well-differentiated gastroenteropancreatic neuroendocrine tumors.”

As Dr. Singh noted, there is no standard of care for high-grade 2 or grade 3 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), but Lu-177 dotatate has proven effective in more advanced disease. In the NETTER-1 trial,² the addition of Lu-177 dotatate to octreotide (at 30 mg) resulted in a median progression-free survival of 28.4 months, vs 8.5 months with octreotide (at 60 mg; hazard ratio [HR] = 0.21; P < .0001), in progressive, somatostatin receptor–positive grade 1 and 2 midgut neuroendocrine tumors. These results provided the rationale for evaluating the radioligand in the first-line setting and in a previously untreated population with more high-grade aggressive disease than in NETTER-1.

About NETTER-2

NETTER-2 enrolled 226 patients with advanced, somatostatin receptor–positive, well-differentiated grade 2 or 3 GEP-NETs and a Ki67 index of ≥ 10% and ≤ 55%. Tumor sites were the pancreas in 55% and the small intestine in 29%. Grade 2 tumors were documented in 65%, and grade 3 tumors were noted in 35%; the median Ki67 index was 17%.

Patients were randomly assigned 2:1 to receive Lu-177 dotatate plus standard-dose (30 mg) octreotide every 8 weeks or high-dose (60 mg) octreotide alone every 4 weeks. Upon disease progression, patients in the experimental arm could be retreated with the radioligand every 8 weeks for up to four cycles, and control arm patients could receive Lu-177 dotatate plus standard-dose octreotide every 8 weeks for four cycles The primary endpoint was progression-free survival.

Key Findings

Most patients (88%) in the experimental arm received all four cycles of Lu-177 dotatate. Median duration of treatment exposure was 71 weeks with Lu-177 dotatate and 40 weeks with high-dose octreotide.

Treatment with the radioligand resulted in a 72% reduction in the risk for disease progression or death (HR = 0.276; P < .0001), with benefit consistent irrespective of age, sex, race, tumor grade, tumor origin (pancreas, intestine, all non-pancreas), or somatostatin receptor uptake, Dr. Singh reported, emphasizing the benefit was seen in those with grade 2 or 3 disease alike. The overall response rate was 43% in the Lu-177 dotatate arm and 9.3% in the control arm, with complete responses achieved by 5.3% and 0%, respectively. “These response rates are some of the highest reported to date in neuroendocrine malignancies,” he pointed out.

Patients receiving the radioligand had an almost eightfold higher chance (odds ratio [OR] = 7.81) of response, as compared with those on high-dose octreotide. Median duration of response was 23.3 months with Lu-177 dotatate arm and was not estimable for high-dose octreotide. Time to deterioration of quality of life, a secondary endpoint, was similar between the two groups. “Somatostatin analogs are some of the most well-tolerated anticancer agents out there, so the fact that we did not see any differences was considered a positive outcome,” Dr. Singh commented.

No new or unexpected treatment-related adverse events occurred with Lu-177 dotatate; rates of grade ≥ 3 toxicities were 16% with Lu-177 dotatate and 4% with high-dose octreotide. One secondary hematologic malignancy occurred in the Lu-177 dotatate arm. “There was slightly more nausea in the lutetium arm than with high-dose octreotide, though this was significantly less than was seen in NETTER-1, probably because of better use of amino acids. There was certainly more diarrhea and abdominal pain in the high-dose octreotide arm,” he noted.

During the discussion, Dr. Singh said more information will be forthcoming to shed light on which patients need the radioligand in the first-line setting. “Things like symptoms, tumor bulk, trajectory of tumor growth, and disease location are going to matter” in selecting treatment, he concluded. 

DISCLOSURE: Dr. Singh reported financial relationships with Sanofi, Advanced Accelerator Applications/Novartis, and Ipsen.

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. 2024 ASCO Gastrointestinal Cancers Symposium. Abstract LBA588. Presented January 19, 2024.

2. Strosberg J, El-Haddad G, Wolin E, et al: Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med 376:125-135, 2017.

EXPERT POINT OF VIEW

Invited discussant of the NETTER-2 trial, Jordan D. Berlin, MD, said this was a “much-needed, “well-conducted” study with a “clearly positive” primary endpoint. He believes these results may help to define the optimal treatment of high-grade 2 and grade 3 gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Dr. Berlin is the Ingram Professor of Cancer Research and Director of the Division of Hematology and Oncology at Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville.

Jordan D. Berlin, MD

“Well-differentiated grade 3 neuroendocrine tumors make up about 6% of all GEP-NETs. But, until now, we had no idea of the effects of any of our approved therapies for this group…. The standard of care has been undefined for newly diagnosed high-grade 2 and grade 3 GEP-NETs,” he explained.

NETTER-2 adds to the “spectacular” results of NETTER-1,¹ which established lutetium-177 dotatate (Lu-177 dotatate) as the standard of care for previously treated, well-differentiated midgut primary tumors, based on the 79% reduction in the risk for disease progression or death and the 60% reduction in mortality. The progression-free survival results in NETTER-2 were similarly impressive, according to Dr. -Berlin, with a difference so large “you could drive a truck between the two [Kaplan-Meier] curves, which is always good to see…. The study met its primary endpoint and its other endpoints,” he added, noting neither treatment was particularly toxic, though it is too early to identify the long-term risk for treatment-related hematologic malignancies.

However, Dr. Berlin would like to eventually see an overall survival benefit in NETTER-2. Although he acknowledged this outcome could be influenced by crossover, he shared these comments: “In the real world, there is crossover…. Overall survival is important, even in a disease with longer overall survival to start with.”

Clinical Implications

“Without survival data or prolonged time to deterioration of quality of life, lutetium dotatate does not have to be used first line,” Dr. Berlin continued. “In my clinic, tumor burden and, if known, the trajectory of tumor growth will be keys for me. NETTER-1 proved there was less benefit with peptide receptor radionuclide therapy in larger tumors, so if the liver metastases are small and the overall tumor burden is low, I would start with a somatostatin analog. If the tumors are large (approaching 3 cm), I’d start with a somatostatin analog and peptide receptor radionuclide therapy. I would start with peptide receptor radionuclide therapy if I was worried that tumor growth would increase retroperitoneal tumor burden, where you’re worried about retroperitoneal scarring fibrosis.” 

DISCLOSURE: Dr. Berlin reported financial relationships with Bayer, Bexion, BioSapien, Bristol Myers Squibb/Celgene, Insmed, Ipsen, MEKanistic Therapeutics, Merck, Merus, Mirati Therapeutics, Oxford BioTherapeutics, Regeneron, AstraZeneca, Boehringer Ingelheim, and Novocure.

REFERENCE

1. Strosberg J, El-Haddad G, Wolin E, et al: Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med 376:125-135, 2017.