177Lu-edotreotide Radiopharmaceutical Therapy Prolongs PFS vs Everolimus in SSTR+ GEP-NETs

The phase 3 COMPETE trial (NCT03049189) met its primary end point of clinically and statistically significant progression-free survival (PFS) improvement with non-carrier–added 177 Lutetium edotreotide (177Lu-edotreotide; ITM-11) vs everolimus (Afinitor) in patients with grade 1 or 2 somatostatin receptor (SSTR)–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).1

Topline data from the trial, which were presented at the 22nd Annual European Neuroendocrine Tumor Society 2025 Conference, showed that the median PFS was 23.9 months with the targeted radiopharmaceutical therapy 177Lu-edotreotide (n = 207) compared with 14.1 months with standard-of-care (SOC) everolimus (n = 102; HR, 0.67; 95% CI, 0.48-0.95; P = .022).

“COMPETE is the first pivotal trial comparing a radiopharmaceutical drug candidate [with] a targeted molecular therapy without the routine use of accompanying somatostatin analogues in this [population of patients with] GEP-NETs,” presenting investigator Jaume Capdevila, MD, PhD, who is also a senior medical oncologist at Vall d’Hebron University Hospital in Barcelona, stated in a news release. “These data show unequivocal support for 177Lu-edotreotide’s potential benefit in extending PFS. Additionally, 177Lu-edotreotide’s convenient dosing schedule and favorable safety results reinforce its potential as a compelling new treatment option.”

The prospective, randomized, controlled, open-label COMPETE trial enrolled 309 patients with inoperable, progressive, grade 1 or 2 SSTR-positive NETs of pancreatic or gastroenteric origin across Europe, the United States, Australia, and South Africa.

Patients were randomly assigned 2:1 to receive either 7.5 GBq of 177Lu-edotreotide with a nephroprotective amino acid solution every 3 months for up to 4 cycles, or everolimus at 10 mg daily for a maximum of 30 months or until disease progression. Patients were stratified by primary tumor origin (gastroenteric NETs vs pancreatic NETs), and by prior lines of medical therapy (1st line vs 2nd line).

Patients were excluded if they had a known hypersensitivity to edotreotide, everolimus, DOTA, lutetium-177, any excipient of edotreotide or everolimus, or any other Rapamycin derivative; prior exposure to any peptide receptor radionuclide therapy; prior exposure to mTOR inhibitors; received prior treatment with external field radiation to GEP-NET lesions within 90 days before randomization or radioembolization therapy; received prior therapy with an investigational compound and/or medical device within 30 days prior to randomization; an indication for potentially curative surgical lesion removal; planned alternative therapy during the study participation period; serious nonmalignant disease; or clinically relevant renal, hepatic, cardiovascular, or hematological organ dysfunction, that had the potential to interfere with the safety of the study treatments.2

Notably, 177Lu-edotreotide consists of non-carrier–­added Lutetium-177—which is a therapeutic β-emitting radioisotope that has a higher isotopic purity than carrier-added lutetium—and the SSTR agonist edotreotide.1177Lu-edotreotide is the first non-carrier–added lutetium radiopharmaceutical to be investigated in patients with GEP-NETs, according to ITM Isotope Technologies, the drug’s developer.

Additional topline data showed that, as of January 21, 2025, the interim median overall survival (OS) was numerically higher, although not conclusive, for 177Lu-edotreotide compared with everolimus, at 63.4 months vs 58.7 months, respectively (HR, 0.78; 95% CI, 0.5-1.1; P = .206). These OS data will continue to mature. Of note, patients who progressed on study treatment were allowed to initiate an alternative therapy, which may confound the OS data.

“The COMPETE results represent a major step forward in the development of new treatment options for people living with progressive, inoperable GEP-NETs,” Jonathan Strosberg, MD, past president of the North American Neuroendocrine Tumor Society and chair of the GI Research Program at Moffitt Cancer Center and Research Institute in Tampa, Florida, added in the news release. “By extending PFS by almost 10 months compared [with] SOC in this trial, 177Lu-edotreotide showed the potential to significantly improve the treatment paradigm for physicians and their patients.”

Regarding safety, the rate of treatment-emergent adverse effects (TEAEs) related to study treatment was lower in the 177Lu-edotreotide arm vs the everolimus arm, at 82.5% vs 97.0%, respectively. Notably, 1 serious TEAE of grade 2 myelodysplastic syndrome was reported in the 177Lu-edotreotide arm and deemed related to 177Lu-edotreotide treatment. Overall, no unforeseen TEAS were observed.

Additional data from the trial, including overall response rate, subgroup analysis findings, quality of life data, and dosimetry, are under evaluation and are planned to be submitted for presentation at future medical conferences. Moreover, ITM Isotope Technologies, the developer of 177Lu-edotreotide, plans to submit a new drug application (NDA) to the FDA in 2025.

“These successful results validate our decision to design a pivotal phase 3 trial directly comparing a targeted radiopharmaceutical against a targeted molecular therapy in Grade 1/2 GEP-NETS, underscoring our commitment to improving the lives of people living with this challenging cancer,” Andrew Cavey, MD, PhD, chief executive officer of ITM Isotope Technologies, concluded in the news release. “With this successful readout, 177Lu-edotreotide becomes the first drug candidate in ITM’s broad portfolio of early- to late-stage radiopharmaceuticals to deliver positive phase 3 results and progress towards NDA submission and commercial launch preparations. Together, with our global isotopes manufacturing business, robust supply chain, and experienced clinical and commercial team, we believe we are uniquely positioned as a standout leader in the fast-growing radiopharmaceutical industry.”

References

1. ITM presents positive topline phase 3 COMPETE trial data with n.c.a. 177Lu-edotreotide (ITM-11), a targeted radiopharmaceutical therapy, in patients with grade 1 or 2 gastroenteropancreatic neuroendocrine tumors at the ENETS 2025 Conference. News release. ITM Isotope Technologies Munich SE. March 6, 2025. Accessed March 6, 2025. https://www.itm-radiopharma.com/news/press-releases/press-releases-detail/itm-presents-positive-topline-phase-3-compete-trial-data-with-nca-177lu-edotreotide-itm-11-a-targeted-radiopharmaceutical-therapy-in-patients-with-grade-1-or-2-gastroenteropancreatic-neuroendocrine-tumors-at-the-enets-2025-conference-688/
2. Efficacy and safety of 177Lu-edotreotide PRRT in GEP-NET patients (COMPETE). ClinicalTrials.gov. Updated November 20, 2023. Accessed March 6, 2025. https://clinicaltrials.gov/study/NCT03049189