Radioligand Therapy in NETs: Evidence Gaps Remain Across Age Groups

Radioligand therapy (RLT) is an important treatment option for adults with neuroendocrine tumors (NETs), but pivotal trials have enrolled few adolescents and young adults (AYAs) and included limited representation of older patients, leaving important evidence gaps at both ends of the age spectrum, according to Jennifer R. Eads, MD, professor of medicine and director of the Penn Neuroendocrine Tumor Program at Penn Medicine, who presented at the 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium.

A Paucity of Data in Approved-Agent Trials

Eads began by reviewing who was actually enrolled in the trials that led to approved radioligands. Although several of these studies allowed adolescents to enroll, few did. Across the approved-agent RLT trials reviewed, only 12 patients aged 18 years or younger were identified, most of them in the dedicated pediatric study NETTER-P (NCT04711135), which enrolled 11 adolescents.¹ At the other end of the spectrum, the median ages of accrued patients were generally in the early 60s, and the main age-based data came from a subgroup analysis of the phase 3 NETTER-1 trial (NCT01578239), which found that the progression-free survival (PFS) benefit associated with lutetium Lu 177 dotatate was consistent in patients older than 65 years and those aged 65 years or younger.²

"We really need to improve our prospective evaluations in the teens, AYA, and [older] populations," Eads said.

Lutetium Lu 177 Dotatate in Adolescents and Young Adults

In children and AYAs, lutetium Lu 177 dotatate is used primarily for gastroenteropancreatic NETs (GEP-NETs). A single-center retrospective study of 19 patients aged 29 years or younger, 8 of whom were adolescents, reported an objective response rate of 41% and a disease control rate of 94%, with a manageable toxicity profile.³ The authors concluded that the agent appeared safe and effective in children and young adults.

The phase 2 NETTER-P study is the only prospective dataset in this space. It enrolled 11 adolescents aged 12 to 17 years with GEP-NETs (n = 4) or pheochromocytoma and paraganglioma (n = 7), who received 4 cycles of lutetium Lu 177 dotatate. Its primary end points were absorbed doses in the kidneys and bone marrow and safety after the first administration. The most common grade 3 or higher adverse events were hematologic. Pharmacokinetics were comparable between adolescents and historical adult patients, and dosimetry was predicted to be safe. The prescribing information now establishes the safety and effectiveness of lutetium Lu 177 dotatate in patients 12 years and older with somatostatin receptor-positive GEP-NETs. Safety and effectiveness have not been established in children younger than 12 years.¹

MIBG and Lutetium Lu 177 Dotatate in Neuroblastoma

Neuroblastoma is the most common extracranial solid malignancy in children. It is where most pediatric RLT is used. Iodine I 131 metaiodobenzylguanidine (MIBG) is used primarily in the relapsed or refractory setting and is under investigation as part of initial multimodal therapy. In a retrospective study of 39 patients aged 10 years or older treated with I 131 MIBG monotherapy, responses were higher among those aged 18 years or older than among those aged 10 to 17 years (56% vs 39%; P = .023), although grade 3 or 4 hematologic toxicity was common.⁴ Eads called it a highly effective agent in this setting.

Lutetium Lu 177 dotatate has been less successful. The phase 2a LuDO trial (ISRCTN98918118) treated 21 children with relapsed or refractory high-risk neuroblastoma, but only 8 received all 4 planned cycles, and none of the 14 evaluable patients responded.⁵ Eads said the disease may progress too quickly for the treatment schedule to take effect.

The ongoing LuDO-N trial (NCT04903899) is testing a dose-dense approach of 2 high-activity administrations given 2 weeks apart, with personalized whole-body dosing.⁶ Results published in 2026 from 14 patients treated with this approach showed that tumor absorbed doses declined with the second administration relative to the first, while no sustained renal toxicity was observed. These findings support further investigation of a front-loaded dosing strategy to maximize tumor irradiation while limiting exposure to organs at risk.⁷

Paraganglioma, Pheochromocytoma, and Alpha Emitters

Multiple societies recommend MIBG therapy for selected patients with MIBG-avid paraganglioma and pheochromocytoma, although outcomes have been suboptimal. High-specific-activity I 131 MIBG, approved by the FDA on the basis of a pivotal phase 2 trial (NCT00874614),⁸ is no longer available. Eads noted that I 131 MIBG shares limitations with lutetium Lu 177 dotatate, including low linear energy transfer, radiation exposure to neighboring tissue, and the need for repeated treatments.

Astatine At 211 meta-astatobenzylguanidine, an alpha emitter, may address some of these issues. A first-in-human phase 1 study in pheochromocytoma and paraganglioma demonstrated preliminary safety, and additional trials, including a US phase 1 study (NCT07661420), are underway.⁹^,¹⁰

Eads also highlighted ongoing and planned pediatric and AYA trials exploring targets not used in adults, including B7-H3 and GD2. These include the planned randomized NANT 2021-02 trial (NCT07261241), which pairs MIBG with vorinostat, dinutuximab, or both in relapsed or refractory neuroblastoma. At the time of writing, the trial was not yet accepting patients, with an estimated start date of December 31, 2026.¹¹ Another study is the phase 1 KinLET trial (NCT06441331) of lutetium Lu 177 edotreotide in pediatric patients with somatostatin receptor-positive tumors.¹²

Radioligand Therapy in Older Adults

Prospective studies specifically evaluating RLT in elderly patients remain lacking. A retrospective matched cohort study compared 48 patients aged 80 years or older with 68 patients aged 60 to 70 years, all treated with peptide receptor radionuclide therapy (PRRT). Investigators found no significant differences in subacute hematologic toxicity, grade 3 or higher renal toxicity, or overall survival, and concluded that PRRT is a valid option in elderly patients.¹³ Eads added that about one-third of patients in the lutetium Lu 177 dotatate prescribing information were 65 years or older, with no observed differences in safety or efficacy.

Other data suggest older patients may be undertreated. In the French LyREMeNET study of 866 patients with metastatic NETs, those aged 70 years or older received fewer lines of therapy and were less likely to receive PRRT than younger patients.¹⁴ Eads suggested this may reflect a bias against treating older patients.

Two smaller retrospective studies supported that view. In 145 patients aged 70 years or older, first-line PRRT was associated with the longest median overall survival compared with somatostatin analogues or chemotherapy, although the study did not establish its superiority.¹⁵ In another study of 71 patients aged 70 years or older treated with lutetium Lu 177 dotatate, nearly 80% completed all 4 cycles, and toxicity and efficacy were similar to those of the broader NET population, with no decline in health-related quality of life.¹⁶

Moving Beyond Age Alone

Eads cautioned against using chronological age as the main basis for treatment decisions. "We really shouldn't be practicing ageism," she said. "We all have those patients who are 55 who look like they're 90. And then we have those patients who are 85 who look great."

She noted that current analyses rarely account for comorbidities or for changes common in older adults: renal function declines over time, cardiovascular disease becomes more prevalent, and bone marrow becomes less robust. Cardiotoxicity studies in older patients have largely examined acute effects, and blood count trends are seldom considered.

In her concluding remarks, Eads said I 131 MIBG has demonstrated activity in children, adolescents, and young adults with relapsed or refractory neuroblastoma, and lutetium Lu 177 dotatate is safe in adolescents with GEP-NETs. In older adults, lutetium Lu 177 dotatate appears safe, and clinicians may be undertreating these patients because of a largely unfounded fear of toxicity. She called for more refined approaches to assessing toxicity in elderly patients, particularly long-term toxicity. "And, of course, we're always advocating for prospective trials," she said.

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