Radioligand Therapy Trials Begin Reshaping Neuroendocrine Tumor Care

After years in which most proposed changes to peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors (NETs) remained in the research realm, new approvals and a wave of maturing clinical trials are beginning to alter how clinicians use radioligand therapy, from first-line treatment and dosimetry to retreatment and next-generation alpha emitters. That was the central message of a presentation given by Erik S. Mittra, MD, PhD, professor of diagnostic radiology and division chief of molecular imaging and therapy at Oregon Health & Science University (OHSU) in Portland, at the 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium.

"What's exciting now, really starting this year, is that things are actually happening," Mittra said, noting that every aspect of current PRRT practice is being evaluated in clinical trials.

New Versions of Lutetium Lu 177 Dotatate

Mittra opened with a development that clinicians are already seeing: for the first time, more than 1 version of lutetium Lu 177 dotatate is available. In September 2026, the FDA approved Curium's lutetium Lu 177 dotatate injection (Bexlutry) for adults with somatostatin receptor (SSTR)-positive gastroenteropancreatic NETs (GEP-NETs).¹ Later that month, the agency granted final approval to Lantheus's lutetium Lu 177 dotatate (Bravnetsa), which it determined to be bioequivalent and therapeutically equivalent to the reference product, lutetium Lu 177 dotatate (Lutathera).²

Mittra explained that the new agents are the same compound as the original but reached the market through different regulatory pathways. The Curium product is commercially available; the Lantheus product is not yet.

Expanding Indications for Lutetium Lu 177 Dotatate

The use of lutetium Lu 177 dotatate itself also continues to evolve. Mittra reviewed the trajectory from NETTER-1, which established the agent in patients with progressive midgut NETs,³ to NETTER-2, which moved PRRT into the first-line setting for patients with newly diagnosed, advanced grade 2 and 3 GEP-NETs.⁴ Both trials met their primary end point of progression-free survival (PFS), and objective response rates were notably higher in NETTER-2.

The ongoing NETTER-3 trial is evaluating first-line PRRT in patients with newly diagnosed, advanced, somatostatin receptor (SSTR)-positive, well-differentiated grade 1 or 2 GEP-NETs, a Ki-67 index less than 10%, and high disease burden. The phase 3 trial is comparing lutetium Lu 177 dotatate plus octreotide LAR with octreotide LAR alone and is designed to evaluate the role of PRRT earlier in the treatment course for this patient population.

Answering the Retreatment Question

Many centers have used PRRT retreatment for years on the basis of retrospective data. The NET RETREAT trial, sponsored by the National Cancer Institute, is the first prospective, multicenter, randomized trial comparing retreatment with lutetium Lu 177 dotatate vs standard therapy in patients with metastatic, unresectable GEP-NETs.⁵ According to Mittra, the trial has been recruiting well, was recently expanded, and is roughly 50% enrolled.

"So this will take, I think, a few more years before we have this data. But I think it will be very important," Mittra said, adding that the results will be especially relevant as alpha therapies begin to compete for the post-PRRT setting.

Lutetium Lu 177 Edotreotide: COMPETE and COMPOSE

Mittra next turned to lutetium Lu 177 edotreotide (ITM-11), a DOTATOC-based agent. The phase 3 COMPETE trial randomly assigned patients with grade 1 or 2 GEP-NETs, who were either treatment naive or had progressed on prior therapy, to lutetium Lu 177 edotreotide or everolimus.⁶ Unlike the NETTER trials, it used a different dosing schedule and did not require concomitant somatostatin analogues.

The trial met its primary end point, with a median PFS of 23.9 months vs 14.1 months with everolimus (HR, 0.67; 95% CI, 0.48-0.95; P = .022). The difference in overall survival was not statistically significant. Despite these results, the FDA issued a complete response letter for the agent inAugust 2026.⁷ Mittra noted that the letter was not related to the design of the study, and he anticipated that approval may come in the next year.

The ongoing phase 3 COMPOSE trial is evaluating the same agent in patients with higher-grade (grade 2 and 3) GEP-NETs, compared with a broader set of standard-of-care options that includes capecitabine plus temozolomide, everolimus, or FOLFOX.⁸ Both COMPETE and COMPOSE include dosimetry substudies, and Mittra noted that early COMPETE dosimetry data showed that tumor-absorbed doses remained higher than kidney doses across treatment cycles, even as lesion doses declined over time.

The Case for Personalized Dosimetry

Mittra also revisited the P-PRRT trial, which used dosimetry to personalize the injected activity of lutetium Lu 177 dotatate according to a target kidney dose.⁹ Compared with simulated fixed-activity dosing, the personalized approach allowed higher cumulative injected activity and delivered higher tumor-absorbed doses while keeping renal doses within the target range.

Acknowledging that dosimetry remains controversial, Mittra said emerging data support its use to optimize individual dosing.

Alpha Emitters Move Toward Phase 3

The final section of the talk focused on 3 alpha-emitting, SSTR-targeted therapies that Mittra expects to influence practice in the coming years.

The phase 3 ACTION-1 trial of actinium Ac 225 dotatate (RYZ101) is enrolling patients with GEP-NETs that progressed after prior lutetium Lu 177-based therapy.¹⁰ The sponsor recently announced that the trial met its primary end point of PFS at a planned interim analysis, making it the first phase 3 alpha therapy trial in this space to report a positive result. Mittra cautioned that the full efficacy and toxicity data have not yet been presented.

Lead Pb 212 VMT-α-NET is being evaluated in a phase 1/2a trial in patients who have not received prior PRRT.¹¹ Recent data presented at the 2026 European Society for Medical Oncology Congress showed objective response rates, including unconfirmed responses, of 33% and 50% in the 5.0-mCi and 6.0-mCi cohorts, respectively. In the 6.0-mCi cohort, 6 of the 10 responses had been confirmed at the time of analysis, with 4 awaiting confirmation. The 18-month PFS rate was 72% across all 3 dose cohorts. "So, again, very, very promising, but this is still phase 2," Mittra said, noting that a phase 3 trial is expected to begin by the end of 2026.

Lead Pb 212 DOTAMTATE was evaluated in a phase 2 trial that enrolled both radioligand therapy-naive (n = 35) and radioligand therapy-exposed (n = 26) patients.¹² Objective response rates were 60% by investigator assessment and 57.1% by blinded independent central review in PRRT-naive patients. Among previously PRRT-treated patients, response rates were 34.6% and 19.2%, respectively. These findings suggest activity in both treatment-naive and previously treated populations, although differences in trial populations and response assessments make direct comparisons with other alpha-emitter studies difficult.

Implications for Clinical Decision-Making

Mittra closed by laying out a timeline for how these trials may change practice, while emphasizing that the projections were estimates. "These are obviously guesses," he said.

In the present, clinicians can use PRRT in the first-line setting for appropriate patients with advanced, well-differentiated grade 2 and 3 GEP-NETs and now have 3 FDA-approved lutetium Lu 177 dotatate products: LUTATHERA, BEXLUTRY, and BRAVNETSA, although BRAVNETSA is not yet commercially available. "Those are all very positive changes that are happening," Mittra said.

Within a year, he anticipates the potential approval of lutetium Lu 177 edotreotide and greater use of dosimetry. Within 2 years, alpha therapies and prospective retreatment data are expected to arrive. Beyond 3 years, he pointed to SSTR antagonists and combination therapies as areas with significant potential but limited data so far.

Mittra cautioned that the growing number of options could make treatment sequencing more complicated, because some alpha therapy trials enroll patients after PRRT while others enroll patients before PRRT. That leaves open questions about long-term toxicity from repeated alpha or beta therapy. "We always talk about [how] we don't really know anything about sequencing," he said, adding that some of the upcoming trials may compound that uncertainty.

References

1. Curium. Curium announces FDA approval of BEXLUTRY lutetium Lu 177 dotatate injection for adults with SSTR-positive GEP-NETs. Published September 14, 2026. https://tinyurl.com/4wck9wef

2. Lantheus Receives Final FDA Approval for BRAVNETSA™ (Lutetium Lu 177 Dotatate), the Only Radiopharmaceutical FDA has Determined to be Bioequivalent and Therapeutically Equivalent to LUTATHERA® for the Treatment of GEP-NETs. News release. September 22, 2026. Accessed September 23, 2026. https://tinyurl.com/ymvsubyf

3. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of ¹⁷⁷Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135. doi:10.1056/NEJMoa1607427

4. Singh S, Halperin D, Myrehaug S, et al. [¹⁷⁷Lu]Lu-DOTA-TATE plus long-acting octreotide versus high-dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. 2024;403(10446):2807-2817. doi:10.1016/S0140-6736(24)00701-3

5. Comparing retreatment of 177Lu-DOTATATE PRRT versus the usual treatment in patients with metastatic unresectable gastroenteropancreatic neuroendocrine tumors, NET RETREAT trial. ClinicalTrials.gov identifier: NCT05773274. Updated October 28, 2026. Accessed November 5, 2026. https://clinicaltrials.gov/study/NCT05773274

6. Walter T, Jann H, Ansquer C, et al. [¹⁷⁷Lu]Lu-edotreotide versus everolimus for gastroenteropancreatic neuroendocrine tumours (COMPETE): a phase 3, multicentre, randomised, open-label, superiority trial. Lancet. 2026;408(10551):234-247.

7. ITM receives complete response letter for 177Lu-edotreotide (ITM-11). News release. ITM. August 10, 2026. Accessed August 11, 2026. https://tinyurl.com/53j27rv4

8. Efficacy and safety of 177Lu-edotreotide PRRT in GEP-NET patients (COMPOSE). ClinicalTrials.gov identifier: NCT04919226. Accessed November 5, 2026. https://clinicaltrials.gov/study/NCT04919226

9. Del Prete M, Buteau FA, Arsenault F, et al. Personalized ¹⁷⁷Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: initial results from the P-PRRT trial. Eur J Nucl Med Mol Imaging. 2019;46(3):728-742. doi:10.1007/s00259-018-4209-7

10. RYZ101 compared with SOC in patients with inoperable SSTR+ well-differentiated GEP-NETs that have progressed following prior 177Lu-SSA therapy (ACTION-1). ClinicalTrials.gov identifier: NCT05477576. Accessed November 5, 2026. https://clinicaltrials.gov/study/NCT05477576

11. [212Pb]VMT-α-NET targeted alpha-particle therapy for advanced SSTR2 positive neuroendocrine tumors. ClinicalTrials.gov identifier: NCT05636618. Accessed November 5, 2026. https://clinicaltrials.gov/study/NCT05636618

12. Targeted alpha-emitter therapy of PRRT naïve and previous PRRT neuroendocrine tumor patients. ClinicalTrials.gov identifier: NCT05153772. Accessed November 5, 2026. https://clinicaltrials.gov/study/NCT05153772