Initial PRRT Benefit May Guide Retreatment Selection in NETs

Retreatment with lutetium Lu 177 dotatate (177Lu-DOTATATE) produced durable disease control with a manageable safety profile in patients with well-differentiated neuroendocrine tumors (NETs). The length of benefit from initial peptide receptor radionuclide therapy (PRRT) also appeared to predict how patients fared with a second course, according to an interim analysis of a multicenter registry presented by Courtney Porfido, research project associate at Memorial Sloan Kettering Cancer Center (MSK), at the 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium.¹

Patients whose progression-free survival (PFS) after initial PRRT exceeded the cohort median of 25.5 months had a median PFS of 22.2 months (95% CI, 13.4-29.4) after retreatment. Patients at or below the median had a median PFS of 13.1 months (95% CI, 10.7-16.0) (P = .005).

A Growing Practice Without Clear Rules

“We all know that 177Lu-DOTATATE, or PRRT as we call it, is a standard treatment for somatostatin receptor-positive, well-differentiated neuroendocrine tumors,” Porfido said.

The radioligand received FDA approval in 2018 for somatostatin receptor-positive gastroenteropancreatic NETs, based largely on the phase 3 NETTER-1 trial (NCT01578239).²^,³ As patients live longer after first-line PRRT, clinicians are increasingly turning to retreatment (rePRRT) at progression. Retrospective series from Europe and the United States have supported the safety and efficacy of this approach.⁴^,⁵ However, they used different thresholds for who qualified, ranging from a minimum PFS after initial therapy to any prior clinical benefit. As a result, selection criteria remain unstandardized.

The ongoing randomized phase 2 NET-RETREAT trial (NCT05773274) is comparing rePRRT with everolimus, sunitinib, or cabozantinib in patients with metastatic gastroenteropancreatic NETs, with PFS as the primary end point.⁶ Meanwhile, Porfido and colleagues sought to describe outcomes from routine practice and to explore whether the duration of initial benefit could help guide patient selection.

Registry Design and Patient Population

Data were drawn from a shared registry built by the University of California, San Francisco, and MSK over the past 6 years, which Porfido noted is still being expanded. Of 543 patients with well-differentiated NETs in the registry, 98 (18%) underwent rePRRT. Investigators collected clinicopathologic features, prior systemic and radiation therapies, and procedural interventions such as liver-directed therapy and surgery. PFS was defined as the time from rePRRT initiation to disease progression or death.

The median age at diagnosis was 56 years, and the cohort was split fairly evenly by sex. Most tumors were grade 1 or 2, and the pancreas and small bowel were the most common primary sites. The liver was the predominant site of metastatic disease, followed by mesenteric or retroperitoneal lymph nodes and bone.

The average interval from the start of initial PRRT to the start of rePRRT was 27 months, and patients received a median of 2 rePRRT cycles. For 42 patients (43%), rePRRT was the first treatment given after initial PRRT.

Efficacy Outcomes

The disease control rate with rePRRT was 86%, based on clinical imaging reports rather than formal RECIST reads. Most patients who had a partial response to initial PRRT achieved stable disease with retreatment. Most of those with initial stable disease again had a partial response or stable disease. Three patients were retreated despite progression during initial therapy, including 1 whose first course was stopped early because of myelosuppression rather than true progression.

Median PFS after initial PRRT was 25.5 months. The number of retreatment cycles did not significantly affect outcomes: median PFS was 14.2 months for 1 to 2 cycles vs 15.8 months for 3 to 4 cycles (P = .31). The clearest signal came from stratifying patients by initial PFS, which showed a difference of roughly 9 months in median rePRRT PFS.

Safety Profile

“As we expected, the most common toxicity was hematologic,” Porfido said, adding that events were mostly grade 1 or 2.

Anemia and thrombocytopenia were the most frequent toxicities, each affecting about a quarter of patients, and grade 3 or 4 events were uncommon. One patient developed myelodysplastic syndrome after rePRRT; the workup was prompted by anemia, thrombocytopenia, and leukocytosis. Another patient, who had a history of small bowel obstruction and resection, developed a grade 2 small bowel obstruction between the third and fourth retreatment cycles. It was managed with a steroid taper and bowel rest without surgery, and the fourth cycle was given at half dose.

Baseline chronic kidney disease (CKD) data were available for 95 patients, 81% of whom had stage 1 or 2 disease. Mean cumulative administered activity was similar regardless of baseline CKD stage, at approximately 1150 mCi. CKD worsened from stage 1 or 2 to stage 3 or higher in 7 patients (7%). No patient with baseline stage 3 or higher disease declined further, and no patient required dialysis.

Implications for Patient Selection

Porfido described the cohort as the largest US multicenter rePRRT experience reported to date. Limitations include the retrospective design and response assessment based on clinical reports. During the question-and-answer session, Porfido noted that genomic sequencing data are not yet captured in the registry but are an important area for future study.

“This leads us to believe that [first-line treatment duration] may be a clinically useful measure for repeat PRRT [patient selection],” Porfido concluded.

References

1. Porfido C, Moradi Tuchayi A, Nwihim S, et al. Retreatment with 177Lu-DOTATATE in well-differentiated neuroendocrine tumors: an interim analysis of a multicenter registry. Presented at: 2026 NANETS Multidisciplinary NET Medical Symposium; November 5-7, 2026; Las Vegas, NV.

2. FDA approves lutetium Lu 177 dotatate for treatment of GEP-NETS. US Food and Drug Administration. January 26, 2018. Accessed November 6, 2026. https://tinyurl.com/3fhm8f5s

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. van der Zwan WA, Brabander T, Kam BLR, et al. Salvage peptide receptor radionuclide therapy with [177Lu-DOTA,Tyr3]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2019;46(3):704-717. doi:10.1007/s00259-018-4158-1

5. Delpassand ES, Yazdi SM, Ghantoji S, et al. Effectiveness and safety of retreatment with 177Lu-DOTATATE in patients with progressive neuroendocrine tumors: a retrospective real-world study in the United States. J Nucl Med. 2024;65(5):746-752. doi:10.2967/jnumed.123.265703

6. 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. Accessed November 6, 2026. https://clinicaltrials.gov/study/NCT05773274