Novel Alpha Emitter Shows Durable Disease Control in SSTR2-Positive NETs

The investigational alpha-emitting radioligand [²¹²Pb]VMT-α-NET continued to produce durable disease control and encouraging responses in patients with advanced, somatostatin receptor subtype 2 (SSTR2)-positive neuroendocrine tumors (NETs) who had not previously received peptide receptor radionuclide therapy (PRRT), according to interim results from the first 3 cohorts of the phase 1/2a VMT-α-NET-T101 study (NCT05636618) presented at the 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium.¹

Rationale for Alpha-Emitting Radioligand Therapy

SSTR2 is an established target in NETs, but patients whose disease progresses after somatostatin analogues have limited treatment options. Compared with beta emitters such as lutetium Lu 177, alpha emitters deliver much higher linear energy transfer over a far shorter path length in tissue, producing clustered double-strand DNA breaks that are largely independent of oxygenation and dose rate. This profile may offer improved safety and efficacy over beta-emitting therapies.

VMT-α-NET is a somatostatin-mimicking peptide linked to a lead-specific chelator. It can carry lead Pb 203 for imaging and lead Pb 212 for therapeutic alpha-particle delivery. Preclinical work showed that this chelator retains about 95% of bismuth Bi 212, the alpha-emitting daughter of lead Pb 212, compared with roughly 64% for a conventional DOTA chelator, which may lower systemic alpha-radiation exposure.²^˒³

"There is a lead-optimized chelator, and that's important because the chelator is the part that holds on to the metal," explained Thorvardur Halfdanarson, MD, a medical oncologist at Mayo Clinic in Rochester, Minnesota.

VMT-α-NET-T101 Study Design and Patient Population

The ongoing, nonrandomized, dose-finding and expansion study VMT-α-NET-T101 enrolled patients with unresectable or metastatic, PRRT-naive NETs with radiologic progression on at least 1 prior systemic therapy and SSTR2 expression on FDA-approved SSTR PET.⁴ Patients received 4 doses of [²¹²Pb]VMT-α-NET every 6 to 8 weeks at 2.5 mCi in cohort 1 (n = 2), 5.0 mCi in cohort 2 (n = 46), or 6.0 mCi in cohort 3 (n = 20). Median follow-up was 128 weeks, 76 weeks, and 34 weeks, respectively, so cohort 3 data remain preliminary.

The primary end points were safety, dose-limiting toxicities (DLTs), and objective response rate (ORR), and the secondary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Across the 68 treated patients, the median age was 62.5 years. Half had gastrointestinal NETs and 45.6% had pancreatic NETs, most tumors were grade 2, and 85.3% had received a prior somatostatin analogue.

Durable Responses and Disease Control

ORRs were 33% in cohort 2 and 50% in cohort 3, and disease control was seen in at least 89% of patients in each cohort. Responses tended to deepen over time, and many patients remained on study without progression.

In a retrospective subgroup of patients with gastroenteropancreatic NETs that were SSTR2 positive in all target lesions, defined using the selection criteria of the phase 3 NETTER-1 trial (NCT01578239),⁵ ORRs rose to 37% and 47% in cohorts 2 and 3, respectively, and disease control rates reached 92% and 100%.

For the full population of cohorts 1 to 3, the estimated 18-month PFS rate was 71.5%. In cohort 2, PFS rates were 82.6% at 6 months, 71.2% at 12 months, and 68.9% at 18 months. Median PFS has not yet been reached.

Favorable Safety Profile for [²¹²Pb]VMT-α-NET

Overall, 82% of patients received all 4 planned doses. TEAEs were mostly grade 1 or 2, and grade 3 TEAEs occurred in 29.4% of patients. No DLTs were observed in DLT-evaluable patients, and there were no grade 4 or 5 treatment-emergent adverse events (TEAEs), treatment-related serious adverse events, or adverse event-related discontinuations within the TEAE window. The most common TEAEs were alopecia, nausea, and fatigue.

The hematologic safety profile was favorable. Grade 3 hematologic TEAEs occurred in 7.4% of patients, no intervention was required for lymphopenia, and no cases of myelodysplastic syndrome or dysphagia have been reported.

Renal function remained stable over time. Two patients developed grade 3 acute kidney injury during long-term follow-up, at 756 days and 255 days after the last dose. Investigators considered the first possibly treatment related and the second, which resolved, unlikely to be related.

Next Steps

Enrollment is underway in cohort 4, which is testing a front-loaded dosing regimen of 6, 5, 5, and 4 mCi, and long-term safety and renal follow-up continue. Response and PFS data are expected to mature further, particularly in cohort 3.

"People should be reminded that a lot of the cohort 3 patients are still [on study]," Halfdanarson said.

References

1. Halfdanarson T, Prasad V, Sukrithan V, et al. Cohort-level safety and efficacy results for [²¹²Pb]VMT-α-NET in advanced somatostatin receptor subtype 2 (SSTR2+)-expressing neuroendocrine tumors (NETs): cohorts 1-3. Presented at: 2026 North American Neuroendocrine Tumor Society Symposium; Las Vegas, Nevada. November 5-7, 2026.

2. Pretze M, Michler E, Runge R, et al. Influence of the molar activity of ²⁰³/²¹²Pb-PSC-PEG₂-TOC on somatostatin receptor type 2-binding and cell uptake. Pharmaceuticals (Basel). 2023;16(11):1605. doi:10.3390/ph16111605

3. Mirzadeh S, Kumar K, Gansow OA. The chemical fate of ²¹²Bi-DOTA formed by β⁻ decay of ²¹²Pb(DOTA)²⁻. Radiochim Acta. 1993;60(1):1-10. doi:10.1524/ract.1993.60.1.1

4. [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

5. 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