Prasad, Vikas

Abstract Background: [212Pb]VMT-a-NET is an alpha therapy agent targeting somatostatin receptor subtype 2 (SSTR2)-expressing tumors. Neuroendocrine tumors (NETs) generally express SSTR2 on their cell surface. Here, we report the results of a prospective, open-label, Phase I/IIa clinical trial evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of [212Pb]VMT-a-NET [NCT05636618]. Methods: The study design follows a Bayesian dose-finding algorithm. Main inclusion criteria include histologically proven well-differentiated unresectable or metastatic NETs, radiological evidence of progression on at least one prior line of systemic therapy, demonstration of lesional SSTR2 expression on an FDA-approved SSTR PET. Main exclusion criteria include: prior treatment with systemic PRRT-based therapies. In the dose finding phase, participants can receive up to four cycles of [212Pb]VMT-a-NET at the assigned dose level. Participants are followed for dose-limiting toxicity (DLT) observation up to 42 days after the first cycle. Efficacy is evaluated by investigators according to RECIST criteria v1.1. Here we report safety and preliminary efficacy data of participants enrolled in cohorts 1 and 2 at 92.5 MBq [2.5 mCi] and 185 MBq [5 mCi], respectively. Results: As of 30-Apr-2025 (data cut-off – DCO), a total of 42 participants were enrolled into the study. Nine of them were followed for DLT observation; thirty-three (33) additional participants were subsequently enrolled into cohort 2 to further evaluate safety and efficacy at the selected dose. For data analysis purposes, participants were divided into two different groups: a safety group and an efficacy group. The safety group included all participants enrolled by the DCO (n=42), while the efficacy group included only nine participants enrolled in cohort 1 (n=2) and cohort 2 (n=7) for DLT observation. Median follow up time for participants included in the safety group was 14 weeks (range:0,77); median follow up time for participants included in the efficacy group was 56 weeks (range: 6,77). In the safety group (n=42) we did not observe any DLTs, any grade 4 or 5 adverse events (AEs), any treatment-related discontinuations, any serious renal complications or myelosuppression, or any dysphagia. In the efficacy group (n=9) seven out of nine participants were with no progression as of the DCO, and four out of the seven participants enrolled in cohort 2 achieved a partial response (PR). Three PRs were confirmed, while one was pending confirmation at the time of DCO. Cohort 3, at a dose level of 222 MBq [6 mCi], has recently been opened for enrollment. Safety data for all treated participants and efficacy results for a mature subset will be presented at the congress. Conclusions: [212Pb]VMT-a-NET showed a favorable safety profile and promising clinical benefit for patients with advanced SSTR2-expressing NETs treated at the dose level of 185 MBq (5 mCi). The study is ongoing with cohort 3 currently open for enrollment. Citation Format: Vikas Prasad, Richard Wahl, Lilja Solnes, Savitha Balaraman, Gregory Sibley, Lowell Anthony, Brandon Mancini, Jason Starr, Vineeth Sukrithan, Chih-Yi Liao, Samuel Mehr, Lucia Baratto, Wenjing Yang, Alaa Hanna, Stephen Keefe, Markus Puhlmann, Thorvadur Halfdanarson. [212Pb]VMT-a-NET for somatostatin receptor subtype 2 (SSTR2)-expressing tumors: safety and preliminary efficacy results in patients with advanced neuroendocrine tumors (NETs) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C095 .

3005 Background: [ 212 Pb]VMT-α-NET, a next generation 212 Pb-based, SSTR2-targeted alpha-particle radiopharmaceutical therapy (RPT), was designed to achieve superior biodistribution via optimized tumor uptake and retention and rapid renal clearance. Results reported here are from the Phase 1/2a first-in-human study [NCT05636618]. Methods: Safety, pharmacokinetics, dosimetry and efficacy using RECIST v1.1 were investigated in the treatment of participants with [ 212 Pb]VMT-α-NET who had SSTR2-expressing, well-differentiated adult NETs of any grade. Participants received ≥1 prior therapy. No prior peptide receptor radionuclide therapy was allowed. The trial has multiple dose cohorts including 92.5 MBq (2.5 mCi, cohort 1) and 185 MBq (5 mCi, cohort 2) of administered activity based on a Bayesian modified toxicity probability interval (mTPI-2) design. Up to 8 participants per cohort were treated with 4 doses of [ 212 Pb]VMT-α-NET for DLT observation. Cohort 2 enrollment was expanded to further define the safety and efficacy profile at this dose level. Results: Nine (9) gastroenteropancreatic NET participants were enrolled into cohorts 1 and 2 for DLT observation. The ninth of these participants was enrolled more than 1 year prior to presentation of these data. Among these participants at the time of abstract submission, no DLTs were observed, and there were no grade 4, 5 or serious adverse events (SAEs). Specifically, no renal insufficiency or dysphagia were observed. Hematologic AEs were low grade and few in number. No treatment discontinuations due to AE occurred. Three (3) of the 7 cohort 2 participants enrolled for DLT observation achieved investigator-assessed partial responses (PRs). Two PRs were unconfirmed at the time of abstract submission. Durable progression-free survival (PFS) was consistently observed. More than 15 additional participants were enrolled in the cohort 2 expansion. Preliminary data for these patients will be reported at the congress. Conclusions: [ 212 Pb]VMT-α-NET is a well-tolerated, next generation RPT showing signs of clinical activity at early dose-levels in this phase 1/2a study. Based on these clinical data, further dose-escalation and development of this promising therapy are warranted. Clinical trial information: NCT05636618 .