Mehr, Samuel H.

9525 Background: Melanocortin-1 receptor (MC1R) is a novel target for radiopharmaceutical therapy and is highly expressed on melanoma tumor cells. VMT01 is an MC1R-targeted peptide. 203 Pb is used for patient selection via SPECT imaging. Peptide radiolabeling with 212 Pb delivers alpha-particle therapy. Here, we present data on the treatment of adult patients with MC1R-positive metastatic melanoma receiving [ 212 Pb]VMT01 either as a monotherapy or in combination with the programmed death-1 (PD-1) checkpoint inhibitor, nivolumab. Methods: This is an ongoing phase I/IIa, first-in-human, prospective, multicenter, open-label, radioactive dose-finding and dose-expansion trial. The objectives are to investigate safety, pharmacokinetics, dosimetry, and efficacy. Participants receive up to 3 treatment cycles with either [ 212 Pb]VMT01 3 mCi, 5 mCi, or 1.5 mCi monotherapy, or combination therapy with [ 212 Pb]VMT01 (1.5 mCi) + nivolumab (480 mg, Q4W) or [ 212 Pb]VMT01 (3 mCi) + nivolumab. Participants are evaluated for any DLTs for the first 6 weeks after cycle 1. Efficacy is assessed by RECIST v1.1 criteria by the investigator. Results: As of 24 December 2025, 26 participants (53.8% male; median age: 68 years [range: 27-81]) with MC1R-positive metastatic melanoma were enrolled. The median prior systemic therapies was 4. All 26 enrolled participants received ≥1 dose of [²¹²Pb]VMT01. No DLTs were reported. All SAEs (including one grade 5 SAE) were attributed to disease progression. Most TEAEs were grade 1 (19.2%) and grade 2 (34.6%). Grade 3 TEAEs occurred in 8 participants (30.8%), 5 on monotherapy and 3 on combination therapy (3 mCi + nivolumab). Of the 22 evaluable participants, 1 PR, 9 SD, and 12 PD were reported. Four participants had progression-free survival of ≥6 months. Conclusions: [ 212 Pb]VMT01 as a monotherapy and in combination with nivolumab was generally safe and well-tolerated in 26 enrolled participants, with antitumor activity observed at the 3 mCi dose level. These data may be supplemented with a more complete follow-up at the time of the meeting. Clinical trial information: NCT05655312 .

4173 Background: [ 212 Pb]VMT-α-NET is an alpha-particle radiation-delivering agent targeted to somatostatin receptor type 2 (SSTR2)-expressing tumors. Here, we present safety and efficacy results from the dose-finding phase 1/2a clinical trial (NCT05636618). Methods: This phase 1/2a dose-escalation study uses a Bayesian algorithm to identify an optimal dose of [ 212 Pb]VMT-α-NET for participants with advanced, well-differentiated NETs expressing SSTR2. Eligible participants must have unresectable or metastatic disease, documented radiologic progression following at least one prior systemic treatment, and evidence of SSTR2 expression (Krenning Score ³2) in ≥1 lesion confirmed on an FDA-approved somatostatin receptor PET scan. Patients previously treated with systemic peptide receptor radionuclide therapy (PRRT) are excluded from enrollment. During the dose-finding phase, participants may receive up to four administrations of [ 212 Pb]VMT-α-NET at their assigned dose level, and they are monitored for dose-limiting toxicities (DLTs) for 42 days and safety throughout the study. Efficacy is evaluated by investigators according to RECIST criteria v1.1. Dosimetry is included as a supportive analysis. Results: As of the 10-Dec-2025 data cut-off (DCO), 56 participants had been enrolled across Cohorts 1, 2, and 3 and received at least one dose of [ 212 Pb]VMT-α-NET: 2 participants in Cohort 1 (2.5 mCi), 46 in Cohort 2 (5 mCi), and 8 in Cohort 3 (6 mCi). No dose-limiting toxicities, grade 5 adverse events, treatment-related discontinuations, serious renal events, dysphagia, or clinically meaningful treatment-related myelosuppression were observed. The median follow-up for all treated participants was 40 weeks (range 6–97). Efficacy has been summarized in this abstract for 25 participants (2 in Cohort 1 and 23 in Cohort 2). Nineteen of these 25 participants remained progression-free at the time of the DCO, with a median efficacy follow-up of 49 weeks (range 6–97). In Cohort 2, investigators observed RECIST v1.1 objective responses in 9 of 23 participants (39%), including 8 confirmed responses. Both participants in Cohort 1 continued to exhibit stable disease after two years of follow-up. Updated safety for all participants and updated efficacy for participants with sufficient maturity beyond the 25 summarized here will be presented at the congress. Conclusions: Treatment with [ 212 Pb]VMT-α-NET continues to demonstrate a favorable safety profile across all treated participants (n = 56) and shows signs of sustained efficacy at the 2.5 mCi and 5 mCi dose levels. The therapy has been well-tolerated with no observed dose-limiting toxicities or serious treatment-related adverse outcomes. Based on these encouraging safety and efficacy findings, the study is ongoing, and enrollment into Cohort 3 (6 mCi) remains active. Clinical trial information: NCT05636618 .

Abstract Background: [212Pb]VMT-a-NET is a novel, next generation alpha therapy agent for advanced somatostatin receptor 2 positive (SSTR2+) neuroendocrine tumors (NETs). Here, we present safety and efficacy update from the dose-finding phase 1/2a clinical trial (NCT05636618). Methods: Adults with well-differentiated unresectable or metastatic NETs, who were peptide receptor radionuclide therapy-naïve, showed progressive disease after at least one prior line of systemic therapy and demonstrated SSTR2-expression on PET images were treated with up to four cycles of study therapy at the assigned dose level. Participants were followed for dose-limiting toxicity (DLT) observation up to 42 days after the first dose. Efficacy was evaluated by investigators according to RECIST criteria v1.1. Results: As of 10-Dec-2025 (data cut-off [DCO]) a total of 56 participants were enrolled into Cohorts 1, 2 and 3, and received at least 1 dose of [212Pb]VMT-a-NET (n=2 in Cohort 1, n=46 in Cohort 2, and n=8 in Cohort 3 at a dose level of 2.5 mCi, 5 mCi, and 6 mCi, respectively). For data analysis purposes, participants were categorized into two different groups: a safety group and an efficacy group. The safety group included all participants treated by the DCO (n=56), while the efficacy group included only the Cohort 1 participants (n=2) and the first half of participants treated in Cohort 2 (n=23). Among all participants treated with at least 1 dose of [212Pb]VMT-a-NET (n=56), no DLTs, no grade 5 adverse events (AEs), no treatment-related discontinuations, no serious renal complications, no dysphagia and no clinically significant treatment-related myelosuppression were observed. Median follow-up time for all patients treated was 40 weeks (range: 6-97). Among the 25 participants followed for efficacy (n=2 in Cohort 1 and n=23 in Cohort 2), 19 out of 25 were with no progression as of the DCO. Median follow-up time for participants included in the efficacy group was 49 weeks (range: 6-97). Investigator-assessed RECIST v1.1 objective responses were observed in 9 out of 23 participants (39%) enrolled in the first half of Cohort 2 (8 confirmed). The 2 patients enrolled in Cohort 1 at 2.5 mCi still have stable disease after 2 years of follow up. Updated safety outcomes for all participants along with updated efficacy findings for participants in Cohorts 1 and 2 with sufficient maturity will be presented during the congress. Conclusions: Treatment with [212Pb]VMT-α-NET continues to be well-tolerated among all patients treated (n=56), and to show promising efficacy at the dose levels of 2.5 mCi and 5 mCi. The study is ongoing with Cohort 3 (6 mCi) currently open for enrollment. Citation Format: Thorvardur R. Halfdanarson, Richard L. Wahl, Vineeth Sukrithan, Brandon R. Mancini, Seyed A. Mosallaie, Savitha Balaraman, Gregory S. Sibley, Jason Starr, Lowell B. Anthony, Chih Y. Liao, Samuel H. Mehr, Jared Weiss, Robert A. Ramirez, Lucia Baratto, Wenjing Yang, Alaa Hanna, Stephen M. Keefe, Markus Puhlmann, Vikas Prasad. [212Pb]VMT-a-NET in advanced SSTR2+ neuroendocrine tumors: safety and preliminary efficacy results from dose-finding cohorts 1,2 and 3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT088.

TPS611 Background: GPC3 is an oncofetal protein expressed in up to 75% of hepatocellular carcinomas (HCCs) and associated with poor prognosis. Its selective expression in tumor and not in normal tissue makes it a promising target for radiopharmaceutical imaging and therapy (theranostics). The GPC3-selective diagnostic RYZ811 ([ 68 Ga]Ga-RAYZ-8009) and therapeutic α particle-emitting RYZ801 ([ 225 Ac]Ac-RAYZ-8009) are a theranostic pair. Previous studies show high uptake of RYZ811 in intrahepatic and extrahepatic HCCs, with low normal liver background uptake. In GPC3+ HCC mouse models, single administrations of RYZ801 significantly inhibited tumor growth. Methods: RYZ801-101 is a single-arm, open-label, phase 1/1b study of RYZ811 and RYZ801 in previously treated patients with GPC3+ unresectable HCC. The study has two parts: dose escalation (part 1) and dose expansion (part 2). Each part consists of two stages: RYZ811 imaging and RYZ801 treatment. The aim of imaging is to determine if RYZ811 safely and adequately identifies patients with GPC3+ tumors. The aim of treatment is to determine the safety, pharmacokinetics (PK), recommended phase 2 dose (RP2D; part 1), and preliminary antitumor activity (part 2) of RYZ801. Key eligibility criteria are: confirmed HCC; Barcelona Clinic Liver Cancer stage B or C; Child-Pugh A; ≥1 RECIST v1.1-measurable lesion (treatment stage); and disease progression after ≥1 systemic therapy in part 1 and 1 prior line in part 2. In part 1, approximately 60 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 30 of these will receive escalating doses of RYZ801 (2.6–5.5 MBq × 4 doses) in the treatment stage. In part 2, approximately 80 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 40 of these will receive RYZ801 at the RP2D in the treatment stage. Primary RYZ811 objectives are to assess the safety/tolerability and biodistribution of RYZ811. Secondary objectives are to determine absorbed doses (ADs) to organs and tissues and any association between RYZ811 uptake and RYZ801 efficacy. Primary RYZ801 objectives are to identify the RP2D and safety/tolerability of RYZ801. Secondary objectives are to assess PK, ADs to critical organs and tumors, and preliminary antitumor activity. Enrollment for Part 1 is ongoing in the USA. Clinical trial information: NCT06726161 .

635 Background: [ 212 Pb]VMT-a-NET is an alpha therapy agent targeting somatostatin receptor subtype 2 (SSTR2)-expressing tumors. Here, we report the results of a prospective, open-label, Phase I/IIa trial (NCT05636618), assessing safety, tolerability, pharmacokinetics, and preliminary efficacy of [ 212 Pb]VMT-a-NET in patients with advanced neuroendocrine tumors (NETs). Methods: Adults with well-differentiated unresectable or metastatic SSTR2-expressing NETs, who are peptide receptor radionuclide therapy (PRRT) naïve, and who progressed on at least one prior line of systemic therapy, are eligible. Participants can receive up to four cycles of [ 212 Pb]VMT-a-NET at the assigned dose level. Participants are followed for dose-limiting toxicity (DLT) observation up to 42 days after the first dose. Efficacy is evaluated by investigators according to RECIST criteria v1.1. Results: As of 16-Aug-2025 (data cut-off [DCO]) a total of 48 participants were enrolled into cohorts 1 and 2 and received at least one dose of [ 212 Pb]VMT-a-NET (n=2 in Cohort 1, and n=46 in Cohort 2 at a dose level of 92.5 MBq and 185 MBq, respectively). Among all participants treated with at least one dose of [ 212 Pb]VMT-a-NET (n=48), no DLTs, no grade 4 or 5 adverse events (AEs), and no treatment-related discontinuations, were observed. Median follow-up time was 28 weeks (range: 6-93). Nine participants were followed for DLT observation (n=2 in cohort 1 and n=7 in cohort 2).Seven of these patients were with no progression as of the DCO. Three out of the seven participants enrolled at the dose level of 185 MBq achieved a confirmed partial response (PR). Median follow-up time for participants included in the efficacy group was 72 weeks (range: 6-93). Cohort 3, at a dose level of 222 MBq, has recently been opened for enrollment. At the DCO, 4 participants were enrolled in this cohort. Updated safety outcome for all participants along with updated efficacy findings for participants in Cohort 1 and 2 with sufficient maturity, will be presented during the congress. Conclusions: [ 212 Pb]VMT-a-NET showed a favorable safety profile and promising clinical benefit for patients with advanced SSTR2-expressing NETs treated at the dose levels of 92.5 MBq and 185 MBq. The study is ongoing with Cohort 3 (222 MBq) currently open for enrollment. Clinical trial information: NCT05636618 .

3099 Background: Immune checkpoint inhibitors (ICI) are effective in melanoma, but many patients experience progression on or after approved ICI +/- MAPK inhibitor therapy. Melanocortin-1 receptor (MC1R) is a novel target for radiopharmaceutical therapy (RPT) and is highly expressed on melanoma tumor cells. VMT01 is an MC1R-targeted RPT that can be radiolabeled with either 203 Pb (patient selection and dosimetry assessments) or 212 Pb (alpha particle therapy). Here, we present data on the first in-human evaluation of [ 203 Pb/ 212 Pb]VMT01 in patients with metastatic melanoma. FDA granted Fast Track Designation to the product on the bases of preclinical experiments combining [ 212 Pb]VMT01 with immunotherapy. Methods: This is a first-in-human dose-finding study to determine the safety, pharmacokinetics, dosimetry and preliminary efficacy of [ 212 Pb]VMT01 in subjects with MC1R-positive metastatic melanoma who progressed on at least 1 approved first-line therapy (NCT05655312). Phase 1 of the trial includes escalating dose cohorts. The first two cohorts incorporate dosimetry evaluations (reported separately) with the imaging surrogate [ 203 Pb]VMT01 prior to receiving up to 3 treatment cycles of [ 212 Pb]VMT01 therapy (injected activity of 111 MBq (3 mCi) or 185 MBq (5 mCi) for Cohort 1 and 2, respectively). Participants are evaluated for any DLT for the first 6 weeks after cycle one. Efficacy is assessed by RECIST 1.1 criteria by the investigator. Following the start of the study the anticipated combination arm with nivolumab was opened as an amendment. Results: Cohort 1 (DCO 04Sep24) was completed with 3 enrolled participants who received 3 treatment cycles without any DLTs or SAEs. Cohort 1 participants showed prolonged stabilization of disease from start of treatment (mean: 11.1 months); one participant developed a confirmed objective response (PR) after completion of all three [ 212 Pb]VMT01 administrations and is still on trial after 13.1 months from start of treatment. Cohort 2 has completed with 7 enrolled participants. No DLTs or related SAEs have been observed. All participants in this Cohort progressed after either the first cycle (3 participants) or the second cycle (4 participants).Based on these preliminary results showing anti-tumor effect at the lower dose, additional cohorts for both monotherapy and in combination with nivolumab were introduced at a de-escalated dose of 55.5 MBq (1.5 mCi). Both cohorts are now open for enrollment. Updated safety and efficacy data will be analyzed and presented at ASCO. Conclusions: At 111 MBq and 185 MBq activity levels, [ 212 Pb]VMT01 was safe and well-tolerated. An objective response and prolonged stabilization of disease were observed at the 111 MBq activity level while no effect was seen at 185 MBq. The study will continue to explore potentially immunostimulating lower doses of administered activity of [ 212 Pb]VMT01 either as a monotherapy or in combination with nivolumab. Clinical trial information: NCT05655312 .

668 Background: After the approval of 177Lu DOTATATE, a new generation of radiopharmaceutical therapies (RPT) utilizing alpha-emitting radiometals is being developed as front-line therapies for advanced NETs with the hope of higher clinical efficacy. In this Phase I study, [ 212 Pb]VMT-α-NET, a novel targeted alpha radionuclide therapy (TAT) to SSTR2, is being evaluated in SSTR2-expressing NETs tumors in patients with no prior PRRT treatment. Here we present interim safety and the first efficacy results from dose escalation cohorts 1 and 2. Methods: In this first-in-human dose-escalation study, safety, PK, and efficacy of [ 212 Pb]VMT-α-NET were investigated in a population of well-differentiated adult NETs of any grade which progressed after prior standard of care therapy as assessed by RECIST v1.1 (NCT05636618). No patient may have received prior 177 Lu-DOTATATE or PRRT. The dose escalation design includes four cohorts, 3 mCi, 5 mCi, 7.5 mCi and 10 mCi based on a Bayesian modified toxicity probability interval (mTPI-2) design. Subjects in cohorts 1 and 2 underwent dosimetry evaluations using the therapeutic surrogate [ 203 Pb]VMT-a-NET. Therapeutic [ 212 Pb]VMT-a-NET was administered for 4 cycles Q8W in combination with reno-protective amino acids. The DLT assessment period is defined as the first 6 weeks of cycle 1. The primary objectives include the evaluation of safety and tolerability, the PK and RP2D of [ 212 Pb]VMT-a-NET as well as ORR as assessed by RECIST 1.1 criteria. Results: The current data cut occurred on September 19 th , 2024. A total of 9 patients were enrolled (2 in cohort 1 and 7 in cohort 2). Median exposure for cohort 1 was 2.5 mCi (2.5 mCi, 2.5 mCi) and for cohort 2 was 5.1 mCi (4.7 mCi, 5.2 mCi). No DLTs were observed. Two grade 3 AEs occurred in Cohort 2 (diarrhea, syncope). The most frequent related TEAE were alopecia, fatigue, anemia, lymphopenia and nausea (all grade 1 or 2). One subject in Cohort 2 was discontinued due to progressive disease. Landmark PFS at 9 months is 89%. ORR is not yet mature and will be shown at the time of the meeting. Safety Monitoring Committee (SMC) meeting was held on July 17 th , 2024, recommended dose escalation to cohort 3 at 7.5 mCi. No nephrotoxicity was reported in either cohort. Conclusions: [ 212 Pb]VMT-α-NET is safe up to 185 MBq (5 mCi) dose level, and the SMC supported dose escalate to cohort 3 at 277.5 MBq (7.5 mCi) following a mandated FDA review in fall. Cohort 2 remains open for dose level expansion. Early efficacy results demonstrate encouraging progression-free survival. Clinical trial information: NCT05636618 .