Morris, Zachary Scott

Abstract FLASH radiotherapy shows promise in reducing normal tissue toxicity while maintaining tumor control. However, preclinical and early clinical evidence reveal biological and technical uncertainties. We review preclinical and veterinary studies, highlight unexpected toxicities, and argue that the fundamental principles of precision and safety in radiotherapy—particularly conformal treatment and ALARA—remain crucial.

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 .

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 .

e21212 Background: Combining local ablative and systemic therapies in patients with oligometastatic NSCLC leads to improved overall survival (OS) and progression-free survival (PFS). The potential immunostimulatory effects of ablating all visible disease with SBRT in combination with dual immune checkpoint inhibition has prompted interest, but the toxicity and benefit are unknown. Methods: We conducted a phase Ib study to investigate the safety of SBRT, with doses between 30 and 50 Gy in five fractions to all sites of disease, followed by durvalumab 1500 mg IV in combination with tremelimumab 75 mg IV every 4 weeks x 4 cycles, followed by durvalumab maintenance until progression. Eligible patients had 1-6 extracranial metastatic sites, allowing multiple metastases per location, with all lesions suitable for SBRT, ECOG performance status 0-1, no actionable driver mutation, and no prior immunotherapy. The primary endpoint was safety of this combination. Secondary endpoints include PFS and OS. Dose-limiting toxicities (DLTs) (any Grade ≥ 3 toxicity) were evaluated from the first administration of SBRT until 28 days post start of durvalumab and tremelimumab. Baseline tumor mutational burden, PD-L1 expression on post-SBRT biopsy and circulating tumor cells will be correlated with outcomes. In this first cohort analysis, we assess the safety and outcomes of the first 17 patients. Results: From 2/2018-2/2021, the first 17 pts were enrolled. Characteristics of those enrolled included: median age 68 years, female/male 4/13, squamous/non-squamous 2/15, median number of non-central nervous system (CNS) metastatic sites 2 (1-5), median number of non-CNS metastatic lesions 2 (1-9), CNS involvement 6/17 (35.3%), previous treatment 4/17 (23.5%). DLTs were seen in 2/17 (11.8%) patients; DLTs were autoimmune hepatitis and autoimmune pancreatitis. Most treatment-related adverse events (TRAEs) were grade (G) 1/2. TRAEs included: all TRAEs n = 188, 88.2% (of patients); G 3 n = 17, 29.4%; G 4 n = 1, 5.8%. There were no treatment-related deaths. Five patients discontinued treatment due to grade 3/4 immune related adverse events (IRAE). At a median follow up of 20 months 11/17 (64.7%) patients are alive with 10/17 (58.8%) with no evidence of disease (NED). Six of 17 (35.2%) patients experienced disease progression and 4/17 (23.5%) patients died of disease progression. Median PFS and OS are not yet reached. Conclusions: There were no unexpected safety signals in the cohort of patients enrolled. The incidence of grade ≥ 3 IRAEs is similar to the treatment of advanced NSCLC and no additional toxicity was observed with the addition of SBRT. Clinical outcomes look promising with median OS and PFS not yet reached at 20 months median follow up. The study continues to enroll a second cohort and results will be updated. Clinical trial information: NCT03275597.