Interim safety and efficacy data of [ ²¹² Pb]VMT01 in MC1R expressing melanoma.

Abstract

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 .