Background – Micvotabart pelidotin (MICVO/PYX-201) is an antibody-drug conjugate that targets the non-cellular extradomain-B of fibronectin (EDB+FN), an extracellular matrix protein that is highly expressed in tumors compared to normal adult tissues. MICVO is designed to kill cancer cells, reduce ECM density, inhibit tumor angiogenesis, and mobilize an anti-tumor immune response. Part 1 of the phase 1 dose escalation study (NCT05720117) assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of MICVO in participants (pts) with select advanced solid tumors. Circulating tumor DNA (ctDNA) was evaluated as a pharmacodynamic biomarker in response to MICVO.

Methods – Blood from study pts was collected at baseline, pre-dose Cycle 3 Day 1(C3D1), and end of treatment to assess longitudinal changes with MICVO treatment. Plasma cell-free DNA was extracted and analyzed for presence of biologically relevant somatic mutations, ctDNA tumor fraction (TF) and blood tumor mutation burden (bTMB) using the Tempus xF+ assay.

Results – Out of the tumor types present in the study, evaluable pts with head and neck squamous cell carcinoma (HNSCC) had significant reductions in both ctDNA TF (n = 4/5 with reduction, 35.3% median reduction, p = 0.05) and bTMB (n = 4/4 with reduction, 10.7% median reduction, p=0.049) around C3D1. Evaluation by dose found that the cohort receiving MICVO at 5.4 mg/kg exhibited a significant reduction in ctDNA TF (n =12/14, 68.5% median reduction, p =0.002), while bTMB showed a trending decrease. Pts with a partial response per RECIST v1.1 at the first scan showed a reduction in ctDNA TF and a trending decrease in bTMB around C3D1.

Conclusions – A pharmacodynamic response to MICVO was observed in blood samples from this heterogeneous population consisting of different tumor types and treated with MICVO at different dose levels. Reductions in both ctDNA TF and bTMB, around C3D1 compared to baseline, occurred within both HNSCC and the cohort dosed at 5.4 mg/kg, which is the dose selected for expansion. Further characterization of ctDNA as a minimally invasive liquid biomarker of pharmacodynamic response to MICVO will be performed in tumor specific expansion cohorts.

Clinical trial identification – NCT05720117.

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