MT-6402, an engineered toxin body (ETB) targeting PD-L1: Interim efficacy and safety data.

person Minal A. Barve Mary Crowley Cancer Research Center, Dallas, TX info_outline Minal A. Barve, Brian Andrew Van Tine, Rebecca A. Redman, Steven Francis Powell, William Jeffery Edenfield, Julio Antonio Peguero, Victoria Meucci Villaflor, Karen Stein, Chris Moore, Rachael Orlandella, Swati Khanna, Joseph Dekker, Silvia Ferrati, Soratree Charoenthongtrakul, Yanning Liu, Kristina Dabovic, David R. Spigel

Authors person Minal A. Barve Mary Crowley Cancer Research Center, Dallas, TX info_outline Minal A. Barve, Brian Andrew Van Tine, Rebecca A. Redman, Steven Francis Powell, William Jeffery Edenfield, Julio Antonio Peguero, Victoria Meucci Villaflor, Karen Stein, Chris Moore, Rachael Orlandella, Swati Khanna, Joseph Dekker, Silvia Ferrati, Soratree Charoenthongtrakul, Yanning Liu, Kristina Dabovic, David R. Spigel Organizations Mary Crowley Cancer Research Center, Dallas, TX, Washington University in Saint Louis, St. Louis, MO, Brown Cancer Center, Louisville, KY, Sanford Cancer Center, Sioux Falls, SD, Prisma Health Cancer Institute, Greenville, SC, Oncology Consultants PA, Department of Research, Houston, TX, City of Hope, Duarte, CA, Molecular Templates, Inc., Austin, TX, Molecular Templates, Austin, TX, Molecular Templates, Jersey City, NJ, Department of Thoracic Medical Oncology, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Molecular Templates, LLC Background: MT-6402, an engineered toxin body (ETB) , has been designed to be effective in patients (pts) previously treated with checkpoint inhibitors (CPIs) by utilizing 3 unique mechanisms of action (MOA): (i) remodeling of the tumor microenvironment by elimination of PD-L1 + immunosuppressive cells like myeloid-derived suppressor cells (MDSCs), (ii) direct cell kill of PD-L1 + expressing tumor cells, (iii) delivery of HLA-A*02 restricted cytomegalovirus (CMV) peptide pp65 to PD-L1 expressing cells to direct a CMV specific CD8 T-cell response against the tumor. Methods: Dose escalation continues with MT-6402 (QW in 4-week cycles) in pts with relapsed/refractory PD-L1 + solid tumors. After clearing doses of 16, 24, 32, 42 and 63 µg/kg, 83 µg/kg is being evaluated. Safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamic data are reported. Results: MT-6402 at 63 µg/kg in 1 pt with metastatic nasopharyngeal carcinoma (NPC) who progressed after radiation, chemotherapy, and CPI (PD-L1 CPS=2%, not HLA-A*02) resulted in a PR (63% reduction in target lesion) after 2 cycles. This pt had an increase in CD8/CD4 and immune activation cytokines (IL-2, TNFα, IFNγ) consistent with elimination of MDSCs. A pt with NSCLC (osseous disease only) that had progressed after CPI showed resolution of 3/4 osseous metastases and decreased radiotracer uptake by the remaining bone metastasis. This patient had high PD-L1 tumor expression and HLA-A*02/CMV + . Complete CMV-specific T-cell extravasation was noted by C1D8 consistent with haplotype-specific CMV antigen delivery for presentation on the tumor surface by MHC class I. All cohorts had reductions in peripheral PD-L1 + MDSCs, monocytes and dendritic cells after MT-6402 without effect on PD-L1 - cells with the most depletion at the highest doses. Most pts displayed CD8 + T-cell expansion and elevations of serum IL-2 and TNFα, consistent with PD-L1-mediated immunotolerance. MT-6402 was well tolerated with 2 dose limiting toxicities reported: Grade (G)2 maculopapular rash at 24 µg/kg, G3 IRR at 63µg/kg. No G ≥ 4 AEs occurred. Infusion-Related Reactions in 3 pts (G1, G2, and G3) and Cytokine Release Syndrome (G1 [2 pts] at both 32 and 42µg/kg and G2 [1 pt] at 16µg/kg) occurred. Conclusions: MT-6402 utilizes three PD-L1-targeted and unique MOAs: direct cell-kill, reduced immunosuppression, and increased immunorecognition. As of Feb 2023, 5 dose cohorts have completed. MT-6402 was well tolerated without CLS or payload-derived toxicity as is observed with traditional immunotoxins and ADCs, respectively. A PR in 1 pt with CPI-refractory NPC (CPS 2%, CMV - ) and regression of osseous metastases in a pt with NSCLC (TPS 80%, HLA-A*02/CMV + ) following disease progression on CPI occurred. These results show MT-6402 monotherapy activity though unique MOAs and provide rationale for MT-6402 dose expansion. Clinical trial information: NCT04795713.

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