19 Phase II Trial of Ubamatamab in MUC16-Expressing SMARCB1-Deficient Renal Medullary Carcinoma and Epithelioid Sarcoma

Abstract Background Mucin 16 (MUC16) is a large integral membrane glycoprotein that is highly expressed in malignancies such as ovarian cancer but only at low abundance in epithelial cells of normal tissues. Proteolytic cleavage of cell surface MUC16 results in the shedding of its extracellular portion, known as cancer antigen 125 (CA-125), into the bloodstream and a short, membrane-associated C-terminal MUC16 domain that remains on the cell surface. Renal medullary carcinoma (RMC) and epithelioid sarcoma (ES) are aggressive SMARCB1-deficient malignancies found to have elevated serum CA-125 levels in 70-80% of cases. Our preclinical studies suggest that upregulation of MUC16 upon SMARCB1 loss is a viable and attractive tumor target for SMARCB1-deficient malignancies such as ES and RMC. Ubamatamab is a human IgG4-based anti-MUC16 x anti-CD3 bispecific antibody that specifically targets the cell surface bound C-terminal MUC16 domain and can thus induce T cell–redirected killing of tumor cells even in the presence of high concentrations of CA-125. It would thus be a rationale therapy to use in SMARCB1-deficient malignancies expressing MUC16, including those such as RMC known to downregulate MHC Class I as a resistance mechanism to conventional immunotherapy. This is because CD3-targeting bispecific antibodies such as ubamatamab replace conventional signal 1 by engaging T cells regardless of MHC class I expression. As proof of concept, a 20-year-old patient with metastatic SMARCB1-negative ES expressing high levels of serum CA-125 achieved a durable (12+ months) partial response to ubamatamab after progressing on multiple prior therapies, including EZH2 inhibition with tazemetostat as well as anti-PD1/CTLA4 immune checkpoint inhibition with nivolumab plus ipilimumab. The patient reported Grade 2 CRS, pleural effusion, and pericardial effusion, all of which resolved without intervention1. This serves as proof-of-concept for the ability of CD3-targeted bispecifics to overcome resistance to immune checkpoint inhibition. Given this strong preclinical and clinical evidence, we have developed a phase II clinical trial of ubamatamab alone or in combination with the anti-PD1 immune-checkpoint inhibitor cemiplimab in patients with MUC16-expressing RMC and ES who have progressed on at least one line of prior therapy. Up to 20 patients will be enrolled from each disease cohort (ES and RMC) for a total of up to 40 patients. Patients enrolled in Stage I of the trial will receive ubamatamab monotherapy. Patients with disease progression on ubamatamab monotherapy during Stage I can proceed to stage II, which will evaluate the combination of ubamatamab with cemiplimab combination. The co-primary endpoints will be objective response rate (ORR) at any time during the trial and disease control rate (DCR) through 18 weeks. Secondary endpoints will include overall survival, progression-free survival, duration of response, and safety. All endpoints will be analyzed and reported separately for each disease cohort (RMC and ES), and for each Stage (ubamatamab monotherapy and combination ubamatamab with cemiplimab). The trial will utilize the time-to-event Bayesian Optimal Phase II (TOP) design, which maximizes statistical power with well-controlled type I errors. For patients with ES, the joint null hypotheses are that the objective response rate (ORR) is 15% and the disease control rate (DCR) is 26%. The regimen will be promising if either ORR is greater than 15% or DCR is greater than 26% with 69.6% power to declare this an interesting regimen if ORR is 30% and the DCR is 43%. For patients with RMC, the joint null hypotheses are that the objective response rate (ORR) is 15% and the disease control rate (DCR) is 15%. The regimen will be promising if either ORR is greater than 15% or DCR is greater than 15% with 71.4% power to declare this an interesting regimen if ORR is 30% and the DCR is 30%. Pre- and post-treatment correlative analyses will be performed in blood and tumor biopsy tissues to identify changes in specific immune cell subsets and elucidate the dynamic evolution of tumor and immune cell compartments as well as their spatial relationships following ubamatamab alone or in combination with cemiplimab. References 1 Revon-Riviere G, Chami R, Mills D, et al. Mucin 16 (cancer antigen 125) Expression in Epithelioid Sarcoma leads to Single-Patient Study with Bispecific T-Cell Engager Ubamatamab (Mucin16xCD3): A Bench-To-Bedside Experience. Connective Tissue Oncology Society, Nov 16–19, 2022, Vancouver, Canada.