CCSG Supplement: ATR Inhibition in Advanced PD(L)1-Refractory Merkel Cell Carcinoma

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EDDOP Leadership Award-P30 Administrative Supplement: The MATRiX Study Title: A Phase 2 Study of ATR Inhibition in Advanced PD-(L)1-Refractory Merkel Cell Carcinoma Abstract (30 lines of text) The success of checkpoint blockade immunotherapy for patients with advanced Merkel cell carcinoma (MCC) has transformed the management of this cancer. Specifically, trials of anti-PD- (L)1 agents led by our Seattle-based translational team resulted in three FDA approvals (avelumab, pembrolizumab, and retifanlimab). Nearly 50% of MCC patients achieve durable disease control with immune checkpoint inhibitors, however, novel salvage treatment options are required to address the unmet clinical need for patients with primary and acquired resistance. Aggressive solid tumors that rapidly multiply, such as MCC, are under increased replication stress (as evidenced by high Ki-67 positivity). This happens in part through loss of early cell cycle checkpoints, biologically characterized by dysregulation of Rb and p53 signaling paired with Myc upregulation. Dividing cells rely on ATR (ataxia telangiectasia and Rad3-related protein) kinase that acts as a ‘quality control’ mechanism to ensure completion of DNA replication prior to the beginning of mitosis, failure of which results in cell death. After more than a decade of effort, multiple potent and specific ATR inhibitors (ATRi) are now available and being explored in relevant preclinical and clinical settings. Excitingly, early preclinical experiments performed by several labs in addition to our preliminary data suggest that ATRi alone or in combination with low-dose radiation induces canonical markers of immunogenic cell death. MCC tumor cells treated with an ATRi (with or without radiation) demonstrate increased innate immune activation as evidenced by expression of calreticulin and MHC-I on the cell surface as well as type I interferon production. In addition, antigen presenting cells (APCs) become activated following exposure to ATRi-treated tumor cells. APCs upregulate MHC-I, CD80 (B7-1) and CD86 (B7-2) expression in this setting augmenting both signals 1 and 2 required for T-cell activation. This suggests that tumors could thus become an in situ vaccine. Importantly, the ability of ATRi to promote MHC-I expression and induce antigen presentation machinery may help overcome immune evasion associated with PD-1 resistance in MCC patients. Excitingly, these studies have led to the recent approval of LOI #10592, an NCI-sponsored multicenter Phase II trial that will explore an ATR inhibitor in patients with MCC resistant to PD-1 pathway blockade. The trial will be randomized to investigate the capacity of ATRi +/- anti-PD-L1 agents for potentiation of anti-tumor immunity in refractory tumors. Detailed characterization of biological correlates of response will help evaluate the immunostimulatory mechanisms underlying ATR inhibition in MCC and other biologically analogous cancers.