Testing the Combination of Two Anticancer Drugs M1774 (Tuvusertib) and Avelumab to Evaluate Their Safety and Effectiveness in Treating Merkel Cell Skin Cancer, MATRiX Trial

PRIMARY OBJECTIVE: I. To compare the potential efficacy, using progression free survival (PFS), of ATR inhibition alone to ATR inhibition plus anti-PD-(L)1 therapy through a randomized clinical trial for patients with advanced Merkel cell carcinoma (MCC) who have progressed on anti-PD(L)1 therapy. SECONDARY OBJECTIVES: I. To compare the clinical activity of ATR inhibition alone to that in combination with avelumab through a randomized clinical trial for patients with advanced MCC that has progressed after PD-1 pathway blockade. II. To identify gene expression-based immunologic (replication stress / neuroendocrine \[NE\] differentiation) signatures predictive of response to ATR inhibition in advanced immunotherapy-refractory MCC tumors through ribonucleic acid sequencing (RNAseq). EXPLORATORY OBJECTIVES: I. To examine the association of various biomarkers with the clinical activity of ATR inhibition alone or in combination with PD-(L)1 pathway blockade. II. To explore the safety and efficacy (PFS, overall response rate \[ORR\], and overall survival \[OS\]) of the addition of avelumab to M1774 (tuvusertib) after documented progressive disease of M1774 (tuvusertib) monotherapy. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1 (CLOSED TO ACCRUAL 5/12/2025): Patients receive tuvusertib orally (PO) once daily (QD) on days 1-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who are deriving clinical benefit despite progression may be allowed to continue treatment beyond progression, following consultation. Patients also undergo computed tomography (CT), positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI), biopsy, and collection of blood and stool/rectal swabs at screening and on study. Patients with documented progression may cross over to Arm 2. ARM 2: Patients receive tuvusertib PO QD on days 1-14 of each cycle and avelumab intravenously (IV) over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who are deriving clinical benefit despite progression may be allowed to continue treatment beyond progression, following consultation. Patients also undergo CT, PET/CT, or MRI, biopsy, and collection of blood and stool at screening and on study. After completion of study treatment, patients are followed up at 30 days and then every 6 months for 2 years from the last dose of treatment.