Background: There are no approved therapies for pts with MCC for whom an anti PD-1/L1 agent has failed. The high rate of non-responsive disease after anti PD-1/L1 therapy together with high mortality rate and the absence of a standard of care in this setting highlight the urgent unmet need for effective novel therapies. Approximately 80% of MCC tumors carry the oncogenic Merkel cell polyoma virus (MCPyV) and most cases are TP53^WT. Oncoproteins from MCPyV inhibit p53 tumor suppressor functions by activating MDM2. Navtemadlin, a potent, selective, orally available MDM2i, overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis of TP53^WT MCC tumors. Navtemadlin is the first targeted therapy to show single-agent activity in pts with metastatic MCC for whom anti-PD-1/L1 has failed (Wong ASCO 2022). In the dose finding study, evaluable pts (n=8) receiving the recommended phase 2 dose of navtemadlin (180 mg QD on Day 1-5/28-day cycle) demonstrated a 25% confirmed objective response rate (ORR), 38% unconfirmed + confirmed ORR, and 63% disease control rate. The median duration of response was not reached (range, 6-16.2+ months [mos]) and median time to treatment response was 4.1 mos (range, 1.2-7). Responses to navtemadlin were highest in those pts with no prior chemotherapy (chemo; Wong ASCO oral 2022). In pts receiving navtemadlin at doses of ≥180 mg, an ORR of 40% was reported with no prior chemo (n=15) versus 14% in those who received prior chemo (n=14, Wong ASCO oral 2022). Navtemadlin demonstrated an acceptable safety profile with the most common treatment emergent adverse events (TEAEs) cytopenias, nausea, vomiting, diarrhea, and fatigue. Grade 3/4 TEAEs were 32% anemia, 32% lymphopenia, and 19% thrombocytopenia (Wong 2022). Based on this encouraging data, the NOTOS study (navtemadlin induces p53-driven apoptosis in Merkel cell carcinoma) will evaluate the safety and efficacy of navtemadlin in two post PD-1/L1 treated cohorts: chemo-naive pts and chemo treated pts. Methods: Adults with MCC for whom anti PD-1/L1 therapy has failed, who have ≥1 measurable lesion per RECIST v1.1, ECOG PS 0-1 and TP53^WT MCC by central testing will receive 180 mg QD on days 1-5 of a 28-day cycle until disease progression, unacceptable toxicity, death or withdrawal of consent. The primary endpoint is ORR per RECIST v1.1 by blinded independent review. Secondary endpoints include ORR per investigator, duration of response, progression-free survival, overall survival, clinical benefit rate (including stable disease for ≥10 wk, partial response or complete response), and safety. The NOTOS trial is currently enrolling (NCT03787602). Clinical trial information: NCT03787602.