Background: Alrizomadlin is a novel, orally active small-molecule MDM2 inhibitor that activates p53-mediated apoptosis in tumor cells, also functions as a host immunomodulator, and may restore antitumor activity in patients with cancer that has progressed on PD-1/PD-L1 inhibitors. Alrizomadlin is currently being investigated for treatment of patients with unresectable or metastatic cutaneous melanoma that progressed on prior immunotherapy. Methods: This multicenter clinical trial was conducted in the United States and Australia in patients with unresectable or metastatic cutaneous melanoma that had progressed on PD-1/PD-L1 immunotherapy. Eligible patients had an ECOG performance status of 0-2. Alrizomadlin 150 mg was administered orally every other day for 2 consecutive weeks, with 1 week off, and pembrolizumab 200 mg intravenously for 30 minutes on Day 1 of a 21-day cycle. Results: As of December 12, 2022, preliminary and interim results are reported for 31 patients with cutaneous melanoma, of whom 21 were male and 10 female, with a median (range) age of 65 (27-84) years. Treatment-related adverse events (TRAE) of any grade ( > 10%) for either alrizomadlin or pembrolizumab were reported in 30/31 (96.8%) patients. These AEs included nausea (71%), vomiting (38.7%), fatigue (35.5%), thrombocytopenia (32.3%), diarrhea (25.8%), neutropenia (19.4%), decreased appetite (16.1%), and decreased leukocyte count (12.9%). A total of 4/31 (12.9%) patients reported treatment-related serious AEs, including anemia, thrombocytopenia, deep vein thrombosis, joint effusion, pulmonary embolism, and vomiting. In 26 efficacy-evaluable patients, the confirmed overall response rate (ORR; partial response [PR] + complete response [CR]) was 23.1%, including 2 patients reporting CRs and 4 reporting PRs based on RECIST v.1.1. The initial analysis indicated that the ORR observed in patients whose disease had failed IO treatment was primarily due to alrizomadlin combined with pembrolizumab, not the delayed effect of prior immunotherapy. Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and demonstrates clinical efficacy in these patients with highly refractory unresectable or metastatic cutaneous melanoma that had progressed on PD-1/PD-L1 immunotherapy. Internal study identifier: APG-115-US002. Clinical trial information: NCT03611868.