Background: Alrizomadlin restores TP53 function, activating p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. Alrizomadlin also functions as a host immunomodulator and may restore antitumor activity in pts with cancers that progressed on PD-1/PD-L1 inhibitors. Methods: This US/Australian multicenter trial evaluated alrizomadlin, an investigational MDM2-selective, small-molecule inhibitor, combined with pembrolizumab, in pts with unresectable/metastatic melanoma that progressed on I-O drugs; pts with malignant peripheral nerve sheath tumor (MPNST), well-differentiated/dedifferentiated liposarcoma, non-small cell lung cancer (NSCLC), or solid tumors with ATM mutations that progressed on available standard therapy; or pts for whom therapy was unavailable. Eligible pts had ECOG performance status of 0-2 and, if present, stable brain metastases. Alrizomadlin 150 mg PO was administered QOD for 2 consecutive weeks, with 1 week off, and pembrolizumab 200 mg IV over 30 minutes on Day 1 of a 21-day cycle. Results: As of November 3, 2021, preliminary and interim results are reported for 130 pts in 6 cohorts: melanoma (n = 44), NSCLC (n = 26), ATM mutation (n = 18), liposarcoma (n = 17), urothelial (n = 13), and MPNST (n = 12). In the melanoma cohort, confirmed ORR by RECIST, (PR + CR) was 13% (2 CRs + 3 PRs/38 efficacy evaluable [EE] pts). In cutaneous and uveal melanoma subcohorts, confirmed ORR was 24% (2 CRs + 2 PRs/17 EE pts) and 9% (1 PR/11 EE pts), respectively. In the MPNST cohort, the clinical benefit rate, defined by confirmed ORR + SD of > 4 cycles, was 40% (4 SDs/10 EE pts). Additional confirmed PRs were reported in NSCLC, urothelial, and liposarcoma cohorts (1 each). Common treatment (alrizomadlin or pembrolizumab)-related adverse events (TRAEs; ≥ 10%) were nausea (62%), thrombocytopenia (39%), vomiting (38%), fatigue (38%), decreased appetite (29%), diarrhea (25%), neutropenia (15%), and anemia (12%). Grade 3⁺ TRAEs (≥ 5%) included thrombocytopenia (23%), neutropenia (10%), and anemia (7%). A total of 16 pts discontinued treatment due to AEs; 6 were treatment related, including grade 4 thrombocytopenia (n = 3), grade 2 vomiting (n = 1), grade 2 fatigue (n = 1), and grade 2 posterior reversible encephalopathy syndrome (PRES; n = 1). A total of 10 pts reported treatment-related SAEs: 1 each of abdominal pain, asthenia, colitis, febrile neutropenia, hypophysitis, peripheral edema, overdose, PRES, pulmonary embolism, pyrexia, and thrombocytopenia.Conclusions: Alrizomadlin, combined with pembrolizumab, is well tolerated and demonstrates preliminary antitumor activity in multiple tumor types and may restore antitumor effects in pts with cancer resistant or intolerant to I-O drugs. Internal study identifiers: APG-115-US-002; Keynote MK-3475-B66. Clinical trial information: NCT03611868.