Phase II results of alrizomadlin (APG-115), a novel MDM2/p53 inhibitor, plus pembrolizumab (pembro) in patients (pts) with metastatic melanoma or advanced solid tumors that have failed immuno-oncologic (I-O) drugs

Abstract

Alrizomadlin restores TP53 function, activating p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. Acting as host immunomodulator, alrizomadlin may restore antitumor activity in cancer that has progressed on PD-1/ PD-L1 inhibitors. This multicenter trial evaluated alrizomadlin plus pembro for pts with unresectable/metastatic melanoma, non-small cell lung cancer (NSCLC), and urothelial cancers that progressed on I-O drugs; pts with other solid tumors progressed on standard treatment. Alrizomadlin 150 mg PO was administered QOD for 2 weeks, with 1 week off, and pembro 200 mg IV on D1 of a 21-day cycle. By June 1, 2022, 162 pts were enrolled in 6 cohorts: melanoma (n = 63); NSCLC (27); ATM mutation (24); liposarcoma (17); urothelial (13); and malignant peripheral nerve sheath tumor (MPNST; 18). In I-O- progressed cutaneous and uveal melanoma subtypes, RECIST-confirmed ORR was 22% (2 CR + 3 PR/23 efficacy evaluable [EE] pts) and 5% (1 PR/20 EE pts), respectively. In the MPNST cohort, clinical benefit rate (ORR + stable disease [SD] ≥ 4 cycles) was 38% (5 SD/13 EE pts). Additional confirmed PRs were reported in NSCLC, urothelial, and liposarcoma cohorts (1 each). Related TEAEs (i.e., TRAEs ≥15%) were nausea (61%), thrombocytopenia (37%), fatigue (36%), vomiting (34%), decreased appetite (25%), diarrhea (23%), neutropenia (16%), and anemia (15%). Grade >3 TRAEs (≥5%) were thrombocytopenia (23%), neutropenia (11%), and anemia (9%); 13 pts reported related SAEs, 2 each of anemia, pulmonary embolism, and thrombocytopenia (≥1%). Alrizomadlin plus pembro is well tolerated, demonstrated antitumor activity in multiple tumors, and may restore antitumor effects in pts with cancer resistant or intolerant to I-O drugs (NCT03611868).