Newly updated activity results of alrizomadlin (APG-115), a novel MDM2/p53 inhibitor, plus pembrolizumab: Phase 2 study in adults and children with various solid tumors.
Meredith McKean, Anthony W. Tolcher, James A. Reeves, Bartosz Chmielowski, Montaser Shaheen, J. Thaddeus Beck, Marlana Orloff, Neeta Somaiah, Brian Andrew Van Tine, Joseph J. Drabick, Alexander I. Spira, Kenneth J. O’Byrne, Christos S. Karapetis, Steven A. Foresto, Sujana Movva, J. Alfredo Martínéz, Mingyu Li, Robert L. Winkler, Dajun Yang, Yifan Zhai
Abstract
9517 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.