Abstract B034: A phase 2 basket study of the oral MDM2 inhibitor milademetan for MDM2-amplified advanced solid tumors (MANTRA-2)
Authors: Dumbrava Ecaterina E. , Chen Christopher T. , Cote Gregory M. , Hanna Glenn J. , Stinchcombe Thomas E. , Sumrall Bradley , Wise-Draper Trisha , Kanaan Mohammed , Duffy Steven , Sumey Christopher , Cobb Patrick , Shah Naisargee , Zhang Bo , Ku Nora , Doebele Robert C. , Gounder Mrinal 
Published: December 2023

Milademetan is an oral, selective, small molecular inhibitor of the MDM2-p53 complex that reactivates p53 to induce cancer cell apoptosis and tumor regressions in nonclinical models. Clinically, MDM2 gene amplification (amp) occurs in 1–2% of advanced solid tumors and is associated with a poor prognosis. Preliminary antitumor activity was seen in patients with MDM2 amp and TP53 wild-type (WT) tumors in a phase 1 clinical trial [Tirunagaru et al. AACR-NCI-EORTC 2021]. We conducted a phase 2 basket study to evaluate the efficacy of milademetan in patients with advanced or metastatic solid tumors (except liposarcoma, intimal sarcoma, and primary CNS tumors) with MDM2 copy number (CN) ≥8 and WT TP53 status based on local next-generation sequencing (NGS) (NCT05012397). Milademetan was administered at 260 mg on days 1–3 and 15–17 of a 28-day cycle. Tumor assessments were performed every 8 weeks (RECIST v1.1). MDM2 CN was retrospectively analyzed centrally using a commercial NGS assay, which also allowed correlation with other co-occurring alterations. As of June 23, 2023, 39 patients were enrolled with 13 distinct tumor types. The most common histologies were biliary tract cancers (8, 20.5%), sarcomas (7, 17.9%), and breast cancer (6, 15.3%). Median number of prior systemic therapies was 3 (range 0–12). Thirty-eight patients were evaluable for safety. The most common hematologic grade 3/4 adverse events (AEs) related to milademetan were thrombocytopenia (26.3%), neutropenia (15.8%), and anemia (10.5%). All grade treatment-related AEs (&gt;15% incidence) included thrombocytopenia (44.7%), nausea (42.1%), fatigue (36.8%), vomiting (31.6%), anemia (23.7%), diarrhea (23.7%) and neutropenia (18.4%). No bleeding or neutropenic sepsis events were reported, and no grade 5 events were observed. The dose reduction rate was 13.2%, and 7.9% of patients discontinued milademetan due to AEs. Central tumor testing was available on 30 (76.9%) patients and only 2 (6.7%) patients demonstrated MDM2 CN below the threshold of 8. Thirty-two patients were efficacy evaluable and had confirmed CN ≥8 or pending central analysis. Five partial responses (15.6%) were observed (4 unconfirmed, 1 confirmed) with one each in lung adenocarcinoma (co-alteration of EGFR + KRAS), pancreatic (KRAS), bladder (pending), gastric cancer (DNAB1-PRKACA) and endometrial sarcoma (CCND2).  No clear correlation between MDM2 CN and tumor regression was observed. The median progression-free survival was 3.3 months (95% CI, 2.5–6.1). The longest patient on milademetan therapy was 41 weeks (biliary, best RECIST 1.1 response SD with –29% tumor reduction). Ten patients are currently ongoing. Milademetan monotherapy demonstrated clinically meaningful antitumor responses with a manageable toxicity profile in a variety of MDM2 amp, TP53 WT solid tumors, including those with other oncogenic drivers such as KRAS. Rational combination strategies with milademetan should be considered in tumors with WT TP53 to further enhance durable anti-tumor activity.

Citation Format: Ecaterina E. Dumbrava, Christopher T. Chen, Gregory M. Cote, Glenn J. Hanna, Thomas E. Stinchcombe, Bradley Sumrall, Trisha Wise-Draper, Mohammed Kanaan, Steven Duffy, Christopher Sumey, Patrick Cobb, Naisargee Shah, Bo Zhang, Nora Ku, Robert C. Doebele, Mrinal Gounder. A phase 2 basket study of the oral MDM2 inhibitor milademetan for MDM2-amplified advanced solid tumors (MANTRA-2) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B034.