Reference Detail

Ref Type

Abstract

PMID

Authors

M. Gounder M.R. Patel N. Yamamoto T.M. Bauer S. Laurie A. Perez-Pitarch J. Geng J. Cheng M. Lahmar P. Lorusso

Title

1548P A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients (pts) with advanced/metastatic sarcoma

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of Oncology	32	Supplement 5	September 01, 2021

URL

https://www.annalsofoncology.org/article/S0923-7534(21)03107-0/fulltext

Abstract Text

Background The MDM2-p53 antagonist BI 907828 showed anti-tumour efficacy in vivo, particularly in TP53 wild-type, MDM2-amplified de-differentiated liposarcoma (DDLPS) pt-derived xenografts and syngeneic models. Methods NCT03449381 is a phase I study of BI 907828 monotherapy in pts with solid tumours evaluating two dosing schedules (Arm A: day 1 of 21-day cycles; Arm B: days 1 and 8 of 28-day cycles). Dose-limiting toxicities (DLTs) were assessed during Cycle 1, along with pharmacokinetics (PK) and anti-tumour activity. Results As of April 2, 2021, 54 pts (29 in Arm A, 25 in Arm B) had been enrolled, among whom 27 had advanced sarcomas. Pts received a median of 2 prior therapies (range, 0–11). Five patients experienced DLTs in arm A: one grade 3 nausea (45 mg), one grade 3 thrombocytopenia (TCP; 45 mg), one grade 3 enterocolitis (60 mg), one grade 4 neutropenia (80 mg), and one grade 4 TCP (80 mg). In arm B, 3 patients experienced DLTs: one grade 4 TCP (45 mg), one grade 4 neutropenia associated with grade 4 TCP (60 mg), and one grade 3 neutropenia (60 mg). The MTD was determined as 60 mg in Arm A and 45 mg in Arm B. The most common G 3/4 AEs were TCP (29.6%) and neutropenia (22.2%). Mean plasma exposures (Cmax and AUC0-inf) increased with dose. In the 27 pts with sarcoma, the disease control rate (DCR defined as CR + PR + SD) was 88.9%. Three of 7 pts with well-differentiated LPS achieved a PR (all were MDM2-amplified); 1 remained on treatment >2 years. All 11 pts with DDLPS achieved SD as best overall response; the median PFS was approximately 10.8 months (range, 1.3–21 months). Osteosarcoma, GIST, rhabdomyosarcoma, dermatofibrosarcoma, leiomyosarcoma, and undifferentiated pleiomorphic sarcoma were among the other sarcoma subtypes included in the study. Of these, disease control was notable in 1 pt with myxoid chondrosarcoma (SD = 10 months), 1 with leiomyosarcoma (SD = 14 months) and 1 with undifferentiated pleiomorphic sarcoma (SD = 18+ months). Conclusions BI 907828 showed a manageable safety profile, favourable PK, and early signs of anti-tumour activity in patients with sarcoma, especially MDM2-amplified well or de-differentiated liposarcomas. The phase Ib dose expansion is ongoing. Clinical trial identification NCT03449381.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
MDM2 amp	liposarcoma	predicted - sensitive	BI 907828	Case Reports/Case Series	Actionable	In a Phase I trial, BI 907828 treatment led to a partial response in 3 of 7 patients with liposarcoma, all responders harbored MDM2 amplification (Ann Oncol 32 (2021): S1294; NCT03449381).	detail...