A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients with solid tumors, including advanced/metastatic liposarcoma (LPS).

3004 Background: The highly potent MDM2–p53 antagonist BI 907828 showed antitumor efficacy in vivo, particularly in TP53 wild-type, MDM2-amplified de-differentiated LPS (DDLPS) patient-derived xenografts and syngeneic models. This phase I study (NCT03449381) is assessing BI 907828 monotherapy in patients with advanced solid tumors, including LPS. In Part A (dose escalation), patients received one of two BI 907828 dosing schedules: Arm A, day 1 of 21-day cycles (q3w); Arm B, days 1 and 8 of 28-day cycles. Based on previously reported results from Part A (LoRusso ASCO 2021), the MTD was 60 mg q3w and the recommended dose for expansion (RDE) was selected as 45 mg q3w. Methods: In Part B (dose expansion), patients received BI 907828 45 mg q3w. The primary endpoint was PFS. Secondary endpoints/objectives included objective response rate, overall survival, the number of patients with grade ≥3 treatment-related AEs, and PK parameters. Here, we report overall safety data and efficacy data in the subgroup of patients with advanced LPS. Results: As of January 10, 2022, 90 patients had been enrolled; 49 (54.4%) were male, 55 (61.1%)/34 (37.8%) were ECOG PS 0/1, the median number of prior systemic therapies was 2 (range, 0–11), 44 had advanced LPS (28 DDLPS, 16 well-differentiated LPS [WDLPS]). At data cut-off, 31/90 patients (34.4%) had received treatment for ≥6 months. In the 41 evaluable patients with advanced LPS, best response of PR or SD was observed in 24/27 patients with DDLPS (88.9%) and 13/14 patients with WDLPS (92.9%). Two DDLPS and 4 WDLPS patients achieved a PR; all had MDM2-amplified disease. In Part A, 5/11 DDLPS patients and 4/8 WDLPS patients have achieved PFS ≥10.5 months. In the 42 patients who received the RDE of 45 mg q3w, 18 patients (42.9%) had grade ≥3 AEs; the most common grade ≥3 AEs were neutropenia (23.8%), thrombocytopenia (21.4%), and anemia (11.9%). Seven patients (16.7%) had SAEs; the most common were thrombocytopenia (4.8%) and pyrexia (4.8%). PK analysis showed that mean plasma exposures (Cmax and AUC0-inf) increased with dose and showed no significant deviation from linearity in the dose range 10–60 mg. A correlation was observed between exposure and GDF-15 levels in plasma, as a target engagement marker. Conclusions: BI 907828 showed a manageable safety profile, high plasma exposure, target engagement and encouraging signs of antitumor activity in patients with advanced DDLPS and WDLPS. The Part B dose expansion is ongoing. Clinical trial information: NCT03449381.