(P 163) PHASE IA/IB, DOSE-ESCALATION/EXPANSION STUDY OF THE MURINE DOUBLE MINUTE 2–TUMOR PROTEIN 53 ANTAGONIST BI 907828 IN COMBINATION WITH IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH ADVANCED SOLID TUMORS

Objective: Preclinical data show that combining a murine double minute 2–tumor protein 53 (MDM2–p53) antagonist with immune checkpoint inhibitors produces anti-tumor effects in multiple tumor types. This Phase Ia/Ib study (NCT03964233) is assessing BI 907828, an MDM2–p53 antagonist, combined with immune checkpoint inhibitors in TP53 wild-type cancers.

Methods: In Phase Ia (dose escalation), patients with advanced/metastatic solid tumors received escalating doses of BI 907828 guided by a Bayesian Logistic Regression Model (starting dose 10 mg orally) plus ezabenlimab 240 mg (anti-PD-1 antibody) and BI 754111 600 mg (anti-LAG-3 antibody) every 21 days (q3w). The primary endpoint was the maximum tolerated dose (MTD) of BI 907828 based on the number of patients with dose-limiting toxicities (DLTs) during cycle one. During Phase Ia, other studies indicated a lack of added efficacy when BI 754111 was combined with ezabenlimab; therefore, the study design was updated to switch the dose escalation to the doublet combination of BI 907828 plus ezabenlimab.

Results: A total of 11 patients received the triplet combination at 10/20/30/45 mg dose levels (DL; n = 3/3/3/2, respectively); all have discontinued treatment. No DLTs were reported in cycle one; MTD was not reached. As of 20th January 2022, 15 patients have received the doublet combination at 30/45 mg DLs (n = 10/5, respectively). One patient (45 mg) had a DLT during cycle one: G2 neutropenia. Four DLTs were reported after cycle one: G3 anemia (30 mg); G2 thrombocytopenia (45 mg); and G3 neutropenia and G4 thrombocytopenia (45 mg). G≥3 adverse events occurred in eight patients; most commonly anemia (n = 6), thrombocytopenia (n = 4) and lymphopenia (n = 3). The recommended dose for expansion (RDE) for BI 907828 monotherapy was identified as 45 mg q3w. Nine of the 15 patients who received doublet therapy were evaluable for response; four had a confirmed partial response (PR; 30 mg, n = 1; 45 mg, n = 3), two biliary tract carcinoma, one urothelial carcinoma, and one myxoid liposarcoma; one had an unconfirmed PR (30 mg) with adenocarcinoma (primary: site intrahepatic cholangiocarcinoma). Four patients with liposarcoma and gastric cancer had stable disease.
In Phase Ib, patients will receive the RDE of BI 907828 plus 240 mg ezabenlimab q3w. Patients will be recruited to two cohorts: soft tissue sarcomas (liposarcoma, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, synovial sarcoma and leiomyosarcoma) and selected MDM2-amplified tumors (NSCLC, gastric adenocarcinoma, urothelial carcinoma, and biliary tract carcinoma). The primary endpoints are progression-free survival and objective response (RECIST 1.1).

Conclusion: The doublet combination of BI 907828 plus ezabenlimab showed a manageable safety profile and early signs of anti-tumor activity. Eleven patients remain on treatment; recruitment is ongoing.