MDM2-p53 Antagonist BI 907828 Demonstrated Promising Activity in Patients with Advanced BTC

A clinical need to enhance first-line treatment outcomes in patients with advanced biliary tract cancer (BTC) is clear, and with a lack of effective second-line therapies, the development of effective targeted treatments is necessary. It has been suggested that blocking the MDM2-p53 interaction has the potential for antitumor activity, as MDM2 is a negative regulator of p53, and MDM2 amplification has been seen as a negative prognostic marker in BTC in preliminary data.

BI 907828 is an MDM2-p53 antagonist that has shown antitumor activity in preclinical studies in a range of tumor types. Currently, BI 907828 is being studied in 2 phase 1a/1b dose-escalation/expansion trials in patients with advanced solid tumors as monotherapy and in combination with anti–PD-1 monoclonal antibody ezabenlimab in a variety of TP53 wild-type cancers. Dr Noboru Yamamoto presented efficacy and safety data for patients with advanced BTC in these trials.

Of the first 10 patients with BTC enrolled in the trials, 6 patients were enrolled in the monotherapy trial and received escalating doses of BI 907828 every 3 weeks (arm A) or days 1, 8, and every 4 weeks (arm B), and 4 patients were enrolled in the combination trial and received escalating doses of BI 907828 plus 240 mg of ezabenlimab every 3 weeks (doublet). In the monotherapy trial, 3 patients had ampullary carcinoma (all received BI 907828 45 mg every 3 weeks), and 3 had cholangiocarcinoma (CCA; 2 patients received BI 907828 45 mg every 3 weeks and 1 patient with intrahepatic CCA [iCCA] received 80 mg every 3 weeks). In the combination trial, 3 patients with iCCA received 30 mg/45 mg BI 907828 doublet or 45 mg triplet (doublet plus the anti–LAG-3 antibody BI 754111), and 1 patient with gallbladder carcinoma (GBC) received BI 907828 45 mg doublet.

The novel MDM2-p53 antagonist BI 907828 demonstrated a manageable safety profile with encouraging efficacy in patients with BTC.

As of December 2022, 2 patients in the monotherapy trial and 3 patients in the combination trial achieved a partial response. In addition, 2 patients in the monotherapy trial and 1 patient in the combination trial achieved stable disease. In the monotherapy trial, 1 responding patient who had iCCA saw 73% tumor shrinkage and a progression-free survival (PFS) event at 404 days. In the combination trial, tumor shrinkage in 1 patient with iCCA was 49% with a PFS event at 230 days, whereas another patient with GBC saw 50% tumor shrinkage with a PFS event at day 241.

In the safety analysis, 71 patients had received BI 907828 every 3 weeks as monotherapy as of April 2022. Of these, 59.2% experienced grade ≥3 treatment-related adverse events (TRAEs), the most common being neutropenia (25.4%), thrombocytopenia (23.9%), decreased white blood cell (WBC) count (11.3%), and anemia (11.3%). A total of 22.5% of patients experienced TRAEs leading to dose reductions, and 7% experienced TRAEs leading to treatment discontinuation. Hematologic adverse events were managed with appropriate treatment or dose modification/interruption. In total, 31 patients had received BI 907828 in combination as of April 2022. Of these, 67.7% experienced a grade 3 or 4 TRAE, and the most common were thrombocytopenia (25.8%), anemia (22.6%), decreased WBC (16.1%) and lymphocyte counts (16.1%), and neutropenia (12.9%). A total of 19.4% of patients required dose reductions due to TRAEs, and there were no discontinuations due to TRAEs. The safety profile in patients with BTC was similar to the overall population.

Overall, the novel MDM2-p53 antagonist BI 907828 demonstrated a manageable safety profile with encouraging efficacy in patients with BTC. A phase 2a/2b trial in patients with BTC is currently recruiting.

Source: Yamamoto N, Tolcher A, Hafez N, et al. Efficacy and safety of the MDM2–p53 antagonist BI 907828 in patients with advanced biliary tract cancer: data from two phase Ia/Ib dose-escalation/expansion trials. Poster presented at: ASCO Gastrointestinal Cancers Symposium, January 19-21, 2023; San Francisco, CA. Abstract 543.