Two phase 1a/1b dose-escalation/expansion trials investigated the efficacy and safety of MDM2-p53 antagonist BI 907828 in patients with advanced biliary tract cancer.
The development of effective targeted treatments for patients with advanced biliary tract cancer (BTC) is necessary to improve first- and second-line treatment outcomes. In preliminary studies, blocking the MDM2-p53 interaction may have antitumor activity, as MDM2 is a negative regulator of p53, and MDM2 amplification has been associated with poor outcomes in BTC.
In preclinical studies, BI 907828, an MDM2-p53 antagonist, has shown antitumor activity in a range of tumor types.
In preclinical studies, BI 907828, an MDM2-p53 antagonist, has shown antitumor activity in a range of tumor types. BI 907828 is currently 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. At the ASCO Gastrointestinal Cancers Symposium 2023, Dr Noboru Yamamoto presented the efficacy and safety data for patients with advanced BTC in these trials.
Of the first 10 patients enrolled in these trials, 6 were assigned to 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.
As of December 2022, 2 patients in the monotherapy trial and 3 patients in the combination trial achieved a partial response and 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 had a 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 had a 50% tumor shrinkage, with a PFS event at day 241.
In the safety analysis, 71 patients received BI 907828 every 3 weeks as monotherapy as of April 2022. Of these patients, 59.2% experienced grade ≥3 treatment-related adverse events (TRAEs). The most common grade ≥3 TRAEs included 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.
The novel MDM2-p53 antagonist BI 907828 demonstrated an acceptable safety profile with encouraging efficacy results in patients with BTC. A phase 2a/2b trial is currently recruiting patients with BTC.
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.
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