Efficacy and Safety of Brigimadlin (BI 907828) in Patients With Advanced BTC: Data From 2 Phase 1a/1b Dose-Escalation/Expansion Trials

Teresa Macarulla, MD, PhD

Chemotherapy is the standard-of-care treatment for advanced biliary tract cancer (BTC); however, outcomes are poor, and there is no clear standard treatment after first-line therapies. Brigimadlin (BI 907828) is a highly potent, orally administered MDM2-p53 antagonist that inhibits the interaction between TP53 and its negative regulator, MDM2. Therefore, TP53 wild-type tumors exhibit cell cycle arrest or apoptosis.^1,2

The safety and efficacy of brigimadlin are currently being assessed in advanced solid tumors in 2 phase 1a/1b dose-escalation/expansion trials, both as a monotherapy (NCT03449381) and in combination with ezabenlimab (BI 744091), an anti–PD-1 monoclonal antibody (NCT03964233).^2,3

The efficacy and safety of brigimadlin in patients with advanced BTC in these 2 trials were presented at ASCO GI by Teresa Macarulla, MD, PhD.

Patients in the monotherapy trial received escalating doses of brigimadlin on day 1 of 21-day cycles (every 3 weeks [Q3W]).⁴ Patients in the combination trial received escalating doses of brigimadlin and ezabenlimab (240 mg) on day 1 Q3W (doublet); 1 patient also received the anti-LAG-3 antibody BI 754111 (which has since been discontinued; triplet).

Key inclusion and exclusion criteria were similar across both trials and have been presented previously.^3,5

This study aimed to assess safety and tolerability. They recommended a phase 2 dose of brigimadlin as a monotherapy and in combination with ezabenlimab (and BI 754111, anti-LAG-3 antibody, in 1 patient) in various TP53 wild-type cancers.

As of October 2023, 23 patients with BTC have been enrolled in both trials (16 in the monotherapy trial and 7 in the combination trial). Of these patients, 19 were evaluable for efficacy evaluations (12 in the monotherapy trial and 7 in the combination trial).

Of evaluable monotherapy patients, 12 patients with BTC received brigimadlin (45 mg Q3W), including 3 with ampullary carcinoma, 2 with cholangiocarcinoma (CCA), 4 with intrahepatic cholangiocarcinoma (iCCA), 2 with gallbladder carcinoma, or 1 with iCCA (80 mg Q3W)

The median age of evaluable monotherapy patients was 62.5 years; 50% were male, and 66.7% were white. Of the evaluable patients who received combination therapy, 7 patients with BTC received brigimadlin 45-mg doublet (1 patient with CCA, 2 patients with iCCA, 2 patients with gallbladder carcinoma); 30-mg doublet, which included 1 patient with iCCA; or 45-mg triplet, which included 1 patient with iCCA. The median age of evaluable combination patients was 74.5 years; 50% were male, and 50% were white.

As of September 2023, 12 of the 16 patients with BTC in the monotherapy trial were response evaluable, 4 patients had confirmed partial response, and 6 had acquired stable disease. As of October 2023, all 7 patients with BTC in the combination trial were response evaluable; 4 patients achieved confirmed partial response and 3 completed stable disease. In patients treated with 45 mg QW3 brigimadlin monotherapy and combination therapy, the most common any-grade treatment-related adverse events (TRAEs) were nausea (67.9% and 70.3%, respectively) and fatigue (53.6% and 39.2%, respectively). The most common grade ≥3 TRAEs were neutropenia (25.0% and 24.3%, respectively) and thrombocytopenia (22.9% and 21.6%, respectively).

A total of 37.9% of adverse events (AEs) led to dose reduction in patients who received brigimadlin monotherapy, and 24.3% of AEs led to dose reduction in patients who received brigimadlin combination therapy. Additionally, 6.4% of AEs led to treatment discontinuation in the brigimadlin monotherapy group, and 10.8% of AEs led to discontinuation in the brigimadlin combination therapy group.

Brigimadlin demonstrated promising preliminary activity and a manageable safety profile in patients with BTC in both phase 1a/1b trials.

Following these encouraging results, brigimadlin (45 mg Q3W) is currently being investigated in patients with MDM2-amplified BTC in the phase 2a/2b Brightline-2 trial (NCT05512377).⁴

References

1. Khankhel ZS, Goring S, Bobiak S, et al. Second-line treatments in advanced biliary tract cancer: systematic literature review of efficacy, effectiveness and safety. Future Oncol. 2022;18(18):2321-2338.
2. LoRusso P, Yamamoto N, Patel MR, et al. The MDM2-p53 antagonist brigimadlin (BI 907828) in patients with advanced or metastatic solid tumors: results of a phase Ia, first-in-human, dose-escalation study. Cancer Discov. 2023;13(8):1802-1813.
3. Yamamoto N, Hafez N, Tolcher AW, et al. A phase Ia/Ib, dose-escalation/expansion study of BI 907828 in combination with BI 754091 (ezabenlimab) and BI 754111 in patients (pts) with advanced solid tumors. J Clin Oncol. 2022;40(suppl 16):
4. Macarulla T, Yamamoto N, Tolcher A, et al. Efficacy and safety of brigimadlin (BI 907828), an MDM2–p53 antagonist, in patients (pts) with advanced biliary tract cancer: data from two phase Ia/Ib dose escalation/expansion trials. San Francisco, CA, & online: presented at ASCO Gastrointestinal Cancers Symposium; January 18-20, 2024: poster C12.
5. Gounder MM, Yamamoto N, Patel MR, et al. 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). J Clin Oncol. 2022;40(suppl 16):