BI 907828 Demonstrates Early Efficacy, Safety in MDM2-amplified Dedifferentiated Liposarcoma

The oral MDM2/p53 antagonist BI 907828 elicited preliminary antitumor activity and had a manageable safety profile in patients with MDM2-amplified dedifferentiated liposarcoma (DDLPS), according to findings from a phase 1a/b trial (NCT03449381) presented at the 2023 ESMO Sarcoma and Rare Cancers Congress.¹

Among evaluable patients (n = 36), the median progression-free survival (PFS) with the agent was 8.1 months (95% CI, 5.4-20.7). Additionally, BI 907828 induced an objective response rate (ORR) of 13.9%, with all 5 responders achieving a partial response (PR) to treatment. Seventy-five percent of patients had stable disease, and 5.6% of patients had an unconfirmed response. The progressive disease rate was 11.1%, and the disease control rate was 88.9%.

Any-grade adverse effects (AEs) were reported in 94.9% of patients, and 56.4% of patients experienced grade 3 or higher AEs. Treatment-related AEs (TRAEs) occurred in 89.7% of patients, 35.9% of which were grade 3 or higher in severity. Any-cause serious AEs were observed in 35.9% of patients.

AEs leading to dose reduction and treatment discontinuation occurred in 15.4% and 5.1% of patients, respectively.

“A considerable proportion of the patients treated with different dose levels of [BI 907828] remained on treatment with stable disease, PR, or any kind of patient benefit, without severe toxicity, for a considerable period of time,” lead study author Patrick Schoffski, MD, MPH, of the Department of General Medical Oncology at Leuven Cancer Institute, University Hospitals Leuven, in Leuven, Belgium, said in a presentation of the data.

The loss of p53 function can stem from TP53 mutations or the downregulation of p53 wild-type by MDM2, thereby inhibiting the tumor-suppressor activity of p53.2 It is hypothesized that blocking the interaction between MDM2 and p53, p53 wild-type function can be restored and this could serve as a potential therapeutic strategy in solid tumors harboring wild-type or functional p53.

Although approximately 7% of tumors display MDM2 amplification, more than 90% of patients with DDLPS have TP53 wild-type and MDM2 amplification.3,4

“It is important to understand that [DDLPS] is one of the most common soft tissue sarcomas that we are dealing with on a daily basis,” Schöffski said. “It’s an aggressive disease, behaving like a lot of other poorly differentiated sarcomas.”

BI 907828 binds to MDM2 and blocks the MDM2–p53 interaction, preventing MDM2 from inactivating p53 and restoring its function.1 Preclinical data have indicated that BI 907828 displayed strong antitumor activity in patient-derived xenograft models of TP53 wild-type, MDM2-amplified DDLPS.

The phase 1 dose-escalation and -expansion study enrolled patients with advanced solid tumors who had an ECOG performance status of 0 or 1. In the expansion portion, patients were required to have a known TP53wild-type status and MDM2 amplification. They also needed to have progressive or relapsed disease with no proven treatment available or have MDM2-amplified sarcomas requiring first-line treatment.

Key exclusion criteria included prior treatment with any MDM2-p53 or MDMX-p53 antagonist, a known TP53mutation, or symptomatic brain metastases.

The phase 1a dose-escalation portion of the trial enrolled approximately 40 patients with locally advanced/metastatic solid tumors. Patients in arm A received oral BI 907828 on day 1 of each 21-day cycle, and those in arm B were given the agent on days 1 and 8 of each cycle. This portion of the study identified 45 mg once every 3 weeks as the recommended dose for in the expansion phase.

Within the expansion phase, patients with TP53 wild-type, MDM2-amplified sarcomas in any line of treatment were enrolled into cohort 1, where they received the recommended dose of BI 907828 once every 3 weeks. Cohort 2 included patients with other TP53 wild-type, MDM2-amplified solid tumors, including non–small cell lung cancer, gastric cancer, urothelial cancer, pancreatic cancer, and biliary tract cancer, who would receive BI 907828 in the second-line setting or later at the recommended dose.

PFS per RECIST v1.1 criteria served as the primary end point of the study. Secondary end points included ORR, as well as rates of any-grade TRAEs and grade 3 or higher TRAEs.

As of the data cutoff date of July 31, 2022, 107 patients with solid tumors received BI 907828 across all dose levels. Thirty-nine of these patients had DDLPS, including 30 who received 45 mg of BI 907828 once every 3 weeks. All patients with DDLPS were included in the analysis presented at the meeting.

Among the 39 patients with DDLPS, the mean age was 58.4 years (range, 36-76), 59% were male, and 66.7% were Caucasian. The majority of patients had an ECOG performance status of 0 (56.4%). The median number of prior lines of systemic therapy received was 2 (range, 0-8).

As of data cutoff, 13 patients with DDLPS were still receiving treatment. Reasons for discontinuation included disease progression (n = 17), AEs (n = 5), patient withdrawal (n = 3), and other (n = 1).

Additional safety data showed that the most common any-grade and grade 3 or higher TRAEs included nausea (76.9%; 5.1%), fatigue (51.3%; 5.1%), vomiting (46.2%; 2.6%), decreased appetite (33.3%; 2.6%); diarrhea (28.2%; 0%), thrombocytopenia (28.2%; 20.5%), anemia (25.6%; 10.3%), and neutropenia (23.1%; 7.7%).

Notably, thrombocytopenia was not associated with bleeding, and patients typically recovered within 1 to 3 weeks. Thrombocytopenia was also with most common serious AE, occurring in 10.3% of patients.

Based on results from the phase 1 trial, BI 907828 is being compared with doxorubicin as first-line treatment for patients with advanced DDLPS in the ongoing phase 2/3 Brightline-1 trial (NCT05218499).

Editor’s note: Dr Schöffski reported receiving financial and institutional research funding from CoBioRes NV, Eisai, G1 Therapeutics, PharmaMar, Genmab, Marck, Sartar Therapeutics, and ONA Therapeutics; and serving in a consulting or advisory role for Deciphera, Ellipses Pharma, Transgene, Exelixis, Boehringer Ingelheim, Studiecentrum voor Kernenergie, SQZ Biotechnology, Adcendo, PharmaMar, and Merck Healthcare KGaA.

References

1. Schöffski P, Yamamoto N, Bauer TM, et al. A phase Ia/b, dose-escalation and expansion study evaluating the MDM2–p53 antagonist BI 907828 in patients with solid tumours: Safety and efficacy in patients with dedifferentiated liposarcoma (DDLPS). Ann Oncol. 2023;8(suppl 3):101026. doi:10.1016/esmoop/esmoop101026
2. Zhao Y, Yu H, Hu W. The regulation of MDM2 oncogene and its impact on human cancers. Acta Biochim Biophys Sin (Shanghai). 2014;46(3):180-189. doi:10.1093/abbs/gmt147
3. Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res. 1998;26(15):3453-3459. doi:10.1093/nar/26.15.3453
4. Asano N, Yoshida A, Mitani S, et al. Frequent amplification of receptor tyrosine kinase genes in well differentiated/dedifferentiated liposarcoma. Oncotarget. 2017;8(8):12941-12952. doi:10.18632/oncotarget.14652