P53 Antagonist Research Articles

Proteomic analysis in patients with dedifferentiated liposarcoma (DDLPS) in a phase Ia/Ib study of the MDM2–p53 antagonist brigimadlin.

Proteomic analysis in patients with dedifferentiated liposarcoma (DDLPS) in a phase Ia/Ib study of the MDM2–p53 antagonist brigimadlin.

A phase (Ph) 0/Ia study of brigimadlin concentration in brain tissue and a non-randomized, open-label, dose escalation study of brigimadlin in combination with radiotherapy (RT) in patients (pts) with newly diagnosed glioblastoma (GBM).

2017 Background: MDM2 inhibits tumor suppressor p53. Brigimadlin, a potent MDM2–p53 antagonist, restores wild-type (wt) p53 function and has shown early efficacy in pts with solid tumors (LoRusso et al Cancer Disc 2023). GBM is an area of unmet need with 5-year survival <10%. In p53 wt GBM pt-derived xenograft models, brigimadlin promotes tumor cell apoptosis and extends survival in combination with RT. Methods: NCT05376800 is a Ph 0/Ia open-label, single-arm trial that aims to measure brigimadlin concentration in brain tumor tissue in pts with histologically or radiologically newly diagnosed GBM eligible for resection (Ph 0) and determine the maximum tolerated dose of brigimadlin plus RT in pts with TP53wt, IDH wt, MGMT promoter unmethylated GBM (Ph Ia). In Ph 0, pts received one brigimadlin dose (30 mg or 45 mg) ~12–24 h before resection. Ph 0 primary endpoints are the measured total concentration and the calculated unbound concentration of brigimadlin in brain tissue homogenate from non-contrast enhancing (NCE) and contrast enhancing (CE) regions. The predefined threshold for trial continuation is 0.5 nmol/L (corresponding to IC50 in GBM cell lines) unbound brigimadlin in CE samples in ≥50% of pts. Brigimadlin concentration was measured using LC/MS and corrected for amount of brigimadlin in residual blood. Unbound concentration was calculated using an in vitro estimate of unbound fraction (fu): 0.654% (rat brain slice). fu in human plasma was 0.22%. Kp,uu (ratio of unbound concentration in brain vs plasma) was calculated. Biomarker testing was performed. Results: Data are available for 11 pts (brigimadlin 30 mg: n=6; 45 mg: n=5). In the 30 mg group, median total brigimadlin concentration in NCE samples was 267 nmol/L (4 samples, range 86–316 nmol/L) and 332 nmol/L (6 samples, range 272–952 nmol/L) in CE samples. In the 45 mg group, median total brigimadlin concentration in NCE samples was 197 nmol/L (5 samples, range 140–347 nmol/L) and 603 nmol/L (5 samples, range 441–905 nmol/L) in CE samples. Unbound concentration exceeded the 0.5 nmol/L threshold in most cases (Table). Post-brigimadlin, an increase in selected p53 target gene expression was observed in CE vs NCE tissue. Conclusions: Unbound brigimadlin concentrations in CE regions in all pts receiving the low dose of 30 mg brigimadlin exceeded the 0.5 nmol/L threshold. Kp,uu in most patients was close to 1 in CE regions. Biomarker data support target engagement in brain tissue. Our findings support continued investigation of brigimadlin in GBM. Recruitment is ongoing. Updated data will be presented. Clinical trial information: NCT05376800 . [Table: see text]

Treatment of patients with dedifferentiated liposarcoma (DDLPS) with the MDM2–p53 antagonist brigimadlin and p53 function: A longitudinal analysis of circulating microRNAs (miRNAs) in a first-in-human phase Ia/Ib study.

Treatment of patients with dedifferentiated liposarcoma (DDLPS) with the MDM2–p53 antagonist brigimadlin and p53 function: A longitudinal analysis of circulating microRNAs (miRNAs) in a first-in-human phase Ia/Ib study.

Ribosome subunit attrition and activation of the p53–MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the ‘WIN’ site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the 'WIN' site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

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.

487 Background: Outcomes remain poor for pts treated with standard-of-care chemotherapy for advanced biliary tract cancer (BTC). Hence, there is a clinical need for novel therapeutic strategies. One such emerging strategy is antagonism of mouse double minute 2 (MDM2), which is amplified in 5–8% of cases of BTC. Brigimadlin (BI 907828) is a MDM2–p53 antagonist that blocks the MDM2–p53 interaction, thereby restoring p53 activity and leading to cell-cycle arrest and apoptosis in TP53 wild-type tumors. Brigimadlin is currently being assessed in two Phase Ia/Ib dose-escalation/expansion trials in pts with advanced/metastatic solid tumors as monotherapy (NCT03449381) and in combination with an anti-PD-1 antibody, ezabenlimab (NCT03964233). Here, we present data in pts with advanced BTCs treated in these trials. Methods: Pts in the monotherapy trial received escalating doses of brigimadlin on day 1 of 21-day cycles (Q3W). Pts in the combination trial received escalating doses of brigimadlin and 240 mg ezabenlimab on day 1 Q3W (doublet); one pt also received the anti-LAG-3 antibody BI 754111 (which has since been discontinued; triplet). Results: At data cut-off (June 2023), a total of 16 pts with BTC have been enrolled (10 in the monotherapy and 6 in the combination trial). In the monotherapy trial, 9 pts received brigimadlin 45 mg Q3W and 1 received 80 mg Q3W. In the combination trial, 5 pts received 30 mg/45 mg brigimadlin doublet and 1 received 45 mg triplet. Across both trials, 7 pts with MDM2 -amplified tumors achieved partial response (PR), 3 in the monotherapy trial and 4 in the combination trial. In the monotherapy trial, the responding pts had intrahepatic cholangiocarcinoma (iCC; 80 mg, 73% tumor shrinkage, progression-free survival [PFS] 13.3 months), ampullary adenocarcinoma (45 mg, 72% tumor shrinkage, PFS censored at 666 days), and extrahepatic cholangiocarcinoma (45 mg, 68% tumor shrinkage, PFS censored at 164 days). In the combination trial, 3 responding pts had iCC (pt 1, 30 mg doublet, 54% tumor shrinkage, PFS 9.6 months; pt 2, 45 mg doublet, 49% tumor shrinkage, PFS 7.5 months; pt 3, 45 mg doublet, 39% tumor shrinkage, PFS censored at 5.5 months) and 1 had gallbladder cancer (45 mg doublet, 50% tumor shrinkage, PFS 7.9 months). A further 7 pts (5 in the monotherapy trial and 2 in the combination trial) achieved stable disease (SD). In both trials, the most common any-grade treatment-related AE (TRAE) was nausea; the most common grade ≥3 TRAEs were thrombocytopenia and neutropenia. Conclusions: Brigimadlin showed a manageable safety profile and encouraging preliminary efficacy in pts with BTC, with 7 PRs and 7 SDs in 16 pts. A Phase IIa/IIb trial of brigimadlin in patients with MDM2 -amplified, TP53 wild-type BTC and other solid tumors is ongoing (Brightline-2). Clinical trial information: NCT03449381 and NCT03964233 .

673P A phase I dose-escalation and expansion study evaluating the safety and efficacy of the MDM2–p53 antagonist brigimadlin (BI 907828) in patients (pts) with solid tumours

673P A phase I dose-escalation and expansion study evaluating the safety and efficacy of the MDM2–p53 antagonist brigimadlin (BI 907828) in patients (pts) with solid tumours

Tau protein binds to the P53 E3 ubiquitin ligase MDM2

Tau gene mutations cause a progressive dementia and neurotoxic Tau forms deposited in neurofibrillary tangles are hallmarks of neurodegenerative tauopathies. Loss of non-canonical Tau functions may contribute to disease. In fact, Tau depletion affects the cellular response to DNA damage and tauopathies exhibit the accumulation of DNA lesions. Moreover, Tau modulates P53 activity and cell fate. Considering that MDM2 is the main antagonist of P53, we investigated, using orthogonal assays, if Tau interacts with MDM2. We report the existence in cells and brain of a Tau-MDM2 complex that, in vitro, exhibits reduced P53 ubiquitination activity in a manner sensitive to a Tau mutation. The Tau-MDM2 interaction involves the microtubule-binding domain of Tau and the acidic domain of MDM2, reminiscent of the binding of Tau to negatively charged microtubules. Notably, MDM2 accumulates aberrantly in neurofibrillary tangles. Aging-associated insults may expose a novel loss-of-function of Tau in neurodegeneration and cancer.

A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients (pts) with solid tumors: Safety and efficacy in patients with dedifferentiated liposarcoma (DDLPS).

11554 Background: Inactivation of p53 is a key mechanism which promotes tumor survival and proliferation. p53 inactivation can be due to mutations in TP53 or downregulation of wild-type (wt) p53 by the key negative regulator mouse double-minute 2 (MDM2). BI 907828 is a highly potent MDM2–p53 antagonist which has demonstrated preclinical antitumor activity, particularly in TP53-wt MDM2-amplified DDLPS models. In this phase I study (NCT03449381), BI 907828 monotherapy is being evaluated in pts with advanced solid tumors, including DDLPS. During dose escalation (phase Ia), BI 907828 had a manageable safety profile and the selected recommended dose for expansion (RDE) was 45 mg q3w. Here we report safety data in all pts who received the RDE of 45 mg q3w and present efficacy data in the subgroup of pts with DDLPS. Methods: In Phase Ia, pts received one of two BI 907828 dosing schedules: Arm A, day 1 of 21-day cycles (q3w); Arm B, days 1 and 8 of 28-day cycles. During Phase Ib (dose expansion), pts were enrolled to Cohort 1 ( TP53wt, MDM2-amplified sarcoma) or Cohort 2 (other TP53wt, MDM2-amplified solid tumors). Here we focus on Cohort 1 (received BI 907828 45 mg q3w). The primary endpoint (phase Ib) was progression-free survival (PFS). Secondary endpoints/objectives included overall response rate (ORR) and grade ≥3 treatment-related AEs (TRAEs). Results: As of December 22, 2022, a total of 137 pts had been enrolled; 72 (52.6%) were male, 77 (56.2%)/59 (43.1%) had ECOG PS 0/1, and the median number of prior systemic therapies was 2 (range, 0–11). In the 73 pts who received the RDE of 45 mg q3w, the most common any-grade TRAEs were nausea (74.0%) and fatigue (61.6%). 33 (45.2%) pts had grade ≥3 TRAEs; the most common were thrombocytopenia (23.3%), neutropenia (21.9%), anemia (11.0%), and leukopenia (11.0%). 22 (30.1%) pts had TRAEs leading to dose reductions and 6 (8.2%) had TRAEs leading to treatment discontinuation. 20 pts (27.4%) had serious AEs; the most common were nausea, pulmonary embolism (each 4.1%), sepsis, small intestine obstruction, vomiting, thrombocytopenia, and pyrexia (each 2.7%). 50/73 pts who received 45 mg q3w had advanced DDLPS; all had MDM2-amplified disease. Of the 42 evaluable DDLPS pts, 8 achieved a confirmed PR (ORR 19.0%; locally assessed) and a further 29 achieved a best response of stable disease (including 2 with unconfirmed PR), giving a disease control rate of 88.1%. Preliminary median PFS was 8.1 months. Conclusions: BI 907828 demonstrated a manageable safety profile overall and encouraging preliminary efficacy was seen in pts with advanced MDM2-amplified DDLPS; Phase Ib is ongoing. BI 907828 is also being evaluated versus doxorubicin as first-line treatment for pts with advanced DDLPS in the ongoing Phase II/III Brightline-1 study (NCT05218499), for which the FDA has granted a Fast Track Designation. Clinical trial information: NCT03449381 .

A phase IIa/IIb, open-label trial of BI 907828, an MDM2–p53 antagonist, in patients with locally advanced/metastatic biliary tract carcinoma or pancreatic ductal adenocarcinoma: Brightline-2.

TPS4179 Background: Biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC) carry a median survival of one year in the advanced stages, and effective therapies are urgently needed. Mouse double minute 2 (MDM2) is amplified in ~5–6% of cases of BTC and ~1% of PDAC. MDM2, an E3 ubiquitin ligase, is an endogenous negative regulator of p53. Aberrations affecting MDM2 may drive oncogenesis, and indeed, preclinical as well as emerging clinical data suggest blocking MDM2 in TP53 wild-type tumors may be a potential therapeutic strategy. BI 907828 is an MDM2–p53 antagonist that binds to MDM2 and blocks its interaction with p53, thereby restoring p53 function, leading to cell-cycle arrest and apoptosis in TP53 wild-type tumor cells. In ongoing Phase I studies, BI 907828 has demonstrated initial signs of activity in selected advanced/metastatic solid tumors, including BTC and PDAC. Methods: Brightline-2 is a Phase IIa/IIb, open-label, single-arm, multicenter study (~60 sites) that aims to assess the efficacy, safety, and tolerability of BI 907828 monotherapy in patients with locally advanced, unresectable, or metastatic MDM2-amplified, TP53 wild-type BTC (adenocarcinoma histology; Cohort 1; n=~90) or PDAC (Cohort 2; n=~10) [NCT05512377]. Cohorts for other solid tumors may be added via protocol amendment. All patients will receive BI 907828 45mg orally once every 3 weeks. Key inclusion criteria include: ≥18 years of age; locally advanced/metastatic, histologically confirmed unresectable BTC/PDAC; progression or intolerance to standard therapies; local test indicating MDM2 amplification or MDM2 copy number ≥8 and TP53 wild-type (liquid biopsy not permitted); ≥1 measurable target lesion (RECIST v1.1); and ECOG PS 0/1. A key exclusion criterion is prior treatment with an MDM2–p53 antagonist. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is objective response rate (ORR; based on blinded central independent review). Secondary endpoints are duration of response, progression-free survival, overall survival, disease control, occurrence of adverse events, and patient-reported health-related quality of life. In Phase IIa, an interim futility analysis will be performed after the initial 30 patients in Cohort 1 have either been followed for ≥12 weeks or have discontinued. If the cohort passes the non-binding interim futility boundary (ORR = 20%), the study will enter Phase IIb, and 60 additional patients will be enrolled onto Cohort 1, totaling 100 patients planned across Cohorts 1 and 2. The final primary analysis will be performed after all treated patients have been followed for ≥12 weeks or until study discontinuation. As of 13 December 2022, 1 patient has been enrolled. Clinical trial information: NCT05512377 .

P-56 Brightline-2: A phase IIa/IIb, open-label trial of the MDM2–p53 antagonist BI 907828 in patients with advanced MDM2-amplified, TP53 wild-type biliary tract cancer, pancreatic ductal adenocarcinoma, or other selected solid tumours

P-56 Brightline-2: A phase IIa/IIb, open-label trial of the MDM2–p53 antagonist BI 907828 in patients with advanced MDM2-amplified, TP53 wild-type biliary tract cancer, pancreatic ductal adenocarcinoma, or other selected solid tumours

Longitudinal mutational analysis of TP53 in plasma circulating tumor DNA (ctDNA) in patients (pts) with solid tumors in a phase I study of BI 907828, an MDM2–p53 antagonist.

3036 Background: Inactivation of p53 can occur due to TP53 mutations or downregulation of wild-type p53 by its primary negative regulator, MDM2. Targeting the MDM2–p53 interaction may therefore restore p53 function. BI 907828, a highly potent MDM2–p53 antagonist, is being evaluated in a phase Ia/b study in pts with advanced solid tumors (NCT03449381). During dose escalation (phase Ia), BI 907828 demonstrated a manageable safety profile and early signs of efficacy. Here we present data from a longitudinal mutational analysis of TP53 using ctDNA. The objective of the analysis was to identify if mutations in TP53 can be associated with possible acquired resistance to BI 907828. Methods: Collection of blood samples for ctDNA analyses was optional and sampled longitudinally from pts at baseline and every cycle until end of treatment (EoT). ctDNA was purified from plasma and analyzed using tumor-specific next generation sequencing (NGS; custom-made 8-gene panel using KAPA HyperCap technology, including TP53) to identify tumor-derived somatic mutations that may be relevant to understanding resistance mechanisms to BI 907828. The limit of detection was determined to be 0.5% mutant allele frequency; common polymorphisms were filtered out. Results: Plasma samples for ctDNA analysis were available from 44/54 (81%) pts enrolled to phase Ia. Baseline plasma samples from 26/54 (48%) pts and EoT samples from 41/54 (76%) pts were analyzed. Mutations were found in 6/26 (23%) samples at baseline. In 2 pt samples, mutations were found in both tumor and ctDNA, but concordant results were limited to 1 pt. At EoT, no (0) mutations were found in 16/41 (39%) samples, 1 mutation in 11/41 (27%), 2 mutations in 6/41 (15%), 3 mutations in 2/41 (5%) and 4 mutations in 6/41 (15%). No sample had more than 4 mutations. The most frequent mutation at EoT (in 9/41 [22%] samples) was R175H, a known p53 loss of function (LOF) mutation, followed by R248Q/W LOF (in 6/41 [15%) samples). Mutations in non- TP53 genes were detectable independent of TP53 mutation status, suggesting ctDNA was present in all samples. No clear association of induction of mutations could be identified for any BI 907828 dose or dosing schedule, treatment duration, or tumor type. 9/20 (45%) pts with no detectable mutations at baseline maintained wild-type TP53 status at EoT. Signs of efficacy were observed in pts with acquired TP53 LOF mutations, suggesting that these mutations have no effect on efficacy. Analysis of TP53 mutational status at EoT in conjunction with correlative clinical efficacy will be presented. Conclusions: This mutation analysis represents one of the most comprehensive assessments of longitudinal ctDNA by NGS for TP53 from a clinical trial of an MDM2–p53 antagonist. Preliminary data suggest that BI 907828 does not systematically lead to broad acquisition of resistance by inducing alterations in TP53. Clinical trial information: NCT03449381 .

The E2F4/p130 Repressor Complex Cooperates with Oncogenic ΔNp73α To Inhibit Gene Expression in Human Papillomavirus 38 E6/E7-Transformed Keratinocytes and in Cancer Cells.

Tumor suppressor p53 and its related proteins, p63 and p73, can be synthesized as multiple isoforms lacking part of the N- or C-terminal regions. Specifically, high expression of the ΔNp73α isoform is notoriously associated with various human malignancies characterized by poor prognosis. This isoform is also accumulated by oncogenic viruses, such as Epstein-Barr virus (EBV), as well as genus beta human papillomaviruses (HPV) that appear to be involved in carcinogenesis. To gain additional insight into ΔNp73α mechanisms, we have performed proteomics analyses using human keratinocytes transformed by the E6 and E7 proteins of the beta-HPV type 38 virus as an experimental model (38HK). We find that ΔNp73α associates with the E2F4/p130 repressor complex through a direct interaction with E2F4. This interaction is favored by the N-terminal truncation of p73 characteristic of ΔNp73 isoforms. Moreover, it is independent of the C-terminal splicing status, suggesting that it could represent a general feature of ΔNp73 isoforms (α, β, γ, δ, ε, ζ, θ, η, and η1). We show that the ΔNp73α-E2F4/p130 complex inhibits the expression of specific genes, including genes encoding for negative regulators of proliferation, both in 38HK and in HPV-negative cancer-derived cell lines. Such genes are not inhibited by E2F4/p130 in primary keratinocytes lacking ΔNp73α, indicating that the interaction with ΔNp73α rewires the E2F4 transcriptional program. In conclusion, we have identified and characterized a novel transcriptional regulatory complex with potential implications in oncogenesis. IMPORTANCE The TP53 gene is mutated in about 50% of human cancers. In contrast, the TP63 and TP73 genes are rarely mutated but rather expressed as ΔNp63 and ΔNp73 isoforms in a wide range of malignancies, where they act as p53 antagonists. Accumulation of ΔNp63 and ΔNp73, which is associated with chemoresistance, can result from infection by oncogenic viruses such as EBV or HPV. Our study focuses on the highly carcinogenic ΔNp73α isoform and uses a viral model of cellular transformation. We unveil a physical interaction between ΔNp73α and the E2F4/p130 complex involved in cell cycle control, which rewires the E2F4/p130 transcriptional program. Our work shows that ΔNp73 isoforms can establish interactions with proteins that do not bind to the TAp73α tumor suppressor. This situation is analogous to the gain-of-function interactions of p53 mutants supporting cellular proliferation.

Brightline-1: phase II/III trial of the MDM2-p53 antagonist BI 907828 versus doxorubicin in patients with advanced DDLPS.

Dedifferentiated liposarcoma (DDLPS) is a rare, aggressive liposarcoma associated with poor prognosis. First-line treatment for advanced/metastatic DDLPS is systemic chemotherapy, but efficacy is poor and toxicities substantial. Most DDLPS tumors have amplification of the MDM2 gene, which encodes a negative regulator of the p53 suppressor protein. BI 907828 is a highly potent, oral MDM2-p53 antagonist that inhibits the interaction between p53 and MDM2, thereby restoring p53 activity. BI 907828 has shown promising activity in preclinical studies and in a phase Ia/Ib study in patients with solid tumors, particularly those with DDLPS. This manuscript describes the rationale and design of an ongoing multicenter, randomized, phase II/III trial (Brightline-1; NCT05218499) evaluating BI 907828 versus doxorubicin as first-line treatment for advanced DDLPS.

42O 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)

42O 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)

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.

543 Background: Standard-of-care treatment for advanced biliary tract cancer (BTC) is chemotherapy and outcomes remain poor; hence, there is a clinical need for effective targeted treatments. As MDM2 is a negative regulator of the tumor suppressor p53, blocking the MDM2–p53 interaction is a potential antitumor strategy. Further, preliminary data indicate that MDM2 amplification is a negative prognostic marker in BTC. The MDM2–p53 antagonist BI 907828 has shown preclinical antitumor activity in a range of malignancies and is currently being assessed in two phase Ia/Ib dose-escalation/expansion trials in patients with advanced solid tumors: as monotherapy (NCT03449381) and in combination with an anti-PD-1 antibody, ezabenlimab (NCT03964233). Here, we present data for patients with advanced BTCs in these trials. Methods: Patients in the monotherapy trial received escalating doses of BI 907828 on day 1 of 21-day cycles (q3w). Patients in the combination trial received escalating doses of BI 907828 and 240 mg ezabenlimab q3w (doublet); one patient also received the anti-LAG-3 antibody BI 754111 (a drug that has since been discontinued; triplet). Results: A total of 8 patients with BTC were enrolled in the 2 trials, 4 in the monotherapy trial and 4 in the combination trial. In the monotherapy trial, 2 patients had ampullary carcinoma (both received BI 907828 45 mg q3w), and 2 had cholangiocarcinoma (CC; 1 received BI 907828 45 mg q3w and 1 with intrahepatic CC [iCC] received 80 mg q3w). In the combination trial, 3 patients with iCC received 30 mg/45 mg BI 907828 doublet or 45 mg triplet, and 1 with gallbladder carcinoma (GBC) received BI 907828 45 mg doublet. Across both trials, 5 patients achieved PR, 2/4 in the monotherapy trial and 3/4 in the combination trial. In the monotherapy trial, the responding patients had iCC (80 mg q3w; MDM2-amplified; 73% tumor shrinkage; PFS event at 404 days) and ampullary adenocarcinoma (45 mg q3w; MDM2-amplified; 51% tumor shrinkage; ongoing, PFS censored at 255 days). In the combination trial, all 3 responding patients had MDM2-amplified biliary tract adenocarcinoma (2 iCC, 1 GBC); tumor shrinkage was 49–54%; PFS was 162–241 days. A further 2 patients (1 in each trial) achieved stable disease (SD). In the monotherapy trial, most common grade ≥3 treatment-related AEs (TRAEs) were thrombocytopenia, decreased white blood cell (WBC) count and neutropenia (2 patients each). In the combination trial, most common grade ≥3 TRAEs were anemia and decreased WBC count (3 patients each), neutropenia and thrombocytopenia (2 patients each). Conclusions: The MDM2–p53 antagonist BI 907828 has shown a manageable safety profile and encouraging preliminary efficacy in patients with BTC, with 5 PRs and 2 SD in 8 patients. A phase IIa/IIb trial of BI 907828 (45 mg q3w) in patients with BTC is planned to start recruitment at the end of 2022 (NCT05512377). Clinical trial information: NCT03449381 and NCT03964233 .

452O A phase I dose-escalation and expansion study evaluating the safety and efficacy of the MDM2–p53 antagonist BI 907828 in patients (pts) with solid tumours

BI 907828, a highly potent mouse double minute-2 (MDM2)–p53 antagonist, has demonstrated preclinical antitumour activity, particularly in TP53 wild-type (wt), MDM2-amplified dedifferentiated liposarcoma (DDLPS) models. This phase I study is evaluating BI 907828 in pts with advanced solid tumours. During dose-escalation (phase Ia), the selected recommended dose for expansion (RDE) was 45 mg q3w (Gounder M, 2021).

Glimmers of Hope for Targeting p53.

In two ongoing phase I trials, PC14586, a Y220C-selective structural corrector of mutant p53, and BI 907828, an MDM2-p53 antagonist, appear safe and tolerable, showing signs of efficacy. These emerging data offer hope that a key tumor suppressor may not be as undruggable as previously thought.

Histone Demethylase JMJD2D: A Novel Player in Colorectal and Hepatocellular Cancers.

Simple SummaryHistone demethylase JMJD2D is a multifunctional epigenetic factor coordinating androgen receptor activation, DNA damage repair, DNA replication, cell cycle regulation, and inflammation modulation. JMJD2D is also a well-established epigenetic facilitator in the progression of multiple malignant tumors, especially in colorectal cancer (CRC) and hepatocellular cancer (HCC). This review aims to summarize the mechanisms of JMJD2D in promoting CRC and HCC progression, which provides novel ideas for targeting JMJD2D in oncotherapy. JMJD2D promotes gene transcription by reducing H3K9 methylation and serves as a coactivator to enhance the activities of multiple carcinogenic pathways, including Wnt/β-catenin, Hedgehog, HIF1, JAK-STAT3, and Notch signaling; or acts as an antagonist of the tumor suppressor p53.Posttranslational modifications (PTMs) of histones are well-established contributors in a variety of biological functions, especially tumorigenesis. Histone demethylase JMJD2D (also known as KDM4D), a member of the JMJD2 subfamily, promotes gene transcription by antagonizing H3K9 methylation. JMJD2D is an epigenetic factor coordinating androgen receptor activation, DNA damage repair, DNA replication, and cell cycle regulation. Recently, the oncogenic role of JMJD2D in colorectal cancer (CRC) and hepatocellular cancer (HCC) has been recognized. JMJD2D serves as a coactivator of β-catenin, Gli1/2, HIF1α, STAT3, IRF1, TCF4, and NICD or an antagonist of p53 to promote the progression of CRC and HCC. In this review, we summarize the molecular mechanisms of JMJD2D in promoting the progression of CRC and HCC as well as the constructive role of its targeting inhibitors in suppressing tumorigenesis and synergistically enhancing the efficacy of anti-PD-1/PD-L1 immunotherapy.

A phase II/III, randomized, open-label, multicenter study of BI 907828 compared to doxorubicin in the first-line treatment of patients with advanced dedifferentiated liposarcoma (DDLPS): Brightline-1.

TPS11586 Background: The standard of care in the first-line treatment of patients (pts) with unresectable/metastatic DDLPS is doxorubicin, despite only moderate efficacy and many associated adverse events (AEs). BI 907828 is a mouse double minute 2 (MDM2)–p53 antagonist that binds to MDM2 and blocks its interaction with p53, leading to p53 stabilization, TP53 target gene induction, cell-cycle arrest and apoptosis in TP53 wild-type tumor cells. In a Phase I study, BI 907828 monotherapy demonstrated a manageable safety profile and preliminary signs of efficacy, particularly in pts with DDLPS (Gounder et al, ESMO 2021). Methods: NCT05218499 is a Phase II/III, randomized, open-label, international, multicenter study (̃125 sites) that aims to evaluate whether BI 907828 is superior to doxorubicin in the first-line treatment of advanced/metastatic DDLPS. In the Phase II part, ≤180 pts will be randomized 1:1:1 to receive BI 907828 30 mg or 45 mg orally every 3 weeks (q3w), or doxorubicin 75 mg/m2 intravenously q3w to a maximum cumulative dose of 450 mg/m2. Main inclusion criteria include: ≥18 years of age; histologically proven advanced/metastatic, unresectable DDLPS; positive MDM2 immunohistochemistry or amplification; ≥1 measurable target lesion (RECIST v1.1); and ECOG PS 0/1. Exclusion criteria include a known TP53 gene mutation and prior systemic therapy for liposarcoma. In the experimental arm, treatment will continue until disease progression, unacceptable AEs, or consent withdrawal. Pts who receive doxorubicin may cross-over to receive BI 907828 after confirmed progressive disease. The primary endpoint is progression-free survival (PFS; based on blinded independent central review), defined as the time from randomization to tumor progression (RECIST v1.1) or death from any cause, whichever occurs first. Secondary endpoints are objective response (OR), duration of OR, overall survival, disease control, and pt-reported health-related quality of life. In Phase II, an interim analysis (based on the totality of safety and PK/PD data) will be used to select the optimal BI 907828 dose. Subsequently, an interim futility analysis will be performed after ̃56 PFS events using a log-rank test stratified by the extent of disease (locally advanced vs metastatic). If the selected BI 907828 dose passes the futility boundary, the trial will proceed to Phase III. In the Phase III part, ≥120 additional pts will be randomized 1:1 to receive the selected BI 907828 dose or doxorubicin. The primary PFS analysis will be performed after ̃92 and ̃65 PFS events in pts enrolled before and after the interim futility analysis, respectively, using a weighted inverse normal method combining one-sided p-values from a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05218499.