MDM2 Pulls Novel Treatments Into Focus for Underserved Liposarcoma Population

Supplements And Featured Publications, Diagnosis and Trial Options in Sarcoma, Volume 1, Issue 1

Amplification of murine double minute 2 represents a promising target to access the so-called cellular gatekeeper p53 protein in human cancers.

Amplification of murine double minute 2 (MDM2) represents a promising target to access the so-called cellular gatekeeper p53 protein in human cancers.1 For individuals with limited treatment options including those with soft tissue sarcoma, MDM2-p53 antagonists may become the premier therapeutic option.

“There [is a lack] of standard of care for patients with soft tissue sarcomas that are MDM2 amplified,” Patricia LoRusso, DO, associate cancer center director of experimental therapeutics and a professor of medicine at the Yale School of Medicine in New Haven, Connecticut, said in an interview with OncologyLive®. “We know that an anthracycline such as [doxorubicin] is considered as one of the primary treatments [for this patient population]. Beyond that, however, there are not a lot of standards of care that work. Oftentimes those patients are referred to an early phase clinical trial.”

The incidence of soft tissue sarcoma for 2022 is estimated to exceed 13,000 new cases with approximately 5000 deaths.2 Standard treatment options for this population include surgery, radiation, or chemotherapy leveraging doxorubicin.3 In the setting of disease recurrence, 3 agents are approved for patients with liposarcoma: eribulin (Halaven), trabectedin (Yondelis), and pazopanib (Votrient); however, advances to introduce new agents in the first-line setting to offset the use of doxorubicin for this patient population have stalled.3

MDM2 is an oncogene that inhibits the activity of p53 through the formation of an autoregulatory feedback loop.1Specifically, the protein-protein interaction occurs via 3 key mechanisms of MDM2: (1) MDM2 leverages its E3 ubiquitin ligase activity to trigger degradation of p53, (2) MDM2 blocks the p53 from binding with targeted DNA and the protein becomes ineffective as a transcription factor, and (3) MDM2 promotes the translocation of p53 from the cell nucleus through its ability to bind to eh N-terminal of the protein.1,4

The overexpression of MDM2 and p53 mutations often occur together in human cancers, making the blockade of MDM2 an attractive target for investigators seeking to reactivate wild-type p53 in tumor cells. Among patients with sarcoma MDM2 is overexpressed or amplified in approximately 40% to 60% of cases, and up to 80% of well-differentiated liposarcomas.1,4,5

Efforts to develop small molecule MDM2 inhibitors are underway for patients with p53 wild-type disease including the investigational agent, BI 907828.

In preclinical studies, the MDM2/p53 agonist demonstrated antitumor efficacy in vivo in MDM2 amplified xenografts and syngeneic models derived from patients with liposarcoma.6 The favorable preclinical findings have led to the initiation of multiple phase 1 trials investigating BI 907828 in patients with multiple types of cancer.

MDM2/p53 Antagonist Displays Promising Early Results

In an ongoing phase 1 trial (NCT03449381), investigators are examining the safety, tolerability, and preliminary efficacy of BI 907828 in patients with advanced or metastatic solid tumors. Additionally, investigators are seeking to determine the maximum-tolerated dose (MTD) based on dose-limiting toxicities (DLTs) observed during the first cycle, as well as the pharmacokinetics, and pharmacodynamics of BI 907828.6

Patients with previously treated solid tumors with TP53 wild-type status are being included in the study. Ineligible patients include those with active or untreated brain metastases, documented TP53 mutation, or those who have been previously treated with an MDM2-p53 agonist.

The dose-escalation portion of the trial (phase 1a) is divided into 2 arms. In arm A patients receive BI 907828 on the first day of a 21-day cycle and in arm B patients receive the agent on days 1 and 8 of a 28-day cycle. The primary end point of phase 1a is MTD and secondary end points include pharmacokinetics, safety, and efficacy. In phase 1b, which is the dose-expansion phase, the primary end point is progression-free survival (PFS). Key secondary end points include safety, overall response rate (ORR), pharmacokinetics, and pharmacodynamics.6

As of the April 4, 2021, data cut-off, 54 patients with a median of 2 (range, 0-11) prior systemic therapies had received BI 907828. In arm A, 29 patients received a dose of BI 907828 ranging from 10 mg to 80 mg. In arm B, 25 patients were treated with doses ranging from 5 mg to 60 mg. Notably, 34.5% of patients in arm A and 48.0% of patients in arm B had soft tissue sarcomas.6

Other baseline characteristics were well-balanced; the median age in arm A was 59.1 years (range, 32-83) and 55.0 years (range, 19-75) in arm B. Most patients in arms A and B were men (55.2% vs 60.0%, respectively) and Caucasian (65.5% vs 72.0%). More patients in arm A (62.1%) had an ECOG performance status of 1 compared with 68.0% of patients in arm B who had an ECOG performance status of 0.

At the data cutoff, partial responses were achieved by 5 patients who received BI 907828. Responses were seen in 1 patient with a MDM2-amplified pancreatic adenocarcinoma, 1 patient with a biliary adenocarcinoma, and in 3 patients with MDM2-amplified, well-differentiated liposarcomas. Among the patients with liposarcomas who achieved a response, 1 patient at the 20-mg dose level in arm A remained stayed on treatment for over 2 years. Notably, 5 of 11 patients with dedifferentiated liposarcoma were progression free beyond 9 months with 3 patients having stable disease for more than 1 year.6

In terms of safety, 92.6% of patients experienced a treatment-related adverse effect (TRAE) of any grade and 33.3% of patients had a serious AE of any cause. Grade 3 TRAEs occurred in 29.6% of patients and investigators reported grade 4 TRAEs in 14.8% of patients. Common TRAEs of any grade included nausea (74.1%), vomiting (50%), thrombocytopenia (44.4%), and fatigue (40.7%).6

“[With this treatment], the gastrointestinal toxicities tend to be quite prevalent,” LoRusso said. “You must be aggressive [with] these toxicities [at onset]. Sometimes prophylaxis is the best medicine. If you can prevent the patient from having the toxicity to begin with, the tolerability will be there, and the patients will be less likely to come off study [and] they can be more likely to derive the greatest benefit possible.”

DLTs were mostly grade 3/4 hematologic AEs. Five patients in arm A experienced a DLT: patients at the 45-mg dose level had grade 3 nausea (n = 1) and grade 3 thrombocytopenia (n = 1), at the 60-mg dose there was one instance of grade 3 enterocolitis, and at the 80-mg dose there was one instance of grade 4 cytopenia and one instance of grade 4 thrombocytopenia. In arm B, there were 3 DLTs: 1 grade 4 thrombocytopenia (45 mg), 1 grade 4 neutropenia that was associated with grade 4 thrombocytopenia (60 mg), and a grade 3 neutropenia (60 mg).6

Investigators concluded that BI 907828 exhibited a manageable safety profile with early signs of efficacy, specifically calling attention to the results in patients with MDM2-amplified disease. The MTDs were determined to be 60 mg in arm A and 45 mg in arm B.

“I have been involved with [the development of] several other MDM2-targeted agents in the past [and] this drug had a quite long half-life [comparatively],” LoRusso noted. The reported geometric mean half-life after the first dose was 27.9 to 59.4 hours.6 “You could dose this drug relatively infrequently relative to some of the other MDM2-targeted drugs that I have worked with in the past that either require daily or every other day drug administration.”

Clinical Trials Push MDM2 to the Frontline

Considering the encouraging preclinical findings and phase 1 data in patients with solid tumors, investigators have initiated the phase 2/3 Brightline-1 trial (NCT05218499) to evaluate BI 907828 as a first-line treatment in adult patients with liposarcoma. The phase 2 portion of the trial will compare 2 dose levels of BI 907828 with standard-of-care doxorubicin. In the phase 3 portion, the efficacy and safety of BI 907828 monotherapy will be compared with doxorubicin.

The trial will enroll approximately 300 patients with unresectable, advanced, or metastatic dedifferentiated liposarcoma with confirmed MDM2 amplification. Eligible patients must have an ECOG performance status of 1 or less, adequate organ function, and be willing to provide blood samples for analysis. Patients with disease harboring a TP53 mutation who have received prior systemic therapy for liposarcoma, or those who are currently enrolled in another investigational device or drug trial will be excluded from enrollment.7

In phase 2, one arm will receive a low-dose tablet of BI 907828 (30 mg) with the second arm receiving a high-dose tablet (45 mg) once every 3 weeks. In phase 2 and phase 3, doxorubicin will be administered via intravenous infusion. Patients will be allowed to crossover into the BI 907828 if they are not benefitting from doxorubicin treatment and patients will continue treatment with BI 907828 if benefit is being observed and the treatment is tolerable.7,8

The primary end point of the study is PFS. Key secondary end points include ORR, duration of response, overall survival, and disease control rate. The trial is currently recruiting patients and is estimated to be completed in May 2026.7

“[In my opinion], you are doing your patient a great disservice by not recommending to them that they get this drug at a site that has the clinical trial opened,” LoRusso said. “This is an important drug for this tumor type. With this particular genomic alteration, this is exactly where we want to go with drug development. I really feel the soft tissue sarcoma community should be alerted to this drug. When patients have these type of soft tissue sarcomas with MDM2 amplification, it is important they have the opportunity to consider a clinical trial with an MDM2-targeted drug, especially a drug such as BI 907828.”

References

  1. 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
  2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. doi:10.3322/caac.21708
  3. PDQ Adult Treatment Editorial Board. Soft tissue sarcoma treatment (pdq): health professional version. National Cancer Institute. Updated January 19, 2022. Accessed May 23, 2022. bit.ly/3NtlzVR
  4. Wang S, Zhao Y, Aguilar A, Bernard D, Yang CY. Targeting the MDM2-p53 protein-protein interaction for new cancer therapy: progress and challenges. Cold Spring Harb Perspect Med. 2017;7(5):a026245. doi:10.1101/cshperspect.a026245
  5. Dembla V, Somaiah N, Barata P, et al. Prevalence of MDM2 amplification and coalterations in 523 advanced cancer patients in the MD Anderson phase 1 clinic. Oncotarget. 2018;9(69):33232-33243.doi:10.18632/oncotarget.26075
  6. LoRusso P, Gounder MM, Patel MR, et al. A phase I dose-escalation study of the MDM2-p53 antagonist BI 907828 in patients (pts) with advanced solid tumors. J Clin Oncol. 2021;39(suppl 15):3016. doi:10.1200/JCO.2021.39.15_suppl.3016
  7. Brightline-1: a study to compare BI 907828 with doxorubicin in people with a type of cancer called dedifferentiated liposarcoma. ClinicalTrials.gov. Updated May 17, 2022. Accessed May 23, 2022. https://clinicaltrials.gov/ct2/show/NCT05218499
  8. MDM2-p53 antagonist. Boehringer Ingelheim. Accessed May 23, 2022. bit.ly/3MKgBUS