Javier Martin-Broto, MD, PhD, medical oncologist, the University Hospital, leader, Villalba General Hospital, discusses future research directions of soft tissue sarcoma.

Targeted therapy could soon be part of the treatment paradigm for synovial sarcoma for the first time in the form of BRD9 inhibitors, Martin-Broto says, adding that an ongoing phase 1 trial (NCT04965753) is investigating FHD-609, a BRD9 inhibitor, in patients with advanced synovial sarcoma.

For patients with chondrosarcoma, DR5 agonists are under investigation, which could provide a key development for a patient population that is historically resistant to chemotherapy, Martin-Broto adds. Moreover, the addition of selinexor to chemotherapy has shown promise in specific subsets of sarcoma, Martin-Broto explains.

With the emergence of some potential targeted therapies, there is hope for improvements to the treatment landscape across soft tissue sarcomas in the coming years, Martin-Broto concludes.

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Javier Martin-Broto, MD, PhD, discusses future research directions of soft tissue sarcoma.


Dr. Martin-Broto on Future Research Directions of Soft Tissue Sarcoma

Articles

Exploring the Interaction of MDM2 and p53 in Soft Tissue Sarcomas

Jean-Yves Blay, MD, professor of Medicine, Université Claude Bernard, scientific director, Canceropole Lyon Rhône Alpes, vice chairman, EORTC Translational Research Advisory Committee, member, the Protocol Review Committee of EORTC, chairman, the Soft Tissue and Bone Sarcoma group of EORTC, the French Sarcoma Group, discusses treatment considerations in patients with soft tissue sarcomas.

Neoadjuvant plus adjuvant treatment is recommended for a small fraction of patients with specific characteristics in soft tissue sarcomas, Blay says. However, debates are ongoing about which patients could most benefit from neoadjuvant treatment, Blay adds. For example, patients with large grade 2 and 3 tumors may benefit from neoadjuvant therapy, which typically consists of doxorubicin plus ifosfamide (Ifex), Blay explains.

In the first-line setting for metastatic or relapsed disease, doxorubicin-based therapy is also recommended, Blay continues. Doxorubicin plus dacarbazine can be used for patients with leiomyosarcoma due increased response rates, progression-free survival rates, and overall survival, Blay explains. However, these benefits need to be tested in a randomized clinical trial, Blay concludes.

Jean-Yves Blay, MD, discusses treatment considerations in patients with soft tissue sarcomas.


Dr. Blay on Treatment Considerations in Soft Tissue Sarcomas

Patricia LoRusso, DO, professor of Medicine (Medical Oncology), associate cancer center director, Experimental Therapeutics, Yale School of Medicine, discusses the benefit of genetic sequencing in soft tissue sarcomas.

Because there are many different subtypes of sarcomas, it is a unique disease, LoRusso says. Oftentimes, this can create a challenge for clinicians to identify the exact subtype of a specific patient’s sarcoma, LoRusso adds. However, genetic sequencing of tumors has helped better identify sarcoma subtypes, and this can be done along with other routine pathologic assays that are conducted for patients, LoRusso explains.

-amplified dedifferentiated soft tissue sarcomas, there is not a preferred standard of care, though anthracycline is considered one of primary treatments, LoRusso continues. However, these patients have limited treatment options, and they are often referred to an early phase clinical trial, LoRusso concludes.

Patricia LoRusso, DO, discusses the benefit of genetic sequencing in soft tissue sarcomas.


Dr. LoRusso on the Benefit of Genetic Sequencing in Sarcomas

Javier Martin-Broto, MD, PhD, medical oncologist, the University Hospital, leader, Villalba General Hospital, discusses the current treatment landscape in the first-line setting for soft tissue sarcomas.

The first-line treatment for patients with soft tissue sarcomas remains doxorubicin alone or in combination with ifosfamide (Ifex), and dacarbazine can be added for patients with leiomyosarcoma, Martin-Broto says. Though new treatments have emerged for the second line and beyond, an unmet need remains in the first-line setting, Martin-Broto explains.

A few targeted therapies have been developed for some soft tissue sarcomas; however, due to the vast number of subtypes of sarcoma, current targeted therapies may only be applicable for around 15% of all patients with soft tissue sarcomas, Martin-Broto continues.

Investigators are evaluating targeted therapies or synergistic combinations with chemotherapy to provide other first-line treatment options for more patients with soft tissue sarcoma, Martin-Broto adds. Correlative studies and prospective trials are required to deliver meaningful improvement to the first-line standard of care in soft tissue sarcoma, Martin-Broto concludes.

Javier Martin-Broto, MD, PhD, discusses the current treatment landscape in the first-line setting for soft tissue sarcomas.


Dr. Martin-Broto on the Current First-Line Treatment of Soft Tissue Sarcomas

Javier Martin-Broto, MD, PhD, medical oncologist, the University Hospital, leader, Villalba General Hospital, discusses the role of MDM2 amplification and p53 inactivation in patients with soft tissue sarcoma.

MDM2 amplification is commonly seen in specific subtypes of soft tissue sarcoma, such as well-differentiated and dedifferentiated liposarcoma, which are some of the most common sarcoma subtypes, Martin-Broto says. The amplification of an extra chromosome is present in these subtypes of sarcomas, leading to patients with well-differentiated and dedifferentiated liposarcomas to experience the inactivation of p53, Martin-Broto explains.

When MDM2 is amplified, it causes the inactivation of p53, which plays a key role in controlling the cell, Martin-Broto continues. This is an underlying mechanism that makes targeted treatments vital for patients with soft tissue sarcomas, Martin-Broto concludes.

Javier Martin-Broto, MD, PhD, discusses the role of MDM2 amplification and p53 inactivation in patients with soft tissue sarcoma.


Dr. Martin-Broto on MDM2 and P53 in Soft Tissue Sarcoma

Javier Martin-Broto, MD, PhD, medical oncologist, the University Hospital, leader, Villalba General Hospital, discusses the ongoing research of MDM2 agonists in patients with soft tissue sarcoma.

It is difficult to make arguments for or against MDM2 inhibitors currently under investigation in phase 3 trials for patients with sarcoma, Martin-Broto says. The first MDM2 agonist to release positive information is milademetan, which is being evaluated vs trabectedin in the phase 3 MANTRA trial (NCT04979442) in patients with dedifferentiated liposarcoma, Martin-Broto explains. Other MDM2 agonists, including BI 907828, are being explored, Martin-Broto continues. The phase 2/3 Brightline-1 trial (NCT05218499) is exploring BI 907828 vs doxorubicin in patients with dedifferentiated liposarcoma.

It may eventually be beneficial to evaluate MDM2 agonists in head-to-head comparative clinical trials, Martin-Broto adds. These agents all carry different affinity and safety profiles, and it remains too early to draw a conclusion as to which could provide the most benefit for patients, Martin-Broto concludes.

Javier Martin-Broto, MD, PhD, discusses the ongoing research of MDM2 agonists in patients with soft tissue sarcoma.


Dr. Martin-Broto on the Ongoing Research of MDM2 Agonists in Soft Tissue Sarcoma

Amplification of murine double minute 2 (MDM2) represents a promising target to access the so-called cellular gatekeeper p53 protein in human cancers.

 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 

. “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.

 Standard treatment options for this population include surgery, radiation, or chemotherapy leveraging doxorubicin.

 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.

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.

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.

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.

 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.

Patients with previously treated solid tumors with 

 wild-type status are being included in the study. Ineligible patients include those with active or untreated brain metastases, documented 

 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.

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.

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.

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%).

“[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).

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.

 “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 

 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 

 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.

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.

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.

“[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.”

Zhao Y, Yu H, Hu W. The regulation of MDM2 oncogene and its impact on human cancers. 

 2014;46(3):180-189. doi:10.1093/abbs/gmt147

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. 

. 2022;72(1):7-33. doi:10.3322/caac.21708

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

Wang S, Zhao Y, Aguilar A, Bernard D, Yang CY. Targeting the MDM2-p53 protein-protein interaction for new cancer therapy: progress and challenges. 

. 2017;7(5):a026245. doi:10.1101/cshperspect.a026245

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. 

. 2018;9(69):33232-33243.doi:10.18632/oncotarget.26075

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. 

. 2021;39(suppl 15):3016. doi:10.1200/JCO.2021.39.15_suppl.3016

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

MDM2-p53 antagonist. Boehringer Ingelheim. Accessed May 23, 2022. bit.ly/3MKgBUS

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

MDM2 Pulls Novel Treatments Into Focus for Underserved Liposarcoma Population

Patricia LoRusso, DO, professor of Medicine (Medical Oncology), associate cancer center director, Experimental Therapeutics, Yale School of Medicine, discusses the importance of clinical trial enrollment for patients with 

-amplified dedifferentiated liposarcoma, enrolling them in a clinical trial for an MDM2 inhibitor, such as BI 907828, at a site that has a clinical trial opened, would be an ideal treatment approach, LoRusso explains. BI 907828 is an important drug for this particular tumor type with an 

 alteration, LoRusso adds. Moreover, BI 907828 demonstrated efficacy in a prior phase 1 trial (NCT03449381), and the soft tissue sarcoma community should be alerted to this drug, LoRusso says. 

BI 907828 is now under further investigation in the phase 2/3 Brightline-1 trial (NCT05218499) in patients with dedifferentiated liposarcoma. Patients with this 

 amplifications could benefit from enrollment, LoRusso concludes. 

Patricia LoRusso, DO, discusses the importance clinical trial enrollment for patients with MDM2-amplified dedifferentiated liposarcoma.


Dr. LoRusso on the Importance of Clinical Trials in MDM2-Amplified Dedifferentiated Liposarcoma

Jean-Yves Blay, MD, professor of Medicine, Université Claude Bernard, scientific director, Canceropole Lyon Rhône Alpes, vice chairman, EORTC Translational Research Advisory Committee, member, the Protocol Review Committee of EORTC, chairman, the Soft Tissue and Bone Sarcoma group of EORTC, the French Sarcoma Group, discusses current treatment challenges in soft tissue sarcomas.

In France, patients with sarcomas or suspected sarcomas are required to undergo a pathology review for soft tissue sarcomas, and this practice has been in place for about 10 years, Blay says. Under this system, all diagnoses of soft tissue sarcoma undergo review and confirmation by an expert pathologist, Blay explains. Each diagnosis also undergoes surgical review and genomic testing when needed, Blay adds.

Because of this process, the main challenge in the soft tissue sarcomas remains in the referral of patients for earlier management of their disease, which is not mandatory, Blay explains. Despite an increase in the quality of care available for these patients, the proportion of patients who are reaching oncologists at a referral center before the first treatment is limited to about 55%, Blay continues. Those 55% of patients tend to have better outcomes than those who are not referred, and more must be done to address the patient population, Blay concludes. 

Jean-Yves Blay, MD, discusses current treatment challenges in soft tissue sarcomas.


Dr. Blay on the Current Treatment Challenges in Soft Tissue Sarcomas

Patricia LoRusso, DO, professor of Medicine (Medical Oncology), associate cancer center director, Experimental Therapeutics, Yale School of Medicine, discusses the efficacy observed of BI 907828 in solid tumors in a phase 1 trial (NCT03449381).

This study evaluated adult patients with different types of advanced solid tumors to find the preferred dose of BI 907828.

Results from this trial showed patients achieved responses and a prolongation of stable disease, LoRusso says. Notably, the responses observed were durable, LoRusso adds.

In patients with MDM2 amplification, BI 907828 generated responses, regardless of the dosage administered or the schedule of treatment, LoRusso adds.

The low dose and high dose of BI 907828 will be further explored in the phase 2/3 Brightline-1 trial (NCT05218499) in patients with dedifferentiated liposarcoma, LoRusso concludes.

Patricia LoRusso, DO, discusses the efficacy observed of BI 907828 in solid tumors in a phase 1 trial.


Dr. LoRusso on the Efficacy of BI 907828 in Solid Tumors

Jean-Yves Blay, MD, professor of Medicine, Université Claude Bernard, scientific director, Canceropole Lyon Rhône Alpes, vice chairman, EORTC Translational Research Advisory Committee, member, the Protocol Review Committee of EORTC, chairman, the Soft Tissue and Bone Sarcoma group of EORTC, the French Sarcoma Group, discusses the exploration of BI 907828 in patients with sarcoma.

BI 907828 is an oral MDM2 inhibitor, and by binding to the MDM2 protein, the agent MDM2 from binding with the tumor suppressor protein, p53.

In preclinical studies, BI 907828 has demonstrated remarkable activity in terms of blocking specific interactions in the cellular pathways, Blay says. Clinical trials have started investigating BI 907828, including a phase 1 trial (NCT03449381) in adults with different types of solid tumors, including sarcomas, to evaluate the most suitable dose of BI 907828 and the agent’s efficacy in various populations.

Prior MDM2 inhibitors have shown the ability to block interactions with the MDM2 protein, though the blockade with BI 907828 appears to be more significant, Blay explains. The level of activity of BI 907828 in MDM2-amplfied tumors has been consistent across preclinical data, Blay adds.

BI 907828 has also displayed higher pharmodynamic activity than other MDM2 inhibitors, though there have been more higher toxicities, Blay notes. However, this agent warrants further investigation in clinical trials, and seeing these studies is good news for patients with these molecular alterations, Blay concludes. 

Jean-Yves Blay, MD, discusses the exploration of BI 907828 in patients with sarcoma.


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