The first patient enrolled in the clinical trial of the innovative drug MDM2-p53 antagonist in the treatment of dedifferentiated liposarcoma in China

On January 5, 2023, Boehringer Ingelheim announced that its innovative drug MDM2-p53 antagonist BI 907828 for the first-line treatment of dedifferentiated liposarcoma (DDLPS) Phase II.
/III clinical trial Brightline-1 (registration number: CTR20222584) was successfully enrolled in the first DDLPS patient
in West China Hospital of Sichuan University 。 Brightline-1 is a randomized, open-label, global multicenter phase II/III clinical trial to compare the efficacy and safety of BI 907828 with doxorubicin as first-line therapy in patients with advanced DDLPS, the Chinese principal investigator (leading PI) is Professor
Zhang Xing of Sun Yat-sen University Cancer Center Prevention and Treatment.

Figure 1 Screenshot of the drug clinical trial registration and information disclosure platform of the Center for Drug Evaluation (NMPA) of the National Medical Products Administration^[1].

"Forgotten cancer" - sarcoma is facing many difficulties

Sarcoma is a rare malignancy that occurs in connective tissues such as bone, cartilage, muscle, nerves, blood vessels, and fat and fibrous tissue, accounting for approximately 1% of all cancers worldwide ^[2].

87.
3% of sarcomas occur in soft tissues, such as muscle, nerve, blood vessels, fat and fibrous tissues, these are called soft tissue sarcomas (STS), there are many subtypes, liposarcoma (LPS) is one of the most common subtypes; Another 12.
7% of sarcomas are osteosarcomas, mostly from bone, but also from cartilage ^[3].

According to the National Cancer Institute's (NCI) SEER database, the overall incidence of sarcomas is less than 5 per 100,000 per year
.

The rarity of sarcomas and insufficient awareness of the disease by clinicians delay accurate diagnosis and subsequent standard treatment
.
Most sarcoma patients are diagnosed with advanced disease and treatment options are scarce – chemotherapy has been the mainstay of treatment
for nearly 50 years.
DDLPS is a highly aggressive LPS subtype, with a recurrence rate of 40%-75% and a metastasis rate of 10%-15%, which is significantly higher than that of other LPS subtypes
.
At the same time, DDLPS chemotherapy is less effective, and these patients urgently need more effective and less toxic treatment regimens
.

The MDM2-p53 antagonist BI 907828 is an orally administered small molecule compound that inhibits interactions
between MDM2 and p53 proteins.
P53 is a tumor suppressor that drives tumor cell death, while MDM2 is the main negative regulator of p53, which can bind to p53 and promote its clearance, and MDM2 gene amplification is the most common genetic alteration in DDLPS, present in 90% of DDLPS cases, laying the foundation for the
wide application of BI 907828 in DDLPS.

Figure 2 Schematic diagram of the mechanism of action of BI 907828

BI 907828 holds the promise to revolutionize the treatment of cancer patients driven by mutations in the MDM2-p53 axis

BI 907828 has shown initial potential in the treatment of DDLPS, and at the 2022 European Society of Medical Oncology (ESMO) Congress, BI 907828 in the treatment of TP53 wild-type, MDM2-amplified solid tumor patients with dose expansion phase I.
b study data showed that the disease control rate (DCR) of BI 907828 against DDLPS was 93%, of which 2 patients achieved partial response (PR) and 5 patients with DDLPS achieved progression-free survival (PFS) > 10.
5 months, and adverse reactions were safe and controllable^[4].

Professor Zhang Xing of Sun Yat-sen University Cancer Prevention and Treatment Center said: "The official launch of BI 907828 phase II/III clinical trial is of great significance, bringing new hope to DDLPS patients in China, enabling patients with these rare tumors to access the first/breakthrough treatment methods and drugs
in the first time 。 In addition, with the help of Boehringer Ingelheim's clinical research cooperation project, Chinese clinical researchers can carry out R&D plans and clinical trials with the global standard of 'zero day difference', which is of self-evident significance to the promotion of clinical research of drugs in China - while improving the clinical research capabilities of Chinese researchers, it also actively promotes the progress of trials in China, so that more Chinese DDLPS patients can use innovative drugs
as soon as possible.
”

Professor Jiang Yu of West China Hospital of Sichuan University said: "DDLPS patients have long lacked effective treatment methods, and the emergence of BI 907828 has undoubtedly opened a 'new door'
for these patients 。 BI 907828 has shown encouraging therapeutic potential in phase I.
b trials, and the successful enrollment of this first patient in our hospital marks that Chinese patients can benefit from innovative drugs earlier, the needs of Chinese patients can be reflected in the R&D plan earlier, and Chinese data can be applied to the clinic in the first time, and I am looking forward to the clinical benefits of BI 907828 bringing clinical benefits
to more patients.
" ”

Dr.
Wei Zhang, Head of Medicine and R&D at Boehringer Ingelheim China, said: "We are pleased to see the phased progress of the Phase II/III clinical trial of BI 907828, successfully enrolling the first patient
in China.
Early efficacy data from BI 907828 has shown potential, and based on evidence-based medical evidence and clinical need, the U.
S.
Food and Drug Administration (FDA) has granted BI 907828 orphan drug designation for the treatment of soft tissue sarcoma, including DDLPS
.
This Brightline-1 study China is another extension of
the 'China Key' project, which enables Chinese patients, Chinese researchers, and Chinese treatment centers to participate in global early-stage research.
" 。 Based on the global strategy of 'Winning in Oncology', Boehringer Ingelheim is actively deploying the oncology drug pipeline, continuously optimizing existing tumor treatment methods and striving to develop innovative therapies, and hopes to work together with Chinese researchers to accelerate the progress of the trial, and ultimately benefit the trial results to patients
around the world.
" ”

[1].
retrieved from

style="margin-bottom: 0px;white-space: normal;line-height: 1.
75em;">[2].
DOI: 10.
1200/PO.
18.
00261 JCO Precision Oncology - published online October 19, 2018

[3].
Burningham, Z.
, Hashibe, M.
, Spector, L.
et al.
The Epidemiology of Sarcoma.
Clin Sarcoma Res 2, 14 (2012).

[4].
Annals of Oncology (2022) 33 (suppl_7): S197-S224.
10.
1016/annonc/annonc1049