Targeting MDM2 in Soft-Tissue Sarcomas (and Other Solid Tumors): The Revival?

Soft-tissue sarcomas (STS) are rare and diverse malignant tumors that originate from mesenchymal tissues. They account for less than 1% of adult malignancies and 12% of pediatric cancers. The World Health Organization's most recent classification of bone and soft-tissue tumors recognizes over 100 distinct subtypes of STS, each with its own histologic and biological characteristics (1).

Although surgical intervention remains the primary treatment for localized STS, up to 40% of patients will eventually develop metastatic disease. Advanced STS pose significant challenges in terms of treatment, with first-line systemic therapy, typically doxorubicin-based chemotherapy, showing limited improvements over the past 50 years. Recent trials involving patients with STS have reported a median progression-free survival (PFS) of 7 months and a median overall survival (OS) of approximately 18 months.

One reason for the lack of progress in STS treatment is the historical “one-size-fits-all” approach to clinical research, disregarding the considerable biological and clinical heterogeneity of these diseases. However, recent advancements in genomic and immunologic profiling have revealed opportunities for a precision medicine approach to enhance outcomes for patients with advanced STS (2, 3).

Targeting MDM2 represents one such opportunity. MDM2 is a protein that plays a crucial role in regulating the activity of the tumor suppressor protein p53. By binding to p53, MDM2 inhibits its activity and promotes its degradation, thus suppressing its tumor-suppressive functions. MDM2 amplification is a genetic hallmark of two distinct types of STS: well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS) and intimal sarcomas (1).

WDLPS, which accounts for over 40% of diagnosed liposarcomas, exhibits low metastatic potential but high rates of local recurrence (up to 90%) and dedifferentiation (up to 20%) in retroperitoneal and paratesticular cases (1). DDLPS, on the other hand, is a biphasic neoplasm composed of a WDLPS component and a nonlipogenic sarcoma component of varying histologic grades. DDLPS is more aggressive than WDLPS, with approximately 30% of cases experiencing distant metastatic relapse. Despite their moderate efficacy (objective response rate <10%; median PFS: 2–4 months; median OS: 8–12 months), anthracycline-containing regimens remain the primary first-line treatment for advanced WDLPS/DDLPS (4).

In this issue of Cancer Discovery, LoRusso and colleagues reported on the safety and preliminary activity of a new MDM2–p53 antagonist, BI 907828, in patients with advanced or metastatic solid tumors (5). The study included 54 patients in the dose-escalation phase, 19 of whom had WDLPS/DDLPS. The long half-life of BI 907828 (30–60 hours) allowed the investigators to explore intermittent schedules of oral administration once every 21 or 28 days. Like previous MDM2–p53 antagonists, the most common grade ≥3 treatment-related adverse events were hematologic, including thrombocytopenia and neutropenia. However, none of the patients had to discontinue treatment due to hematologic toxicity. Overall, the safety profile of BI 907828 appears manageable, and the authors attribute this to the compound's exceptionally long half-life, which allows for an intermittent schedule of administration and hematologic recovery between cycles. Pharmacodynamic target activity was demonstrated by the induction of GDF-15 (MIC-1) in plasma. Regarding efficacy, six out of 54 patients achieved a partial response, all of whom had MDM2-amplified tumors (four WDLPS/DDLPS, one biliary tract cancer, one pancreatic cancer). Among the 19 patients with WDLPS/DDLPS, 13 had some level of tumor shrinkage, and nine achieved PFS lasting more than 12 months. These results are promising, particularly when compared with previous studies with other TP53–MDM2 antagonists that showed only modest antitumor activity (6).

One possible explanation for the higher activity observed with BI 907828 compared with previous MDM2–TP53 antagonists may be attributed to the unique pharmacokinetics of this compound, characterized by a long half-life. This longer half-life may facilitate the management of hematologic toxicity and improve drug exposure. However, caution is necessary when interpreting the results from early-phase studies with a limited number of patients, especially considering the heterogeneous natural histories of WDLPS/DDLPS. Nonetheless, based on the results reported by LoRusso and colleagues, a randomized, open-label phase II/III study has been designed to evaluate the efficacy, safety, and tolerability of BI 907828 versus doxorubicin as the first-line systemic therapy for advanced or metastatic DDLPS. The study aims to randomize up to 180 patients in a 1:1:1 ratio to BI 907828 at 30 mg (first investigational arm), BI 907828 at 45 mg (second investigational arm), or doxorubicin (control arm). In the phase III part, at least an additional 120 patients will be randomized 1:1 to either the selected investigational arm or the doxorubicin control arm (i.e., 60 additional patients per arm). The primary endpoint will be PFS, with the ambitious objective of increasing PFS from 4 months with doxorubicin to 7.5 months for the selected BI 907828 arm (7).

In another article in this issue, Koyama and colleagues reported on the safety and activity of milademetan, another MDM2–p53 antagonist, in patients with intimal sarcoma (8). Intimal sarcoma is an extremely rare mesenchymal neoplasm that originates from large blood vessels and the heart (1). Despite its rarity, it is considered one of the most common primary cardiac histologies (1). Intimal sarcoma is classified as a high-grade tumor characterized by the amplification of the 12q12–15 region, which includes MDM2 (1). These molecular features suggest the involvement of this pathway in tumor development, making MDM2 inhibition a potential treatment approach for this disease. In this study involving 10 patients evaluable for response, two (20%) achieved an objective response, meeting the primary endpoint. The main expected adverse events included hematologic issues (thrombocytopenia and neutropenia) and nausea. Although the study's small sample size limits its conclusions to hypothesis generation, the authors should be commended for their work, which demonstrates the feasibility of prospective precision medicine studies even in ultrarare cancers.

Although these two studies appear promising, the development of TP53–MDM2 antagonists targeting MDM2 in sarcomas and other solid tumors faces several challenges. Despite the high levels of MDM2 gene amplification in WDLPS/DDLPS and intimal sarcomas, the clinical activity of TP53–MDM2 antagonists in these tumors remains somewhat modest compared with what is observed in other oncogene-addicted tumors treated with targeted agents. One explanation for the limited activity of TP53–MDM2 antagonists in solid tumors is the cross-talk with other pathways that can promote tumorigenesis. For example, TP53–MDM2 antagonists have been shown to paradoxically activate the MAPK pathway in preclinical models of DDLPS and other tumor types (9).

The narrow therapeutic index of TP53–MDM2 antagonists also limits their clinical development in combination with other anticancer agents, as demonstrated by studies investigating their combination with chemotherapy or small molecules (10, 11). However, combining them with immune-oncology agents, such as immune-checkpoint inhibitors, should not pose a challenge and is currently being explored in clinical settings given the immunomodulatory role of MDM2 and the potential synergy suggested by preclinical experiments (12).

The emergence of TP53 mutations under treatment with TP53–MDM2 antagonists may represent a concern. This phenomenon, initially described in preclinical models (13), has also been observed in the study by Koyama and colleagues in five patients at the time of progression. Whether these mutations play an important role in secondary resistance remains to be investigated.

Finally, it is important to consider that MDM2 plays numerous roles independent of TP53 that can promote tumorigenesis (14). In this regard, the new class of proteolysis-targeting chimeras (PROTAC) may represent a more attractive approach. PROTACs are heterobifunctional molecules composed of a targeting ligand and an E3 ubiquitin ligase recruiting ligand, which induce selective degradation of specific cellular proteins (15). Due to their catalytic activity, PROTACs are expected to be used at lower concentrations than small-molecule inhibitors, making them less toxic. The first-in-class MDM2 degrader KT-253 entered clinical development earlier this year (NCT05775406) and others will follow, allowing investigation of the safety and efficacy profile of this new class of agents in patients with cancer.

More than 10 years after the first clinical report of MDM2 targeting in patients (6), it is important to acknowledge that only modest progress has been made in this field. Whether this class of agents has the potential for registration in patients with cancer is still questionable. The recent announcement of the failure of milademetan to improve PFS compared with standard trabectedin in patients with advanced DLLPS enrolled in the phase III MANTRA study (16) highlights the need for innovative but careful clinical trials designed with realistic hypotheses.

A. Italiano reports grants, personal fees, and nonfinancial support from Roche, Merck, and Parthenon, grants and personal fees from Bayer, AstraZeneca, MSD, and Kymera Therapeutics, grants and non­financial support from Novartis, and grants from Bristol Myers Squibb and PharmaMar outside the submitted work.