Ascentage Pharma Presents Its First Dataset on MDM2-p53 Inhibitor Alrizomadlin (APG-115) in Pediatric Solid Tumors at ASCO 2026

Ascentage Pharma Presents Promising Alrizomadlin Data in Pediatric Solid Tumors at ASCO

Ascentage Pharma presented its initial clinical data for alrizomadlin (APG-115), an MDM2-p53 inhibitor, at the 2026 ASCO Annual Meeting. The data, from a multicenter trial in China, evaluated alrizomadlin as monotherapy or in combination with lisaftoclax (APG-2575) in heavily pretreated pediatric patients with relapsed/metastatic rhabdomyosarcoma (RMS) or other soft-tissue sarcomas (STSs). Results demonstrated preliminary antitumor activity and a manageable safety profile. Monotherapy achieved one complete response (CR) in a pediatric RMS patient. The combination regimen showed an objective response rate (ORR) of 23.5% among 17 evaluable patients, including one CR in Ewing sarcoma and three partial responses. Alrizomadlin has also been included in China's "SPARK Plan" for pediatric anti-tumor drug R&D.

• Alrizomadlin monotherapy demonstrated initial clinical benefit in pediatric rhabdomyosarcoma (RMS), with one heavily pretreated patient achieving a complete response (CR). This significant outcome highlights the drug's potential as a standalone treatment for this challenging pediatric cancer, addressing a critical unmet medical need.
• When combined with the investigational selective Bcl-2 inhibitor lisaftoclax, alrizomadlin showed encouraging antitumor activity. The combination achieved an objective response rate (ORR) of 23.5% among 17 response-evaluable pediatric patients, including one complete response in a patient with Ewing sarcoma and three partial responses. The disease control rate (DCR) was 70.6%, further supporting the therapeutic potential of dual-target combination approaches.
• Both alrizomadlin monotherapy and its combination with lisaftoclax exhibited a manageable safety profile in pediatric patients with solid tumors. Adverse events were primarily gastrointestinal and hematologic, with no dose-limiting toxicities (DLTs), treatment-related deaths, or discontinuations. Furthermore, alrizomadlin has been included in China's "SPARK Plan" for pediatric anti-tumor drug R&D, underscoring its potential and the urgent need it addresses.

Addressing Unmet Needs in Pediatric Solid Tumors

Current treatment approaches for pediatric solid tumors face significant challenges that distinguish them from adult cancers. These limitations stem from unique tumor biology, treatment resistance patterns, and the special considerations required when treating children with cancer.

• Tumor biology differences - Immunotherapies and targeted therapies show disappointing results in pediatric cohorts compared to adults, primarily due to extreme tumor heterogeneity and generally low tumor mutational burden

• Hostile tumor microenvironment - Limited efficacy of immunotherapeutic approaches results from scarcity of tumor-infiltrating T cells and abundance of stromal cells with lymphocyte suppressor and tumor-growth-promoting activity

• Treatment resistance in advanced disease - Resistance to intensive chemotherapy is common, with targets for molecular therapies largely undefined, and only a few pediatric patients having identifiable therapeutic targets

• Limited therapeutic options - For metastatic or recurrent solid tumors, external-beam radiotherapy utility is limited, and tumor-targeting radiopharmaceuticals for molecular radiotherapy are nonexistent or limited for most pediatric solid tumors

• Stagnant outcomes in high-risk cases - Recent survival improvements have been confined to low- and moderate-risk cancers, with minimal improvement observed in high-risk and advanced-stage childhood tumors

• Clinical trial challenges - Low participant numbers due to cancer rarity and heterogeneity limit the ability to conduct adequately powered studies, with most antiangiogenic drug studies including only small patient numbers or isolated cases

• Long-term toxicity concerns - Potential long-term effects have much stronger impact in children compared to adults, requiring careful balance between treatment benefits and complications that may affect lifelong development

• Access inequities - Persistent disparities in access to high-quality treatment and supportive care exist both in the United States and worldwide, limiting optimal outcomes for many patients

Alrizomadlin Shows Early Promise in Pediatric Sarcomas

Recent clinical trials in pediatric solid tumors have explored diverse therapeutic approaches, from risk-stratified chemotherapy regimens to novel targeted agents and immunotherapies. These studies provide valuable insights into both safety profiles and efficacy outcomes across different tumor types and treatment modalities.

United Kingdom Relapsed Wilms Tumour (UKW-R) Trial (2002-2008):
• Enrolled 78 children with relapsed/refractory Wilms tumour using risk-stratified interventions including intensive chemotherapy combinations and melphalan with autologous stem cell rescue for high-risk patients
• Demonstrated 4-year overall survival of 68% for the entire cohort, with Group A+B achieving 81% overall survival compared to 63% in the higher-risk Group C
• Reported no transplant-related mortality among 38 children receiving melphalan with autologous stem cell rescue, with all 25 deaths attributed to tumor progression rather than treatment toxicity

Phase I Carfilzomib with Cyclophosphamide and Etoposide Study:
• Evaluated a 5-day combination regimen in children, adolescents, and young adults with relapsed/refractory leukemia or solid tumors, establishing a recommended phase 2 dose of 36 mg/m² for solid tumor patients
• Identified maximum tolerated dose limitations in leukemia patients (11 mg/m²/day) due to thrombocytopenia, pericarditis, and posterior reversible encephalopathy syndrome
• Showed particular benefit in sarcoma patients, with the combination well-tolerated in solid tumor cohorts and 20 patients receiving multiple treatment cycles

CAR-T Cell Therapy Development Program:
• Demonstrated promising clinical activity in neuroblastoma and diffuse midline glioma through GD2 ganglioside targeting, and in pediatric sarcomas via Her2 targeting
• Established proof-of-concept across multiple pediatric malignancies including Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma using armored CAR-T cell approaches
• Identified novel target antigens including GPC2 and GPC3 as broadly expressed oncofetal surface antigens on pediatric solid and brain tumors

Alrizomadlin's Broader Development and Regulatory Path

Alrizomadlin is being investigated across multiple adult cancer indications beyond pediatric solid tumors, with trials primarily focusing on TP53 wild-type and MDM2-amplified tumors. The intervention models have evolved from combination approaches to monotherapy designs due to tolerability considerations.

MDM2-BCL-2 Inhibition: A Promising Path in Pediatric Sarcomas

The recent presentation of initial clinical data for alrizomadlin (APG-115) in pediatric relapsed/metastatic rhabdomyosarcoma (RMS) and other soft-tissue sarcomas (STSs) marks a significant step forward in a therapeutic area characterized by profound unmet needs. These aggressive pediatric cancers often have limited systemic treatment options, making any signal of efficacy particularly noteworthy. Alrizomadlin, an MDM2-p53 inhibitor, targets a pathway frequently dysregulated in sarcomas, where MDM2 amplification is common. The preliminary results, including a complete response in a pediatric RMS patient with monotherapy and an objective response rate of 23.5% with the combination regimen, offer a glimmer of hope for these heavily pretreated young patients.

A key aspect of this development is the exploration of a novel combination strategy, pairing alrizomadlin with lisaftoclax (APG-2575), a BCL-2 inhibitor. Lisaftoclax has already demonstrated robust efficacy and a manageable safety profile in hematologic malignancies, including its recent approval in China for chronic lymphocytic leukemia. The rationale for combining MDM2 and BCL-2 inhibition in solid tumors is compelling, aiming to induce apoptosis through multiple pathways and potentially overcome resistance. This dual-targeting approach could represent a new paradigm for treating sarcomas and other cancers.

However, as with all early-stage data, important considerations remain. The current findings are from a small, multicenter trial, and larger, confirmatory studies will be crucial to validate the durability of responses and the overall safety profile in a broader pediatric population. Previous studies with alrizomadlin monotherapy in advanced solid tumors have highlighted common Grade 3/4 hematologic adverse events, such as thrombocytopenia and neutropenia, which will require careful monitoring, especially in vulnerable pediatric patients. Furthermore, the efficacy of MDM2 inhibitors like alrizomadlin appears to be significantly enhanced in tumors with wild-type TP53, suggesting that patient selection based on TP53 status may be critical for optimizing treatment outcomes. The inclusion of alrizomadlin in China's 'SPARK Plan' for pediatric anti-tumor drug R&D underscores the strategic importance of this program and could accelerate its path to patients, potentially reshaping the treatment landscape for these challenging pediatric malignancies.