Breakthrough Clinical Results
OS Therapies announced positive one-year event-free survival (EFS), overall survival, and safety data from its Phase 2b trial of OST-HER2 in patients with fully resected, lung metastatic osteosarcoma. The 12-month EFS rate was statistically significantly higher in the OST-HER2 group (35%) compared to a historical control group (20%). The company also provided a regulatory update, indicating that it is working with the FDA to utilize external control data to support a Biologics Licensing Application (BLA) under the Accelerated Approval program. The FDA's feedback suggests that external control data may suffice for approval in this rare disease setting. The company is also collaborating with the UK's MHRA to leverage the Clinical Practice Research Datalink (CPRD) for potential worldwide marketing authorizations.
Key Highlights
- Statistically significant improvement in 1-year EFS (35% vs. 20% historical control) in Phase 2b trial of OST-HER2.
- Favorable safety profile observed in the OST-HER2 treatment arm.
- Company working with FDA to utilize external control data for BLA submission under Accelerated Approval.
- Collaboration with UK's MHRA to leverage CPRD for global marketing authorizations.
Incidence and Prevalence
Global Epidemiology of Osteosarcoma: Incidence and Prevalence
Overview
Osteosarcoma is the most common type of primary bone malignancy, deriving from primitive bone-forming mesenchymal cells. Among childhood cancers, osteosarcoma occurs eighth in general incidence (2.4%), after leukemia (30%), brain and other nervous system cancers (22.3%), neuroblastoma (7.3%), Wilms tumor (5.6%), Non-Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), and retinoblastoma (2.8%).
Global Incidence Rates
Recent worldwide average incidences of osteosarcoma in people aged 0 to 24 years were 4.3 and 3.4 per million for males and females respectively, with a ratio of 1.4:1. The incidence rates and 95% confidence intervals of osteosarcoma for all races and both sexes are 4.0 (3.5-4.6) for the range 0-14 years and 5.0 (4.6-5.6) for the range 0-19 years per year per million persons.
In Canada, the annual incidence rate of primary bone cancer was estimated to be 6.3 per million population, with osteosarcoma accounting for more than half of all confirmed cases of primary bone cancer.
Prevalence Statistics
The limited-duration prevalence of malignant bone tumors has increased significantly from 0.00069% in 2000 to 0.00749% in 2018.
Regional Variations
Western Australia
In Western Australia, there were 263 cases of primary malignant bone tumors from 1972 to 1996. Osteosarcoma (94 cases), chondrosarcoma (64 cases), and Ewing's sarcoma (49 cases) represented 78.7% of all primary bone sarcomas. Age-sex-standardized incidence rates for osteosarcoma in Western Australia were 28% lower than in the USA.
Thailand
In Thailand's upper northern region, the overall annual incidence of osteosarcoma was 1.67 per million with a male:female ratio of 1.36:1. Incidences by age group (male and female) at 0 to 24, 25 to 59, and over 60 years were 3.5 (3.9 and 3.0), 0.8 (0.9 and 0.6), and 0.7 (0.8 and 0.5), respectively. The peak incidence in Thailand occurred at 15 to 19 years for males and at 10 to 14 years for females.
Africa
Osteosarcoma is more prevalent in Africa with high numbers of cases reported in Nigeria, Uganda, and Sudan. Higher rates of osteosarcoma are detected in African Americans, suggesting a genetic predisposition linked to race.
Demographic Variations
Age Distribution
Osteosarcoma has a bimodal age distribution, with the first peak during adolescence (10-14-year-old age group), coinciding with the pubertal growth spurt, and the second peak in adults older than 65 years of age.
Racial/Ethnic Differences
The incidence rates vary by race/ethnicity: Blacks (6.8/year/million), Hispanics (6.5/year/million), and Caucasians (4.6/year/million). Blacks had the highest incidence in all aged cases combined and a significant increase in incidence throughout the study period. For cases 0 to 24 years old, the incidence of subsequent osteosarcoma increased 3-fold since the 2000s.
Gender Differences
The incidence is higher in males than in females, occurring at a rate of 5.4 per million persons per year in males vs. 4.0 per million in females.
Anatomical Distribution
Osteosarcoma commonly occurs in the long bones of the extremities near the metaphyseal growth plates, with the most common sites being the femur (42%), the tibia (19%), and the humerus (10%). Other locations include the skull or jaw (8%) and the pelvis (8%).
Survival and Mortality
Cancer deaths due to bone and joint malignant neoplasms represent 8.9% of all childhood and adolescent cancer deaths. Death rates for osteosarcoma have been declining by about 1.3% per year. The overall 5-year survival rate for osteosarcoma is 68%, without significant gender difference.
Key Unmet Needs in Osteosarcoma Treatment
Current Treatment Challenges
Osteosarcoma is the most common malignant bone tumor in young patients and the most common primary malignant bone tumor overall. Despite standard multimodality treatment including chemotherapy and surgery, survival rates have remained stagnant over the past four decades. The same agents have been in use since the mid-1970s, highlighting the urgent need for new therapeutic approaches.
Major Unmet Needs
Metastatic Disease Management
One of the most significant challenges in osteosarcoma treatment is addressing metastatic disease. Osteosarcoma is associated with high rates of metastasis and poor 5-year survival rates. Currently, there is a lack of studies detailing the immunosuppressive mechanisms within the metastatic osteosarcoma microenvironment, making this an important area for future research.
Immunotherapy Optimization
Despite promising results in other cancer types, response rates to immunotherapy like immune checkpoint inhibitors have been disappointing in osteosarcoma. This is largely due to the profoundly immunosuppressive tumor microenvironment. Suppressive myeloid cells play a significant role in tumor progression and immune evasion, suggesting that targeting suppressive myeloid cells via novel agents could be an effective strategy. Research indicates that combination strategies will likely be important for achieving durable responses.
Development of Targeted Therapies
The highly mutable genome of osteosarcoma has made identifying a key oncogene challenging, hindering the development of targeted treatments. However, several promising targets have been identified:
- CXCR4 has been identified as an actionable immunomodulatory target that bridges both intratumoral and extratumoral microenvironments
- GPC3 (Glypican-3) has emerged as a novel prognostic parameter and a promising therapeutic target
- PDE1B gene was discovered to be a tumor suppressor gene in osteosarcoma, with high expression related to better overall survival
Novel Therapeutic Approaches
Several innovative approaches are being investigated to address these unmet needs:
- Maintenance therapy (MT), particularly antiangiogenic approaches such as metronomic chemotherapy (MC), has shown promise in solid tumors
- Antivascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI) are increasingly explored in pediatric sarcomas
- Combination of pazopanib (PZP) and crizotinib (CRZ) offers synergic anti-tumor effects against osteosarcoma
- DeltaRex-G tumor-targeted gene therapy is being investigated with Phase 2/3 randomized studies recommended
- CAR-T cell therapy and unmodified IL-2 primed Gamma Delta (NK) cell therapy are being explored
Predictive Factors for Treatment Response
Understanding predictive factors is crucial for optimizing treatment. Research has shown that:
- Tumor necrosis independently predicts outcome in osteosarcoma
- Patients with smaller tumor size (≤10 cm), lower serum alkaline phosphatase (≤450 IU/L), and who had surgery earlier (<115 days) are more likely to achieve favorable necrosis
- Response-adapted treatment escalation fails to overcome the adverse impact of poor necrosis
Addressing these unmet needs through innovative research and clinical approaches will be essential to improving outcomes for patients with osteosarcoma, particularly those with advanced or metastatic disease.
Study Design Parameters
Study Design Parameters and Endpoints in Key Osteosarcoma Trials
Study Designs and Patient Populations
Osteosarcoma trials have employed various study designs including prospective diagnostic studies, cohort studies, and retrospective reviews. One notable prospective diagnostic study included 54 consecutive osteosarcoma and Ewing sarcoma patients conducted between March 2018 and June 2019. A cohort study of 53 osteosarcoma patients utilized immunohistochemistry analysis, while another study performed whole-genome transcriptional profiling using serial analysis of gene expression.
Patient populations typically included individuals aged between 4 and 37 years with histopathologically proven diagnoses. One study included 72 patients with bone sarcomas without distant metastases, of which 26 (36%) were osteosarcomas. Another study enrolled 21 patients (15 male, 6 female) diagnosed with osteosarcoma. Control groups in various studies included patients with benign non-inflammatory bone tumors and age-matched healthy controls.
The European Osteosarcoma Intergroup (EOI) conducted two randomized trials between 1983-1993 involving patients with high-grade, nonmetastatic, biopsy-proven osteosarcoma of the extremity. These trials used a common treatment arm of doxorubicin (DOX) 75 mg/m² and cisplatin (CDDP) 100 mg/m² planned for six cycles at 3-week intervals, with definitive surgery scheduled at week 9 after three cycles.
A retrospective single-institutional study included non-metastatic osteosarcoma patients treated with neoadjuvant therapy between 2004-2019. Patients received three cycles of neoadjuvant cisplatin/doxorubicin. Post-operatively, patients with favorable necrosis (≥90%) received 3 cycles of cisplatin/doxorubicin, while patients with poor necrosis (<90%) received escalated treatment with alternating six cycles of cisplatin/doxorubicin and ifosfamide/etoposide.
Key Endpoints and Statistical Methods
The primary endpoints across multiple studies included:
- Overall survival (OS), analyzed by the Kaplan-Meier method
- Disease-free survival (DFS) and progression-free survival (PFS)
- Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of imaging modalities
- Tumor response to various therapeutic interventions
In the EOI trials, survival time was calculated from 122 days, the scheduled end of chemotherapy. A study comparing metastasectomy vs. chemotherapy divided patients into three groups: A) patients with resectable metastases treated with metastasectomy (n=29), B) patients with resectable metastases who received systemic therapy (n=17), and C) patients with unresectable metastases (n=25).
Statistical methods employed included multivariate Cox proportional hazards model for survival analysis, forward stepwise approach to screen minimal set of immune cell types, and LASSO algorithm for developing prognostic models. ROC curve analysis was used to evaluate model performance, while correlation with clinicopathological parameters was assessed using Pearson chi-square and Spearman-rho tests.
Biomarkers and Prognostic Factors
Several biomarkers and prognostic factors were evaluated:
- TfR1 and VEGF expression levels correlated to histologic grade, Enneking stage, and distant metastasis
- Immune-related glycosylation genes (IRGGs) risk score containing 6 genes
- Arachidonic acid metabolism-related genes (AAMRGs) prognostic signature
- Tumor infiltrating immune cells (TIICs) associated with clinical outcomes
- Cytokines and soluble cytokine receptors (IL-6, IL-8, IL-10, VEGF, bFGF, M-CSF, G-CSF, IL-1ra, sIL-2Ralpha, TNF RI, TNF RII)
Factors evaluated for impact on overall survival and event-free survival included primary tumor site, age, sex, ethnicity, histologic response, and presence of metastatic disease at diagnosis.