The future of osteosarcoma therapy is centered on innovative clinical trial designs that prioritize progression-free survival and the identification of potentially effective agents, such as regorafenib and cabozantinib. These trials aim to explore targeted combinations in patients with tumors that have been genomically and immunologically characterized.
Recent advances in genetic sequencing have uncovered significant complexity in osteosarcoma, including chromosome duplications and other alterations. While these genetic insights point to potential therapeutic targets—such as gene amplifications and disrupted signaling pathways (e.g., PTEN loss)—they also complicate clinical trial designs due to the disease’s rarity. Nevertheless, the success of MAP chemotherapy indicates that broad chemotherapy strategies can be integrated with precision medicine approaches.
Approximately 10 to 15% of patients diagnosed with osteosarcoma present with metastatic disease, predominantly in the lungs. The five-year survival rate for localized osteosarcoma exceeds 60%, but this drops to around 20% for those with metastases or recurrent illness. Despite stagnation in survival rates over the past three decades, advances in genetic profiling and clinical trial methodologies suggest that the field may be on the cusp of significant transformation.
Key challenges in improving treatment outcomes for high-grade osteosarcoma compared to other solid tumors include:
- Prognostic Subclassification: There is a lack of reliable prognostic categories beyond the presence of metastases, making treatment stratification difficult.
- Tumor Microenvironment: Limited understanding of how the tumor microenvironment affects treatment response hinders the development of effective therapies.
- Patient Enrollment: The rarity of osteosarcoma results in a small pool of patients for clinical trials, compounded by a relatively high survival rate (60%) among localized cases.
- Inappropriate Endpoints: The RECIST criteria, which require measurable tumor shrinkage for assessing treatment response, have proven ineffective in osteosarcoma. Studies have shown that despite favorable survival rates, RECIST-defined responses were absent. Alternative endpoints, such as event-free survival over 4 months for recurrent cases and over 12 months for resected tumors, are proposed for better evaluation.
- Recent Trials: Promising outcomes from trials using novel agents have emerged. Regorafenib has demonstrated improved progression-free survival in recurrent cases, while cabozantinib has shown activity with limited objective response rates.
Immunotherapeutic approaches are also under exploration, with significant findings from recent clinical trials:
- Interferon Alfa-2b: Tested in patients responding to chemotherapy, results were inconclusive due to treatment discontinuation from toxicity.
- HER2 Targeting: Trastuzumab, combined with chemotherapy for HER2-expressing metastatic osteosarcoma, showed no added benefit.
- Immune Checkpoint Inhibitors: Pembrolizumab demonstrated minimal activity in recurrent cases.
- CAR-T Cell Therapy: HER2-specific CAR-T cells were tested, resulting in stable disease in some patients.
- Adoptive T-Cell Therapy: T-cells expressing a TCR specific to MAGE-A3 showed brief responses in one patient.
The limited effectiveness of some immunotherapies may stem from an unfavorable tumor microenvironment that restricts T-cell infiltration, prompting research into strategies to enhance this microenvironment.
Image: Molecular Routes, Global Market and its Analysis for treatment of Osteosarcoma; Image Source: Malini Gupta
Lisata Therapeutics has announced that its lead candidate, LSTA1, has received Orphan Drug Designation from the U.S. FDA for treating osteosarcoma, following its recent Rare Pediatric Disease Designation. Dr. Kristen K. Buck highlighted the urgent need for improved treatments for this rare cancer. LSTA1 is designed to enhance the delivery of cancer therapies to solid tumors and may also improve the tumor microenvironment for better immunotherapy response. The drug has also received ODD for other cancers and a Fast Track designation for pancreatic cancer. Lisata expects to make significant advancements in clinical studies and business development through early 2026, while noting that future outcomes involve risks and uncertainties.
Data Bridge Market Research reports that the osteosarcoma drug market, valued at USD 1.2 billion in 2022, is projected to reach USD 1.84 billion by 2030, with a compound annual growth rate (CAGR) of 5.50%.
Overall, while progress is being made in osteosarcoma treatment, significant challenges remain in effectively leveraging immunotherapy and other novel strategies.
Dr. Malini Gupta, Ph.D.
Sources
- https://rarediseases.org/rare-diseases/osteosarcoma/
- https://www.orpha.net/en/disease/detail/668#
- https://www.curesarcoma.org/sarcoma-resources/patient-resources/sarcoma-information-links/
- https://www.cancer.org/cancer/types/osteosarcoma/about/what-is-osteosarcoma.html
- Figure derived from: https://www.nejm.org/doi/full/10.1056/NEJMra2103423
- Figure derived from: https://www.nature.com/articles/nrendo.2017.16#MOESM146
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