Considerations for Clinical Trial Design in Relapsed and Refractory Osteosarcoma: An FDA Symposium

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, with a peak incidence coinciding with the pubertal growth spurt. Metastatic disease occurs in approximately 10% to 20% of newly diagnosed patients, most commonly in the lung. Although 5-year overall survival (OS) for patients with localized disease at diagnosis is approximately 70% after standard upfront treatment of multi-agent chemotherapy and surgical resection, patients with metastatic or recurrent disease have a 5-year OS of approximately 30% in the pediatric age group. Currently, there is no standard treatment or FDA-approved therapy for relapsed and refractory osteosarcoma. Progress in identifying promising new treatments has been limited by its complex disease biology and rarity, as well as unique challenges of clinical trial design, including unreliability of objective response rate as a predictor of drug activity. Given these challenges and the unmet need for new therapies, the FDA Oncology Center of Excellence hosted an educational symposium, "Current Challenges in Clinical Trial Design for Relapsed and Refractory Osteosarcoma," in May 2023. During this mini symposium, patient advocates, regulators from the FDA, and academic thought leaders in the field of pediatric sarcoma discussed challenges in clinical trial design and implementation. Achieving progress in relapsed and refractory osteosarcoma will require intentional collaboration among all stakeholders to identify trial designs that are acceptable to patients and will provide sufficient evidence of efficacy and safety to support a marketing application. Herein, we summarize the key points and future directions discussed at this meeting.