Wessel Kristin M, Drezner Nicole, Shord Stacy S, Shah Mirat, Theoret Marc R, Donoghue Martha
Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
Oncology Center of Excellence, U.S. Food and Drug Administration, Silver Spring, Maryland.
Clin Cancer Res. 2025 Jul 1;31(13):2552-2555. doi: 10.1158/1078-0432.CCR-24-4325.
Despite survival gains for many pediatric cancers since the 1970s, cancer remains the leading cause of death by disease for children and adolescents in the United States. Survivors of pediatric cancer often experience acute and long-term toxicities resulting in diminished quality of life and reduced life expectancy. Thus, development of new therapies that offer a better balance between efficacy and safety remains an urgent unmet need. Dose-finding trials for pediatric oncology products have traditionally focused on identifying the maximum tolerated dose based on evaluation of acute, dose-limiting toxicities. However, oncology drug development has largely shifted from cytotoxic chemotherapies to targeted therapies such as kinase inhibitors, mAbs, antibody-drug conjugates, and cellular products, which often have different dose-response relationships for efficacy and safety and are sometimes administered on a chronic basis. These differences between cytotoxic chemotherapies and newer targeted therapies necessitate adoption of new, tailored approaches to identify the recommended dosage for oncology products in pediatric patients. The FDA Oncology Center of Excellence's Project Optimus is working to help develop such approaches, and an FDA guidance containing recommendations for optimizing the dosage of oncology products was finalized in 2024. Some members of the pediatric oncology community have expressed concerns about the potential impact of ongoing dosage optimization efforts on development of new treatments for pediatric cancers. Herein, we clarify the FDA's perspectives on dosage optimization in pediatric oncology and affirm our commitment to collaborating with stakeholders to expedite development of more effective, better-tolerated drugs and biologics for pediatric patients with cancer.
自20世纪70年代以来，尽管许多儿童癌症的生存率有所提高，但癌症仍是美国儿童和青少年因病死亡的主要原因。儿童癌症幸存者常常经历急性和长期毒性反应，导致生活质量下降和预期寿命缩短。因此，开发在疗效和安全性之间取得更好平衡的新疗法仍然是一项迫切未满足的需求。儿科肿瘤产品的剂量探索试验传统上侧重于根据急性剂量限制性毒性的评估来确定最大耐受剂量。然而，肿瘤药物研发已在很大程度上从细胞毒性化疗转向靶向疗法，如激酶抑制剂、单克隆抗体、抗体药物偶联物和细胞产品，这些疗法在疗效和安全性方面往往具有不同的剂量反应关系，并且有时是长期给药。细胞毒性化疗与更新的靶向疗法之间的这些差异使得必须采用新的、量身定制的方法来确定儿科患者肿瘤产品的推荐剂量。美国食品药品监督管理局（FDA）卓越肿瘤中心的擎天柱项目正在努力帮助开发此类方法，并且一份包含优化肿瘤产品剂量建议的FDA指南于2024年最终确定。儿科肿瘤学界的一些成员对正在进行的剂量优化努力对儿童癌症新疗法开发的潜在影响表示担忧。在此，我们阐明FDA在儿科肿瘤学剂量优化方面的观点，并申明我们致力于与利益相关者合作，以加快为患有癌症的儿科患者开发更有效、耐受性更好的药物和生物制品。
