Paediatric Therapeutic Development Workshop on rhabdomyosarcoma

The third in a series of Paediatric Therapeutic Development Workshops focused on rhabdomyosarcoma. Rhabdomyosarcoma is the most common soft tissue sarcoma in children, with 90% survival for those with the lowest risk disease, but just 20–30% in children with metastatic disease. An urgent unmet need exists to develop targeted therapeutics for high-risk disease and to reduce the toxicity of treatment. The results of trials of CAR T-cells and ADCs against FGFR4 are awaited with great interest, and developing a FGFR4 degrader is a priority. Directly targeting PAX3::FOXO1 and PAX7::FOXO1 fusion proteins is a high priority. An in vivo study of a MYOD1 degrader approach is required prior to clinical development. Degraders of P300/CBP should be evaluated preclinically with a view to clinical investigation. ROR2 is an interesting target for the L122R mutant MYOD1 rhabdomyosarcoma. Development of a TEAD degrader is a high priority, and this should be evaluated in combination with a Notch inhibitor. Considering targets with existing clinical agents, antibody-drug conjugates targeting cell-surface antigen B7-H3/CD276 are showing preclinical promise in other paediatric cancers and are also deemed a high priority for evaluation in rhabdomyosarcoma. Based on currently available evidence, MEK inhibitors should be evaluated, potentially with BRAF or PI3K inhibitors, in combination with chemotherapy in the maintenance setting. Understanding the mechanism of action underpinning drug combinations, gaining access to therapeutics and optimising clinical trial design will be essential to enable combinatorial testing in patients.