Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children’s Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force

Abstract

Rhabdomyosarcoma is the most common soft tissue sarcoma diagnosed in children and adolescents. Patients that are diagnosed with advanced or relapsed disease have exceptionally poor outcomes. The Children’s Oncology Group (COG) convened a rhabdomyosarcoma new agent task force in 2020 to systematically evaluate novel agents for inclusion in phase 2 or phase 3 clinical trials for patients diagnosed with rhabdomyosarcoma, following a similar effort for Ewing sarcoma. The task force was comprised of clinicians and basic scientists who collectively identified new agents for evaluation and prioritization in clinical trial testing. Here, we report the work of the task force including the framework upon which the decisions were rendered and review the top classes of agents that were discussed. Representative agents include poly-ADP-ribose polymerase (PARP) inhibitors in combination with cytotoxic agents, mitogen-activated protein kinase (MEK) inhibitors in combination with type 1 insulin-like growth factor receptor (IGFR1) inhibitors, histone deacetylase (HDAC) inhibitors, and novel cytotoxic agents.

An update on rhabdomyosarcoma risk stratification and the rationale for current and future Children's Oncology Group clinical trials

“…Although knowledge of the molecular mechanisms driving RMS has advanced quickly, the availability of agents that target these molecular drivers has lagged. Current investigational therapies for patients with relapsed or refractory RMS include the use of kinase inhibitors, insulin‐like growth factor antibodies, histone deacetylase inhibitors, and poly ADP ribose polymerase (PARP) inhibitors among other agents and are used alone or in combination with various salvage chemotherapy backbones 73,74 . As the data utilizing molecular biomarkers for risk stratification mature, thus identifying smaller cohorts of patients with different prognoses, our ability to offer appropriate risk‐based therapy for all patients should improve, including for those with the most dismal prognoses.…”

Children's Oncology Group's 2023 blueprint for research: Soft tissue sarcomas

“…Since the completion of ARST0921, a few RMS‐specific relapsed trials have been conducted outside of COG 42,62,63 . The COG RMS Task Force has identified novel agents for inclusion in RMS trials, including for relapsed RMS 64,65 . Early‐response data on mocetinostat, an HDAC inhibitor, in combination with vinorelbine for relapsed/refractory RMS, are promising, growing the interest for this class of agents for future trials 42 …”

Pathogenic Roles of RNA-Binding Proteins in Sarcomas

“…Targeting the insulin growth factor (IGF) pathway is considered an attractive therapeutic target for RMS [ 78 , 79 ]. RMS has a survival advantage by switching isoforms of IR, the receptor for insulin growth factor.…”