CTP-06. Molecular insights into response and resistance in children with relapsed/refractory brain tumors on ribociclib combination therapy: results from SJDAWN

Abstract Effective therapies for recurrent brain tumors remain scarce, leading to persistently high mortality rates following relapse. With cell cycle dysregulation playing a pivotal role in disease pathology, preclinical studies investigating CDK4/6 inhibitors (CDK4/6i) have elicited survival benefit across multiple brain tumor models. These studies simultaneously cautioned against prolonged single-agent treatment due to concerns for tumor progression. Combination therapy featuring the highly selective, brain-penetrant CDK4/6i, ribociclib, was evaluated in 68 relapsed/refractory brain tumor patients enrolled on SJDAWN (NCT03434262). Patients were molecularly stratified into 3 treatment groups: n=33 in A (Group 3/4 medulloblastoma, ependymoma); n=28 in B (high-grade glioma, other); and n=7 in C (skeletally mature SHH-activated, TP53 wildtype medulloblastoma). Safety, tolerability, and recommended phase 2 dosing for ribociclib combinations with gemcitabine (A), trametinib (B), and sonidegib (C) were previously reported. 12-month progression-free survival (PFS) was 18% (95% CI: 7-33%) in A, 4% (95% CI: 0-15%) in B, and 43% (95% CI: 10-73%) in C. 24-month PFS declined to 12% (95% CI: 4%-26%) in A and 0% in B and C. To investigate whether resistance contributed to disease progression, we analyzed n=143 cell-free DNA (cfDNA) methylomes derived from serial cerebrospinal fluid of 34 of the 68 patients. From trace amounts of cfDNA (<500 picograms), we were able to observe emerging resistance mechanisms marked by focal amplifications in positive cell cycle regulators (i.e., CDK6, CCND2, and MYCN), coinciding with a shift in cell cycle based on computational inference. These findings notably foreshadowed radiographic progression by 6 to 13 months. For patients who achieved PFS >18 months, cfDNA analyses predicted stable disease until tumor evolution. Further analyses resolving tumor microenvironment dynamics from cfDNA are underway. Collectively, ribociclib combination therapy exhibited clinical benefit in select patients before resistance emerged. cfDNA assessment enabled early detection of resistance, unveiling a window for therapeutic adjustment.