Safety of the BRD9 heterobifunctional degrader CFT8634 in synovial sarcoma and SMARCB1-null tumors: an open-label, dose-escalation, phase 1 clinical trial

CFT8634, an orally bioavailable, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), showed robust and dose-dependent BRD9 degradation and antitumor activity in preclinical synovial sarcoma and SMARCB1-null tumor models. This study characterizes the safety, tolerability, and preliminary efficacy of CFT8634 in patients with these indications. This first-in-human, open-label, multicenter, phase 1, dose-escalation clinical trial (NCT05355753) of CFT8634 enrolled patients with synovial sarcoma or SMARCB1-null tumors who received ≥1 prior line of systemic anticancer therapy. The primary endpoint was safety; secondary endpoints included assessment of pharmacokinetics, pharmacodynamics, and best overall response. Prior to enrollment completion, the trial was terminated due to insufficient efficacy. Here we show 23 out of 49 (47%) patients experience at least 1 grade ≥3, possibly treatment-related, treatment-emergent adverse event after receiving at least 1 dose of CFT8634, with a median duration of treatment of 1.7 months. Electrocardiogram data reveal frequent T-wave abnormalities during the treatment period across all dose levels, with 6 (12%) patients developing heart rate–corrected QT interval (QTc) prolongation. Plasma exposure of CFT8634 is dose proportional, and pharmacodynamic data show robust and continuous BRD9 degradation. These findings also show 1 patient (2%) achieving best overall response, which is a confirmed partial response, and 7 patients (14%) achieving stable disease during the dose-escalation phase. CFT8634 effectively degrades BRD9, providing proof-of-principle that heterobifunctional degraders are a viable strategy for clinical development. However, further exploration of CFT8634 is inhibited due to patients experiencing unanticipated nonspecific T-wave abnormalities and QTc prolongation in this study. Synovial sarcoma and SMARCB1-null tumors are soft tissue cancers. About half of the people with these cancers do not respond to treatment and have poor outcomes, especially when the tumor is advanced. This study assessed CFT8634, a new, investigational treatment for people with synovial sarcoma or SMARCB1-null tumors. CFT8634 works by breaking down BRD9, an important protein for these cancer types. We found that CFT8634 successfully broke down BRD9 in patients; however, 47% of patients experienced severe side effects, including heart rhythm problems. These findings suggest that although CFT8634 successfully targets BRD9, research is needed to understand the link between side effects associated with the heart and BRD9 before CFT8634 can become an available option for patients. van Tine et al. conducts a first-in-human, phase 1, dose escalation, clinical trial assessing CFT8634, a selective degrader of bromodomain-containing protein 9 (BRD9), in patients with synovial sarcoma or SMARCB1-null tumors refractory to therapy. CFT8634 demonstrates significant BRD9 degradation and dose-proportional pharmacokinetic properties.