Safety and Efficacy of a Selective Inhibitor of Cyclin-dependent Kinase 9 (KB-0742) in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma.

PURPOSE: Adenoid cystic carcinoma (ACC) is a rare salivary gland malignancy of the head and neck. Recurrent or metastatic ACC has very limited therapeutic options. Cyclin-dependent kinase 9 (CDK9) is a key factor in the oncogenic transcriptional regulatory network, and inhibition of CDK9 may prove beneficial in MYC-dependent tumors such as ACC.

PATIENTS AND

METHODS

A first-in-human, phase I, two-part dose-escalation and -expansion clinical trial (NCT04718675) enrolled patients with advanced solid tumors reliant on transcription factor activation to receive KB-0742, an oral selective inhibitor of CDK9. The primary endpoint was to establish safety/tolerability while nominating a recommended phase II dose (RP2D). Secondary endpoints included characterization of pharmacokinetics and assessment of preliminary efficacy.

RESULTS

Among 19 patients with ACC enrolled in dose expansion at the RP2D (60 mg orally 3 days on and 4 days off each week during a 28-day cycle), the regimen was well tolerated with mild gastrointestinal toxicity and fatigue; a single grade 3 treatment-related adverse event was observed (elevated γ-glutamyl transferase). One patient discontinued for gastrointestinal toxicity. Although no responses were observed, nine of 16 (56%) eligible patients had stable disease, with four experiencing >6 months of stability. Six-month progression-free survival was 37% (95% confidence interval, 14.2-59.8). Most patients had the more indolent type II ACC phenotype and 10 (53%) had MYB alterations.

CONCLUSIONS

This dose-expansion cohort exploring the novel CDK9 inhibitor KB-0742 in patients with advanced ACC established favorable tolerability at the RP2D. Disease stabilization was observed in some patients despite a limited efficacy signal.

SIGNIFICANCE: A first-in-human, phase I trial explored the safety and preliminary efficacy of the CDK9 inhibitor KB-0742 in patients with advanced, transcription factor-dependent solid tumors including ACC. KB-0742 was well tolerated with evidence of disease stabilization observed among some patients with ACC, but overall therapeutic efficacy was limited.