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

Abstract

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.