Kronos Bio, Inc. announced positive preliminary data from the Phase 1 dose escalation portion of the ongoing Phase 1/2 clinical trial of KB-0742 at the AACR-NCI-EORTC International Conference in Boston, Mass. KB-0742 is the company?s internally discovered, highly selective, orally bioavailable cyclin dependent kinase 9 (CDK9) inhibitor being developed to treat transcriptionally addicted solid tumors. These tumors include transcription factor fusion driven cancers such as sarcomas, as well as MYC-dependent tumors, such as triple negative breast, ovarian, and lung cancer.

The preliminary analysis included 28 patients enrolled in a dose escalation study who received doses from 10 mg up to 60 mg (data cut-off September 1st, 2023). KB-0742 demonstrated on-mechanism single agent anti-tumor activity in heavily pre-treated patients with transcriptionally addicted tumor types and exhibited a manageable safety profile, with no grade 3/4 neutropenia observed. KB-0742 also demonstrated dose proportional exposure and target engagement and a 24-hour plasma half-life, enabling intermittent dosing.

The long plasma half-life enabled KB-0742 to achieve sustained pharmacologically active concentrations while avoiding potentially toxic peak (Cmax) concentrations. The most common tumor types of these patients were colorectal (5), chordoma (4), sarcoma (4), lung (3) and breast (3). Because the maximum tolerated dose has not yet been identified, enrollment in the dose escalation portion continues and dosing of patients at the 80 mg dose level is underway.

In parallel, the ongoing dose expansion portion of the study, which commenced in January 2023, is enrolling patients with MYC-dependent and other transcriptionally addicted tumors across two cohorts at the 60 mg dose level. Data from this dose expansion portion of the study are expected in mid-2024. Single Agent Anti-Tumor Activity in Heavily Pre-Treated Patients with Transcriptionally Addicted Tumor Types: As of the September 1st, 2023 data cut-off date, 28 patients were enrolled in the dose escalation portion of the trial with doses ranging from 10 mg to 60 mg.

Patients had received a median of 3.5 prior lines of therapy and the median treatment duration was 57 (range 2 to 398) days and median follow up was 86 (range 57 to 114) days. At the 60 mg dose level (n=14), evidence of target engagement was observed by pSER2 reduction and proportional changes to CDK9 responsive genes. Tumor reduction (1 PR, 1 SD) was observed in two patients with myxoid liposarcoma, a transcriptionally addicted tumor type characterized by a chimeric fusion TF, consistent with on-mechanism activity.

Of these two patients with myxoid liposarcoma, one (7th line) had a partial response (per RECIST v1.1) lasting 113 days and the second achieved a 26% reduction in tumor diameters with stable disease. Nine (44%) patients across numerous cancer types had stable disease as the best response, and the overall disease control rate was 48% (defined as a complete response, partial response, or stable disease). Myxoid liposarcomas are driven by a transcription factor fusion supporting the therapeutic hypothesis that CDK9 inhibition with KB-0742 can selectively target these and other transcriptionally addicted tumors.

Manageable Safety Profile with No Grade 3 or 4 Neutropenia: Treatment-emergent adverse events (TEAEs) that occurred in >20% of patients included nausea (64%), vomiting (68%) and fatigue (29%), all of which were grade 1/2. No grade 3/4 neutropenia was observed, and no treatment-related deaths were observed. The most common reasons for treatment discontinuation were progressive disease, TEAEs, and withdrawal of consent.