Kronos Bio, Inc. shared preclinical data on its internally discovered, highly selective, oral cyclin dependent kinase 9 (CDK9) inhibitor, KB-0742, adding to evidence that the compound has the potential to treat certain MYC-amplified and transcriptionally addicted solid tumors. The data will be presented in three posters at the American Association for Cancer Research (AACR) Annual Meeting 2022, which begins in New Orleans. The company will also present findings on a liquid biopsy assay platform that it has developed to potentially assess patient responses in the next stage of the ongoing Phase 1/2 clinical trial of KB-0742.

Kronos Bio began enrolling patients in the Phase 1/2 KB-0742 trial in February 2021 and presented initial positive findings from the study in November 2021. The company anticipates presenting additional data from the Phase 1 stage of the study, including the recommended Phase 2 dose, in the fourth quarter of 2022. The data at AACR assess KB-0742 in multiple preclinical translational model systems and will be used to help the company prioritize specific tumor types for the expansion stage of the Phase 1/2 clinical study.

In the first poster, researchers evaluated 11 tumor types using immortalized cell lines, including patient-derived cell line (PDC), patient-derived organoid (PDO) and patient-derived xenograft (PDX) models. Of the 11 cancer types, triple-negative breast cancer, ovarian cancer and lymphoma showed good responses to KB-0742. Tumor regressions were observed in the three models of ovarian cancer.

For triple-negative breast cancer and ovarian cancer, immortalized cell lines and patient-derived cell lines indicated lower half maximal inhibitory concentration (IC50) values with increased MYC amplification or expression, and in vivo assessments using PDX models showed good correlation of tumor growth inhibition and MYC amplification/expression. The data also showed antitumor activity of greater than 50% tumor growth inhibition in several xenograft models of lymphoma, including one double-hit model. Based on the analysis, the researchers concluded that triple-negative breast and ovarian cancer showed the strongest correlation between sensitivity to KB-0742 and MYC expression.

In a second poster, KB-0742 was evaluated in certain tumors that rely on dysregulated activity of a particular transcription factor to drive their malignant phenotype. These include the fusion gene EWS-FLI1 in Ewing sarcoma, PAX3/7-FOXO1 fusions in rhabdomyosarcoma, and brachyury (T) in chordoma. The activity of KB-0742 was assessed in vivo using two PDX models of chordoma.

In model CF466, a dose-dependent response was observed as evidenced by increased tumor growth inhibition activity and target engagement. Researchers then evaluated KB-0742 both as a single agent and in combination with afatinib (the standard-of-care EGFR inhibitor) in the CF539 model. KB-0742 as a single agent showed similar tumor growth inhibition activity as afatinib, and the combination showed an increased response.

These findings provide additional rationale for the use of KB-0742 as a potential treatment for chordoma, sarcoma and other transcriptionally addicted tumors. In a third poster at AACR, the company evaluated KB-0742 in small-cell lung cancer. In a panel of six PDO small-cell lung cancer models with different treatment histories, KB-0742 was active in the models, regardless of treatment history.

In a separate study of four treatment-naive PDO models, KB-0742 was active in three transcription factor-driven subtypes of small-cell lung cancer, and the response correlated significantly with c-MYC and MYCL expression. Lastly, researchers used four PDX models to evaluate KB-0742 activity in vivo. The tumor growth inhibition rate ranged from 54% to 92%, with tumor regressions observed in two of the four models, and one model showed greater tumor growth inhibition with KB-0742 when compared with standard of care.

Together, these data support the evaluation of KB-0742 as a potential treatment for small-cell lung cancer. The company also presented data on its cell-free DNA (cfDNA) liquid biopsy assay, which is designed to allow for real-time assessment of the tumor mutational landscape. The assay has the potential to serve as an accelerated and cost-effective approach to monitor response to KB-0742 in the ongoing Phase 1/2 trial by tracking changes in tumor cell burden over time.