KB-0742 Exhibits Tolerable Safety and Activity in Relapsed/Refractory Solid Tumors

Miguel Villalona-Calero, MD

The selective CDK9 inhibitor KB-0742 displayed anti-tumor activity and manageable safety as a single agent in heavily pretreated patients with relapsed/refractory, transcriptionally addicted solid tumors, according to data from a phase 1 trial (NCT04718675) presented at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Findings showed that among evaluable patients treated in during the dose-escalation portion of the first-in-human, open-label study who underwent at least 1 overall response assessment (n = 21), 1 patient with myxoid liposarcoma treated with 60 mg of KB-0742 experienced a partial response. The other enrolled patient with myxoid liposarcoma, who was also in the 60-mg cohort, achieved stable disease. In total, 9 patients (43%) had stable disease across all doses, and the disease control rate for all evaluable patients was 48%.

Regarding safety, no instances of grade 3/4 neutropenia observed at doses ranging from 10 mg to 60 mg, and the dose escalation portion of the trial is ongoing with the maximum tolerated dose yet to be reached. Any-grade treatment-related adverse effects (TRAEs) occurred in all patients, and the rate of grade 3/4 TRAEs was 39%.

“The main adverse effects [AEs] that were observed in this study were nausea and vomiting. That's something that was eventually managed well with use of antiemetics,” lead study author Miguel Villalona-Calero, MD, said in an interview with OncLive®. “We also observed some central nervous system [activity], a potential AE in patients. For example, 2 patients in the study developed seizures, though they were controlled with medications. This may indicate the possibility of the drug crossing the blood-brain barrier.”

Villalona-Calero is a medical oncologist and professor in the Department of Medical Oncology and Therapeutics Research, director of the Early Phase Therapeutics Program, and co-program leader of the Developmental Cancer Therapeutics Program at City of Hope in Duarte, California.

Transcription deregulation is a characteristic feature of cancer, which can confer selective tumor dependence on components of the cellular transcriptional machinery, necessitating elevated transcription rates of oncogenes, such as MYC or chimeric fusion transcription factors (TFs). CDK9 plays an important role in transcriptional control, forming interactions with numerous oncogenic TFs, making it a potential therapeutic target for these tumors.

KB-0742 is an orally bioavailable, potent, and selective CDK9 inhibitor. The phase 1/2 dose-escalation portion of the trial is evaluating the agent for patients with solid tumors and NHL, with cohort expansion will include patients with transcription-dependent tumors.

“[KB-0742] inhibits an enzyme called CDK9, which is present in a number of tumors correlating with tumor progression and multiplication,” Villalona-Calero explained.

The study is enrolling patients at least 18 years of age with any relapsed/refractory solid tumor who have acceptable organ function and an ECOG performance status of less than 2. Tumor types of interest include small cell lung cancer; epithelial ovarian cancer; triple-negative breast cancer; non–small cell lung cancer; diffuse-large B-cell lymphoma with documented MYC translocation or Burkitt’s lymphoma; sarcoma with documented TF fusion; chordoma; NUT midline carcinoma; or adenoid cystic carcinoma.

During dose escalation, patients received an oral administration of KB-0742 on a 3-days-on/4-days-off schedule. Dosing started at 10 mg (n = 3) and continued to 20 mg (n = 4), 40 mg (n = 7), and 60 mg (n = 14). Dose escalation will continue until the recommended phase 2 dose is established, and that will be subsequently evaluated in expansion cohorts.

The primary end points of the study are safety, dose-limiting toxicities, and laboratory assessments. Notable secondary end points include pharmacokinetics, progression-free survival, overall response rate, and duration of response.

In the safety population (n = 28), the median age was 59.5 years (range, 29-84), 61% of patients were female, and 86% of patients were White. The overall median number of prior systemic therapies was 3.5 (range, 0-11).

Across all dosing cohorts, the most common any-grade TEAEs were vomiting (68%), nausea (64%), fatigue (29%), peripheral edema (21%), increased cholesterol (18%), and proteinuria (18%). The most common grade 3/4 TEAEs were hypertension (7%) and increased lactate dehydrogenase (4%).

Any-grade hematologic abnormalities that were recorded across all dose levels included anemia (75%), lymphopenia (64%), neutropenia (7%), and thrombocytopenia (14%). The only grade 3/4 hematologic abnormalities recorded consisted of lymphopenia (32%).

Enrollment for the trial in ongoing.

“We are accruing patients, so we'll be glad to see any of your patients [who] are interested in participating in the study. We have several expansion cohorts open because we have faith that in a number of patients, this drug will have activity and a couple of years of benefit,” Villalona-Calero concluded.

Reference

Villalona-Calero M, Mita M, Mita A, et al. A first-in-human study of CDK9 inhibitor KB-0742 demonstrates evidence of tolerability and clinical activity. Presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 11-15, 2023; Boston, MA. Abstract B159.