Zentalis to Present Phase 1 Results of Azenosertib and Gemcitabine in Osteosarcoma at ASCO 2024

Zentalis Pharmaceuticals, a clinical-stage biopharmaceutical company, announced promising results from a Phase 1 trial evaluating the combination of azenosertib and gemcitabine in relapsed or refractory osteosarcoma. This announcement was made during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. The trial results have shown that this combination treatment is well tolerated and has led to a significant extension in event-free survival compared to historical data.

Dr. Kimberly Blackwell, CEO of Zentalis, highlighted that azenosertib, when combined with gemcitabine, has shown substantial clinical activity and good tolerance in patients. The study identified a suitable dose for future research, demonstrating a threefold increase in the proportion of patients surviving without disease progression or death at 18 weeks compared to historical controls. These promising results will pave the way for a Phase 2 trial initiated by investigators, aimed at further evaluating this combination in patients battling aggressive osteosarcoma.

The Phase 1 study enrolled 31 patients, with 31 assessable for safety, 29 for dose-limiting toxicities, and 28 for efficacy. The median age of the participants was 27 years, ranging from 12 to 76 years, with 68% being 39 years or younger. Prior to the trial, patients had received a median of three therapies, with approximately one-third having previously been treated with gemcitabine. The event-free survival rate at 18 weeks was 39%, which is notably higher compared to a historical cohort that reported a 16-week event-free survival rate of around 12%.

The maximum tolerated dose (MTD) for azenosertib was determined to be 150 mg daily on a 5:2 schedule (five days on, two days off), in combination with gemcitabine at 800 mg/m2. Common grade 3 or higher adverse events, seen in at least 20% of patients, included thrombocytopenia and lymphopenia, each affecting 33% of participants. No grade 4 thrombocytopenia or cases of febrile neutropenia were reported at the MTD. The data strongly support further investigation of this combination therapy in a forthcoming Phase 2 trial.

Dr. Viswatej Avutu from Memorial Sloan Kettering Cancer Center acknowledged the limited treatment options historically available for relapsed or refractory osteosarcoma. He noted that azenosertib shows promise as a new drug class, offering hope for an effective and well-tolerated treatment option.

The Phase 1 study (NCT04833582) aimed to determine the appropriate dose of azenosertib when combined with gemcitabine in patients aged 12 and older. The primary endpoint was the identification and severity of dose-limiting toxicities, while secondary endpoints included the incidence and severity of adverse events and the 18-week event-free survival rate as per RECIST v1.1.

Azenosertib is an orally bioavailable inhibitor of WEE1, a regulator of cell cycle checkpoints. By inhibiting WEE1, azenosertib promotes cell cycle progression despite high DNA damage levels, leading to cancer cell death. Zentalis Pharmaceuticals is actively developing azenosertib for various solid tumors and hematologic malignancies, exploring its efficacy both as a monotherapy and in combination with other treatments.

Zentalis Pharmaceuticals is dedicated to advancing the development of small molecule therapeutics that target fundamental biological pathways of cancer. Their lead candidate, azenosertib (ZN-c3), shows potential as a first-in-class WEE1 inhibitor, with ongoing research assessing its utility across multiple tumor types. The company operates from New York and San Diego, leveraging its expertise in cancer biology and medicinal chemistry to innovate cancer treatments.