Exelixis to Present the Preclinical Profile and Initial Clinical Pharmacokinetics of XL092, Its Next-Generation Oral Tyrosine Kinase Inhibitor

Exelixis announced new data that support the ongoing clinical development of XL092, the company’s next-generation oral tyrosine kinase inhibitor that targets VEGF receptors, MET, AXL, MER, and other kinases implicated in cancer’s growth and spread. The new data will be presented in a poster discussion session (Abstract 33) as part of the 32nd EORTC-NCI-AACR (ENA) Symposium, which is being held virtually October 24-25; abstracts for the meeting were released earlier today.

Peter Lamb, Ph.D., Executive Vice President of Scientific Strategy and Chief Scientific Officer of Exelixis Says: “When the XL092 program began, we wanted to develop a novel tyrosine kinase inhibitor that retained the target profile of cabozantinib, our flagship medicine that is now a global oncology franchise, while also improving on certain important characteristics, The data to be presented at the ENA Symposium suggest XL092 has a desirable therapeutic profile that pairs the potential for significant anti-tumor activity with a much shorter clinical half-life than cabozantinib. The data also support a potential synergistic effect for XL092 in combination with immune checkpoint inhibitors, which is why we’re excited to expand our ongoing phase 1 clinical trial to include an exploration of the combination of XL092 and atezolizumab in multiple solid tumors.”

The abstract released today provides a summary of results from a detailed characterization of XL092 in cancer cell lines and animal tumor models, as well as initial PK data from the ongoing phase 1 trial of the compound. Additional data will be presented in the poster discussion, which is scheduled to begin at 22:40 CEST / 4:40 p.m. EDT / 1:40 p.m. PDT on Saturday, October 24. Key findings included in the abstract are:

  • XL092 is an ATP-competitive inhibitor of multiple receptor tyrosine kinases including MET, VEGFR2, AXL and MER, with IC50 values in cell-based assays of 15, 1.6, 3.4, and 7.2 nM, respectively.
  • In xenograft studies, XL092 caused substantial tumor growth inhibition following 10 mg/kg daily oral dosing for 14 days, which was accompanied by significant inhibition of MET, AXL and VEGFR2 phosphorylation.
  • When XL092 was combined with an immune checkpoint inhibitor (ICI) in a syngeneic tumor model, the combination was significantly more efficacious than either XL092 or anti-PD1 alone.
  • PK data from the ongoing phase 1 clinical trial assessing daily dosing of XL092 in patients with advanced solid tumors shows a terminal half-life of 24 hours versus a 99-hour terminal half-life for cabozantinib.

The ongoing phase 1 trial (NCT03845166) is a multi-center study designed to evaluate the pharmacokinetics, safety, tolerability, and preliminary anti-tumor activity of XL092, both as a single agent and in combination with ICIs. The study protocol was recently amended to include dose-escalation and expansion cohorts for XL092 in combination with the ICI atezolizumab (TECENTRIQ®). The dose-escalation evaluation of XL092 as a single agent is ongoing, and Exelixis anticipates patient enrollment in the dose-escalation evaluation of the combination regimen imminently. As recommended doses of single-agent XL092 and XL092 in combination with atezolizumab are established, the trial will proceed to enroll expansion cohorts in patients with clear cell and non-clear cell renal cell carcinoma, hormone-receptor positive breast cancer, and metastatic castration-resistant prostate cancer.

About XL092

XL092 is a next-generation oral tyrosine kinase inhibitor that targets VEGF receptors, MET, AXL, MER, and other kinases implicated in cancer’s growth and spread. In designing XL092, Exelixis sought to build upon the experience and target profile of cabozantinib, the company’s flagship medicine, while improving key characteristics, including clinical half-life. The compound is the subject of an ongoing phase 1 trial (NCT03845166) evaluating its pharmacokinetics, safety, tolerability, and preliminary anti-tumor activity when administered alone and in combination with the ICI atezolizumab (TECENTRIQ®); pending positive data, further development is planned.

Source: Exelixis, Inc

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