Exelixis, Arcus Biosciences enter clinical trial collaboration to evaluate zanzalintinib in combo with AB521 in patients with advanced RCC

Exelixis, Inc. and Arcus Biosciences announced that the companies have entered into a clinical trial collaboration for STELLAR-009, a phase 1b/2 trial evaluating zanzalintinib, Exelixis’ next-generation tyrosine kinase inhibitor (TKI), in combination with AB521, an inhibitor of the transcription factor HIF-2?, in patients with advanced solid tumours, including clear cell renal cell carcinoma (ccRCC). Exelixis is sponsoring STELLAR-009, and Arcus is co-funding the study and providing AB521 for use in the trial. Patient enrollment for STELLAR-009 is expected to begin before the end of 2023.

“We are excited to learn more about the potential effects of zanzalintinib plus Arcus’ HIF-2? inhibitor, as these two molecules approach the inhibition of cancer cell proliferation and tumour angiogenesis from differing angles, and combination therapy may provide better outcomes than either therapy alone,” said Amy Peterson, M.D., executive vice president, product development & medical affairs, and chief medical officer, Exelixis. “We have a long-established commitment to advancing treatment options in kidney cancer, and we are eager to maximize the potential of zanzalintinib through this collaboration with Arcus and look forward to advancing the combination in the clinic.”

“We are excited to partner with Exelixis on the STELLAR-009 study to determine the best-in-class potential of AB521 in combination with zanzalintinib and look forward to generating a robust set of data to move this combination into full development,” said Dimitry S.A. Nuyten, M.D., Ph.D., chief medical officer of Arcus Biosciences. “The STELLAR-009 study is an important step in the development of AB521 and enables a cost-effective path to evaluating our HIF-2? inhibitor with a next-generation TKI.”

The dose-finding stage of this open-label study will determine a recommended dose for zanzalintinib in combination with AB521 in patients with advanced solid tumours and in patients with advanced ccRCC. Expansion cohorts will further evaluate the tolerability and activity of this combination in ccRCC as well as investigate the contribution of components, supported by activity data generated from monotherapy studies in ccRCC patients, to support full development.

Zanzalintinib is a next-generation oral TKI that inhibits the activity of receptor tyrosine kinases implicated in cancer growth and spread, including VEGF receptors, MET, AXL and MER. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumour angiogenesis and resistance to multiple therapies, including immune checkpoint inhibitors (ICIs). With zanzalintinib, Exelixis sought to build upon its extensive experience with the target profile of cabozantinib, the company’s flagship medicine, while improving key characteristics, including pharmacokinetic half-life. Zanzalintinib is currently being developed for the treatment of advanced solid tumors, including genitourinary, colorectal and head and neck cancers.

AB521 is a small molecule inhibitor of HIF-2?, a transcription factor involved in oxygen sensing in multiple organs as well as in tumours. Clear cell RCC is almost universally associated with HIF-2? dysregulation as a result of genetic abnormalities in the VHL pathway. This creates a situation of pseudohypoxia and the abnormal increase in HIF-2?-mediated expression of a wide array of proteins involved in cancer cell proliferation and survival, treatment resistance and angiogenesis. Arcus is currently evaluating AB521 in ARC-20, a phase 1/1b study in cancer patients. Enrollment for the dose-expansion stage in ccRCC patients is complete for the target dose of 100 mg, and efficacy data from this stage are expected in 2024. In the dose-escalation stage up to 100 mg, as of December 1, 2023, pharmacokinetic and pharmacodynamic data were consistent with the data generated in healthy volunteers, and no dose-limiting toxicities were observed. AB521 has the potential to achieve substantially greater HIF-2? inhibition than the approved dose of the marketed competitor.

Kidney cancer is among the top ten most commonly diagnosed forms of cancer among both men and women in the US. An estimated 81,800 Americans will be diagnosed with kidney cancer in 2023. Clear cell RCC is the most common type of kidney cancer in adults. If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 15%. In 2022, approximately 32,200 patients with advanced kidney cancer required systemic therapy in the US, with over 20,000 patients receiving first-line treatment.

Exelixis is a globally ambitious oncology company innovating next-generation medicines and regimens at the forefront of cancer care.

Arcus Biosciences is a clinical-stage, global biopharmaceutical company developing differentiated molecules and combination medicines for people with cancer.

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