STELLAR-303: randomized phase III study of zanzalintinib + atezolizumab in previously treated metastatic colorectal cancer

Abstract

Most patients with metastatic colorectal cancer (mCRC) have limited treatment options following standard-of-care therapy. VEGFR-tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity in mCRC in combination with immune checkpoint inhibitors (ICIs), particularly in patients without liver metastases. The TKI zanzalintinib (XL092) targets VEGFR, MET and TAM kinases, proteins that are involved in tumor growth, angiogenesis, metastasis and immunosuppression. Zanzalintinib has immunomodulatory properties that may enhance response to ICIs. Presented is the design of STELLAR-303, a global, phase III, open-label, randomized study evaluating zanzalintinib plus atezolizumab versus regorafenib in patients with non-MSI-H mCRC who progressed during/after or are refractory/intolerant to standard-of-care therapy. The primary end point is overall survival in patients without liver metastases.Clinical Trial Registration: NCT05425940 (ClinicalTrials.gov).

Keywords: Phase III; XL092; atezolizumab; immune checkpoint inhibitor; liver metastases; metastatic colorectal cancer; microsatellite instability-high; regorafenib; tyrosine kinase inhibitor; zanzalintinib.

Figure 1.

Zanzalintinib inhibits kinases involved in multiple processes.  A)(A) VEGFR, MET and TAM kinases are overexpressed in CRC and their activation by VEGF, HGF and GAS6, respectively, results in CRC angiogenesis, proliferation and metastasis [33,47,48]. Under the hypoxic conditions of the tumor microenvironment, there is overproduction of the pro-angiogenic kinase VEGF, which promotes tumor vascularization [35,47]. (B) VEGFR, MET and the TAM kinases contribute to immunosuppression and tumor cell immune-evasion and survival [34,38,49–52]. Dysregulation of these signaling pathways affects steps in the anti-tumor immune response and leads to increased expression of immunosuppressive checkpoints such as PD-1/PD-L1, which regulate T-cell function, proliferation of immunosuppressive immune cells such as Tregs and myeloid-derived suppressor cells and macrophage polarization to the anti-inflammatory M2 phenotype [34,37,41,49]. VEGFR, MET and TAM kinases are expressed on DCs and activation of these receptors can impair dendritic maturation and function, including T-cell activation in the lymph nodes [34,41,42]. (C) Combining zanzalintinib with atezolizumab may overcome the immunosuppressive tumor microenvironment and immunotherapy resistance observed in patients with mCRC [53]. Atezolizumab binds to PD-L1, leading to activation of cytotoxic T-cell activity and T-cell proliferation [54]. By inhibiting VEGFR, MET and TAM kinases, zanzalintinib has the potential to facilitate the activity of atezolizumab by driving T-cell infiltration, dendritic cell maturation and M1 macrophage differentiation, and decreasing Tregs and myeloid-derived suppressor cells, which promotes an immunopermissive tumor microenvironment. APC: Antigen-presenting cell; CRC: Colorectal cancer; DC: Dendritic cell; M1: M1 macrophage; M2: M2 macrophage; mCRC: Metastatic colorectal cancer; PD-1: Programmed dealth-1; PD-L1: Programmed death ligand-1; Treg: Regulatory T cell.

Figure 2.

STELLAR-303 study design. *Patients without liver metastases are defined as having no active liver metastases. Those with definitively treated liver metastases (surgical resection, microwave/radiofrequency ablation or stereotactic body radiation therapy, but not yttrium-90 or chemoembolization alone) are considered to have non-active liver metastases if treated at least 6 months before enrollment with no evidence of radiologic progression on subsequent imaging. AE: Adverse event; AESI: Adverse event of special interest; dMMR: Deficient mismatch repair; DOR: Duration of response; ECOG: Eastern Cooperative Oncology Group; mCRC: Metastatic colorectal cancer; MSI-H: Microsatellite instability-high; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; R: Randomized; RECIST: Response Evaluation Criteria in Solid Tumor; SAE: Serious adverse event; SOC: Standard of care.