Zanzalintinib (XL092): a next-generation tyrosine kinase inhibitor-comprehensive review of early safety & efficacy data.

Introduction: Zanzalintinib (XL092) is a next-generation anti-VEGFR-related multi-targeted TKI that exhibits immunomodulatory effects.

Areas covered: This review explores preclinical and clinical data, along with the future directions associated with zanzalintinib and its combination with immune checkpoint inhibitors (ICIs).

Expert opinion: In addition to its anti-VEGFR activity, zanzalintinib demonstrates potential synergistic effects with ICIs through its immunomodulatory impact, attributed to its inhibition of MET and TAM kinases. Recent preclinical studies provide compelling evidence supporting this synergistic potential. Furthermore, a recent phase 1 dose escalation study confirmed the tolerability of the zanzalintinib and anti-PDL1 combination without major safety concerns.Multiple ongoing clinical trials are investigating the combination of zanzalintinib and ICIs across various solid tumor types, including phase 3 studies for renal cell carcinoma, colorectal, and head and neck cancer. These trials aim to elucidate the therapeutic role of this new-generation TKI and ICI combination.However, the identification of reliable predictive biomarkers for the zanzalintinib and ICI combination presents significant challenges. Given the intricate nature of their mechanistic rationale and the difficulties in identifying reliable biomarkers for combined anti-angiogenesis and ICI therapies, addressing this challenge remains a priority for ongoing and future research.