Zanzalintinib (XL092): A Next-Generation Tyrosine Kinase Inhibitor—Comprehensive Review of Early Safety & Efficacy Data

ABSTRACT

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.

KEYWORDS:

• XL092
• zanzalintinib
• cabozantinib
• tyrosine kinase inhibitor

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Article highlights

• Zanzalintinib (XL092): A novel anti-VEGFR-related multi-targeted tyrosine kinase inhibitor with immunomodulatory effects.

• Synergistic Potential: Recent preclinical studies strongly support the synergistic/complementary anti-cancer effects of zanzalintinib when combined with immune checkpoint inhibitors (ICIs).

• Clinical Tolerability: Results from the phase 1 dose-escalation study (STELLAR-001) confirm the tolerability of zanzalintinib in combination with anti-PDL1 therapy, with no unexpected adverse effects reported.

• Ongoing Clinical Trials: Multiple clinical trials are currently underway to evaluate the efficacy of zanzalintinib in combination with ICIs across various solid tumor types. Notably, phase 3 studies are investigating its potential in renal cell carcinoma, colorectal cancer, and head and neck cancer.

• Biomarker Exploration: Identifying reliable predictive biomarkers for the zanzalintinib -ICI combination represents an intriguing yet challenging area of research

Declaration of interest

Anwaar Saeed reports a leadership role with Autem therapeutics, Exelixis, KAHR medical, and Bristol-Myers Squibb; consulting or advisory board role with AstraZeneca, Bristol-Myers Squibb, Merck, Exelixis, Pfizer, Xilio therapeutics, Taiho, Amgen, Autem therapeutics, KAHR medical, and Daiichi Sankyo; institutional research funding from AstraZeneca, Bristol-Myers Squibb, Merck, Clovis, Exelixis, Actuate therapeutics, Incyte Corporation, Daiichi Sankyo, Five prime therapeutics, Amgen, Innovent biologics, Dragonfly therapeutics, Oxford Biotherapeutics, Arcus therapeutics, and KAHR medical; and participation as a data safety monitoring board chair for Arcus therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed they have received financial compensation as a paid consultant/advisor to Abbive, Pfizer, AVEO oncology, Janssen, Astellas, Bristol-Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology, Lilly, Sanofi, Telix, Xencor, NCCN and Peloton Therapeutics; Huntsman Cancer Institute has received research funding from Exelixis, Bavarian-Nordic, Clovis and Bristol-Myers Squibb on my behalf. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.