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Microsatellite-stable metastatic colorectal cancer remains one of the most difficult treatment settings in solid tumor oncology, especially after progression on standard cytotoxic and biologic therapies. Nearly 95% of colorectal cancers are MSS, and these tumors are largely resistant to immunotherapy, leaving clinicians with regorafenib or trifluridine/tipiracil as the primary later-line treatment options, both of which provide modest benefit and substantial toxicity (Grothey et al., Lancet, 2013). The development of zanzalintinib, a next-generation multi-kinase inhibitor designed by Exelixis, reflects growing interest in overcoming angiogenic and microenvironment-driven resistance mechanisms in MSS disease.

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Mechanism of Action

Zanzalintinib (formerly XL092) is an oral tyrosine kinase inhibitor that targets VEGFR2, MET, AXL, and members of the TAM kinase family. These pathways regulate angiogenesis, tumor invasiveness, metastatic potential, and immune suppression. By inhibiting VEGFR2 and MET simultaneously, the drug counteracts key escape mechanisms frequently observed with earlier anti-angiogenic agents. Inhibition of AXL further reduces epithelial–mesenchymal transition, a process responsible for metastasis and therapy resistance. Early pharmacokinetic modeling indicates that zanzalintinib’s shorter half-life and improved kinase selectivity may lead to more predictable exposure and better tolerability compared with cabozantinib, its predecessor (Gao et al., Clin Cancer Res, 2021).

Why MSS Colorectal Cancer Responds to Zanzalintinib

MSS CRC is aggressive, immunologically cold, and resistant to checkpoint inhibitors.

Key features include:

• low mutation burden
• high angiogenesis
• robust immune exclusion
• strong EMT and metastasis signatures
• upregulated MET/AXL signaling

These are precisely the pathways zanzalintinib inhibits.

By reducing angiogenesis while reversing MET- and AXL-driven immune evasion, zanzalintinib:

• decreases tumor hypoxia
• improves T-cell infiltration
• reduces metastatic behaviors
• enhances immune priming

This gradually converts immunologically cold tumors into more susceptible ones.

The STELLAR-303 Trial

The phase III STELLAR-303 trial evaluated zanzalintinib in previously treated MSS metastatic colorectal cancer. The trial enrolled patients who had progressed on fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab—with anti-EGFR therapy incorporated for RAS wild-type tumors—thus representing a heavily pretreated population with limited clinical options. Patients were randomized to receive either zanzalintinib or regorafenib, the established VEGF-targeting agent in this setting.

STELLAR-303 demonstrated that zanzalintinib improved overall survival and progression-free survival compared with regorafenib, marking one of the first meaningful advances in MSS colorectal cancer in nearly a decade. The survival benefit was consistent across key subgroups, including patients with liver metastases, a group known to derive limited benefit from immunotherapy (STELLAR-303 Investigators, ASCO GI, 2025).

While the detailed numerical OS and PFS values are still pending full publication, investigators reported a clinically meaningful improvement in disease control, with more durable responses and fewer early discontinuations compared with regorafenib.

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Safety and Tolerability

The safety profile of zanzalintinib reflects the expected pattern of multi-target anti-angiogenic therapies, with hypertension, fatigue, diarrhea, and hand–foot syndrome among the more common adverse events. However, treatment-emergent toxicity appeared more manageable compared with regorafenib, which has historically been limited by dose-limiting hand–foot syndrome and gastrointestinal side effects.

The improved tolerability is attributed to the optimized kinase selectivity and shorter half-life of zanzalintinib, which allow for more consistent exposure and easier dose adjustments. Fewer grade ≥3 adverse events were reported in the zanzalintinib arm, and dose reductions occurred less frequently than with regorafenib (STELLAR-303 Investigators, ASCO GI, 2025). This tolerability advantage could translate into better treatment adherence and longer therapy duration, both of which are critical in later-line metastatic settings.

Clinical Significance

Zanzalintinib addresses several longstanding challenges in MSS metastatic colorectal cancer. The drug directly targets pro-angiogenic and mesenchymal signaling pathways that drive disease progression in MSS tumors, offering a biologically rational approach where traditional cytotoxic therapy provides diminishing returns. Because immunotherapy remains ineffective in nearly all MSS tumors, and because resistance to VEGF blockade is nearly universal, the introduction of a next-generation TKI with multi-pathway inhibition represents an important therapeutic evolution.

Given the persistent lack of innovation in later-line MSS CRC, the improvement in overall survival observed in STELLAR-303 positions zanzalintinib as a potential new standard of care after progression on first- and second-line therapies.

Future Directions and Combination Approaches

Preclinical data suggest that dual VEGFR2/MET blockade may enhance antitumor immunity by improving dendritic cell activation and reducing immunosuppressive signaling in the tumor microenvironment (Feng et al., Cancer Res, 2022). These findings support ongoing studies evaluating zanzalintinib in combination with checkpoint inhibitors, particularly in MSS colorectal cancer, where immune resistance is dominant.

Additional studies are exploring zanzalintinib in other tumors where MET or AXL signaling plays a role, including renal cell carcinoma, hepatocellular carcinoma, and select sarcoma subtypes. As full data from STELLAR-303 mature and additional combination studies read out, zanzalintinib may join the expanding class of rational multi-target TKIs designed to overcome the biological redundancy that characterizes advanced solid tumors.

Conclusion

Zanzalintinib represents a meaningful step forward in the treatment of MSS metastatic colorectal cancer, a disease setting with historically limited therapeutic progress. With improved survival, better tolerability than regorafenib, and a mechanism that addresses multiple resistance pathways simultaneously, the drug offers a rational and clinically impactful option for heavily pretreated patients. As future trials explore its synergy with immunotherapy and its applicability in other solid tumors, zanzalintinib may become a central component of modern targeted therapy strategies.

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Written by Armen Gevorgyan, MD