Investigational Drug
Zanzalintinib
TrialFetch AI Analysis
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Overview
Zanzalintinib (XL092) is an investigational, orally administered multikinase inhibitor being developed for solid tumors, both alone and with immune-checkpoint inhibitors. The most mature evidence comes from metastatic colorectal cancer (mCRC); studies are also evaluating renal cell, head and neck, prostate, liver, and other cancers. (pubmed.ncbi.nlm.nih.gov)
Mechanism of action
Zanzalintinib inhibits receptor tyrosine kinases involved in angiogenesis, tumor growth, metastasis, treatment resistance, and immune suppression—notably VEGFR2, MET, and the TAM-family kinases TYRO3, AXL, and MER. This profile provides the rationale for combining it with PD-1/PD-L1 checkpoint inhibitors. Its reported half-life of approximately 16–22 hours supports once-daily dosing. (cancer.gov)
Efficacy
Metastatic colorectal cancer: In the randomized phase 3 STELLAR-303 trial, 901 previously treated patients with non-MSI-H/non-dMMR mCRC received zanzalintinib plus atezolizumab or regorafenib. Median overall survival was 10.9 versus 9.4 months, respectively (hazard ratio 0.80; 95% CI 0.69–0.93; p=0.0045). Objective response rates were 4% versus 1%, and disease-control rates were 54% versus 41%. In the subgroup without liver metastases, final median survival was 15.9 versus 12.7 months, but the difference was not statistically significant (HR 0.83; p=0.1185). (pubmed.ncbi.nlm.nih.gov)
Earlier phase 1 STELLAR-001 results in refractory mCRC found response rates of 7.4% with zanzalintinib–atezolizumab and 1.9% with zanzalintinib alone; median progression-free survival was 4.0 and 3.0 months, respectively. (ascopubs.org)
Renal cell carcinoma: Early, nonrandomized results also suggest activity. Single-agent zanzalintinib produced a 38% response rate and 88% disease-control rate in 32 previously treated patients with clear-cell RCC. In first-line STELLAR-002, zanzalintinib plus nivolumab produced a 63% response rate in 40 patients, whereas the combination with nivolumab and relatlimab produced a 33% response rate in a separate 40-patient cohort. These findings remain preliminary and require confirmation in randomized trials. (ascopubs.org)
Safety
In STELLAR-303, grade 3 or worse treatment-related adverse events occurred in 60% of patients receiving zanzalintinib–atezolizumab and 37% receiving regorafenib. The most common severe treatment-related events with the combination were hypertension (15%), proteinuria (6%), fatigue (6%), and diarrhea (6%). Treatment-related deaths occurred in five patients (1%) receiving the combination and one patient receiving regorafenib. (pubmed.ncbi.nlm.nih.gov)
Across early studies, frequently reported toxicities included diarrhea, nausea, decreased appetite, fatigue, and hypertension. Dose reductions were common in the renal-cell carcinoma combinations, although treatment discontinuation rates were relatively low in the zanzalintinib–nivolumab cohort. (ascopubs.org)
Further reading
- Phase 3 STELLAR-303 results in The Lancet
- Phase 1 STELLAR-001 colorectal-cancer results
- STELLAR-002 renal-cell carcinoma results
- Peer-reviewed review of zanzalintinib
- NCI Drug Dictionary entry
Last updated: Sep 2026
Active trials using Zanzalintinib
Found 20 active trials using this drug:
TrialFetch AI summary: Adults with unresectable or metastatic predominantly clear cell RCC, at least three bone metastases, and 1–3 prior treatment lines including an immune checkpoint inhibitor receive oral zanzalintinib plus a bone-strengthening agent. Zanzalintinib is an investigational tyrosine kinase inhibitor targeting VEGFR2, MET, and the TAM kinases TYRO3, AXL, and MER.
ClinicalTrials.gov ID: NCT07043608
TrialFetch AI summary: Patients with measurable, recurrent or progressive WHO grade 1–3 meningioma after standard therapy receive once-daily oral zanzalintinib. Prior radiotherapy is required unless contraindicated; zanzalintinib is an investigational multikinase inhibitor targeting VEGFR2, MET, TYRO3, AXL, and MER.
ClinicalTrials.gov ID: NCT07428616
TrialFetch AI summary: This study enrolls patients with unresectable stage IV clear-cell RCC that has progressed after both PD-1/PD-L1 and VEGF-TKI therapy, with no more than three prior systemic regimens. Patients receive the HIF-2α inhibitor belzutifan plus either investigational zanzalintinib, a VEGFR2/MET/TAM kinase inhibitor, or placebo.
ClinicalTrials.gov ID: NCT07489495
TrialFetch AI summary: Adults with unresectable advanced HCC, ECOG 0–1, and Child-Pugh A or B7–B8 cirrhosis who have progressed on or cannot tolerate up to two prior systemic therapies receive once-daily oral zanzalintinib. This investigational multikinase inhibitor targets VEGFR2, MET, and TYRO3/AXL/MER; prior cabozantinib or zanzalintinib is excluded.
ClinicalTrials.gov ID: NCT07042919
TrialFetch AI summary: Adults with measurable metastatic or unresectable soft tissue sarcoma, ECOG 0–1, and usually 1–3 prior lines of metastatic therapy receive zanzalintinib plus ipilimumab and nivolumab; patients with alveolar soft part sarcoma may enroll without prior metastatic therapy. Zanzalintinib is an investigational multikinase inhibitor targeting VEGFR2, MET, TYRO3, AXL, and MER; prior treatment with it, cabozantinib, or PD-1/PD-L1 or CTLA-4 inhibitors is excluded.
ClinicalTrials.gov ID: NCT06968988
TrialFetch AI summary: Adults with measurable advanced or metastatic undifferentiated pleomorphic sarcoma, myxofibrosarcoma, high-grade pleomorphic sarcoma, or high-grade undifferentiated sarcoma who have not received prior checkpoint inhibitors or zanzalintinib receive zanzalintinib plus pembrolizumab. Zanzalintinib is an investigational oral inhibitor of VEGFR2, MET, and the TAM kinases TYRO3, AXL, and MER; pembrolizumab blocks PD-1.
ClinicalTrials.gov ID: NCT07283731
TrialFetch AI summary: Adults with unresectable locally advanced or metastatic osteosarcoma, Ewing sarcoma, grade 2–3 conventional chondrosarcoma, or another primary bone sarcoma receive zanzalintinib monotherapy, generally after at least one prior systemic therapy; prior VEGF-targeted tyrosine kinase inhibitors are excluded. Zanzalintinib is an oral multikinase inhibitor targeting VEGFR2, MET, and the TAM-family kinases TYRO3, AXL, and MER.
ClinicalTrials.gov ID: NCT07193550
TrialFetch AI summary: Adults with unresectable stage IV clear-cell RCC that recurred during or within 24 months after adjuvant anti-PD-1/L1 therapy, and no other prior systemic RCC therapy, receive oral belzutifan plus zanzalintinib or oral cabozantinib. Belzutifan inhibits HIF-2α; investigational zanzalintinib inhibits VEGFR2, MET, and TAM-family kinases.
ClinicalTrials.gov ID: NCT07227402
TrialFetch AI summary: Adults with unresectable or metastatic leiomyosarcoma or adipocytic sarcoma progressing after 1–4 prior therapies receive oral zanzalintinib plus intravenous eribulin. Zanzalintinib is an investigational multikinase inhibitor targeting VEGFR2, MET, TYRO3, AXL, and MER.
ClinicalTrials.gov ID: NCT06957431
TrialFetch AI summary: Men with metastatic aggressive variant prostate cancer that has progressed after a second-generation androgen receptor pathway inhibitor receive single-agent oral zanzalintinib; pure small-cell prostate carcinoma is excluded. Zanzalintinib is an investigational multikinase inhibitor targeting VEGFR2, MET, TYRO3, AXL, and MER.
ClinicalTrials.gov ID: NCT07218666
TrialFetch AI summary: Adults with measurable recurrent or metastatic HNSCC not curable with local therapy, ECOG 0–1, and no more than two prior systemic lines receive oral zanzalintinib plus pembrolizumab and cetuximab; previously untreated patients must have PD-L1 CPS ≥1, and prior EGFR- or VEGFR-targeted therapy is excluded. Zanzalintinib is an investigational multikinase inhibitor targeting VEGFR2, MET, TYRO3, AXL, and MER.
ClinicalTrials.gov ID: NCT06912087
TrialFetch AI summary: Adults with unresectable locally advanced or metastatic clear-cell RCC that recurred during or within 24 months after adjuvant anti-PD-(L)1 therapy, and who have received no systemic therapy for advanced disease, receive oral zanzalintinib plus belzutifan. Zanzalintinib inhibits VEGFR2, MET, TYRO3, AXL, and MER; belzutifan inhibits HIF-2α.
ClinicalTrials.gov ID: NCT07049926
TrialFetch AI summary: Adults with measurable, progressive, locally advanced or metastatic radioiodine-refractory differentiated thyroid cancer who have not received prior treatment in the radioiodine-refractory setting receive oral zanzalintinib as first-line therapy. Zanzalintinib is an investigational multikinase inhibitor targeting VEGFR2, MET, and TAM-family kinases.
ClinicalTrials.gov ID: NCT06959641
TrialFetch AI summary: Adults with previously treated, progressing, unresectable locally advanced or metastatic well-differentiated grade 1–3 pancreatic or extrapancreatic NETs are randomized to oral zanzalintinib or everolimus; prior VEGFR-targeting tyrosine kinase inhibitors or mTOR inhibitors are excluded. Zanzalintinib is an investigational multikinase inhibitor targeting VEGFR2, MET, TYRO3, AXL, and MER.
ClinicalTrials.gov ID: NCT06943755
TrialFetch AI summary: Adults with measurable advanced or metastatic clear-cell RCC that progressed on or after adjuvant PD-1/PD-L1 therapy, with no other prior systemic therapy, are randomized to zanzalintinib (XL092) alone or with nivolumab. Zanzalintinib is an investigational inhibitor of VEGFR2, MET, and the TAM kinases TYRO3, AXL, and MER; nivolumab inhibits PD-1.
ClinicalTrials.gov ID: NCT06863311
TrialFetch AI summary: Adults with measurable recurrent high-grade endometrial cancer or uterine carcinosarcoma after platinum therapy receive paclitaxel plus dose-escalated zanzalintinib, with zanzalintinib maintenance available if disease does not progress. Zanzalintinib is an investigational oral multikinase inhibitor targeting VEGFR2, MET, and the TAM kinases TYRO3, AXL, and MER.
ClinicalTrials.gov ID: NCT06795009
TrialFetch AI summary: Adults with previously untreated unresectable HCC, ECOG 0–1, and adequate organ function receive oral zanzalintinib, an investigational VEGFR/MET/AXL multikinase inhibitor, with durvalumab (anti–PD-L1) and a single priming dose of tremelimumab (anti–CTLA-4). The study establishes a combination dose and assesses tumor response.
ClinicalTrials.gov ID: NCT06698250
TrialFetch AI summary: Adults with metastatic castration-resistant prostate adenocarcinoma that has progressed on or after 177Lu-PSMA-617 receive oral zanzalintinib (XL092) once daily. Zanzalintinib is an investigational multikinase inhibitor targeting VEGFR2, MET, and the TAM-family kinases TYRO3, AXL, and MER.
ClinicalTrials.gov ID: NCT06568562
TrialFetch AI summary: Adults with metastatic or unresectable, measurable leiomyosarcoma after more than two prior lines of therapy (including no more than two tyrosine kinase inhibitors) receive oral zanzalintinib until progression or unacceptable toxicity. Zanzalintinib is an investigational multikinase inhibitor targeting VEGFR2, MET, TYRO3, AXL, and MER.
ClinicalTrials.gov ID: NCT06571734
TrialFetch AI summary: Adults with unresectable locally advanced or metastatic solid tumors, including renal, prostate, urothelial, liver, lung, colorectal, and head and neck cancers, receive oral zanzalintinib alone or with nivolumab, nivolumab plus ipilimumab, or nivolumab plus relatlimab. Zanzalintinib inhibits VEGFR2, MET, and TAM kinases; the checkpoint inhibitors target PD-1, CTLA-4, and LAG-3, respectively.
ClinicalTrials.gov ID: NCT05176483
