Systematic review maps tyrosine kinase inhibitor evidence in canine solid tumours

A systematic review of 200 publications found that tyrosine kinase inhibitors have established the strongest clinical evidence in canine mast cell tumours, while evidence across other solid tumours remains uneven and insufficient for firm comparisons. The analysis identified 36 publications that directly investigated clinical use of tyrosine kinase inhibitors in dogs. Mast cell tumours, osteosarcomas, hepatocellular carcinomas and transitional cell carcinomas were the most frequently reported tumour types.

Toceranib was the most widely studied agent, appearing in 41 publications, whereas clinical evidence for several other inhibitors consisted of only a few studies or remained largely preclinical. The researchers searched PubMed on 3 July 2025 for English-language studies published from 1986 through that date, using a strategy adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eligible studies evaluated tyrosine kinase expression in neoplastic processes and the use of inhibitors in canine in vitro or in vivo settings.

The researchers excluded non-original reports, work without clear ethical approval, studies involving other species, articles not available in open access, publications in languages other than English, and single case reports. Across the 200 eligible publications, the largest clinical dataset contained 1,139 inhibitor-treated cases. Mast cell tumours accounted for 481 cases, carcinomas for 428 and sarcomas for 135.

Smaller groups included 30 insulinomas, 27 chemodectomas, 26 lymphomas, 23 melanomas, five pheochromocytomas and three gastrointestinal stromal tumours. Toceranib appeared in 41 of the 200 publications, followed by masitinib in five, imatinib in four and sorafenib in three. Trametinib appeared in two publications, while vemurafenib, lapatinib and dasatinib appeared in one each.

Sunitinib was included in the broader review because of indirect translational and toxicity evidence, but the search identified no study directly investigating it as treatment for a canine tumour. Toceranib had the broadest clinical record. It inhibits c-KIT, vascular endothelial growth factor receptors and platelet-derived growth factor receptors, allowing it to affect tumour cells as well as vascular and stromal components of solid cancers.

The review reported objective response rates of up to 75% in mast cell tumours, compared with generally lower or more variable rates of 20–45% for carcinomas and sarcomas. Partial responses were also reported with toceranib monotherapy in dogs with apocrine gland anal sac adenocarcinoma. Across the literature, combination regimens generally produced higher partial- and complete-response rates than monotherapy, particularly for toceranib, although the comparison was descriptive rather than the result of uniformly randomised trials.

Masitinib targets c-KIT and platelet-derived growth factor receptors and has been studied mainly in mast cell tumours carrying activating c-KIT mutations. One analysis in the review reported an objective response rate of 70%, comparable to findings for toceranib. Evidence for masitinib in other tumour types was limited to isolated reports in melanoma, lymphoma and selected sarcomas and carcinomas.

Imatinib, which inhibits c-KIT, BCR-ABL and platelet-derived growth factor receptors, has also been evaluated in mast cell tumours and gastrointestinal stromal tumours. Response rates of 60% and 75%, respectively, were reported in the review’s corresponding groupings. Imatinib has additionally been studied in dogs intolerant of or resistant to toceranib or masitinib, often alongside chemotherapy or corticosteroids.

Several less extensively studied inhibitors showed activity in molecularly defined settings. Sorafenib inhibits VEGFR, PDGFR, RAF and KIT; in a first-line study of 13 dogs with hepatocellular carcinoma, it produced a 56% objective response rate. Vemurafenib inhibits BRAF and was evaluated in 24 dogs with BRAF-mutated invasive urothelial carcinoma, of whom 38% achieved a partial response.

Lapatinib, which targets EGFR1 and HER-2, produced a 27.3% objective response rate in one invasive urothelial carcinoma study; higher HER-2 immunohistochemical scores were associated with stronger responses in that analysis. Evidence for trametinib, dasatinib and sunitinib remains preliminary. Trametinib acts on ERK, AKT and mitogen-activated protein kinase pathways and has been investigated in melanoma, carcinoma and sarcoma models.

A canine histiocytic sarcoma study reported a 49.9% response and a progression-free survival of 78 days. Dasatinib showed mild-to-moderate activity in sarcomas and has been explored as a possible option after resistance to other inhibitors. Sunitinib has been examined mainly in experimental studies and off-label cases involving vascular tumours and sarcomas.

The review found that it was generally well tolerated and produced fewer cardiovascular effects than imatinib, but it found insufficient direct clinical evidence and no established dose-escalation schedule for canine solid tumours. Safety findings varied by drug and regimen, although gastrointestinal toxicity was the most frequently reported adverse effect across the class. Toceranib was also associated with proteinuria, thyroid dysfunction and acquired tumour resistance.

Imatinib produced diastolic dysfunction and ventricular early-repolarisation changes in experimental dogs, while masitinib was associated with vomiting, diarrhoea, reduced appetite, lethargy and mild neutropenia. Grade 3 toxicities including hypertension, proteinuria, elevated alkaline phosphatase and lethargy were described with trametinib, vemurafenib and dasatinib. Lapatinib was generally well tolerated, although diarrhoea, rash, fatigue, nausea and vomiting occurred, and vemurafenib produced dermatological lesions in some dogs.

The apparent benefits of combination therapy require caution. Higher response and disease-stability rates, together with longer progression-free survival, were commonly reported when tyrosine kinase inhibitors were combined with chemotherapy, radiotherapy or other treatments. These observations came from studies with different tumour types, disease stages, doses, follow-up periods and response definitions, and the review did not pool them into comparative effect estimates.

Some included studies also lacked overall- or progression-free-survival data. The English-language and open-access eligibility requirements may have excluded unpublished findings or negative reports, further limiting the evidence base. As a result, the review does not establish that combination therapy is superior in every canine solid-tumour setting or support a definitive ranking of most inhibitors.

The authors identified molecular selection as a central unresolved issue. Canine use of tyrosine kinase inhibitors is not generally guided by a validated predictive-marker panel, unlike biomarker-directed treatment in human oncology. Candidate indicators discussed in the literature include KIT mutations, phosphorylated KIT, VEGFR-2, HER-2, HER-2V659E mutations and components of the MAPK pathway.

A proposed receptor panel covering KIT, VEGFR-2, PDGFR-beta, EGFR-1, ERK1/ERK2 and HER-2 requires further validation before it can guide routine drug selection. Prospective controlled trials using standardised veterinary response criteria, serial molecular profiling and clearer toxicity reporting are needed to define which dogs are most likely to benefit from each inhibitor and which combinations offer meaningful clinical advantage. Overall, the review portrays tyrosine kinase inhibitors as an increasingly important but still incompletely validated part of canine oncology.

Toceranib remains the most extensively studied agent, particularly for mast cell tumours, and masitinib has comparable results in that tumour group. Imatinib has a clear role in some KIT-mutated tumours and haematopoietic malignancies. Sorafenib, vemurafenib and trametinib show promise in selected BRAF- or MAPK-associated contexts but require further clinical validation, while lapatinib and dasatinib remain largely experimental.

Sunitinib has potential in vascular or treatment-resistant sarcomas but remains underexplored. The present synthesis supports targeted treatment as an active area of veterinary cancer research, but its descriptive findings cannot yet define uniform efficacy, optimal sequencing or comparative safety across the wider group of canine solid tumours.

Subject of Research: Systematic review of tyrosine kinase inhibitor indications, responses and safety in canine solid tumours

Article Title: Tyrosine kinase inhibitors in canine solid tumours: a systematic review of indications, response and safety

Article References: de Moura, F. B. C., Amorim, R. L., & Fonseca-Alves, C. E. (2025). Tyrosine kinase inhibitors in canine solid tumours: a systematic review of indications, response and safety. Veterinary Oncology, 2(1), Article 21. https://doi.org/10.1186/s44356-025-00036-1

Image Credits: AI Generated

DOI: 10.1186/s44356-025-00036-1

Keywords: canine cancer, tyrosine kinase inhibitors, veterinary oncology, systematic review, mast cell tumours, toceranib, masitinib, targeted therapy, drug safety, canine solid tumours, Tyrosine, kinase