Phase I/II Trial of Vemurafenib in Dogs with Naturally Occurring, BRAF-mutated Urothelial Carcinoma

Abstract

BRAF-targeted therapies including vemurafenib (Zelboraf) induce dramatic cancer remission; however, drug resistance commonly emerges. The purpose was to characterize a naturally occurring canine cancer model harboring complex features of human cancer, to complement experimental models to improve BRAF-targeted therapy. A phase I/II clinical trial of vemurafenib was performed in pet dogs with naturally occurring invasive urothelial carcinoma (InvUC) harboring the canine homologue of human BRAFV600E. The safety, MTD, pharmacokinetics, and antitumor activity were determined. Changes in signaling and immune gene expression were assessed by RNA sequencing and phosphoproteomic analyses of cystoscopic biopsies obtained before and during treatment, and at progression. The vemurafenib MTD was 37.5 mg/kg twice daily. Anorexia was the most common adverse event. At the MTD, partial remission occurred in 9 of 24 dogs (38%), with a median progression-free interval of 181 days (range, 53–608 days). In 18% of the dogs, new cutaneous squamous cell carcinoma and papillomas occurred, a known pharmacodynamic effect of vemurafenib in humans. Upregulation of genes in the classical and alternative MAPK-related pathways occurred in subsets of dogs at cancer progression. The most consistent transcriptomic changes were the increase in patterns of T lymphocyte infiltration during the first month of vemurafenib, and of immune failure accompanying cancer progression. In conclusion, the safety, antitumor activity, and cutaneous pharmacodynamic effects of vemurafenib, and the development of drug resistance in dogs closely mimic those reported in humans. This suggests BRAF-mutated canine InvUC offers an important complementary animal model to improve BRAF-targeted therapies in humans.

Validation of a Liquid Biopsy Protocol for Canine BRAFV595E Variant Detection in Dog Urine and Its Evaluation as a Diagnostic Test Complementary to Cytology

“…In this instance, one may require the dPCR BRAF assay in addition to a diagnosis reached using histological examination to decide whether to use a BRAF inhibitor. In this regard, it should be noted that BRAF inhibitors are being evaluated for use in dogs ( 19 ), and it is possible that they will soon be part of the veterinary oncologist armory.…”

“…The discovery of the high prevalence of the cBRAF V595E driver mutation in canine UC has two main implications; the first is the identification of a potential therapeutic target ( 17 – 19 ) and the second is the possibility of developing liquid biopsy protocols, i.e., non-invasive procedures for diagnosing canine UC ( 8 ). Traditional diagnostic sampling of the urogenital system can be invasive and may require biopsy; however, the identification of BRAF mutations in urine and cytological smears prepared from urine sediment or the plasma of affected patients would provide minimally invasive diagnostic techniques ( 14 , 15 , 20 ).…”

Molecular Markers in Urinary Bladder Cancer: Applications for Diagnosis, Prognosis and Therapy

“…Similar to what has been observed in humans treated with this drug, new tumours developed in some of the patients (cutaneous SCC, papillomas). Resistance to therapy also occurred in some animals over time [ 65 ].…”

Comparative Evaluation of Tumor-Infiltrating Lymphocytes in Companion Animals: Immuno-Oncology as a Relevant Translational Model for Cancer Therapy

“…Urothelial carcinomas (UC) are the most common genitourinary tumors in dogs and closely mimic the muscle-invasive phenotype that is seen in humans [ 33 , 36 , 161 ] ( Figure 6 ). The BRAF V595E mutation is seen in roughly 85% of canine patients with UC, which has prompted recent investigation into the efficacy of vemurafenib in dogs [ 162 , 163 , 164 , 165 , 166 ]. Several groups have documented the immune landscape and mRNA expression of canine UC, revealing its utility as a relevant translational model [ 37 , 38 , 167 , 168 , 169 ].…”