Lapatinib as first‑line treatment for muscle‑invasive urothelial carcinoma in dogs
Maeda, S., Sakai, K., Kaji, K. et al. Lapatinib as first-line treatment for muscle-invasive urothelial carcinoma in dogs. Sci Rep 12, 4 (2022). https://doi.org/10.1038/s41598-021-04229-0
Nature, January 2022
In a nutshell
- In a scientific report recently published in Nature, researchers from the University of Tokyo, evaluated using lapatinib as a first-line treatment for canine TCC and whether HER2 over-expression could predict its efficacy.
- The study, which encompassed 86 dogs, showed that for dogs with TCC, the outcomes in terms of survival time, with laptinib, were comparable or better than dogs that received injectable chemo (cisplatin or mitoxantrone).
- Most side effects were grade 1 and 2 representing a better side effect profile than traditional chemotherapy, while being much easier to administer (oral vs. injectable).
- For FidoCure®, this is important validation of our approach to treat TCC with lapatinib. Note: This study was performed with no FidoCure involvement. The researchers have no affiliation or connection to FidoCure®.
Urothelial carcinoma is an aggressive malignancy in people and is histologically classified into either low grade or high grade. The low grade, superficial type is more prevalent and carries a good prognosis. The high grade, invasive type is not as common (~30% of cases) but has a high mortality rate due to metastasis.
Urothelial carcinoma in dogs resembles bladder cancer in people in multiple aspects: genetic and environmental heterogeneity, clinical signs, histopathology, disease progression, metastatic behavior, and response to platinum-based chemotherapy. The one difference is that the more aggressive, muscle-invasive type is more prevalent in our canine population (~90% of cases).
A review article in Veterinary Journal (Fulkerson et. al. 2015), showed multiple chemotherapy protocols and non-steroidal anti-inflammatory medications (NSAIDs) that have been used to treat canine TCC. Despite this, the average survival time remains only 10-12 months when a combination of chemotherapy and NSAIDs are used.
Epidermal growth factor receptors 1 and 2 (EGFR and HER2) are commonly over-expressed in varying solid tumors, including about 60-70% of canine urothelial carcinoma cases. Cronise et. al. used BRAF mutant and wild-type cells to determine the role of BRAF mutations in transitional cell carcinoma (TCC) pathogenesis and evaluate the effectiveness of MAPK inhibition as a treatment for canine TCC. They were not only able to identify a combination treatment that targeted the ErbB/MAPK pathway but also show the utility of canine bladder cancer as a naturally-occurring model for people.
In a previous study, the authors of this scientific report evaluated the anti-tumor effect of lapatinib in TCC cell lines. Using RNA sequencing, this group showed that human epidermal growth factor 2 (HER2) was the most activated upstream regulator relative to canine TCC carcinogenesis. Lapatinib, a tyrosine kinase inhibitor of HER2, inhibited phosphorylation and cell growth in a dose-dependent manner.
In this current study, the authors wanted to evaluate using lapatinib as a first-line treatment for canine TCC and whether HER2 over-expression could predict its efficacy.
A total of 86 dogs were enrolled and were assigned to two groups based on owner’s preference: those that received lapatinib and piroxicam and those that received piroxicam alone. The previous use of NSAIDs was allowed, but all patients were unified to piroxicam at the beginning of the study. There were no significant differences in clinical variables between the two groups, including age, gender, weight, tumor characteristics, presence of metastasis, and BRAF gene status.
Most dogs in the lapatinib/piroxicam group showed a reduction in their tumor burden. Median progression-free survival (PFS) was 193 and 90 days for the lapatinib/piroxicam group and piroxicam alone group, respectively. Median overall survival (OS) for dogs treated with the combination therapy was 435 days versus 216 days for those treated with piroxicam alone.
Of the 44 dogs on combination treatment, 36 (82%) reported an adverse event. Most of these were grade 1 or 2 and were transient in nature. The most common side effects were increases in ALT and ALP, vomiting, diarrhea, anorexia, increase in total bilirubin and creatinine. Other side effects reported were dermatologic in nature, like hyperpigmentation, pruritus, skin ulceration, and alopecia. Only 4 of the 36 dogs had their lapatinib dose reduced due to side effects. 17 of the 42 dogs (40%) treated with piroxicam alone reported adverse events. These included increases in creatinine and ALP, anorexia, and vomiting.
HER2 positivity was observed in 29 of 44 (66%) cases and was associated with a favorable response in dogs treated with lapatinib/piroxicam. Likewise, PFS and OS for HER2 positive cases were longer than those for HER2 negative cases.
A somatic point mutation in the BRAF gene (BRAFV595E), which is homologous to the human BRAFV600E mutation, is found in over 70% of dogs diagnosed with urothelial carcinoma. Of the 44 dogs treated with lapatinib/piroxicam, BRAFV595E mutation was detected in 32 (73%) cases. There was no association between BRAFV595E mutation and clinical response in these 44 dogs. PFS and OS were also not related to the BRAFV595E mutation.
This study showed that first-line lapatinib in combination with piroxicam was associated with clinical benefit in a canine muscle-invasive urothelial carcinoma model, especially in those with HER2 positive tumors. The objective response rate (ORR) for those receiving combination therapy was 55%, and the median PFS and OS were 193 and 435 days, respectively. This is comparable to those who historically have received cisplatin-based protocols or mitoxantrone in combination with piroxicam.
The authors discussed several limitations with this study. First, even though it was a prospective trial, it was not randomized by design. The designation to the treatment group was governed by the owner’s preference. Second, histological grading found in previous reports could not be applied as most biopsy samples were not full-thickness. Third, HER2 status was only evaluated in dogs receiving the combination of lapatinib/piroxicam. The prevalence of HER2 over-expression could differ between treatment groups affecting survival. The authors did not evaluate EGFR, another target of lapatinib, based on their previous data that lapatinib’s antitumor effect is associated with HER2. However, some dogs in this study did not over-express HER2 but still responded to lapatinib. For that reason, it would be necessary to evaluate the association between EGFR expression and therapeutic effects of lapatinib.
In order to assess response, a single ultrasound operator measured bladder and/or urethral masses and recorded the estimated tumor volume. Ultrasound was used for imaging as it could be done without general anesthesia (which would be required for CT). There is subjectivity with this modality even when using a single operator. Despite this concern, ultrasound is still used as the most common modality to assess response given there is often no need for sedation or anesthesia.
This study not only validates the safety of lapatinib in dogs but also its benefit in treating aggressive urothelial carcinoma in our canine patients. In addition, it presents data that suggests dogs can safely tolerate higher dosages or laptinib than previously thought. In this study a dosage of 20-30 mg/kg/day lapatinib was used. In another paper, Evaluation of the proper dosage of lapatinib and its safety in dogs (Translat Regulat Sci. 2(3): 68–71, 2020; doi: 10.33611/trs.2020-013), found that dogs tolerated a dosage of up to 35 mg/kg/day. This higher dosage may allow us to be more aggressive in our approach while maintaining a good quality of life for our patients.
FidoCure is pleased that these studies validate the use of targeted therapy in dogs with TCC, the safety of lapatinib's use in dogs and the suggested dosage recommendations for lapatinib.