Cabozantinib May Have Clinical Activity For Platinum-Refractory Urothelial Cancer

Author: By Lynda Williams, Senior medwireNews Reporter

medwireNews: Phase II trial findings suggest that the multikinase inhibitor cabozantinib might offer a novel treatment for patients with metastatic urothelial carcinoma who have progressed on or after platinum-based chemotherapy. 

The open-label study included 68 patients with urothelial carcinoma (n=55) or a rare genitourinary tract tumour diagnosis, such as squamous cell, adenocarcinoma or neuroendocrine histology (n=13) who formed three cohorts. The patients all received at least one dose of cabozantinib 60 mg/day and were followed up for a median of 61.2 months. 

The primary endpoint of objective response rate was 19% for the 42 evaluable patients with urothelial carcinoma in cohort 1. These patients had received a mean of 2.1 prior therapies and the majority had bladder (60%) or upper tract (36%) tumours and visceral metastases (80%). 

The response rate included one complete and seven partial responses. And although 95% of this cohort subsequently died following disease progression, one patient achieved stable disease for 8 months with cabozantinib, followed by a complete response on a subsequent checkpoint inhibitor, say Andrea Apolo, from the National Cancer Institute in Bethesda, Maryland, USA, and co-workers. 

Analysis of a second cohort of five evaluable patients with bone-only urothelial carcinoma metastases after a mean of 1.8 prior therapies showed a bone response in 60% of the group on imaging. 

A third cohort was formed from 13 patients with rare histology tumours of the bladder (92%) or upper tract (8%) and visceral metastases, who had previously received a mean of 2.1 therapies. Of the 10 evaluable patients, 50% had stable disease as the best response to cabozantinib and the remainder progressive disease.  

This finding “is most probably related to the different underlying oncogenic drivers in these histologies compared with urothelial carcinoma”, the researchers postulate. 

Median progression-free survival in cohort 1 was 3.7 months and median overall survival (OS) was 8.1 months, with corresponding rates in cohort 2 of 5.3 and 9.3 months, and 2.9 and 5.8 months in cohort 3. 

Post-hoc analysis indicated that receipt of radical surgery and use of cisplatin-based first-line chemotherapy did not significantly influence OS, whereas the number of Bellmunt poor risk factors and liver metastases were associated with both survival endpoints. 

Safety analysis in the full study group indicated that cabozantinib was “generally well tolerated” despite 66% of patients requiring at least one dose reduction and 7% discontinuing treatment because of adverse events (AEs), say Andrea Apolo et al. 

The most common grade 3–4 AEs were fatigue (9%), hypertension (7%), proteinuria (6%) and hypophosphataemia (6%). Severe events included single cases of grade 3 pulmonary embolism and rectovaginal fistula, as well as other skin manifestations that resolved after treatment discontinuation. There were no treatment-related deaths. 

“The clinical activity observed in this study provides a basis for further clinical investigations of cabozantinib for the treatment of metastatic urothelial carcinoma and other patient populations with rare genitourinary malignancies”, the researchers summarise in The Lancet Oncology.

Noting that cabozantinib was associated with increased PD-1 expression on regulatory T cells “consistent with decreasing regulatory T cell immunosuppressive activity”, the investigators believe that cabozantinib in combination with immune checkpoint inhibitor therapy “might lead to new therapeutic options” for these patients. 

Reference 

Apolo AB, Nadal R, Tomita Y, et al. Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial. Lancet Oncol; Advance online publication 6 July 2020. https://doi.org/10.1016/S1470-2045(20)30202-3