Cabozantinib Shows Activity in Metastatic Urothelial Carcinoma

By Will Boggs MD

July 24, 2020

NEW YORK (Reuters Health) - Monotherapy with the multikinase inhibitor cabozantinib provides objective responses in some patients with platinum-refractory metastatic urothelial carcinoma, according to findings from a phase 2 trial.

"Cabozantinib has monotherapy activity in this setting and has innate and adaptive immunomodulatory properties that might counteract tumor-induced immunosuppression, providing a rationale for combining with checkpoint inhibitors," Dr. Andrea B. Apolo from the National Cancer Institute, Bethesda, Maryland told Reuters Health by email.

When combination platinum-based chemotherapy fails in patients with metastatic urothelial carcinoma, one of five immune checkpoint inhibitors approved by the U.S. Food and Drug Administration can be employed, but the objective response rate for all of these inhibitors is modest. Erdafitinib and enfortumab vedotin are also approved for use in these patients.

Cabozantinib, approved for first-line and second-line metastatic clear-cell renal cell carcinoma, progressive medullary thyroid cancer, and advanced progressive hepatocellular carcinoma, has been shown to suppress hepatocyte growth factor (HGF)-MET (oncogene)-mediated tumor cell growth in xenograft models of urothelial carcinoma.

Dr. Apolo and colleagues evaluated the clinical activity of cabozantinib in 68 patients with platinum-refractory metastatic urothelial carcinoma with measurable disease (cohort 1), bone-only metastases (cohort 2), and rare variant histologies of the genitourinary tract (cohort 3) in their phase 2, single-arm, open-label study.

Among the 42 patients in cohort 1 who were evaluable for response, there was one complete response and seven partial responses, for an objective response rate of 19%. The best response was stable disease in 19 patients (45%). Fifteen patients (36%) had progressive disease.

Three of five evaluable patients in cohort 2 had a bone response, and five of 10 evaluable patients in cohort 3 had stable disease as a best response. All other patients in these 2 cohorts had progressive disease, according to the online report in Lancet Oncology.

In cohort 1, median progression-free survival was 3.7 months and median overall survival was 8.1 months. Progression-free survival rates were 37% at six months and 10% at 12 months, and overall survival rates were 64% at six months and 26% at 12 months.

Median progression-free survival was 5.3 months in cohort 2 and 2.9 months in cohort 3, and median overall survival was 9.3 months in cohort 2 and 5.8 months in cohort 3.

Cabozantinib modulated peripheral blood myeloid populations and significantly increased the expression of PD-1 on regulatory T cells while significantly downregulating the checkpoint protein TIM-3 on regulatory T cells.

Common adverse events included fatigue (68%) and diarrhea (66%), but only five patients (7%) discontinued treatment because of adverse events. Most patients had at least one dose reduction (66%) or required dose delays (74%).

"I see cabozantinib as monotherapy in patients that have progressed after platinum-based chemotherapy, check-point inhibition, erdafitinib (if they harbor an FGFR 2 or 3 alteration), and enfortumab vedotin with lymph nodes, lung and/or bone metastases," Dr. Apolo said.

"Based on these findings, we have conducted and completed a phase 1 study of cabozantinib + nivolumab and cabozantinib + nivolumab + ipilimumab that has also demonstrated activity in urothelial carcinoma and other genitourinary tumors," she said. "The activity of the combination has served as a backbone for large phase 3 studies."

"Considering these results, the combination of cabozantinib with an immune checkpoint inhibitor might be a reasonable therapeutic strategy against metastatic urothelial cancer," write Dr. Eiji Kikuchi and Dr. Nozomi Hayakawa from St. Marianna University School of Medicine, Kawasaki, Japan in a related editorial. "Currently, various clinical trials evaluating cabozantinib plus an immune checkpoint inhibitor for the treatment of metastatic urothelial cancer (NCT02496208, NCT03170960, and NCT03824691) are being done."

"The adverse events associated with tyrosine kinase inhibitor therapy must not be underestimated in a palliative setting, which is the case for the majority of patients with metastatic urothelial cancer who are platinum-refractory," they add. "Further study is warranted to pursue the quality-of-life assessment and the extent of long-term adverse events in patients with metastatic urothelial cancer treated with cabozantinib."

SOURCE: https://bit.ly/3j6ia0R and https://bit.ly/2OtLznC Lancet Oncology, online July 6, 2020.

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