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ASCO GU 2019

ASCO GU 2019: A Phase II study of Cabozantinib as First-line Treatment in Metastatic Collecting Duct Carcinoma: The BONSAI Trial

San Francisco, CA (UroToday.com) Metastatic collecting duct carcinoma is a rare and aggressive disease, characterized by a poor prognosis. This histology of kidney cancer is diagnosed based on several histologic features: high-grade atypia, desmoplastic stromal reaction, medullary location, infiltrative growth, tubular architecture, and exclusion of clear cell and translocation cell carcinoma. These tumors have been characterized by upregulation of genes involved in T-cell activation and proliferation, as well as those involved in lymphocyte infiltration1.   Many collecting duct carcinomas also have alterations in CDKN2A, as well as Hippo NF2 (30%), SETD2 and SMARCB12. Despite being a rare histologic subtype of RCC, collecting duct carcinoma treatment represents an unmet medical need. At GU ASCO renal cancer poster session, Dr. Procopio and colleagues presented results of their study evaluating the activity and safety of cabozantinib in metastatic collecting duct carcinoma. The author’s hypothesis was that cabozantinib might be active in blocking multiple intracellular pathways and could be effective in achieving good response rates, and hopefully improvements in progression-free survival (PFS) and overall survival (OS).

The BONSAI trial is a prospective, monocentric, single-arm phase II trial evaluating cabozantinib in patients with untreated metastatic collecting duct carcinoma. Cabozantinib was administered at the dose of 60 mg orally once daily until disease progression, evaluated by RECIST 1.1 criteria, or unacceptable toxicity. The main inclusion criteria included untreated, unresectable, advanced or metastatic collecting duct carcinoma and ECOG performance status of 0-1. The primary endpoint of this study was objective response rate and secondary endpoints included PFS, OS, and safety profile. Exploratory objectives include the identification of somatic mutations and the mutational load on tissue samples, whereby plasma and viable peripheral blood mononuclear cells were studied for immune related biomarker profiling. The authors note that the study design is based on a Simon’s two-stage optimal design: in the first step, at least two responses in nine patients enrolled are needed to go to the second stage of the study (14 additional patients).

From January 2018 to September 2018, 9 patients with metastatic collecting duct carcinoma were enrolled, nine of which started study treatment. Median age was 58 years, eight patients were male, and seven patients received a previous radical nephrectomy. The most common metastatic sites were bone and abdominal lymph nodes (five patients each), followed by liver and lung (two patients each). Two patients had a partial response as best response, two had a stable disease, three had progressive disease, and three patients died from early progression. Treatment was feasible and well tolerated, albeit all patients reported at least one Grade 1-2 adverse events, most commonly asthenia, diarrhea, anorexia and nausea, hand-foot syndrome, hypertension and dysgeusia. There were no Grade 3-4 adverse events reported. The authors report that genetic and immunological assays are ongoing to assess the immunomodulatory properties of cabozantinib and potential predictive factors.

For a rare histologic subtype of renal cell carcinoma that desperately needs advances in systemic therapy, these results suggest that cabozantinib may be safe and active in metastatic collecting duct carcinoma. The authors note that the second stage and biomarkers analyses are ongoing for this clinical trial. Clinical trial information: NCT03354884

Presented by: Giuseppe Procopio, Medical Oncology Unit, Istituto Nazionale Tumori Milano, Milan, Italy

Written By: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter:@zklaassen_md at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

References:
1. Malouf GG, Comperat E, Yao H, et al. Unique Transcriptomic Profile of Collecting Duct Carcinomas Relative to Upper Tract Urothelial Carcinomas and other Kidney Carcinomas. Sci Rep. 2016;6:30988.
2. Pal SK, Choueiri TK, Wang K, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol. 2016;70(3):516-521.