ASCO GU 2018: Phase Ib Trial of Cabozantinib in Combination with Atezolizumab in Patients with Locally Advanced or Metastatic Urothelial Carcinoma or Renal Cell Carcinoma

San Francisco, CA (UroToday.com) Dr. Neeraj Agarwal presented the phase Ib trial design for combining cabozantinib with atezolizumab in patients with locally advanced or metastatic urothelial carcinoma or renal cell carcinoma (RCC). Cabozantinib is an oral receptor tyrosine kinase inhibitor of MET, VEGFR, and TAM family receptors (TYRO3, AXL, and MER). It is approved for patients with RCC after prior therapy with antiangiogenic therapy, and has demonstrated clinical activity in urothelial carcinoma [1]. In clinical studies, cabozantinib exposure increased circulating CD8+ T cells and reduced immune-suppressive monocytes and Tregs. Additionally, in preclinical tumor models, cabozantinib increased MHC class 1 expression on tumor cells and reduced myeloid-derived suppressor cells. Cabozantinib may facilitate an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors. Atezolizumab, an anti-PD-L1 monoclonal antibody, and is approved for locally advanced/metastatic urothelial carcinoma in patients who are cisplatin-ineligible or have disease progression during/following platinum-containing chemotherapy, and patients with metastatic NSCLC and disease progression during/following platinum-containing chemotherapy.

Trial Design: This is multicenter, phase 1b, open-label study aims to assess safety, tolerability, preliminary efficacy, and pharmacokinetics of cabozantinib in combination with atezolizumab. Study centers are located in the US, UK, France, Spain, Germany, Italy and The Netherlands. The study will enroll patients with advanced urothelial carcinoma (bladder, renal pelvis, ureter, urethra) or RCC, and consists of a dose escalation and expansion phase. Pertinent exclusion criteria include prior treatment with cabozantinib or immune-checkpoint inhibitors, prior TKI therapy within 2 weeks of study treatment, and untreated brain metastases. In the dose-escalation stage, a recommended cabozantinib dose for the combination will be established. In the expansion stage, four tumor-specific cohorts will be enrolled: (i) patients with urothelial carcinoma who have progressed on/after platinum-containing chemotherapy, (ii) chemo-naïve patients with urothelial carcinoma who are cisplatin ineligible, (iii) chemo-naïve patients with urothelial carcinoma who are cisplatin eligible, and (iv) untreated patients with RCC with clear cell histology. The primary objective is to determine the objective response rate in each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, and changes in immune cell profiles with clinical outcome. The study has been initiated and enrollment target is 120 patients across the four expansion cohorts.
Clinical trial information: NCT03170960

Speaker: Neeraj Agarwal, Huntsman Cancer Hospital, Salt Lake City, UT

Co-Authors: Ulka N. Vaishampayan, Bradley Alexander McGregor, Marjorie C. Green, Nehal Mohamed, Pei-Yun Chang, Thomas Powles, Sumanta K. Pal, For the XL184-021 Study Group

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md, at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA

Reference:
1. Nadal R, Mortazavi A, Stein M, et al. Final results of a phase I study of cabozantinib (cabo) plus nivolumab (nivo) and cabonivo plus ipilimumab (Ipi) in patients (pts) with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies. ESMO 2017, abstr 846O.

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