Cabozantinib Plus Durvalumab in Patients With Advanced Urothelial Carcinoma After Platinum Chemotherapy: Safety and Preliminary Activity of the Open-Label, Single-Arm, Phase 2 ARCADIA Trial

Published:April 20, 2021DOI:



      Durvalumab and cabozantinib have shown single-agent activity in patients with metastatic urothelial carcinoma (UC). ARCADIA is a phase 2 study evaluating their combination in patients with platinum-treated, advanced UC (NCT03824691). Herein, we report the results of the planned interim safety analysis and the preliminary activity.

      Patients and Methods

      Patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1, UC and non-UC histology, and failure of a maximum of two regimens received cabozantinib 40 mg daily, orally, in combination with durvalumab 1500 mg, intravenously, every 28 days. Response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 every two cycles and by fluorodeoxyglucose positron emission tomography (FDG-PET) scans.


      As of August 20, 2020, 16 patients were enrolled with a median follow-up of 6.7 months (range, 2-11). Four patients (25%) had ECOG PS 1 and had received two prior regimens. No grades 3 or 4 treatment-related adverse events (TRAEs) occurred within the first two cycles. The most common grades 1 and 2 TRAEs were fatigue (7, 43.8%), diarrhea (5, 31.3%), and dysphonia (5, 31.3%). Objective responses were seen in six patients (37.5%; 95% confidence interval, 15.2-64.6), including two complete responses (12.5%). One additional patient with bone-only disease obtained a decrease in FDG uptake and in circulating tumor DNA consistent with response. Angiogenesis-related gene alterations were found in 57% responders versus 0% nonresponders.


      The durvalumab and cabozantinib combination was safe and endowed with preliminary clinical activity in patients with advanced UC. Mature results will clarify the role of cabozantinib and that of tumor biomarkers in this tumor type.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Genitourinary Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Niglio S.A.
        • Jia R.
        • Ji J.
        • et al.
        Programmed death-1 or programmed death ligand-1 blockade in patients with platinum-resistant metastatic urothelial cancer: a systematic review and meta-analysis.
        Eur Urol. 2019; 76: 782-789
      1. Necchi A., Marandino L., Raggi D., et al. Is it time to consider eliminating surgery from the treatment of locally advanced bladder cancer? [epub ahead of print]. Eur Urol10.1016/j.eururo.2020.08.022, accessed May 6, 2021.

        • Massard C.
        • Gordon M.S.
        • Sharma S.
        • et al.
        Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer.
        J Clin Oncol. 2016; 34: 3119-3125
        • Powles T.
        • O'Donnell P.H.
        • Massard C.
        • et al.
        Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study.
        JAMA Oncol. 2017; 3e172411
        • Yakes F.M.
        • Chen J.
        • Tan J.
        • et al.
        Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.
        Mol Cancer Ther. 2011; 10: 2298-2308
        • Bergerot P.
        • Lamb P.
        • Wang E.
        • Pal S.K.
        Cabozantinib in combination with immunotherapy for advanced renal cell carcinoma and urothelial carcinoma: rationale and clinical evidence.
        Mol Cancer Ther. 2019; 18: 2185-2193
        • Apolo A.B.
        • 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. 2020; 21: 1099-1109
        • Agarwal N.
        • Vaishampayan U.
        • Green M.
        • et al.
        Phase 1B study (COSMIC-021) of cabozantinib with atezolizumab: results of the dose escalation stage in patients (pts) with treatment-naïve advanced renal cell carcinoma (RCC).
        Ann Oncol. 2018; 29: viii303-viii331
        • Nadal R.
        • Mortazavi A.
        • Stein M.
        • et al.
        Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies.
        J Clin Oncol. 2018; 36: 515
        • Agarwal N.
        • Loriot Y.
        • McGregor B.A.
        • et al.
        Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): results of Cohort 6 of the COSMIC-021 Study.
        J Clin Oncol. 2020; 38: 139
        • Yau T.
        • Zagonel V.
        • Santoro A.
        • et al.
        Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040.
        J Clin Oncol. 2020; 38: 478
        • Pal S.K.
        • Agarwal N.
        • Loriot Y.
        • et al.
        Cabozantinib in combination with atezolizumab in urothelial carcinoma previously treated with platinum-containing chemotherapy: results from cohort 2 of the COSMIC-021 study.
        J Clin Oncol. 2020; 38: 5013
        • Raggi D.
        • Miceli R.
        • Sonpavde G.
        • et al.
        Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis.
        Ann Oncol. 2016; 27: 49-61
        • Bellmunt J.
        • de Wit R.
        • Vaughn D.J.
        • et al.
        Pembrolizumab as second-line therapy for advanced urothelial carcinoma.
        N Engl J Med. 2017; 376: 1015-1026
        • Balar A.V.
        • Castellano D.
        • O'Donnell P.H.
        • et al.
        First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study.
        Lancet Oncol. 2017; 18: 1483-1492
        • Frampton G.M.
        • Fichtenholtz A.
        • Otto G.A.
        • et al.
        Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing.
        Nat Biotechnol. 2013; 31: 1023-1031
        • Chalmers Z.R.
        • Connelly C.F.
        • Fabrizio D.
        • et al.
        Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.
        Genome MED. 2017; 9: 34
        • Clark T.A.
        • Chung J.H.
        • Hughes J.D.
        • et al.
        Analytical validation of a hybrid capture-based next-generation sequencing clinical assay for genomic profiling of cell-free circulating tumor DNA.
        J Mol Diagn. 2018; 20: 686-702
        • Forbes S.A.
        • Beare D.
        • Gunasekaran P.
        • et al.
        COSMIC: exploring the world's knowledge of somatic mutations in human cancer.
        Nucleic Acids Res. 2015; 43: 805-811
        • Trabucco S.E.
        • Gowen K.
        • Maund S.L.
        • et al.
        A novel next-generation sequencing approach to detecting microsatellite instability and pan-tumor characterization of 1000 microsatellite instability-high cases in 67,000 patient samples.
        J Mol Diagn. 2019; 21: 1053-1066
        • Petrylak D.P.
        • de Wit R.
        • Chi K.N.
        • et al.
        Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial.
        Lancet Oncol. 2020; 21: 105-120
      2. AstraZeneca. Update on phase III Danube trial for Imfinzi and tremelimumab in unresectable, stage IV bladder cancer. Available at: Accessed: July 13, 2020.

        • Drilon A.
        • Rekhtman N.
        • Arcila M.
        • et al.
        Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial.
        Lancet Oncol. 2016; 17: 1653-1660
        • Drilon A.
        • Wang L.
        • Hasanovic A.
        • et al.
        Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas.
        Cancer Discov. 2013; 3: 630-635
        • Elisei R.
        • Schlumberger M.J.
        • Müller S.P.
        • et al.
        Cabozantinib in progressive medullary thyroid cancer.
        J Clin Oncol. 2013; 31: 3639-3646
        • Cancer Genome Atlas Research Network
        Comprehensive molecular characterization of urothelial bladder carcinoma.
        Nature. 2014; 507: 315-322
        • Wells S.A.
        • Robinson B.G.
        • Gagel R.F.
        • et al.
        Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.
        J Clin Oncol. 2012; 30: 134-141
        • Schlumberger M.
        • Elisei R.
        • Müller S.
        • et al.
        Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma.
        Ann Oncol. 2017; 28: 2813-2819
        • Zhang Q.
        • Luo J.
        • Wu S.
        • et al.
        Prognostic and predictive impact of circulating tumor DNA in patients with advanced cancers treated with immune checkpoint blockade.
        Cancer Discov. 2020; 10: 1842-1853