Phase II study of everolimus in metastatic urothelial cancer

Authors

  • Matthew I. Milowsky,

    Corresponding author
    1. Weill Cornell Medical College, New York, NY, USA
    • Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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  • Gopa Iyer,

    1. Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    2. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    3. Weill Cornell Medical College, New York, NY, USA
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  • Ashley M. Regazzi,

    1. Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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  • Hikmat Al-Ahmadie,

    1. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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  • Scott R. Gerst,

    1. Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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  • Irina Ostrovnaya,

    1. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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  • Lan L. Gellert,

    1. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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  • Rana Kaplan,

    1. Division of Pulmonary Medicine, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    2. Weill Cornell Medical College, New York, NY, USA
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  • Ilana R. Garcia-Grossman,

    1. Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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  • Deepa Pendse,

    1. Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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  • Arjun V. Balar,

    1. Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    2. Weill Cornell Medical College, New York, NY, USA
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  • Anne Marie Flaherty,

    1. Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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  • Alisa Trout,

    1. Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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  • David B. Solit,

    1. Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    2. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    3. Weill Cornell Medical College, New York, NY, USA
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  • Dean F. Bajorin

    1. Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
    2. Weill Cornell Medical College, New York, NY, USA
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Correspondence: Matthew I. Milowsky, Lineberger Comprehensive Cancer Center, University of North Carolina, 170 Manning Drive, Chapel Hill, NC 27599-7305, USA.

e-mail: matt_milowsky@med.unc.edu

Abstract

What's known on the subject? and What does the study add?

  • No recent advances have been made in the treatment of patients with advanced bladder cancer and, to date, targeted therapies have not resulted in an improvement in outcome. The mammalian target of rapamycin pathway has been shown to be up-regulated in bladder cancer and represents a rational target for therapeutic intervention.
  • In the present phase II study of everolimus, one near-complete response, one partial response and several minor responses suggest that everolimus possesses biological activity in a subset of patients with bladder cancer. To maximize benefit from targeted agents such as everolimus, the preselection of patients based on molecular phenotype is required.

Objective

  • To assess the efficacy and tolerability of everolimus in advanced urothelial carcimoma (UC).

Patients and Methods

  • The present study comprised a single-arm, non-randomized study in which all patients received everolimus 10 mg orally once daily continuously (one cycle = 4 weeks).
  • In total, 45 patients with metastatic UC progressing after one to four cytotoxic agents were enrolled between February 2009 and November 2010 at the Memorial Sloan-Kettering Cancer Center.
  • The primary endpoints were 2-month progression-free survival (PFS) and the safety of everolimus, with the secondary endpoint being the response rate.
  • A Simon minimax two-stage design tested the null hypothesis that the true two month PFS rate was ≤50%, as opposed to the alternative hypothesis of ≥70%.

Results

  • The most common grade 3/4 toxicities were fatigue, infection, anaemia, lymphopaenia, hyperglycaemia and hypophosphataemia.
  • There were two partial responses in nodal metastases, with one patient achieving a 94% decrease in target lesions and remaining on drug at 26 months.
  • An additional 12 patients exhibited minor tumour regression.
  • There were 23 of 45 (51%) patients who were progression-free at 2 months with a median (95% CI) PFS of 2.6 (1.8–3.5) months and a median (95% CI) overall survival of 8.3 (5.5–12.1) months.
  • No clear association was observed between mammalian target of rapamycin pathway marker expression and 2-month PFS.

Conclusions

  • Although everolimus did not meet its primary endpoint, one partial response, one near-complete response and twelve minor regressions were observed.
  • Everolimus possesses meaningful anti-tumour activity in a subset of patients with advanced UC.
  • Studies aiming to define the genetic basis of everolimus activity in individual responders are ongoing.

Ancillary