EURURO Vol. 72 No. 4

477 656

Platinum Opinion
Immune Checkpoint Inhibition in Metastatic Urothelial Cancer
Tom Powles Kate Smith Arnulf Stenzl Jens Bedke
a Barts Cancer Institute, London, UK; bDepartment of Urology, University of Tu¨bingen, Tu¨bingen, Germany
1. Introduction
Patients with newly diagnosed advanced or metastatic
urothelial carcinoma (UC) have a median survival of
approximately 1 yr with platinum-based chemotherapy
. The immune checkpoint inhibitor (ICI) atezolizumab
was approved in May 2016 for platinum-refractory disease
in the USA on the basis of impressive phase 2 data In
addition, a randomised phase 3 study has shown superiority
of pembrolizumab over standard chemotherapy in the same
population . Together, these drugs, along with others in
development, herald a new era for patients with this disease
).
2. Phase 1 data for ICI in metastatic UC
The phase 1 studies are challenging to interpret, as patient
populations are heterogeneous and the inclusion criteria
vary between trials . Response rates (according to
Response Evaluation Criteria in Solid Tumours v1.1) in
unselected patients are in the region of 20%. This picture is
further complicated, because different methods of measur-
ing the PD-L1 biomarker were used for each drug, with
distinct antibodies and different definitions of the cells
required to define positivity (tumour cell vs immune
component staining; . In addition, the tissue analysed
is often derived from surgical specimens rather than per-
protocol biopsies at defined time points. Another consid-
eration is the proportion of PD-L1–positive cells required to
define positivity (from 1% to 25% for nivolumab and
durvalumab, respectively). For avelumab, for example,
the Dako 72-10 antibody is used, and >5% tumor cell
expression and >10% immune cell (IC) expression define
positivity, while the SP142 antibody is used for atezolizu-
mab and 5% IC defines positivity. Therefore, each drug has
efficacy data in a unique biomarker population. For this
reason, validation of each biomarker in randomised trials is
required before definite conclusions can be drawn despite
the establishment of harmonization protocols .
Overall it is difficult to make any direct comparisons
from the phase 1 data . However, the following
conclusions can be drawn. Each drug is well tolerated and
associated with long-termdurable remission in a significant
proportion of patients ( 20%). In addition, it is usually
possible to enrich for response using the PD-L1 biomarker
(up to 50%; ). However, repeat biomarker testing with
different methodologies within the same trial raises the risk
of a significant type 1 error. It is unlikely that all of these
biomarkers will stand the test of time.
3. Phase 2 data in platinum-refractory UC
After impressive response rates for atezolizumab in a
phase 1 trial of 67 UC cases , a phase 2 trial was designed
to achieve regulatory approval. Atezolizumab was admin-
istered in 310 platinum-refractory mUC cases . The trial
met its primary endpoint of response rate >10%, which was
set as a benchmark based on data from mUC chemotherapy
trials . Some 32% of patients were PD-L1–positive (IC 2 or
3+). The response rate was 27% (95% confidence interval [CI]
19–37%) for PD-L1–positive patients and 15% (95% CI
11–19%) in the whole population. The median duration of
response was not reached at median follow-up of 11.7 mo
(95% CI 11.4–12.2). Progression-free survival (PFS) was
ava ilable at
journal homepage:
* Corresponding author. Experimental Cancer Medicine Centre, Barts Cancer Institute, Barts Health and the Royal Free NHS Trusts, Queen Mary
University of London, London EC1A 7BE, UK. Tel. +44 207 6018522; Fax: +44 207 6018522.
E-mail address: (T. Powles).
** Corresponding author. Department of Urology, Eberhard Karls University Tu¨ bingen, Hoppe-Seyler-Strasse 3, 72076 Tu¨ bingen, Germany.
Tel. +49 7071 2980349; Fax: +49 7071 295092.
E-mail address: (J. Bedke).
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.