EURURO Vol. 72 No. 3

377 476

Platinum Priority – Editorial
Referring to the article published on pp. 368–376 of this issue
RECISTing the Temptation to Prematurely Stop Nivolumab
Michael S. Humeniuk Andrew J. Armstrong
a Department of Medicine, Duke University, Durham, NC, USA; bDepartments of Medicine and Surgery, Pharmacology, and Cancer Biology, Divisions of
Medical Oncology and Urology, Duke Cancer Institute, Durham, NC, USA
Ever since the development of chemotherapy, there has
been a need to quantify the change in the area or volume of
cancer over time to measure the benefits of therapy through
surrogate measures. In 1979 the World Health Organization
(WHO) issued the first large consensus guidelines to
consistently define measures of response or progression
. Although seemingly straightforward in introducing
concepts such as partial response and progressive disease,
challenges with the WHO guidelines included determining
the nature of ‘‘evaluable’’ lesions and whether to record all
lesions or just representative lesions. They were further
confounded by the development of technologies with
higher resolution such as computed tomography (CT) and
magnetic resonance imaging. This led to the formation of
the Response Evaluation Criteria in Solid Tumors (RECIST)
group, who re-established uniform measurement guide-
lines in 2000 RECIST was widely used but left vagaries
including details on lymph node assessment and the
documentation of progression in patients with no measure-
able disease at baseline. These concerns were addressed in
2008 with RECIST version 1.1 and have been consistently
used in global phase 3 clinical trials However, these
guidelines were developed primarily to quantify radio-
graphic changes in a reproducible manner, without clear
connections to the clinical benefits of therapy.
Fundamental to both the WHO and RECIST guidelines is
the assumption that drug therapies work via either a
cytotoxic or a cytostatic mechanism, with shrinkage
anticipated for drugs that kill cancer cells, and delays in
progression anticipated for drugs with static properties.
However, application of these models to immunotherapy in
cancer, for which a number of novel patterns of response
and progression are noted, remains work in progress. Since
immunotherapies have a well-documented phenomenon [1_TD$DIFF] of
transient enlargement of tumor size before tumor shrink-
age, referred to as pseudoprogression, there will invariably
be misclassifications of therapeutic efficacy when response
is measured using cytotoxic criteria Such alternative
patterns of response and progression may explain the
clinical benefit of the first approved checkpoint inhibitor,
ipilimumab, in melanoma, for which there was a significant
benefit in overall survival (OS) but similar progression-free
survival (PFS) when compared to a vaccine control The
relationship between response, progression, and overall
survival may also be context-dependent, as demonstrated
in the first successful phase 3 immune therapy outside of
melanoma, in which nivolumab improved both PFS and OS
over docetaxel in the second-line setting in squamous-cell
lung cancer . Since immunotherapies such as PD-1
and PD-L1 inhibitors can improve survival and quality of life
without delaying radiographic progression, we should
question our current metrics for measuring radiographic
progression.
In the study published in this issue of European Urology,
Escudier et al examined the outcomes for patients with
metastatic renal cell carcinoma (mRCC) treated with
nivolumab versus everolimus in the CHECKMATE 025 phase
3 trial who met RECIST 1.1 progression criteria and yet
continued on the study drug because of perceived clinical
benefits The primary endpoint of the phase 3 trial, OS,
was met, leading to regulatory approval of nivolumab;
however, PFS was not improved with nivolumab over
everolimus. The question the authors have asked here was
whether there was a post-progression benefit to continued
therapy that led to the improved OS observed with
nivolumab.
ava ilable at
journal homepage:
DOI of original article: .
* Corresponding author. Departments of Medicine and Surgery, Divisions of Medical Oncology and Urology, Duke Cancer Institute, DUMC Box 103861,
Duke University, Durham, NC 27710, USA. Tel. +1 919 6684667; Fax: +1 919 6606608.
E-mail address: (A.J. Armstrong).
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.