EURURO-5317; No. of Pages 2

Platinum Priority – EditorialReferring to the article published on pp. x–y of this issue

Mammalian Target of Rapamycin Inhibitors: The Beginning of the

End or the End of the Beginning?

Thomas Powles a,b,*, Rachel Davies a, Brian Rini c

a Barts Cancer Institute, Centre for Experimental Cancer Centre, Queen Mary University of London, London, UK; b Royal Free Hospital NHS Foundation Trust,

London, UK; c Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA

E U R O P E A N U R O L O G Y X X X ( 2 0 1 3 ) X X X – X X X

ava i lable at www.sc iencedirect .com

journa l homepage: www.europea nurology.com

Mammalian target of rapamycin (mTOR) inhibitors have

been used for some time in transplant medicine [1]. More

recently, randomised trials have supported their use in the

treatment of a number of malignancies [2,3]. It is thought

that their antitumour activity works via partial disruption

of the PI3K pathway.

Both temsirolimus and everolimus are licensed in

metastatic renal cell cancer (RCC), with activity in two

specific settings [3,4]. First, temsirolimus is associated with

an overall survival (OS) advantage compared to interferon

in untreated patients with modified Memorial Sloan-

Kettering Cancer Center (MSKCC) poor-risk disease [3].

Second, everolimus delays progression-free survival (PFS)

compared to placebo in vascular endothelial growth factor

(VEGF)-refractory metastatic disease [4]. These two studies

resulted in the widespread use of mTOR inhibitors in both

untreated and previously treated patients with RCC.

The results of these positive mTOR studies led to two

further randomised trials that directly compared VEGF-

targeted therapy with mTOR inhibition. The first compared

temsirolimus and sorafenib in patients with metastatic clear

cell renal cancer who had failed sunitinib (INTORSECT) [5].

The results were perplexing in that there was no difference in

the PFS between the two drugs. There was, however, a

significant (>4 mo) survival benefit for the sorafenib arm

(12.2 vs 16.6 mo; p < 0.001). Possible explanations for this

include the influence of subsequent therapies following

progression (although no difference was noted in a limited

subset of patients with available postprogression therapy

data) or long-term effects (after progression) of one of the

agents effecting survival, such as immune modulation.

DOI of original article: http://dx.doi.org/10.1016/j.eururo.2013.08.055.* Corresponding author. Experimental Cancer Medicine Centre, Barts CanceTel. +44 (0) 207 601 8522; Fax: +44 (0) 207 601 8522.E-mail addresses: thomas.powles@bartshealth.nhs.uk, tompowles@yahoo.co

Please cite this article in press as: Powles T, et al. Mammalian Targeof the Beginning? Eur Urol (2013), http://dx.doi.org/10.1016/j.eu

0302-2838/$ – see back matter # 2013 Published by Elsevier B.V. on behalhttp://dx.doi.org/10.1016/j.eururo.2013.09.026

A second, more recent study compared sunitinib and

everolimus in untreated patients with metastatic renal

cancer (Efficacy and Safety Comparison of RAD001 versus

Sunitinib in the First-line and Second-line Treatment of

Patients with Metastatic Renal Cell Carcinoma [RECORD III])

[6]. It was designed as a switch study, where patients

received sunitinib followed by everolimus at progression, or

the reverse sequence. The most interesting data from this

study focused on the direct comparison of upfront sunitinib

and everolimus. First-line PFS came out in favour of

sunitinib (hazard ratio [HR]: 1.43; 95% confidence interval

[CI], 1.14–1.77). Subset analysis was hampered by small

numbers (<75 patients), but suggested that sunitinib

outperformed everolimus in both MSKCC poor-risk disease

and non–clear cell disease (HR: 1.77 [95% CI, 0.96-3.12] and

HR: 1.54 [95% CI, 0.86-2.75], respectively). Immature OS

analysis also indicated a nonsignificant trend favouring the

sequence of sunitinib followed by everolimus (HR: 1.24;

95% CI, 0.94–1.64). These two studies suggest that while

mTOR inhibitors may be preferable to historical treatments,

and a viable alternative in the case of VEGF-refractory

disease, their activity compared to VEGF-targeted therapy is

debatable.

A valid question at this stage is whether the two licensed

mTOR inhibitors are interchangeable in terms of activity.

While both drugs have the same active metabolite, their

metabolism is distinct. Also, due to a different route of

administration, dosing, and frequency of administration,

their activity is likely to be somewhat different. Neverthe-

less, there do appear to be some issues around the use of

both temsirolimus and everolimus when compared to

r Institute, Queen Mary University of London, London EC1A7BE, UK.

m (T. Powles).

t of Rapamycin Inhibitors: The Beginning of the End or the Endruro.2013.09.026

f of European Association of Urology.

E U R O P E A N U R O L O G Y X X X ( 2 0 1 3 ) X X X – X X X2

EURURO-5317; No. of Pages 2

VEGF-targeted therapy (sorafenib and sunitinib, respec-

tively).

In this month’s edition of European Urology, temsiroli-

mus is investigated in a large, single-arm, stage IV study in

metastatic RCC [7]. The patient population included both

untreated (42%) and previously treated patients (58%).

Patients with clear cell carcinoma (77%) and those with

non–clear cell carcinoma (33%) were included, as were a

spectrum of MSKCC risk groups (although details were

unknown in 40% of these patients). Overall, the PFS was

4.9 mo (95% CI, 4.2–5.6 mo), which appears short for a study

in which 42% of participants were first line. Indeed, subset

analysis showed a PFS and OS of 5.3 and 10.5 mo,

respectively, in the first-line setting, which is very short

for good- or intermediate-risk disease, but in line with

previous data for patients with poor-risk disease [3,8]. It is

likely that a high proportion of untreated patients included

in the study presented had poor-risk disease.

A surprising observation is that there appears to be no

significant difference in outcome (PFS or OS) in the

untreated and previously treated patients. This is almost

certainly due to the imbalance of prognostic groups. Again, a

high proportion of poor-risk patients within the untreated

patient group is a likely explanation.

The survival for the previously treated population in this

study was 12.2 mo [7], which was similar to those results

seen for temsirolimus in the INTORSECT study (second-line

temsirolimus vs sorafenib) [5]. This shows some consistency

with previous data for temsirolimus in this setting and, in

indirect comparisons, does not compare favourably with the

OS results of VEGF-targeted therapies in this setting [5,9].

Overall, these data are in line with others seen with

temsirolimus in RCC. They highlight the need to improve

mTOR inhibition in RCC. MTOR consists of two complexes,

TORC1 and TORC2. Targeting only TORC1 (as is the case for

temsirolimus and everolimus) may result in early resistance

due to signalling through the TORC2 complex [10]. A second

generation of mTOR inhibitors has been developed to

address the need to target both complexes (GDC0980

and AZ2014). They are currently under investigation in

randomised trials (NCT01793636, NCT01442090). It is

Please cite this article in press as: Powles T, et al. Mammalian Targeof the Beginning? Eur Urol (2013), http://dx.doi.org/10.1016/j.eu

hoped that these agents, along with a greater understanding

of how TORC1 and TORC2 are interlinked, will lead to a new

dawn of mTOR inhibition in RCC and beyond.

Conflicts of interest: Thomas Powles has received honoraria and an

educational grant from GlaxoSmithKline, Novartis, and Pfizer. Brian Rini

has received honoraria and an educational grant from GlaxoSmithKline

and Pfizer. Rachel Davies has nothing to disclose.

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