NcXHF

CHALLENGING THE TREATMENT PARADIGM FOR ADVANCED RENAL CELL CARCINOMA
Challenging the Treatment Paradigm for Advanced Renal Cell
Carcinoma: A Review of Systemic and Localized Therapies
Axel Bex, MD, PhD, James Larkin, FRCP, PhD, and Martin Voss, MD
OVERVIEW
The current standard of care for the management of advanced renal cell carcinoma (RCC) revolves around systemic therapy with
molecularly targeted agents. Over the last decade, a total of seven targeted drugs have been approved but, altogether, only exploit
two molecular targets in this disease: the vascular endothelial growth factor (VEGF) axis and the mammalian target of rapamycin
(mTOR). Introduction of these agents has markedly improved outcomes compared with those in the cytokine era, yet comparatively
little progress has been made since registration of the first targeted therapeutics occurred 10 years ago. In this article, we review
efforts to improve on this current treatment paradigm. We discuss novel targets in this disease and corresponding new agents under
investigation. The article dedicates particular attention to targeted immunotherapeutics, which are rapidly emerging as a new category
of interest in this disease. Last, we review current data supporting the use of surgical interventions to improve outcomes in patients
with metastatic disease.
Targeted therapy for kidney cancer has revolutionized the
management of metastatic disease in the last 5 years, but
major challenges remain. First, these drugs typically control
disease for approximately 9 months in fıt patients in the fırstline
setting and for approximately 5 months in subsequent
lines of therapy. As such, there is a clear scope for identifying
new pathways and targets as well as better selection of patients
for therapy. Second, a new generation of immunotherapy
agents is in development; should these drugs be approved
for use, their integration into current treatment paradigms
requires investigation. Third, local therapy for metastatic disease
plays a signifıcant role in the management of metastatic
kidney cancer and is associated with prolonged survival, despite
the lack of a high-quality evidence base. We review here
these three areas of clinical and scientifıc literature in kidney
cancer in 2015.
NEW PATHWAYS AND TARGETS IN CLEAR CELL
KIDNEY CANCER
Since the approvals of the multitargeted kinase inhibitors
sorafenib and sunitinib and the mTOR inhibitor temsirolimus
almost 10 years ago for the treatment of advanced kidney
cancer, it could be argued that relatively little progress
has been made with targeted therapy for this disease. A number
of new, but similar, agents, such as pazopanib, axitinib
and everolimus, have subsequently been approved. However,
gains in effıcacy, if any, have been modest compared with the
effıcacy of the earlier generation of agents, and sunitinib remains
a standard of care for the fırst-line treatment of advanced
disease in 2015. Furthermore, all of the approved
targeted agents, with the exception of the anti–VEGF
monoclonal antibody bevacizumab, are either mTOR inhibitors
or multitargeted kinase inhibitors. Moreover, the
multitargeted kinase inhibitors all inhibit at least one
isoform of the VEGF receptor in addition to, sometimes,
dozens of other targets. Notably, there is currently no
strong evidence that any of the other targets inhibited by
these agents is of therapeutic relevance in clear cell renal
carcinoma.
Augmenting Anti-VEGF and mTOR Strategies
Two recent approaches to developing new agents for the
treatment of kidney cancer have focused, fırst, on broader
targeting of the phosphoinositide 3-kinase (PI3K)/mTOR
signaling pathway and, second, on the evaluation of multitargeted
kinase inhibitors and drug combinations that in addition
to targeting the VEGF axis also target other putative
drivers in advanced renal cell carcinoma (RCC) and potential
mediators of resistance to VEGF inhibition (e.g., fıbroblast
growth factor receptor [FGFR] and c-MET).
Initial attempts to better target the mTOR signaling pathway
have not met with success to date. For example, a small,
randomized, phase II study of the dual pan-PI3K and
TORC1/2 inhibitor apitolisib (GDC0980) versus everolimus
in patients refractory to anti-VEGF therapy reported inferior
From the Netherlands Cancer Institute, Amsterdam, Netherlands; The Royal Marsden NHS Foundation Trust, London, United Kingdom; Memorial Sloan Kettering Cancer Center, New York, NY; Weill
Cornell Medical College, New York, NY.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Axel Bex, MD, PhD, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands; email: a.bex@nki.nl.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e239