Frontline Strategies in RCC: Capturing Pivotal
New Data, Optimizing Treatment Options
Toni K. Choueiri, MD
Director of the Lank Center
for Genitourinary (GU)
Oncology at Dana-Farber
Cancer Institute/Brigham
and Women’s Hospital
Associate Professor of Medicine,
Harvard Medical School
Boston, Massachusetts
Editor’s note: This report by the Kidney Cancer Journal integrates recently published peer-reviewed
medical literature and results presented at two meetings, the European Society of Medical Oncology
(ESMO) sessions and the Society for Immunotherapy of Cancer (SITC) meeting, both held in late 2017.
The content, compiled independently by the journal, was assessed for accuracy, clarity, and relevance
by the three peer reviewers whose investigative work has focused on trends covered in this report.
ompelling evidence for the approval of two therapies as
frontline strategies in intermediate and poor-risk advanced
renal cell carcinoma (RCC) has raised expectations
that significant improvements in progression-free survival
and overall survival are possible with a manageable safety profile
in patients previously treated with the conventional antiangiogenic
standard of care. Cabozantinib was approved for
all first-line RCC patients on December 19, 2017 so it can be
considered a new standard of care option. Clinicians can look
forward to a broader spectrum of therapy to optimize outcomes,
based on results from two pivotal trials analyzed here.
The momentum of two clinical trials has generated expectations
and excitement that a realignment of strategies
in the first-line treatment of renal cell carcinoma has
indeed arrived. For 10 years, the focus of frontline therapy
generally has been antiangiogenic agents that target the
vascular endothelial growth factor (VEGF) and its receptors,
and the blockade of the VEGF signaling pathway has
been the standard treatment based on improved clinical
outcomes in randomized phase III trials.1 However, recent
results presented at the European Society of Medical
Oncology (ESMO) meeting in 2017 suggest how this realignment
of strategies may take shape in the coming
year as the FDA considers approval of new options for
frontline therapy in RCC.
As we look beyond ESMO and attention turns toward
94 Kidney Cancer Journal
further exploration of immunotherapy, including the
combination of ipilimumab-nivolumab, and the rationale
for using the TKI cabozantinib, there is wide speculation
on how the treatment algorithm will change, what special
considerations, including PD-L1 status, could be important
in selecting appropriate therapy, and how new
combinations can be sequenced to achieve optimal outcomes.
As much as ESMO helped clarify these choices, it
also presented even more challenges and questions still to
be addressed as phase III investigations further explore
the importance of:
• multi-pathway inhibition involving not only VEGF
but also MET and AXL.
• the role of biomarkers such as PD-L1 status and how
that could be integrated into assessments to identify
patients who may benefit from immune-oncology
based treatment.
• the tolerability of various agents
• the presence or absence of bone metastases and other
pre-existing conditions, such as autoimmune disease.
• risk status and how that may stratify patients for various
treatments, including the use of sunitinib.
Two Therapies and their Mechanisms of Action
Cabozantinib
Cabozantinib (Cabometyx) is a small-molecule inhibitor
of the VEGF receptor and, in addition, inhibits MET and
AXL, receptors shown to be upregulated in VHL-deficient
RCC cells and associated with resistance to VEGF-directed
therapy in preclinical RCC models.1 Furthermore, cabozantinib
has been shown to directly inhibit migration and
invasion in RCC cell lines that have been stimulated with
hepatocyte growth factor, the ligand for MET.1 Cabozantinib
tablets were approved by regulatory authorities on
the basis of a randomized phase III trial in patients with
Keywords: renal cell carcinoma, intermediate and poor risk-patients,
cabozantinib, CABOSUN, Checkmate214, ipilimumab, nivolumab,
AXL, MET, sunitinib, standard of care, progression-free survival,
overall survival.
Corresponding Author: Toni K. Choueiri, MD, Dana Farber Cancer
Institute, 440 Brookline Ave, Boston, MA 02215
Email address:Toni_Choueiri@dfci.harvard.edu
Daniel J. George, MD
Professor of Medicine
Professor in Surgery
Member of the Duke
Cancer Institute
Durham, North Carolina
Gisela M. Schwab, MD
Chief Medical Officer
Exelixis, Inc.
South San Francisco,
California
C