Kidney Cancer Journal 83
Evolving Role of TKI Monotherapy in
Front Line Metastatic Clear Cell RCC
yrosine kinase inhibitors (TKI) directed against the Vascular
Endothelial Growth Factor (VEGFR) were unquestionably
the gold standard for front-line therapy in
advanced renal cell carcinoma for years. Results from combination
immunotherapy trials have challenged this approach.
The field is in flux as we await data from several ongoing already
accrued phase 3 trials comparing the combinations of
immunotherapy and VEGF/VEGFR inhibitors with TKI monotherapy.
Nevertheless, it is important to revisit guidelines on
the use of front-line TKI monotherapy, not only to identify special
considerations and recognize subsets of patients who could
still benefit from them, but also to consider how other hypothesis
generating studies could further refine current strategies
in the context of biomarkers development.
As the biology of renal cell carcinoma (RCC) has unraveled,
the molecular rationale for the use of targeted therapy
has been clearly delineated in numerous reports.
With the recognition that the majority of sporadic clearcell
RCC (ccRCC) tumors are characterized by VHL tumor
suppressor gene inactivation leading to VEGF overexpression,
small molecules with inhibitory effects against
the VEGF receptor transformed the landscape and displaced
cytokine therapies, established during the 1990s
as the first-line standard of care. As such, tyrosine kinase
inhibitors (TKIs), initially sunitinib and pazopanib and
more recently, cabozantinib, profoundly affected the
management of first line advanced RCC, ushering in new
treatment algorithms.
With new combinations of immunotherapies with
and without VEGF/VEGFR targeted agents showing
promising results in the first-line setting, it is tempting
to suggest that the era of TKI monotherapy is over (Figure).
Already, the combination of nivolumab and ipilimumab
has been approved by the FDA for the first line
treatment of those with poor or intermediate risk RCC.
As the time of writing of this article, two large phase 3 trials
of atezolizumab or avelumab (both PD-L1 inhibitors)
in combination with VEGF inhibitors met their primary
end- point of superiority in term of progression-free survival
(PFS) over single agent sunitinib.1,2 Yet, depending
on prognostic factors and patient risk profiles, TKI monotherapy
may still play a role in the frontline setting. This
report will review most recent trials evaluating frontline
TKIs, offering perspectives on their sustained importance
in the therapeutic sequence and essential considerations
about patient selection.
Prognostic Considerations
The importance of TKI monotherapy for metastatic
ccRCC should be put into perspective with the IMDC or
MSKCC prognostic classifications,3 of which the IMDC
was the first validated model to assess overall survival
(OS) in the era of VEGFR-directed TKIs. Since then, numerous
clinical trials of TKI monotherapy and immunotherapy
stratified the study population according to these
prognostic factors.
In the IMDC model, 6 factors were independently associated
with poor survival: hemoglobin less than the
lower limit of normal, corrected calcium greater than the
upper limit of normal, Karnofsky performance status less
than 80%, time from diagnosis to treatment of less than
1 year, neutrophils greater than the ULN and platelets
Bradley A. McGregor, MD
Clinical Director
Lank Center of Genitourinary Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
Ronan Flippot, MD
Lank Center of Genitourinary Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
Toni Choueiri, MD
Director, Lank Center for
Genitourinary Oncology
Dana-Farber Cancer institute
Boston, Massachusetts
T
Keywords: tyrosine kinase inhibitor, monotherapy, front-line, prognostic
classification, IMDC model, sunitinib, cabozantinib.
Corresponding Author: Bradley A. McGregor, MD, Dana-Farber Cancer
Institute, 450 Brookline Avenue, Boston MA, 02215
Email: Bradley_McGregor@DFCI.HARVARD.EDU
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