NcXHF

CHALLENGING THE TREATMENT PARADIGM FOR ADVANCED RENAL CELL CARCINOMA
Finally the issue of intratumor heterogeneity is potentially
relevant for the further development of targeted therapy in
kidney cancer. 10 A critical consideration is whether or not a
particular molecular aberration is a driver of tumor progression
at all tumor sites—that is, a truncal driver. To make a
further analogy with melanoma, activating mutations in
BRAF are truncal drivers in BRAF-mutant melanoma. That
is, disease progression at primary and metastatic sites is
driven by this aberration, and BRAF-targeted therapy results
in disease regression, at least temporarily, in the vast majority
of cases. Some data in clear cell renal carcinoma suggest that
mutations in VHL may be the only bona fıde truncal driver in
this disease. 11 Other mutations, for example those in SETD2
or PBRM1, may not be present at all tumor sites. This may be
therapeutically relevant, because aberrations in the mTOR
signaling pathway are relatively common in clear cell RCC,
but the overall activity of mTOR inhibitors is less than that of
anti-VEGF therapy. One possible explanation for this is that
mTOR signaling aberrations are rarely truncal drivers. This
contention, however, requires further study, particularly in
characterizing the genomic architecture of the disease at metastatic
sites.
Agents like cabozantinib may be approved in due course
for the treatment of advanced RCC, and combination therapy
remains of interest as an approach to treating this disease.
Nevertheless, without molecular characterization of patients
who have advanced RCC and clinical trials directed at resultant
specifıc populations, it is diffıcult to see how the next
decade will see the same progress in molecularly targeted
therapy that we have witnessed in the last 10 years.
INTEGRATING IMMUNOTHERAPY INTO THE
CURRENT TREATMENT PARADIGM IN ADVANCED
RENAL CELL CARCINOMA
Immunotherapy has a longstanding history in the management
of advanced renal cancer. Although monotherapy with
interferon alfa largely has been abandoned since the introduction
of targeted agents, high-dose interleukin-2 remains
an approved standard in the fırst-line setting, albeit only utilized
for a select subgroup of patients (as reviewed by McDermott
et al 12 ). Recently, a novel class of immunotherapeutics is
rapidly gaining recognition for RCC and other diseases.
These so-called checkpoint inhibitors interfere with inhibitory
cell-cell interactions that suppress the tumor-directed
T-cell response via molecules like cytotoxic T-lymphocyteassociated
protein 4 (CTLA4) and programmed death-1
(PD-1).
With a number of phase II and III trials underway, checkpoint
inhibitors presently are being tested on their own and
in combination with approved targeted agents. This growing
body of clinical data, particularly around agents targeting
PD-1 or its binding partner PD-ligand 1 (PD-L1), raises the
question of how to integrate this class of agents into the present
treatment paradigm for this disease.
Checkpoint Inhibitors in Advanced RCC: Monotherapy
Since the early 2000s, RCC drug development has chiefly revolved
around inhibition of VEGF and mTOR, which relies
on the sequential use of different agents targeting the same
pathway in any given patient who has metastatic disease (e.g.,
following VEGF inhibition with another VEGF inhibitor).
The advent of targeted immunotherapy may provide an opportunity
to add a novel class of agents to this sequence of
therapies.
Furthest in clinical development for metastatic RCC is the
fully human IgG4 monoclonal antibody nivolumab (Bristol-
Meyer Squibb, New York, NY), which targets PD-1. A doserandomized,
phase II study in patients pretreated with one to
three prior antiangiogenic therapies was recently reported. 13
Objective response rates (ORRs) of approximately 20% and a
median PFS of approximately 4 months were comparable to
effıcacy data for approved targeted agents in the pretreated
space. 14,15 OS exceeded historic controls (median OS, approximately
25 months in the higher dose-levels versus approximately
15 months for approved targeted agents in
pretreated patients). Such cross-trial comparisons are of limited
value, but this marked difference in the reported OS may
reflect longer-lasting immunomodulatory effects that may
enhance the effectiveness of subsequent agents, particularly
in the light of the modest PFS fındings. This would argue in
favor of using nivolumab maximally early, ideally fırst line, in
a patient’s course of disease. The sponsor has chosen to develop
nivolumab for monotherapy in pretreated patients
(with parallel development of combination strategies in
fırst-line settings); a phase III trial that randomly assigned
patients to nivolumab versus everolimus after one or two
prior antiangiogenic therapies (NCT01668784) has completed
accrual. The primary endpoint is OS, prompted by the
phase II signal; this endpoint represents a paradigm shift for
this disease, in which registration studies have typically pursued
PFS as the primary endpoint.
It has been suggested that the antitumor effects of nivolumab
and other compounds can extend beyond the end of
treatment; anecdotally, a number of patients have not required
further therapies for extended periods of time. For
those patients who experience disease progression during
treatment, however, it is unclear if and how immune modulation
with checkpoint inhibitors affects effectiveness
and tolerability of subsequent, nonimmunotherapy treatments.
As the fıeld’s clinical experience with these compounds
increases, it will be important to investigate these
questions prospectively to optimize the clinical use of targeted
immunotherapy.
There are no established biomarkers for the use of approved
VEGF- and mTOR-directed agents, and patients are
not selected for therapy on the basis of molecular features.
With the introduction of a novel class of agents, the question
of whether this paradigm should change has arisen. The signifıcance
of the expression of PD-L1 on tumor cells or
tumor-infıltrating lymphocytes is best studied for PD-1 inhibition.
With monotherapy, stronger expression levels appear
to correlate with higher response rates, but patients who have
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