Flare Phenomenon or Pseudoprogression
During ICI Therapy in RCC: Potential Value of
Treatment Beyond First Progression
Saby George, MD
A
consistent theme emerging from recent studies across
tumor types is that a fraction of patients will potentially
benefit from treatment beyond progression in
terms of tumor shrinkage as well as overall survival advantage
suggested by the hazard ratios from Kaplan Maier analysis.
New guidelines for patient assessment after first progression
are evolving as the concept of pseudoprogression underscores
the pitfalls in relying on RECIST criteria alone. Careful consideration
by treating physicians after informed consent to
continue beyond progression is the appropriate strategy and
is supported by mounting evidence in the literature. This review
highlights the translational impact of pivotal studies
such as CheckMate 025 and other evidence from pooled and
subgroup analyses.
A dramatic shift in the treatment paradigm for renal cell
carcinoma (RCC), characterized by the introduction of
newer agents such as immune checkpoint inhibitors, has
ushered in new thinking on the management of the
disease. These newer agents such as nivolumab for the
treatment of advanced RCC in patients who have received
prior antiangiogenic therapy provide a unique mechanism
of action as opposed to many of the traditional
targeted therapies for mRCC.1 Although the era of targeted
therapy resulted in significant improvements in objective
response rate and progression-free survival (PFS),
the limitations of such strategies soon became apparent
because the majority of patients eventually experience
treatment resistance and disease progression.2,3 As a result,
the focus turned toward the need for novel treatment
options and within the last 5 years, immune
checkpoint inhibitors have shown durable responses
and have improved OS for a broad range of patients.
The wider use of immune checkpoint inhibitors has
dramatically reshaped the debate—not only on how
such therapies can more effectively be applied but on the
need to address many questions and uncertainties, including
the criteria used to measure response and the duration
of therapy needed to optimize outcomes. As part
68 Kidney Cancer Journal
of this review, we will focus on these issues, including
the extent to which standard criteria, such as the Response
Evaluation Criteria in Solid Tumors (RECIST) still
need to be adhered to or reexamined in the light of emerging
data suggesting whether RECIST-defined first progression
after immunotherapy is a valid endpoint for
determining whether such treatment needs to be discontinued.
And if RECIST-defined first progression is accepted
as a compelling argument for discontinuing immune
checkpoint therapy, would many patients have benefited
from treatment beyond progression (TBP)? Although
there is compelling evidence in recent literature clearly
favoring TBP, there is still controversy over the practice
that is becoming the standard of care. A review of the literature,
including recommendations from the FDA on
this question, will help put these issues in context.
In its mechanism of action, nivolumab, for example,
offers a useful guide to understanding the rationale for
using checkpoint inhibitors. This agent is a fully human
IgG4 programmed cell death 1 PD-1) immune checkpoint
inhibitor antibody that selectively blocks the interaction
between PD-1 and its ligands PD-L1 and PD-L2.
This interaction is the mechanism that normally leads
to immune tolerance.4 We have abundant data supporting
the use of nivolumab vs antiangiogenic therapy. In
the CheckMate 025 trial, evaluating 821 patients with
mRCC who had received earlier treatment with antiangiogenic
regimens, the use of nivolumab produced a significant
survival advantage aver everolimus (25 vs 19.6
months) and this checkpoint inhibitor also had a more
favorable side effect profile.5
Treatment with immunomodulatory agents such as
nivolumab has been controversial because of the issue
of “tumor flare” (Figure 1). This phenomenon, also referred
to as pseudoprogression, refers to what appears to
be an increase in tumor burden or the appearance of new
lesions that may be observed prior to a clinical response
in patients receiving immunotherapy.6 The cause of
tumor flare is thought to be caused by transient immune
cell infiltration into the tumor or continued tumor
growth that can occur while the immune system is priming
for an antitumor response, according to Wolchok
et al.6 The key concept in understanding the phenomenon
has been suggested by other authors: namely, the
time required to achieve an effective immune response
Saby George, MD
Associate Professor
Department of Medicine
Roswell Park Cancer Institute
Buffalo, New York
Keywords: Advanced renal cell carcinoma, everolimus, nivolumab, Phase
3 , treatment beyond progression, immune checkpoint inhibitors.
Corresponding Author: Saby George, MD, Roswell Park Cancer Institute,
Elm & Carlton St., Buffalo, NY 14263.
Email: saby.george@roswellpark.org
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