Optimal Duration of Therapy in Metastatic RCC: Exploring Treatment-Free Survival with Checkpoint Inhibitors
Grayce N. Selig, MD1 Christopher J. Hoimes, DO,2 Joe Bible, PhD,3 Daniel J. George, MD,2 Michael R. Harrison, MD2
1. Duke University Medical Center
2) Duke Cancer Institute Center for Prostate and Urologic Cancers
CORRESPONDENCE:
ABSTRACT
The optimal duration of treatment for patients with metastatic renal cell
carcinoma (mRCC) on dual immune checkpoint inhibitor (ICI) therapy
remains unknown. However, there is evolving evidence that a portion of patients
who achieve a complete or partial response will have a durable response, even
after therapy discontinuation, leading to a prolonged treatment free survival
(TFS). TFS with dual ICI is a phenomenon not seen with targeted agents and has
the potential to improve patient reported outcomes and quality of life, without
altering overall survival (OS). Despite this understanding, treatment of mRCC
remains lifelong, as there has yet to be a prospective, randomized control trial to
evaluate this key question. In this review, we analyze available studies in patients
with mRCC on dual ICI therapy and propose considerations for early treatment
discontinuation. Additionally, we discuss vital questions and next steps to
help physicians and patients navigate these challenging treatment decisions.
INTRODUCTION
E ach year there are approximately 79,000 new cases of kidney
cancer in the United States 1
. This
number has steadily risen since early 1990s, at least in part due to more
sensitive imaging techniques. Over
the last 10 years the number of new
kidney and renal pelvis cases has increased by 0.6%, though death rates
over this period have fallen by 1.6%
2. Nevertheless, despite our diagnostic and therapeutic advances, kidney
cancer ultimately results in about
13,920 deaths per year in the United States1
. Over the last 20 years,
treatment of metastatic renal cell
carcinoma has drastically changed
resulting in prolonged survival. Systemic therapeutic options now include immune checkpoint inhibitors
(ICI) and targeted therapies (TT) in
combination or sequence based on
Phase III clinical trials demonstrating an overall survival advantage.
Most of these studies were designed
for treatment to continue indefinitely, until disease progression or unacceptable toxicities. Historically, this
approach made sense since most
patients progressed or developed
unacceptable toxicities by year two.
However, in the setting of immune
checkpoint inhibitors, a substantial percentage of patients tolerate
therapy without disease progression
for several years. By protocol, these
patients should continue therapy indefinitely, but is that necessary? To
date, few if any studies have been
designed to address this question.
Prognosis and Phases of Overall
Survival.
As we continue to investigate novel
biomarkers to help predict how
patients may respond to therapy,
many other factors, both patientand disease-specific, should be
examined to help determine optimal
treatment duration. Overall survival
is considered the gold standard
when evaluating new therapeutics
in RCC. However, in patient-centric
oncologic care, other endpoints are
also important to consider. Overall
survival can be broken down into
three distinct phases: time on
therapy, treatment-free survival
(TFS) and time on subsequent
therapy or death (Figure 1). In the
targeted therapy era, monotherapies
were typically sequenced, with
little TFS, since outcomes were
linked to dose intensity; however,
in the ICI era, there may be an
opportunity for meaningful TFS
without compromising OS3.
Critically evaluating these intervals
are of the utmost importance when
determining the optimal treatment
strategy. Median overall survival
for intermediate/poor risk mRCC
has dramatically improved with the
use of combination therapy, with OS
approaching 47 months with dual
ICI and 37.7 months with nivolumab
plus cabozantinib4,5. Despite
these significant advancements, a
large majority of this time is spent
in the clinic, between lab draws,
scans, provider visits and infusion
appointments. This does not
account for any unplanned hospital
admissions to address severe adverse
events. Time spent interacting
with the healthcare system, in
addition to the potential for a wide
spectrum of side effects, limits the
quality of life(QOL). Identifying a
finite treatment duration, without
reducing OS, would provide
patients with the needed balance
between maintaining an adequate
QOL outside of the hospital while
continuing to battle their disease.
.
Immunotherapy for mRCC
The systemic treatment landscape
for metastatic renal cell carcinoma
has been dramatically changed
by the advent of immunotherapy,
initially with nivolumab (N), a
PD-1 inhibitor and later with
combination therapy including PD-
(L)1 inhibitors with TKI as well as
dual immune checkpoint inhibitor
therapy. Based on the groundwork
laid by CheckMate 025, 016 and 214,
ipilimumab (I) and nivolumab (N)
are currently the only combination
immunotherapies approved in
the metastatic, treatment-naïve
intermediate and poor-risk (I/P)
setting. However, the optimal
duration of maintenance therapy
with N has yet to be elucidated. This
vital piece of information is critical,
yet there is no robust data to predict
who will respond to treatment
and when to consider treatment
discontinuation.
CheckMate 025 was the first
phase III study to evaluate singleagent nivolumab versus everolimus
in patients with previously treated
metastatic RCC. Nivolumab
demonstrated an improvment in OS
and toxicity profile when compared
to everolimus6. Given the benefits
seen with ICI monotherapy,
CheckMate 016, a phase I study,
evaluated the efficacy and safety
of dual ICI with ipilimumab and
nivolumab (I+N) in the first-line
setting. Patients were randomized
into three treatment arms to evaluate
varying dosing schema, ultimately
concluding that N at 3 mg/kg plus I
at 1 mg/kg provided similar ORR and
2-year-OS to other dosing regimens,
while minimizing toxicity7. Based on
these results, a larger, randomized
phase III multicenter placebo
control study, CheckMate 214, began
enrolling patients with previously
untreated, I/P, and metastatic
RCC8. Patients were randomized to
either N at 3 mg/kg plus I at 1 mg/kg
every 3 weeks for 4 doses followed
by N at 3mg/kg every 2 weeks (I+N)
or sunitinib (S), continued until
disease progression or unacceptable
toxicity. Notably, a protocol
amendment was made 3 years into
data collection, which allowed for
nivolumab discontinuation at 2
years in the absence of progression
or toxicity. Initial 18 month follow-up demonstrated improved median
progression-free survival (PFS),
overall response rate (ORR),
treatment-free survival (TFS),
median overall survival (OS) and
patient-reported outcomes (PRO) in
those treated with I + N vs S8.
Treatment with dual immune
checkpoint inhibitor (ICI) therapy
has improved overall survival for
patients with metastatic RCC, with
about 10% of patients achieving a
durable complete response (CR),
and another 28% achieving a partial
response (PR) with varying degrees
of tumor shrinkage8. There are many
theories as to why patients have
such a heterogeneous response to
ICIs, with two possibilities involving
the “cancer-immune set point” and
tumor microenvironment (TME).
The “cancer-immune set point” is
defined as the equilibrium between
anti-tumor immunity promoters
and suppressors. A certain
threshold must be surpassed for
a patient to optimally respond to
immunotherapy. This “set-point”
is felt to vary widely between
patients, and likely contributes
to the heterogeneous treatment
responses9. This equilibrium can
wax and wane overtime, reflecting
the tumor’s development of novel
resistance patterns. In such cases,
the continued priming of the immune
system with ongoing therapy may be
vital to maintain a durable response.
Varying dosing schema is currently
under investigation10,11. The
presence of immune cell infiltration
in the tumor and the surrounding
microenvironment are also thought
to be necessary, though not
sufficient, to achieve a response to
ICI. Checkpoint inhibitor therapy is
known to decrease T cell exhaustion
and promote the conversion to
effector and memory T cells, which
is likely necessary to achieve a
durable treatment response despite
treatment discontinuation9. This
unique durable response has not
been seen with other cancerdirected therapies and has allowed
physicians to consider treatment
discontinuation; allowing patients to
benefit from a prolonged treatmentfree survival.
Definition of Treatment-free
Survival and Key Questions
Treatment-free survival (TFS) is an
important metric to understand how
patients live with their cancer. TFS is
defined as the time from treatment
discontinuation until the start of
subsequent therapy or death. While
overall survival is the gold standard
to determine optimal therapy,
treatment-free survival should not
be overlooked, as it almost certainly
leads to improved financial,
physical, and psychological burdens
that come along with chronic
monthly infusional therapy. The
key question is, what treatment-free
interval is meaningful to patients?
If overall survival is similar, would
a prolonged treatment-free survival
be appealing, or would it simply
promote increased anxiety and fear
of recurrence? These important
questions will need to be explored
further in subsequent studies to
help physicians and patients make
important treatment decisions.
TFS in CheckMate 214
The treatment-free survival has
been evaluated as a secondary
endpoint in numerous studies. One
such study included work by Regan
et. al, who sought to evaluate the
TFS following the discontinuation
of therapy in patients with I/P
risk disease treated on CheckMate
214. Treatment-free survival and
overall survival were evaluated at 42
months. At time of evaluation 20% of
patients treated with a dual immune
checkpoint inhibitor (ICI) compared
to 9% treated with sunitinib were
treatment-free. Over the 42-month,
the mean TFS and OS for patients
with I/P risk mRCC was significantly
longer when treated with I+N vs S,
6.9 (22.9% of OS) and 30.1 months
versus 3.1 months (11.9% of OS) and
25.9 months respectively (Figure
2). In the favorable risk population,
TFS was even longer, 11.0 months vs
3.7 months12. When TFS was further
broken down, it was significantly
longer for patients who had an
objective response to therapy and
even longer in those who achieved
a CR, a median (range) of 23.5
months and 34.6 months (0.5-49.7
months) respectively 13, 14. Ongoing
studies across risk groups are aimed
at predicting who is mostly like to
objectively respond to treatment.
The median treatment duration
reported in the 42-month analysis
in the I/P risk population was
14.1 months on I+N versus 10.8
months on S. Responders remained
on therapy longer, with a median
duration of treatment of 20.6
months (17.7-23.2) and 21.2 months
(18.9-24.4) for the I+N and S
cohorts respectively 8, 12, 15. Despite
differing time on protocol therapy,
the median time between treatment
discontinuation until death was
similar, at 16 months on I+N vs 15.1
months on S; but the differences
were seen in the percentages of
patients reaching a TFS, with 43%
vs 20% of patients recording a TFS
for I+N vs S respectively (Figure 2).
When critically evaluating the TFS in
patients treated on CheckMate 214,
one must take into consideration
that the initial protocol did not allow
discontinuation of therapy until
disease progression or TRAE until
an amendment almost 3 years into
the trial. Presumably, there are a
portion of patients with CR/PR who
could have stopped therapy at 2
years, or earlier, if protocol allowed,
which would have further prolonged
the treatment-free survival 12.
Since the initial publication of
CheckMate 214, updated analyses
have been performed. At 4 years
since randomization (median follow
up 55 months), 53 (10%) of 547
patients in I+N arm and 15 (3%) of
535 patients in S arm were continued
on therapy. The median OS in I/P
risk groups was an impressive 48.1
months with I+N vs 26.6 months for
sunitinib (HR 0.65; 95% CI, 0.54-
0.78). Dual ICI demonstrated a fouryear OS probability of 50%, vs 35.8%
with sunitinib (53.4% vs 43.3% in
the ITT population)4. Five-year data
was recently published (median
follow-up 67.7 months), which again
confirmed superior OS for I/P risk
patients with I+N vs S, median OS
47.0 vs 26.6 months (HR 0.68 and
95% CI 0.58 to 0.81), respectively.
Five-year OS probabilities were
43% on I+N versus 31% on S16,17. Responders to I+N appeared
to have decreased disease burden
and higher PD-L1 expression as
compared to nonresponders, with
75% of responders achieving an
objective response by 4 months 15.
TFS with Complete Response (CR).
At 4 years, 10.7% (59) of patients
achieved a complete response
on I+N, with over 75% of these
responses occurring by 11.3 months
(3.8-15.4). Most converted from a
PR (75.9%) or SD (19%), as opposed
to achieving a CR at the time of initial
scan15. Of the fifty-nine patients who
achieved a CR on I+N, 19 (32.2%)
remained on therapy for 4 years.
94.7% (18/19) of patients who were
continued on I+N had an ongoing
response at the time of analysis.
45.8% (27) patients treated with
I+N discontinued therapy and did
not require additional treatment.
92.5% (25/27) of patients on I+N
who discontinued therapy after
a CR, had an ongoing response
off treatment. This is in stark
contrast to only 2.6% (14) patients
who achieved a CR on S. Of the 14
patients with a CR, 3 remained
on therapy, 3 had treatment
discontinued and an additional 8
were started on subsequent therapy
with 3 (100%), 2 (66%) and 7(87.5%)
patients demonstrating an ongoing
response4,14.
The percentage of patients with
the ongoing response on I+N was
almost identical for patients who
continued on therapy compared to
those who discontinued, 94.7% and
92.5%, respectively. Notably, only
21.4% (3/14) patients on S who had
a CR discontinued therapy with 66%
(2/3) of patients demonstrating
an ongoing response. 22% (13) of
patients treated with I+N went on
to subsequent therapy after ICI
discontinuation, though only 23%
(3/13) of these patients had findings
of progressive disease. Strikingly,
in the favorable risk group treated
with I+N, thirteen patients
discontinued treatment with 5/13
receiving subsequent therapy
despite only 7.6% (1/13) of patients
demonstrating evidence of disease
progression. Conversely, even
after achieving a CR, 57% (8/13) of
patients treated with S were started
on subsequent therapy with 87.5%
(7/8) with an ongoing response
(Table 1)4. Based on these data, it
may be reasonable to conclude that
patients who achieve a CR on I+N
can safely discontinue therapy with
a high likelihood of having a durable
response. Discontinuation may be
further supported in patients with
favorable risk disease who achieve
a CR, though notably, combined
immunotherapy is not approved
in this setting. Further analysis of
this group should include time to
first response, time to complete
response and time on therapy
before discontinuation. Evaluation
of minimal residual disease (MRD),
circulating tumor DNA (ctDNA)
and other pathologic factors should
be investigated further, to help
clinicians make educated treatment
decisions.
TFS with Partial Response (PR)
One-hundred and fifty-six (28.5%)
patients achieved a partial response
on I+N. 17.9% (28) remained on
treatment for 4 years, with 78.5% (22)
of these patients demonstrating an
ongoing response. In contrast, only
5.5% (9) of patients on S remained on
treatment at 4 years, with 88% (8/9)
maintaining an ongoing response.
42.9% (67) of patients treated with
I+N discontinued therapy without
the need for subsequent treatment.
31.3% (21/67) of patients with a
PR off I+N eventually progressed,
whereas 51.2% (20/39) of patients
who discontinued therapy with S
eventually progressed (Table 2)4.
So, in summary, the CheckMate
214 data suggests there is about a
31% chance of disease progression
for patients who discontinue I+N
after a PR vs a 51% chance of disease
progression in patients treated with
S. This is in comparison to a 21%
chance of disease progression in
those who remain on therapy after
PR compared to 11% of disease
progression on S. These odds may give
physicians pause when considering
therapy discontinuation in patients
with a PR. In the future, the Depth
of Response (DepOR) should be
further evaluated to see if patients
who achieve a greater DepOR have
improved durable responses after
treatment discontinuation.
Depth of Response in
Contemporary Studies
In the analysis above, patients
who achieved a PR were not
further separated by their Depth
of Response (DepOR). Suarez et al
looked at the association between
DepOR and clinical outcomes in
patients with advanced RCC, treated
on CheckMate 9ER. This phase
III trial compared cabozantinib
plus nivolumab versus sunitinib in
patients with advanced, previously
untreated RCC. The depth of
response was defined as the best
percent tumor reduction from
baseline. This study concluded that
deeper responses led to improved
12-month PFS and 18-month OS
rates. Interestingly, patients with
a CR and PR1 (≥80% reduction in
tumor burden) achieved similar
OS18. The median time to respond
was similar across groups,
suggesting that time to respond
may not be as vital. Further analysis
should be pursued, to see if patients
with varying DepOR can discontinue
therapy early.
TFS for Dual ICI Therapy in
Context
Based on what we learned from
CheckMate 214, when treated with
dual checkpoint inhibitors, the
TFS appears to be far longer than
with targeted therapy alone. Tzeng
et al sought to expand this data,
performing a systematic review
and meta-analysis to evaluate
the treatment-free survival in
objective responders with mRCC
who discontinued ICIs13. Sixteen
cohorts were analyzed, comprising
1833 patients treated with either
ICI monotherapy, dual ICI or an
ICI plus targeted therapy. A total
of 572 (31.2%) patients had either
a partial or complete response
and 327 (57%) of those patients
discontinued therapy. Interestingly,
85 (26%) patients demonstrated an
ongoing response off therapy with
TFS of 35%(95% CI 20-50%) and
20% (95% CI 8 to 35%) at 6 and
12 months respectively. However,
these 16 studies were extremely
heterogeneous. Differences in TFS
between patients achieving a CR vs
PR were not analyzed. When this data
was broken down by treatment, the
TFS was significantly higher when
treated with dual immunotherapy
as compared to an immunotherapy
plus VEGF combination. Six- and
12-month TFS rates were 57% (95%
CI, 41-73%) and 50% (95% CI, 32-
68) when treated with dual ICI as
compared to only 20% (95% CI,
2-45%) and 5% (95% CI 0-17%) when
treated with and an ICI plus VEGR
TKI combination13. This significant
difference should be considered
when choosing initial therapy for
patients whose goal is to achieve a
period of TFS.
Correlation of Immune-Related
Adverse Events and TFS
The durability of response and
treatment-free survival is especially
important for patients who have
had severe immune-related adverse
events (irAE), as these are often
a driving factor for treatment
discontinuation. While some
patients have mild irAE and can be
restarted on therapy, others develop
life-threatening issues mandating
that treatment be halted. Treatmentrelated adverse events leading to
discontinuation were more common
with dual checkpoint inhibitor
therapy vs sunitinib, occurring in
22% vs 13% respectively. Patients
treated with ICI spent more time off
treatment, with two-thirds of this
time without a grade ≥2 treatmentrelated adverse events (TRAE).
Conversely, patients treated with
sunitinib had a shorter treatmentfree survival with about two-thirds
of this time with a grade ≥ 2 TRAE12.
Understanding the depth and
durability of response, as well as the
safety of restarting therapy following
an irAE, is of utmost importance. A
multicenter retrospective review by
Alaiwi et. al. evaluated patients with
mRCC who required at least a 1-week
break on immunotherapy. Sixteen
percent (80 patients) of patients
required treatment interruptions
with 45% able to restart therapy,
while 55% percent discontinued
treatment permanently. The median
treatment break was 0.9 months
(0.2-31.6 months). Following
retreatment, half experienced a
second irAE. Interestingly, only onethird of these patients experienced
the same adverse reaction while
two-thirds experienced a new side
effect with the the median time to
recurrent irAE of 2.8 months, which
was similar to the time of first irAE,
2.7 months19. Future studies should
investigate if patients who have an
irAE have an increased chance of
achieving a durable response. This
should be further broken down by
degree and type of irAE.
Dosing Strategies to Promote TFS
with IO Therapy
While prolonged TFS has the
potential to improve QOL,
alternative dosing strategies may
also improve toxicity profiles
and patient-reported outcomes,
without reducing OS. Intermittent
dosing strategies have been under
investigation to help answer these
questions. Ornstein et al conducted
a small phase II trial to evaluate
the role of intermittent nivolumab
dosing for patients with IMDC I/P
risk mRCC, previously treated with
antiangiogenic therapy with the
hope of gaining additional insights
into optimal treatment schedule
and duration. Patients were treated
with nivolumab monotherapy for
twelve weeks at which point disease
response was assessed. Patients
with less than 10% tumor burden reduction
were continued on nivolumab
monotherapy and reassessed at
3-month intervals. However, if
patients had ≥10% tumor burden
reduction they were placed in a
treatment-free observation phase,
again with imaging every 3 months.
This classification and intervention
were continued until the RECISTdefined progression of disease (PD).
Patients who did not achieve at least
10% tumor burden reduction at
6 months were removed from the
study and treated with nivolumab
standard of care 10.
Fourteen patients were
included in the study. ORR was 29%,
with 4 patients (29%) achieving a
PR, 6 with SD (49%) and 4 with
PD (29%) at a median follow-up
of 6 months. Median PFS was 7.97
months. Five out of fourteen (38%)
of patients were eligible to stop
therapy and all agreed. Four out
of the five patients achieved this
response after only 12 weeks of
treatment. At median follow up of
48 weeks only 1 patient needed to
restart therapy. The four remaining
patients have had a clinical response
for a median of 34 weeks (range 16-
54) off therapy and a median tumor
burden decrease of 46.5% (38-
80%)10. This study demonstrates
that patients may be interested
in less frequent therapy, with the
notion that treatment breaks result
in decreased cumulative toxicity,
with the possibility for decreased
adverse events along with possibly
reduced financial toxicity.
CONCLUSION AND SUMMARY
Systemic treatment of metastatic
renal cell carcinoma has dramatically
improved in the last 5 years with the
use of immune checkpoint inhibitors
and targeted therapy. These
treatment breakthroughs have led
to improved overall survival, though
currently, treatment for mRCC
remains indefinite.
When it comes to first-line
treatment, physicians have a
variety of therapeutics to choose
from including dual ICI and ICI/
TT combinations. There are many
patient and disease-specific factors
that can help guide these important
treatment decisions. For example,
a critically ill patient with the need
for a rapid treatment response
would likely choose the ICI+TT
combination over dual ICI. Similarly,
a patient with a strong history of
autoimmune disorders may choose
to forego ICI therapy altogether and
begin TT monotherapy. However,
for the right patient, dual ICI therapy
offers the potential for a more
durable response with improved
TFS and QOL8, 12, 13.
Overall survival is the hallmark
of effective treatment. However,
many other factors should be
considered when determining the
ideal treatment strategy, including
treatment tolerability, risk of TRAE,
the durability of response, and
the ability to discontinue therapy
in favor of close monitoring.
CheckMate 214 and subsequent subanalyses provided great insight into
answering these questions. Patients
treated with dual ICI were noted
to have more durable and deeper
responses, as compared to ICI/TT
combination or TT monotherapy12,
13. Overall, TFS was more than two
times longer with dual ICI vs S, 6.9
months compared to 3.1 months
which represents meaningful time
away from the hospital and clinic12.
Patients treated with dual ICI
also had a significantly higher
chance of achieving a CR, 10.7% as
opposed to only 2.6% of patients
treated with S. In this subset of
patients, the mean TFS after dual
ICI was 34.6 months (0.5-49.7) with
objective responders treated for an
average of 20.6 months (17.7-23.2)
before treatment discontinuation14,15
Secondary analyses noted that
patients with lower disease burden
and higher PD-L1 status were more
likely to achieve this coveted CR,
though more robust data is needed
to help predict who will best respond
to therapy15.
Ultimately, there are many
questions still left unanswered.
The optimal treatment duration for
patients treated with dual ICI is still
unknown. After considering that
the data presented above, it may be
reasonable to consider treatment
discontinuation for patients who
achieved a CR, in favor of active
surveillance. Ongoing response
rates after CR was similar regardless
of whether therapy was continued
or stopped, 94.7% versus 92.5%
respectively. However, based on the
data currently available, the risk of
discontinuing therapy after a PR in
the I/P risk population may be too
great. Future studies should further
evaluate TFS based on the depth of
response (DepOR), as patients with
a deeper DepOR may also have a
prolonged TFS, similar to those
with a CR. Additionally, biomarkers,
such as the use of next-generation
sequencing results, ctDNA and
MRD, may prove beneficial to help
predict who may best respond to ICI
therapy. For example, patients with
more favorable mutations, such as
PBRM1, may be able to discontinue
therapy earlier than patients with
BAP1 alterations, which have been
traditionally associated with a
worse prognosis20. Finally, while
CheckMate 214 reported improved
patient-reported outcomes on dual
ICI vs S, there is limited QOL data
during the treatment-free period.
These and other questions must be
answered to provide patients with
improved treatment strategies and
QOL, Table 3.
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