cytoreductive nephrectomy in renal cell carcinoma 4.7/15… · cytoreductive nephrectomy in renal...
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Cytoreductive nephrectomy in renal cell
carcinoma: still required in the combined targeted and immunotherapy era ?
Urologists view
Axel Bex, MD, PhD
The Netherlands Cancer Institute
FOIU, 4 July 2018
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Financial and Other Disclosures Off-label use of drugs, devices, or other agents: None or FILL IN HERE; including your
local regulatory agency, such as FDA, EMA, etc.
Data from IRB-approved human research is presented [or state: “is not”]
2
I have the following financial interests or
relationships to disclose: Disclosure code
Pfizer C, S
Roche C
Genentech C
Ipsen C
Novartis C
BMS C
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CARMENA investigated the role of CN
SURTIME the sequence of CN
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SURTIME and CARMENA included
patients who require sunitinib
N=28 from an institutional
database of 202 primary
mRCC patients
Bex et al., GU ASCO, J Clin Oncol 34, 2016 (suppl 2S; abstr 604)
Median timo to TT
14 months
Time to targeted therapy in patients with low-volume but non-resectable metastatic
disease after CN
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Study design
5
Progression status
at week 16 Progression status
at week 28
N E P H R E C T O M
Y
Cycle 1 (6 wk) Cycle 2 Cycle 3
Cycle 4
N E P H R E C T O M Y
Progression
status every
12 weeks
Cycle 4 Cycle 5 Cycle 1 (6 wk) Cycle 2 Cycle 3 (4 wk)
R
Immediate Nephrectomy
Deferred Nephrectomy
= Progression status 4 weeks after CN
= Sunitinib
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Baseline characteristics
6
Immediate nephrectomy
(N=50)
Deferred nephrectomy
(N=49)
Median age (years) 60 58
Performance status (WHO)
- WHO 0 36 (72.0%) 31 (63.3%)
- WHO 1 14 (28.0%) 18 (36.7%)
Male 41 (82.0%) 39 (79.6%)
MSKCC intermediate risk 43 (86.0%) 44 (89.8%)
≥ 2 measurable metastatic sites 43 (86.0%) 46 (93.9%)
Mean (SD) primary tumor size (mm)
93.1 (37.8) 96.8 (31.3)
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Progression-free survival (ITT)
7
Progression-free status at w28 (±15 days)
Immediate nephrectomy
(N=50)
Deferred nephrectomy
(N=49)
Progression-free at week 28
21 (42.0%) 21 (42.9%)
[95% CI] [28.2% – 56.8%] [28.8% – 57.8%]
p-value (one-sided Fisher exact test)
0.61
Progression ≤ week 28 or treatment failure
25 (50.0%) 24 (49.0%)
Not assessable 4 (8.0%) 4 (8.2%)
HR (95%CI)=0.88 (0.56, 1.37), p=0.569 Stratified by WHO performance status (0 versus 1)
Week 1
6 e
valu
ation
(+
/-1
5 d
ays w
ind
ow
)
Week 2
8 e
valu
ation
(+
/-1
5 d
ays w
ind
ow
)
Immediate
Deferred
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Overall Survival (ITT)
8
HR (95%CI)=0.57 (0.34, 0.95), p=0.032 Stratified by WHO performance status (0 versus 1)
Immediate nephrectomy
(N=50)
Deferred nephrectomy
(N=49)
Survival status
Dead 35 (70.0) 28 (57.1)
Reason of death
Progression 30 25 Surgery related toxicity 1 0 Progression and surgery related
toxicity 1 0
Cardiovascular disease (not due to toxicity or progression)
1 0
Other (not due to toxicity or progression)
1 0
Unknown 1 3
Immediate
Deferred
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Overall Survival – Landmark analysis at week 16
9
Assessment of progression status at week 16 prior to planned CN in the deferred arm
0 6 12 18 24 30 36 42 48 54 60
0
10
20
30
40
50
60
70
80
90
100
Patients-at-Risk
13 2 1 0 0 0 0 0 0 0
12 8 6 2 1 1 0 0 0 0
10 8 4 3 3 2 1 1 1 1
27 26 21 15 12 10 8 4 2 1
32 31 26 23 19 17 12 8 6 3
Excluded-
Immediate-
Deferred-
Immediate-
Deferred-
Overa
ll s
urv
ival
aft
er
week 1
6 (
%)
Months
PD
before w16
No PD
before w16
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Patient characteristics (1)
Presented By Arnaud Mejean at 2018 ASCO Annual Meeting
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Overall survival (ITT)
Presented By Arnaud Mejean at 2018 ASCO Annual Meeting
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Secondary nephrectomy in Arm B (sunitinib alone)
Presented By Arnaud Mejean at 2018 ASCO Annual Meeting
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Conclusions from both SURTIME and
CARMENA
• Despite its limitations, CARMENA is a practice
changing trial and SURTIME complements the
results
• Patients with poor risk MSKCC should not
undergo CN
• Patients with intermediate MSKCC risk who
require systemic therapy should not undergo
immediate CN but receive sunitinib first
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Finally, open questions remain
• Should CN be performed at a later stage in all patients
except those who progress (SURTIME) or only when
necessary (CARMENA)?
• First-line therapy with nivolumab plus ipilimumab will
replace sunitinib for intermediate and poor risk
patients.
• Will we need new studies or treat patients with primary
metastatic RCC with the tumour in place followed by
resection when necessary ?
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Checkpoint inhibitor combination trials in
first-line: Changing the paradigm
Study Sponsor N Therapy Endpoint Subtype
MK-3475-
426/KEYNOTE-426
NCT02853331¹
Merck Sharp & Dohme 840 Pembrolizumab 200 mg IV Q3W PLUS axitinib
5 mg PO BID
vs
sunitinib 50 mg PO QD 4/2 weeks
PFS central
review
OS
clear cell
component with
or without
sarcomatoid
features
JAVELIN Renal 101
NCT02684006¹
Pfizer 583 Avelumab administered at 10 mg/kg IV Q2W in
combination with axitinib, 5 mg PO BID
vs
sunitinib given at 50 mg PO QD 4/2 weeks
PFS, OS clear cell
component
NCT02420821¹ Hoffmann-La Roche 900 Atezolizumab as a fixed dose of 1200 mg via IV
infusion on days 1 and 22 of each 42-day plus
bevacizumab 15 mg/kg via IV infusion on days
1 and 22 of each 42-day cycle
vs
sunitinib given at 50 mg PO QD 4/2 weeks
PFS investigator
reviewed
OS in
participants with
detectable PD-
L1
clear cell
histology and/or
a component of
sarcomatoid
carcinoma
Checkmate 214
NCT02231749¹
Bristol-Myers Squibb 1070 Nivolumab 3 mg/kg combined with ipilimumab 1
mg/kg solutions IV Q3W for 4 doses then
nivolumab 3 mg/kg solutions IV Q2W
vs
sunitinib given at 50 mg PO QD 4/2 weeks
PFS
OS
clear-cell
component
NCT02811861¹ Eisai Inc. 735 Lenvatinib 18 mg PO QD, plus everolimus 5 mg
PO, QD or lenvatinib 20 mg PO QD, plus
pembrolizumab 200 mg IV, Q3W
vs
sunitinib 50 mg PO QD 4/2 weeks
PFS, OS clear-cell
component
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Check-SUR-STAM-MENA-PEDE phase III trial of all
potential combinations with CN you ever dreamt of
Primary objective: Is IO + X alone superior to nephrectomy
plus IO + X or IO + X plus nephrectomy in terms of OS?
Stratification by IMDC risk factors
Nephrectomy
IO + X
IO + X
R
A
N
D
O
M
I
Z
A
T
I
O
N
N =
1500 +
each
new
arm
Metastatic
clear cell RCC
ECOG 0-1
Biswas et al, 2009; US NIH, 2010c.
IO + X Nephrectomy
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Does CN have a future ?
• For those who require VEGFR-TKI
Indication Frequency Rationale
Patients with solitary or
oligometastasis not requiring
immediate systemic therapy
low
(in NKI dataset 40/244 =
16.4 %)
• Cure
• Delay of systemic therapy
Intermediate risk patients
without systemic progression
during immediate TKI
probably 80 % of
intermediate risk patients
who constitute 60 % of RCC
risk groups
• Identification of long-term
survivors
• Potentially longer OS
Remember: VEGFR-targeted therapy is non-curative !
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Does CN have a future ?
• For immunecheckpoint combination therapy
Scenario Rationale of CN Probability
CR of primary and
metastases
CN not required unlikely
CR at metastatic sites
only
CN advised in all
instances:
• to stop treatment
• potentially curative
May occur in a few
cases
SD or PR but median
OS substantially longer
than in VEGFR-TT era
with 10-20% ‘cured’
CN may be of benefit:
• in case of symptoms
• potentially curative
likely
CR=complete remission; PR=partial remission; SD=stable disease; OS=overall survival; TT=targeted therapy