Bernard Escudier Gustave Roussy, Villejuif FRANCE · 2020. 12. 23. · [TFE3] Transloc. (6;11)...
Transcript of Bernard Escudier Gustave Roussy, Villejuif FRANCE · 2020. 12. 23. · [TFE3] Transloc. (6;11)...
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Non Clear Cell RCC
Bernard Escudier
Gustave Roussy, Villejuif
FRANCE
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From morphology to molecular profile of RKCs
RKC, rare kidney cancer.
Albiges L, et al. J Clin Oncol 2018:JCO2018792531 [Epub ahead of print].
Papillary Chromophobe TranslocationCollecting
DuctMedullary Sarcomatoid
Cytogenetic Alterations
Type 1
Gain Chr. 7,17
Type 2
Del Chr. 9p
Del Chr. 1, 2, 6, 10, 13, 17
Transloc. Xp11.2 [TFE3]Transloc. (6;11) [TFEB]
Del Chr. 8p, 16p, 1p, 9pGain Chr. 13q
Del. 22q –
Molecular Alterations
Type 1
METTERTCDKN2A/BEGFR
Type 2
SETD2CDKN2A/BNF2FHTERT
TP53PTENTERT fusionMTOR, TSC1/2MT-ND5
TFE3 fusionTFEB fusion
NF2SETD2SMARCB1CDKN2A
SMARCB1 rearrangements
TP53CDKN2ANF2RELNBAP1ARID1A
Pathway Deregulartions
ActivationCell cycleMAP
kinases
DeregulationChromatin
remodeling
ActivationCell cycleHippoNRF2-ARE
DeregulationChromatin
remodelingMetabolismMethylation
ActivationMTORAPOBEC
DeregulationMetabolism
ActivationTNFTGF-βMOTOR
DownregulationHIF/VEGF
DeregulationChromatin remodeling
ActivationImmune responseCell cycle
DeregulationMetabolism
– ActivationCell cycleTGF-β
DeregulationChromatin
remodeling
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Outcome of papillary vs. clear cell RCC
CSS, cancer-specific survival; cRCC, clear cell RCC; pRCC, papillary RCC; RCC, renal cell carcinoma.
Steffens S et al. Eur J Cancer. 2012;48:2347–52.
pRCC ccRCC P
value
Lymph
node mets
9.0% 7.3% 0.17
Visceral mets 9.6% 15.2%
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Outcome of chromophobe vs. clear cell RCC
• Outcomes between metastatic chrRCC and ccRCC are similar when treated withconventional targeted therapies
ccRCC, clear-cell renal cell carcinoma; chrRCC, chromophobe renal cell carcinoma; mRCC, metastatic renal cell carcinoma; OS, overall survival; TTF, time-to-treatment failure.
Yip SM et al. Kidney Cancer. 2017;1:41–7.
0
Months
20 40 8060
0.25
0.00
0.50
0.75
1.00
100 120 140 0
Months
20 40 8060
0.25
0.00
0.50
0.75
1.00
100 120
Overall Survival: Kaplan-Meier Curve (N=4970)
Metastatic chrRCC OS 23.8 mo (95% CI 16.7–28.1) (N=109)
Clear cell mRCC OS 22.4 mo (95% CI, 21.4–23.4) (N=4861)
P=0.0908
Time–to-Treatment Failure
Metastatic chrRCC TTF 6.9 mo (95% CI 4.1–8.5) (N=109)
Clear cell mRCC TTF 7.6 mo (95% CI, 7.2–8.0) (N=4861)
P=0.53
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Non clear cell RCC(first line)
Papillary Chromophobe CDC/medullary
Standard: Sunitinib [II, B]
Pazopanib [V, C]
Option: Everolimus [II, C]
Cabozantinib[IV, C]
Option: Sunitinib [II, C]
Pazopanib, [IV, C]Everolimus [II, C]
Option: Cisplatin-based regiment [IV, C]Sunitinib [V, C]
Pazopanib, [V, C]
Sarcomatoid(predominant)
Option: Nivolumab +
Ipilimumab[IV, A]Sunitinib [II, B]
Pazopanib, [V, C]
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What is the first-line standard of care?
Identifier Population Pts (n) Non-clear cell
histology
Line Comparator
Armstrong (2015) ASPEN
NCT01108445
Non-clear cell 108 Papillary 76/108 First Everolimus vs
sunitinib
Tannir (2014) ESPN
NCT01185366
Non-clear cell 68 Papillary 27/68
Chromophobe 12/68
Translocational
Unclassified
Sarcomatoid
First
Second
Everolimus vs
sunitinib
Motzer (2014) RECORD3
NCT
00903175
Clear +
non-clear cell
66 Papillary 50/66
Chromophobe 12/66
Unclassified
First
Second
Everolimus vs
sunitinib
Twardowski
(2015)
SWOG 1107
NCT01688973
Non-clear cell 50 Papillary 50/50 First
Second
Tivantinib vs
tivantinib +
erlotinib
Dutcher (2009) ARCC
NCT00065468
Clear +
non-clear cell
73 Papillary 55/73
Unclassified
First IFN-α vs
temsirolimus
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Evidence for of RKCs: The ASPEN trial
Armstrong AJ et al. Lancet Oncol 2016; 17: 378–88.
Sunitinib
(n=51)
Everolimus
(n=57)
Histological subtype
- Papillary histology overall 33 (65%) 37 (65%)
- Papillary histology type 1 4 (8%) 2 (4%)
- Chromophobe 10 (20%) 6 (10%)
- Unclassified 8 (16%) 14 (25%)
- Translocation carcinoma 6 (12%) 2 (4%)
- Minor clear cell
component
5 (10%) 8 (14%)
- Sarcomatoid
differentiation
5 (11%) 11 (27%)
Prior nephrectomy 41 (80%) 45 (79%)
Elevated lactate
dehydrogenase
14 (27%) 13 (25%)
Liver metastases 16 (31%) 15 (26%)
Lung metastases 30 (59%) 25 (44%)
Bone metastases 12 (24%) 15 (26%)
MSKCC risk group
0 15 (29%) 14 (25%)
1-2 32 (63%) 32 (56%)
≥3 4 (8%) 11 (19%)
Events/patients
Median progression-free survival (months, 80% CI)
Hazard ratio(80% CI)
Sunitinib Everolimus
MSKCC risk group
Good 21/29 14 (11.5–19.7) 5.7 (5.6–8.4) 2.9 (1.5–5.7)
Intermediate 51/64 6.5 (5.7–11.0) 4.9 (3.0–5.6) 1.4 (0.9–2.0)
Poor 15/15 4.0 (0.9–5.8) 6.1 (3.1–7.3) 0.3 (0.1–0.7)
Histology
Papillary 60/70 8.1 (5.8–11.1) 5.5 (4.4–5.6) 1.6 (1.1–2.3)
Chromophobe 12/16 5.5 (3.2–19.7)11.4 (5.7–19.4)
0.7 (0.3–1.7)
Unclassified 15/2211.5 (5.3–Not reached)
5.7 (2.8–7.2) 1.9 (0.8–4.9)
Baseline LDH
≤ULN 62/75 8.4 (5.8–13.0) 5.6 (5.5–6.1) 1.5 (1.1–2.2)
>ULN 19/26 5.8 (3.2–15.4) 4.1 (2.6–6.0) 1.1 (0.6–2.3)
Total 87/108 8.3 (5.8–11.4) 5.6 (5.5–6.0) 1.4 (1.0–1.9)-3.0-2.5 2.52.01.51.00.50-2.0-1.5-1.0-0.5
Favours everolimusFavours sunitinibLog (HR)
0Time since randomisation (months)
6 12 18 24 30
20
0
40
60
80
100
Pro
gre
ss
-fre
e s
urv
ival (%
)
Sunitinib
Everolimus
HR 1.41 (80% CI, 1.03–1.92)
P=0.16
36
5157
2621
178
104
83
42
11
No. at riskSunitinib
Everolimus
0Time since randomisation (months)
6 12 18 24 30
20
0
40
60
80
100
Ov
era
ll s
urv
ival (%
)
Sunitinib
Everolimus
HR 1.12 (95% CI, 0.70–2.1)
P=0.60
36
5157
4044
3427
1915
149
106
42
No. at riskSunitinib
Everolimus
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Molecular profile of rare kidney tumours
pRCC, papillary renal cell carcinoma. Linehan WM, et al. N Engl J Med 2016;374:135–45.
Methylation and
metabolic profile
of pRCC
Somatic
mutational
profile of
pRCC
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Mutations within the MET
receptor
MET in RKCs
RKC, rare kidney cancer.
Adapted from Sánchez-Gastaldo A et al. Cancer Treat Rev 2017;60:77–89;. 2. Linehan WM, et al. N Engl J Med 2016;374:135–45.
Transcriptional activation of
HIF target genes: expression
of VEGF, PDGF, TGFα
Energy and
nutrient sensing
RENAL CELL
CANCER
MET
RECEPTOR
Cell survival
AMPK
FNIP1 FNIP2
FLCN
LKB1
HGF
FORETINIB
SAVOLITINIB
CABOZANTINIB
AMG1
02
PI3K-AKT-
mTOR
PATHWAY
HIFα
GAB1GAB2
PP
PP
1. 2.
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Screened ptsPRCC1 per local pathology
N=41
MET+ n=4 MET- n=16 MET? n=3
Eligible and evaluableN=4
Eligible and evaluableN=16
Eligible and evaluableN=3
Centrally confirmed PRCC1and enrolled
N=23
MET+ analysis set
PRCC1 analysis set
(incl. 1 MET amplified) (incl. 1 MET amplified)
MET?: Technical failure, mutational analysis could not be done
CREATE phase II (EORTC study)
MET- analysis set
Schoffski et al, AACR Annual Meeting, April 17, 2016, New Orleans
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Treatment duration (considering METamplification)
MET+ (mutation in exons 16-19) and/or MET amplification
MET- (no mutation in exons 16-19), no METamplification
RECIST PR first documented
Treatment ongoing
Treatment stopped due to
Adverse event
Progression
Patient’s decision or
other reason
MET amplification (exploratory)
MET? (technical failure)
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Maximum shrinkage of target lesions
MET+ MET- MET?
MET amplification
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MET/VEGFR inhibitors in papillary RCC
• Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma
• 65 patients with locally-advanced, bilateral multifocal, or metastatic sporadic PRCC or known HPRC
• Foretinib bisphosphate (GSK1363089A), formerly XL880, is an oral, multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGF receptors
HPRC, hereditary papillary RCC; PR, partial response; PRCC, papillary renal cell carcinoma; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor.
Choueiri TK, et al. J Clin Oncol. 2013;31:181–6.
0
Time to progressive disease or death (months)
2 1416 200
0.6
1.4
Pro
bab
ilit
y o
f p
ati
en
ts s
urv
ivin
g
wit
ho
ut
dis
ease p
rog
ressio
n
Median PFS
All patients, 9.3 months
Intermittent dosing, 11.6 months
Daily dosing, 9.1 months
304 24
0.10.20.30.40.5
0.70.80.91.01.11.21.3
282622186 8 1012
100
Best
perc
en
tag
e c
han
ge
fro
m b
aselin
e
Germline mutations
MET aberration (MET amplification, gain of chromosome 7 or somatic mutation;
exluding germline mutations)
No germline mutation; testing for MET aberration profile incomplete
* Confirmed PR
80
60
40
20
0
-20
-40
-60
-80
-
MET independent
pRCC
MET/VEGFR inhibitors in papillary RCC
Biomarker-Based Phase II Trial of Savolitinib in Patients with Advanced Papillary Renal Cell Cancer
• 109 Patients with metastatic pRCC
• Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective MET tyrosine kinase inhibitor.
• MET-driven pRCC was defined as any of the following: chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations
NE, not evaluable; PD, progressive disease; PR, partial response; pRCC, papillary RCC; RECIST, Response Evaluation Criteria in Solid Tumours; RCC, renal cell carcinoma; SD, stable disease, VEGF, vascular endothelial growth factor.Choueiri TK, et al. J Clin Oncol 2017,35:2993–3001.
RECIST Response
No. (%)
MET Driven(n=44)
MET Independen
t (n=46)
MET Unknown
(n=19)
Total(N=109)
PR 8 (18) 0 (0) 0 (0) 8 (7)
SD 22 (50) 11 (24) 5 (26) 38 (35)
PD 11 (25) 28 (61) 9 (47) 48 (44)
NE 3 (7) 7 (15) 5 (26) 15 (14)
Tumour
responses in
overall
treatment
population and
by MET status
0
Time (months)
8 12 14 160.0
0.2
0.4
0.6
1.0
PF
S p
rob
ab
ilit
y
20
0.8
10 18
MET independentMET drivenMET unknown
642
Best
ch
an
ge f
rom
baselin
e
in t
arg
et
lesio
n s
ize (
%) 100
8060
4020
0-20-40-60-80
-100
MET driven pRCC
Best
ch
an
ge f
rom
baselin
e
in t
arg
et
lesio
n s
ize (
%) 100
8060
4020
-40-60-80
-100
0-20
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Fumarate
hydratase
(FH)
Fumarate
Fumarate
Fumarate
PHD 2
Fumarate
HIF-α
HIF
-αHIF
-α
HIF
-α
HIF
-α
HIF
-α
GLUT1
TGFα/
EGFR
VEGF
HIF prolyl-hydroxylase. Ubiquitin-
proteasome
degradation
pathway
Erlotinib
Bevacizumab
Fumarate hydratase pathway in RKC
EGFR, epidermal growth factor receptor; GLUT 1, glucose transporter 1; HIF, hypoxia-inducible factor; PHD, HIF prolyl hydroxylase; RKC, rare kidney cancer; TCA cycle , tricarboxylic acid (Krebs) cycle; TGFα, transforming growth factor alpha; VEGF, vascular endothelial growth factor.
Adapted from Srinivasan R, et al. Clin Cancer Res 2015; 21(1):10–17.
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41 patients
with pRCC
Fumarate hydratase pathway in RKC
HLRCC, hereditary leiomyomatosis and renal cell carcinoma; NR, not reached; ORR, overall response rate; PFS, progression-free survival; pRCC, papillary RCC; RECIST, Response Evaluation Criteria in Solid Tumours; RCC, renal cell carcinoma; RKC, rare kidney cancer.
Modified from Srinivasan R. Presented at Genitourinary Cancers Symposium 2016, San Francisco, USA, 7−9 January 2016.
Best response
by RECIST
HLRCC Sporadic
pRCC
Total
ORR 65% 29% 46%
Stable disease 35% 62% 95%
Disease control
rate
100% 91% 95%
Bevacizumab 10 mg/kg
Q15,
Erlotinib 150mg/day
Cohort 1 (n=20)
HLRCC
Cohort 2 (n=21)
sporadic pRCC
0
Time since study entry (months)
5 15 20 250.0
0.2
0.4
0.6
1.0
Pro
po
rtio
n f
ree f
rom
pro
gre
ssio
n
Median PFS 12.8 (95% CI 7.47–26.3)
35
0.8
10 30 0
Time since study entry (months)
5 15 20 250.0
0.2
0.4
0.6
1.0
Pro
po
rtio
n f
ree f
rom
pro
gre
ssio
n
35
0.8
10 30
40
Be
st
pe
rce
nta
ge
ch
an
ge
fro
m b
as
elin
e
20
0
-20
-40
-60
-80
-100
Non-HLRCC HLRCC
Entire study: 12.8 (95% CI 7.47–26.3)HLRCC: 24.2 mo (95% CI 12.8–NR)Non-HLRCC: 7.4 mo (95% CI 3.73–10.2)
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PD-L1 expression in rare kidney tumours
Ch-RCC, chromophobe RCC; PD-L1, programmed death ligand-1; p-RCC, papillary RCC; RCC, renal cell carcinoma; TIMC, tumour-infiltrating mononuclear cells.
Choueiri TK et al. Ann Oncol 2014;25:2178–84.
N=101 %
Histology
Chromophobe 36 36
Papillary 50 49
Translocation 10 10
Collecting duct
carcinomas
5 5
Metastatic
disease
No 78 77.2
Yes 23 22.8
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PD-L1 expression in RKCs
PD-L1, programmed death ligand-1; RKC, rare kidney cancer.
Choueiri TK et al. Ann Oncol 2014; 25: 2178–2184.
0Years from diagnosis
1 2 3 4
0
0.2
0.4
0.6
1.0
Ov
era
ll s
urv
ival p
rob
ab
ilit
y
-
KEYNOTE-427: (NCT02853344)
aPD-L1 positive defined as combined positive score [CPS] ≥1.
Pembrolizumab
200 mg Q3W
Cohort A
clear cell
RCC
(N = 110)
Cohort B
nccRCC*
(N = 165)
Response
assessed at
week 12
and Q6W until
week 54, and
Q12W
thereafter
• Endpoints
• Primary: ORR per RECIST v1.1 (blinded
independent central review)
• Secondary: DOR, DCR, PFS, OS,
safety, and tolerability
• Exploratory: ORR by histology (blinded
independent central review) and PD-L1
expression;a tissue-based biomarkers
(eg, IHC, RNA sequencing)
Screen for
eligibility
Patients
• Recurrent or advanced/metastatic disease
• Measurableper RECIST v1.1
• No prior systemic therapy
• Karnofsky performance status ≥70%
*nccRCC diagnosis
confirmed by central
pathology
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Baseline Characteristics
Database cutoff: September 7, 2018.
Characteristic, n
(%)N = 165
Age, median (range), 62 (22-86)
Men 109 (66)
Karnofsky
performance scale
90-100 124 (75)
70-80 41 (25)
Characteristic, n (%) N = 165
Confirmed RCC histology
Papillary 118 (71)
Chromophobe 21 (13)
Unclassified 26 (16)
IMDC risk category
Favorable 53 (32)
Intermediate/poor 112 (68)
PD-L1 status
CPS ≥1 102 (62)
CPS
-
Confirmed ORR by Blinded Independent Central Review
aIncludes patients who discontinued or died before first postbaseline scan. bIncludes patients with insufficient data for response assessment.
Database cutoff: September 7, 2018.
N = 165
n % 95% CI
ORR 41 24.8 18.5-32.2
DCR (CR + PR + SD ≥6 months) 67 40.6 33.0-48.5
Best overall response
CR 8 4.8
PR 33 20.0
SD 53 32.1
PD 61 37.0
No assessmenta 8 4.8
Not evaluableb 2 1.2
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Maximum Change From Baseline in Target Lesions by Central Review
Includes patients who received ≥1 dose of pembrolizumab, had a baseline scan with measurable disease per RECIST v1.1, and had a postbaseline assessment (n = 155).
*Patient had an increase in target lesions above 100%.
Database cutoff: September 7, 2018.
• 91/165 (55.2%) experienced a reduction in tumor burden
• 20/165 (12.1%) experienced a tumor burden reduction ≥80%
• 7/165 (4.2%) experienced 100% tumor burden reduction
+20%
–30%
–80%
Pe
rce
nta
ge
Ch
an
ge
Fro
m B
as
eli
ne
Papillary
Chromophobe
Unclassified
–100
–80
–60
–40
–20
0
20
40
60
80
100 **
-
Time to Response and Response Duration
Data are presented for responders.
Database cutoff: September 7, 2018.
Time to last scan
CR
PR
PD
Time to last dose
Ongoing response*
Continued response after last dose
Months
0 5 10 15 20
-
Time to Response and Response Duration
Database cutoff: September 7, 2018.
Time to Response,
median (range), months
DOR,median (range),
months
Response≥6
Months, %
2.8 (0.1-8.3) NR (2.8-15.2+) 81.5
Months
Re
ma
inin
g in
Re
spo
nse
, %
41 37 22 12 6 3 0
No. at risk
0 3 6 9 12 15 18
0
20
40
60
80
100
-
ORR by Confirmed RCC Histology per Blinded Independent Central Review
aDCR = CR + PR + SD ≥6 months. bIncludes patients who discontinued or died before first postbaseline scan. cIncludes patients with insufficient data for response assessment.
Database cutoff: September 7, 2018.
Papillary
n = 118
Chromophobe
n = 21
Unclassified
n = 26
Confirmed ORR, %
(95%CI)25.4 (17.9-34.3) 9.5 (1.2-30.4) 34.6 (17.2-55.7)
DCR, % (95%CI)a 43.2 (34.1-52.7) 33.3 (14.6-57.0) 34.6 (17.2-55.7)
Confirmed BOR, %
CR
PR
SD
PD
No assessmentb
4.2
21.2
34.7
33.9
5.1
4.8
4.8
47.6
42.9
0.0
7.7
26.9
7.7
46.2
7.7
Not evaluablec 0.8 0.0 3.8
-
ORR by PD-L1 Expression
CPS ≥1
n = 102
CPS
-
Progression-Free Survival and Overall Survival in the Total Population
Database cutoff: September 7, 2018.
Median OSNR (95% CI, NR)
OS,
%
165 151 140 108 75 42 14 1
No. At Risk
0
Months
0 3 6 9 12 15 18 21 24
0
20
40
60
80
100
72%
Median PFS4.1 months (95% CI, 2.8-5.6 months)
165 91 62 38 20 9 3 1 0
No. at risk
Months
PFS
, %
0 3 6 9 12 15 18 21 24
0
20
40
60
80
100
23%
-
Nivolumab
Ipilimumab
200 pts
Cohort 1:
ccRCC
Cohort 2:
RKCs
Phase: IIIb/IV
Primary endpoint: Safety
Lenvatinib
Everolimus
31 pts with
RKCs
Phase: II
Primary endpoint: ORR
Bevacizumab
Atezolizumab
60 pts with
RKCs
Phase: II
Primary endpoint: ORR
Nivolumab
Cabozantinib
37 pts with
RKCs
Phase: II
Primary endpoint: ORR
Cabozantinib48 pts with
RKCs post-
CPIs
(or CPI
unsuitable)Phase: II
Primary endpoint: ORR
Nivolumab
Sunitinib
306 pts
with RKCs
Phase: II
Primary endpoint: 12-mos
OS
Ipilimumab
Current trials for RKCs
ccRCC, clear cell RCC; CPI, checkpoint inhibitor; ORR, overall response rate; OS, overall survival; RCC, renal cell carcinoma; RKC, rare kidney cancer1. https://clinicaltrials.gov/ct2/show/NCT02982954; 2. https://clinicaltrials.gov/ct2/show/NCT02915783; 3. https://clinicaltrials.gov/ct2/show/NCT02724878; 4. https://clinicaltrials.gov/ct2/show/NCT03635892; 5. https://clinicaltrials.gov/ct2/show/NCT03685448; 6. https://clinicaltrials.gov/ct2/show/NCT03075423. (All accessed February 2019).
+
+
+ +
+
https://clinicaltrials.gov/ct2/show/NCT02982954https://clinicaltrials.gov/ct2/show/NCT02915783https://clinicaltrials.gov/ct2/show/NCT03635892https://clinicaltrials.gov/ct2/show/NCT03685448https://clinicaltrials.gov/ct2/show/NCT03075423
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Exploratory Analysis in Sarcomatoid Patients
• Minimum follow-up 30 months as of August 6, 2018 database lock
• Endpoints: OS, PFS (per investigator), ORR (per investigator), best overall response, and safety
• No central pathology review leading to unknown tumor sample origin (nephrectomy vs biopsy) and percent sarcomatoid dedifferentiation
IMDC, International Metastatic Renal Cell Carcinoma Database Consortium
All randomized CheckMate 214 patients (n = 1096)
Excluded; no available pathology report (n = 254)
Available local pathology report accompanying tumor sample (n = 842)
Excluded; “sarcomatoid” not present (n = 592)
Had “sarcomatoid” keyword (n = 250)
• Identified as sarcomatoid positive (n = 115)
‒ IMDC intermediate/poor risk (n = 111)
‒ IMDC favorable risk (n = 4)
Intermediate/poor risk NIVO+IPI (n = 60)
• Treated (n = 59) / not treated (n = 1)Intermediate/poor risk SUN (n = 52)
• Treated (n = 52)
CheckMate 214
Excluded; sarcomatoid negative (n = 135)
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Baseline Characteristics
Sarcomatoid
intermediate/poor riskAll intermediate/poor risk1
NIVO + IPI
N = 60
SUN
N = 52
NIVO + IPI
N = 425
SUN
N = 422
Median age, years 58 60 62 61
Male, % 70 75 74 71
IMDC prognostic score, %
Intermediate (1–2)
Poor (3–6)
75
25
71
29
79
21
79
21
Previous nephrectomy, % 88 81 80 76
No. of sites with ≥1 lesion, %a
1
≥2
17
83
25
75
21
79
20
80
Sites of metastasis, %a
Lung
Lymph node
Bone
Liver
76
51
20
15
81
54
19
13
69
45
22
21
70
51
23
21
Quantifiable tumor PD-L1 expression, %b
-
Sarcomatoid
intermediate/poor riskAll intermediate/poor risk1
NIVO + IPI
N = 60
SUN
N = 52
NIVO + IPI
N = 425
SUN
N = 422
Confirmed ORR (95%
CI), %56.7
(43.2–69.4)
19.2 (9.6–32.5)
41.9 (37.1–46.7)
29.4 (25.1–34.0)
P value
-
Best Tumor Reduction Investigator:
Intermediate/Poor-Risk Sarcomatoid Patients
* = respondersPatients with target lesion at baseline and at least 1 on-treatment tumor assessment are included. Best reduction is maximum reduction in sum of diameters of target lesions. A negative value
means true reduction, positive value means increase only observed over time. Dashed reference line indicates the 30% reduction consistent with a RECIST v1.1 response
Be
st
red
ucti
on
fro
m b
as
eli
ne
in
ta
rge
t le
sio
n (
%)
NIVO+IPI SUN
50
100
25
75
0
–25*
******
****
**
****
************* ***
–50
–75
–100* ** **
*****
*
CheckMate 214
-
PFS per Investigator:
Intermediate/Poor-Risk Sarcomatoid PatientsP
rog
res
sio
n-f
ree
su
rviv
al
(pro
ba
bil
ity)
Months
0.8
1.0
0.7
0.9
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 63 9 12 15 18 21 24 27 30 33 36 39 42
60 41 35 28 23 23 21 19 19 17 16 10 4 2 0
52 32 20 11 8 7 6 6 5 4 4 2 1 0 0
No. at risk
NIVO+IPI
SUN
CheckMate 214
NIVO + IPI
N = 60
SUN
N = 52
Events, n (%) 37 (62) 40 (77)
Median PFS, (95% CI), mo 8.4 (5.2–24.0) 4.9 (4.0–7.0) Hazard ratio (95% CI)
P value0.61 (0.38‒0.97)
0.0329
-
OS: Intermediate/Poor-Risk Sarcomatoid
Patients
NE, not estimable
OS probability,
% (95% CI)
NIVO + IPI
N = 60
SUN
N = 52
12 month 80 (67‒88) 56 (41‒68)
24 month 58 (45‒70) 35 (22‒47)
30 month 53 (39‒65) 29 (17‒41)
Ove
rall
su
rviv
al
(pro
ba
bil
ity)
Months
0 63 9 12 15 18 21 24 27 30 33 36 39 42 45
60 56 52 49 47 45 43 37 32 30 29 22 10 5 1 0
52 48 36 32 29 23 22 19 18 17 15 15 9 3 1 0
No. at risk
NIVO+IPI
SUN
CheckMate 214
NIVO + IPI
N = 60
SUN
N = 52
Events, n (%) 31 (52) 39 (75)
Median OS, (95% CI),
mo31.2 (23.0‒NE) 13.6 (7.7‒20.9)
Hazard ratio (95% CI)
P value0.55 (0.33‒0.90)
0.0155
0.8
1.0
0.7
0.9
0.6
0.5
0.4
0.3
0.2
0.1
0.0
-
OS: PD-L1–Evaluable Sarcomatoid Patients
-
Translocation RCC
Malouf GG et al. Clinical Cancer Research, 2014
Activation of CTLA4 and PDL 1
-
Young patient
• June 2014: right RN + LND for translocation RCC (TFEB) with lung netastases and lymph nodes
• Sunitinib July 2014 (stopped for liver toxicity)
• Pazopanib July 2014-Sept 2014
• Everolimus Sept 2014-Jan 2015
-
17q gain is common in translocation RCC
Malouf GG et al. Clinical Cancer Research, 2013
-
Activation of CTLA4 in tumors with 17q gain
Malouf GG et al. Clinical Cancer Research, 2013
-
Ipilimumab initiated in 4th line
-
CR in abdominal lesion
-
Initial tumor left kidney 01/2015
Collecting duct tumor
-
Treatment schedule
1/15
Nephrectomy Oophorectomy
4/15
CT scanBrain MRI
CT scan
Cisplatin Gemcitabine
Bevacizumab
-
Ovarian metastasis: origin of the PDX
MRI 04/2015
CT 04/2015
-
Genomic Alterations (oophorectomy)
BRAF G466A mutation (Foundation Medicine)
FBXW7 mutation
SMARCB1 mutation
High-level MET amplification (Oncoplex)
IHC: PDL1 5% tumor cells
Molecular biology
-
Treatment schedule
1/15
Nephrectomy Oophorectomy
4/15 8/15 1/16 2/16
CT scanBrain MRI
PET-CTCT scan
Cisplatin Gemcitabine
PET-CT
Bevacizumab
Trametinib
Gene
sequencing
-
PET-CT 01/2016 PET-CT 02/2016
M1 MEKi
-
PET-CT 01/2016 PET-CT 02/2016
M1 MEKi
-
PET-CT 01/2016 PET-CT 02/2016
M1 MEKi
-
PDX treatment with
trametinib alone
PDX treatment with
trametinib+INC280
0
100
200
300
400
500
600
4 9 13 16 20 23 27 30 34 37
TumorVolume(%)
Days
Vehicle
Trametinib
- 100
0
100
200
300
400
500
600
7 11 14 16 21 24 28 32 35
TumorVolume(%)
Days
Vehicle
INC280
Trametinib + INC280
-
Treatment schedule
1/15
Nephrectomy Oophorectomy
4/15 8/15 1/16 2/16
CT scanBrain MRI
PET-CTCT scan
Cisplatin Gemcitabine
PET-CT
Bevacizumab
Trametinib
6/16
Trametinib +Crizotinib
10/16
Gene
sequencing
Gene
sequencing
-
Rare kidney tumors
• Young lady (25 years)
• Hematuria
-
What is your diagnosis?
• Radical nephrectomy: choriocarcinoma
• HCG 10 times normal
• Chemotherapy with BEP
• Relapse one year later: lung surgery and TIP
• Currently in CR…..
-
Conclusions
• RKCs are heterogeneous and represents 25% of RCC
• The outcome of patients with RKC depends on the histotype and stage at diagnosis
• Sunitinib remains a standard of care
• The discovery of MET- and FH-driven disease suggests interesting possibilities for tailored therapy in specific patient groups and paved the way for subtype-driven studies
• IO revealed promising clinical activity in RKCs
• Some rare tumors might have different treatments