Non Clear Cell RCC
Bernard Escudier
Gustave Roussy, Villejuif
FRANCE
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
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%
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
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]
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
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
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
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.
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
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)
Maximum shrinkage of target lesions
MET+ MET- MET?
MET amplification
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
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.
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)
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
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
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
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
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)
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
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