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

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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