Prospettive future nel trattamento medico del mRCC ...€¦ · CheckMate 025: Overall survival by...

Prospettive future nel trattamento medico del mRCC

Francesco MassariOncologia Medica

Policlinico S Orsola-Malpighi – Bologna

3rd YOUNG SPECIALIST RENAL CARE – Firenze, 09 Aprile 2016

Renal cell

carcinoma

Clear cell

RCC 70%

Non-Clear

cell RCC 30%

Papillary type I 9%

Papillary type II 6%

Chromophobe 4-5%

Oncocytoma 3-5%

Xp11 traslocation

Associated to

neuroblastoma

Tubulocystic

Neuroendocr. tumors

Mesenchymal

Ducts of Bellini <1%

Tubulo-papillary

t(6,11) traslocation

Mucinous tubular

Her. leiomyomathosis

Unclassified

Tubulocystic

Massari F, Santoni M 2015

Linehan WM, et al. In: Cancer: Principles and Practice of Oncology. 2006:1139-1140.

BHD = Birt-Hogg-Dubé

FH = Fumarate hydratase

VHL = von Hippel-Lindau

Clear cell (75%)

Gene: VHL

Papillary Type 2 (10%)

Gene: FH

Papillary Type 1 (5%)

Gene: C-Met

Chromophobe (5%)

Gene: BHD

Other

RCC is not a single disease

A lot of new genes: SEDT2, PBRM1, BAP1, KMD61, NF2…

Renal cell

carcinoma

Clear cell

RCC 70%

Non-Clear

cell RCC 30%

Papillary type I 9%

Papillary type II 6%

Chromophobe 4-5%

Oncocytoma 3-5%

Xp11 traslocation

Associated to

neuroblastoma

Tubulocystic

Neuroendocr. tumors

Mesenchymal

Ducts of Bellini <1%

Tubulo-papillary

t(6,11) traslocation

Mucinous tubular

Her. leiomyomathosis

Unclassified

Tubulocystic

Primary

refractory

10-20%

Late

relapsing

10-13%

Poor risk

15-25%

Intermediate

risk

50-70%

Good risk

10-20%

«Poor»

poor risk

45%

Interm.

poor risk

40%

«Good»

poor risk

15%

PrognosisResponse

to TKIs

Slow

progressor

Massari F, Santoni M 2015

Brugarolas J., KCA Chicago 2014

RCC classification based on 400 genes

Durinck S, Nature Genetics 2015; 47(1): 13-21

Integrative Genomic Analyses of nccRCC

Durinck S, Nature Genetics 2015; 47(1): 13-21

Integrative Genomic Analyses of nccRCC

• Exome sequencing: higher average of protein-coding alterations in nccRCC compared to ccRCC

Modified by Ciccarese C, Journal Club 25.11.2015

N Engl J Med. 2015 Nov 4. [Epub ahead of print]

Papillary Renal Cell Carcinoma - Histology

Type 1 pRCC Type 2 pRCC

• Single line of small basophilic cells with

scanty cytoplasm

• Small, regular, round nuclei

• Often bilateral or multifocal

• Several layers of large eosinophilic

cells coating papillae

• Irregular and polymorphic nuclei, with

prominent nucleoli

New entity characterization by pathologist


Hereditary Papillary Renal Cell Carcinoma

Type 1 pRCC Type 2 pRCC

• Autosomal dominant hereditary

papillary RCC syndrome (HPRC)�

activating germline mutations of MET

oncogene

• Hypovascularized, low-grade pRCC,

with slow growth rate, and low

tendency to metastasize. [Schmidt LS, Nat Genet.

1997; 16: 68–73.]

• Hereditary leiomyomatosis and RCC

syndrome (HLRCC)� germline

mutations of the fumarate hydratase

(FH) gene

• High pathological grade and stage,

aggressive behavior with shorter

survival [Tomlison IP, Nat Genet. 2002; 30: 406-10]


Papillary RCC type I

• Met activation is common

• Distinct alterations involving MET in pRCC

• Germline mutation TK domain

• Somatic mutation TK domain

• Copy number alteration

• Fusion

Albiges L, Clin Cancer Res. 2014; 20(13):3411-21

Papillary RCC type II

Escudier B, ECCO-ESMO 2015

The Somatic Genomic Landscape of Chromophobe RCC

Davis CF et al, Cancer Cell 2014; 26:319–

330,

Combined mtDNA and gene expression analysis implicates changes in

mitochondrial function as a component of the disease biology, while suggesting

alternative roles for mtDNA mutations in cancers relying on oxidative

phosphorylation

Chromophobe RCC

Davis CF et al, Cancer Cell 2014; 26:319–

330,

ChRCC originates from the distal nephron compared with other kidney

cancers with more proximal origins.

Translocation RCC

Malouf GG et al, Clin Cancer Res 2014; 20(15): 4129–40

The genomic spectrum of TRCC by identifying novel MITF/TFE partners

involved in RNA splicing

Clear Cell RCC is VHL driven

AA Hakimi et al. Nature Genetics 2013, 45(8), 849-850

VHL has a key role in Angiogenesis and in Therapy

Kaelin WG. Nat Rev Cancer 2002;2:673–82

VHL HIF=

VEGFR EGFRPDGFR

Raf

mTOR

Sorafenib

Sunitinib

PazopanibSorafenibSorafenib

Temsirolimus

Everolimus

Bevacizumab

mTOR = mammalian target of rapamycinEGFR = endothelial growth factor receptorVEGFR = VEGF receptor; PDGFR = PDGF receptor

Raf

PDGFVEGF TGF-α

Treatment might be different in the future

based on observed mutation

BAP1 activity in RCC

Santoni M, Massari F , Expert Rev. Mol. Diagn 2015. Early online, 1–10

BAP1 and PBRM1 are mutually exclusive

Peña-Llopis S et al. Nat Genetics 2012

Lancet Oncol 2013; 14: 159–67

BAP1 and PBRM1 as prognostic factor for OS

Rini BJ et al. J Clin Oncol 2009; 27(19): 3225-32

Full blockade of Pi3K/AKT/mTOR pathway is attractive

Ortolani S, Ciccarese C et al. Future Oncol. 2015;11(12):1809-28

Full blockade of Pi3K/AKT/mTOR pathway is attractive

but NOT efficient!

1. Powles T et al, ASCO Symposium 2014; Abs #4525

2. Powles T et al, ASCO-GU Symposium 2015; Abs #409

Hitting both mTORC-1 and -2 looked smart …

Timing is everything …

• If mTORC2 is activated, as an escape mechanism, when

mTORC1, which is Rapamycin-sensitive, is blocked by

Everolimus …

• … then, does make sense to administer a dual mTORC1

and mTORC2 inhibitor from the very beginning?

• Probably really a bad study design …

A better study would have been …

Everolimus

10 mg o.d.

PROGRESSION

RANDOMIZATIONRANDOMIZATION

mTORC-1/2 inhibitor BSC or 3rd line Tx

Some drugs inhibit directly HIF

• CRLX101 is a dual inhibitor of HIF1a and HIF2a

– Phase I/II reported in 22 patients

– PFS 9.9 months in refractory patients (Keefe et al., ASCO 2015)

• Further development is ongoing

Should we continue to investigate more

potent VEGF inhibitor?

0.01

1000 VEGFR-1

VEGFR-2 Less

potent

More potent

100

10

1

0.1

VEGFR-3

Motesanib3

Cediranib3 Sunitinib3

Tivozanib1,2 Axitinib3

ABT-8693 Sorafenib3 Vandetanib3

Pazopanib3 Vatalanib3

IC50, half-maximal inhibitory concentration.1. Eskens F et al. Presented at 2008 annual meeting of the

American Association for Cancer Research (abstract); 2. Nakamura K et al. Cancer Res. 2006;66:9134-42;

3. Chow LQ, Eckhardt SG. J Clin Oncol. 2007;25:884-96.

Drugs to overcome resistance

Modified by Ellis L M, Hicklin D J Clin Cancer Res 2009;15:7471-7478

FGF Mediates Escape From Antiangiogenic Therapy

Massari F, Ciccarese C et al. Expert Rev Anticancer Ther. 2015 Nov 14:1-3

Third-line Trial in mRCC:Dovitinib vs Sorafenib

Phase III, randomised, open-label,

multi-centre trial

Eligibility criteria

• Advanced clear cell or

a component of clear

cell mRCC

• ≥1 measurable lesion N = 550

by CT or MRI

• 1 prior anti-VEGF and

1 prior mTOR inhibitor

• Karnofsky PS ≥70

Principal Investigator: Dr Robert Motzer

Trial Sites: United States, Canada, Germany

Dovitinib 500 mg/day

5 days on/2 days off

Sorafenib 400 mg bid

Primary end point: PFS

Secondary end points: OS, ORR, safety, and patient-reported outcomes

R

A

N

D

O

M

I

S

A

T

I

O

N

Motzer RJ et al, Lancet Oncol. 2014;15(3):286-96.

Motzer RJ et al, Lancet Oncol. 2014;15(3):286-96.

Lenvatinib± Everolimus in mRCC: Study Design

Motzer R, et al. ASCO 2015. Abstract 4506.

Randomized open-label phase II trial compared lenvatinib± everolimus vs everolimus

alone in RCC pts who progressed on VEGF therapy

Courtesy of Ciccarese C

Lenvatinib± Everolimus in mRCC: Patients Characteristics

Motzer R, et al. ASCO 2015. Abstract 4506.

Characteristic Lenvatinib/

Everolimus

(n = 51)

Lenvatinib

(n = 52)

Everolimus

(n = 50)

Male, % 69 75 76

Median age, yrs 61 (44-79) 64 (41-79) 59 (37-77)

ECOG PS 0/1, %53/47 56/44 56/44

Low hemoglobin, %65 69 62

Corrected serum

calcium < 10 mg/dL, % 88 85 84

Prior VEGF therapy, %

• Sunitinib

• Pazopanib

• Sorafenib

• Other

71

18

2

10

67

25

0

8

56

26

4

14

Courtesy of Ciccarese C

Lenvatinib± Everolimus in mRCC: Efficacy

Response Lenvatinib/

Everolimus

(n = 51)

Lenvatinib

(n = 52)

Everolimus

(n = 50)

ORR, % 43

P < .001 vs everolimus

27

P = .007 vs everolimus

6

Median PFS, mos 14.6

HR: 0.40; P < .001

vs everolimus

7.4

HR: 0.61; P = .048

vs everolimus

5.5

Median OS, mos 25.5

HR: 0.51; P = .024

vs everolimus

19.1

HR: 0.68; P =.118

vs everolimus

15.4

Courtesy of Ciccarese C Motzer R, et al. ASCO 2015. Abstract 4506.

• Hypoxia triggers increase in

cMET expression and activity:

– Cell invasion and migration

– Cell proliferation

– Cell survival

• Inhibition of cMET may help

overcome acquired resistance

to the VEGF pathway

• Dual inhibitors of cMET and

VEGFr2 such as Cabozantinib

are active

MET and Acquired Resistance to VEGF-targeted Therapies

Aftab DT et al. Clin Transl Oncol, 2011; 13: 703-9

cMET expression in clear cell RCC

Courtesy of Bin Teh

Lancet Oncol 2013; 14: 81–87

Patients with localised renal-cell carcinoma and the MET

polymorphism rs11762213 might have an increased risk

of recurrence after nephrectomy

Choueiri T et al. J Clin Oncol 30, 2012 (suppl; abst 4504)

CABOZANTINIB (XL 184) in Patients with Metastatic, Refractory RCC

METEOR Study

• Primary endpoint: PFS

• Secondary endpoints: OS, ORR

• Exploratory endpoints: safety, tolerability, tumour MET status, circulating tumour

cells, serum bone markers and plasma biomarkers, skeletal-related events, and

HRQoL

• Stratification: MSKCC risk criteria; number of prior VEGFR TKIs

Eligibility:

• mRCC with clear-cell component

• At least 1 prior

VEGFR TKI

• Progression on prior

VEGFR TKI within 6

months of study

enrolment

• Karnofsky PS ≥70

Cabozantinib

60 mg orally daily

Everolimus

10 mg orally daily

R

A

N

D

O

M

I

S

A

T

I

O

N

N=658 1:1

Choueiri T et al. NEJM 2015

METEOR Study: PFS

Choueiri T et al. NEJM 2015

METEOR Study: OS

Choueiri T et al. NEJM 2015*Interim analysis (49% information fraction)

Medians cannot yet be estimated due to frequent early censoring

ALK 1: a new target

Activin receptor-like 1 (ALK1) and its high-affinity ligand, bone morphogenetic

protein 9 (BMP9), are TGF-beta superfamily members ALK1 is selectively

expresses on vascular and lymphatic endothelial cell

ALK 1: a new target

Escudier B; ECCO-ESMO 2015

Phase I ongoing study

Escudier B; ECCO-ESMO 2015

Blocking PD-1/PD-1L in RCC tumor microenvironment

Massari F, Santoni M, Ciccarese C. et al, Cancer Treat Rev. 2015;41(2):114-21.

CheckMate 025

Motzer RJ et al, N Engl J Med. 2015; 373(19):1803-13

Previously treated

mRCC

Stratification factors

Region

MSKCC risk group

Number of prior anti-

angiogenic therapies

Nivolumab

3 mg/kg intravenously every

two weeks

Nivolumab

3 mg/kg intravenously every

two weeks

Everolimus

10 mg orally

once daily

Everolimus

10 mg orally

once dailyR

an

do

miz

e 1

:1

• Patients were treated until progression or intolerable toxicity occurred

• Treatment beyond progression was permitted if drug was tolerated and

clinical benefit was noted

MSKCC, Memorial Sloan-Kettering Cancer Center.

CheckMate 025: Overall survival


Median OS, months (95% CI)

Nivolumab 25.0 (21.8–NE)

Everolimus 19.6 (17.6–23.1)

HR (98.5% CI): 0.73 (0.57–0.93)

P = 0.0018

0 3 6 129 15

Months

18 21 24 27 30 33

No. of patients at riskNivolumab 410 389 359 337 305 275 213 139 73 29 3 0

411 366 324 287 265 241 187 115 61 20 2 0Everolimus

0.0

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0O

ve

rall

Su

rviv

al

(Pro

ba

bil

ity

)

Nivolumab

Everolimus

Minimum follow-up was 14 months.

NE, not estimable.

CheckMate 025: Overall survival by PD-L1 expression


PD-L1 <1% (n = 76%)


Nivolumab 21.8 (16.5–28.1)

Everolimus 18.8 (11.9–19.9)

No. of patients at risk

Nivolumab 94 86 79 73 66 58 45 31 18 4 1 0

Everolimus 87 77 68 59 52 47 40 19 9 4 1 0

0.0

0 3 6 129 15

Months

18 21 24 27 30 33

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ov

era

ll S

urv

iva

l (P

rob

ab

ilit

y)

Nivolumab

Everolimus

PD-L1 ≥1% (n = 24%)


Nivolumab 27.4 (21.4–NE)

Everolimus 21.2 (17.7–26.2)

Nivolumab

0 3 6 129 15

Months

18 21 24 27 30 33

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.0

Everolimus

HR (95% CI): 0.79 (0.53–1.17) HR (95% CI): 0.77 (0.60–0.97)

276 265 245 233 210 189 145 94 48 22 2 0

299 267 238 214 200 182 137 92 51 16 1 0

PD-Lomas

Marabelle A et al,Oncoimmunology 2015Courtesy of Escudier B – ECCO-ESMO 2015

PD-1 blockade is a promising

strategy for mRCC patients

However, it is still unclear if this

approach may be used alone or in

combination with other strategies

PD-1 blockade: alone or in combination?

Anti –LAG3

BMS-986016

Anti PD-L1

MEDI4736

Anti-CTLA-4

Ipilimumab

Tremelimumab

PD-1

blockade

NK cell therapy

Tyrosin kinase

inhibitors

IDO1

inhibitors

41BB agonist

monoclonal

antibody

DC vaccines

PD-1 blockade….in combination with…?

Modified by Santoni M , AIOM 2014

Hammers H et al. ESMO 2014; Abstract 7843 (Presentation 1050O)

Hammers H et al. ESMO 2014; Abstract 7843 (Presentation 1050O)

Ipilimumab + Nivolumab in mRCC

Prospettive future nel trattamento medico del mRCC ...€¦ · CheckMate 025: Overall survival by...

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