Prospettive future nel trattamento medico del mRCC ...€¦ · CheckMate 025: Overall survival by...
Transcript of 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
Modified by Ciccarese C, Journal Club 25.11.2015
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]
Modified by Ciccarese C, Journal Club 25.11.2015
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
Rini BJ et al. J Clin Oncol 2009; 27(19): 3225-32
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
Rini BJ et al. J Clin Oncol 2009; 27(19): 3225-32
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
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
Motzer RJ et al, N Engl J Med. 2015; 373(19):1803-13
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
Motzer RJ et al, N Engl J Med. 2015; 373(19):1803-13
PD-L1 <1% (n = 76%)
Median OS, months (95% CI)
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%)
Median OS, months (95% CI)
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