Post on 15-Apr-2017
Futuro del tratamiento del cáncer renal metastásico: papel de la inmunoterapia y las terapias blanco dirigidas
Mauricio Lema Medina MD
Clínica de Oncología Astorga, Clínica SOMA, Medellín
Simposio ACHO GU, Septiembre 23-24 de 2016, Bogotá
Page ▪ 2
ο άνθρωπος είναι το μέτρο όλων των πραγμάτων
Πρωταγόρας
εὐδαιμονία
“Florecer”
Avanzar
Mejorar
Adquirir bienestar
εὐδαιμονία ο άνθρωπος είναι το μέτρο όλων των πραγμάτων
Πρωταγόρας
Timeline of Development of Targeted Agents for RCC
US Food and Drug Administration.
Sorafenib[advanced RCC]
Sunitinib(advanced
RCC)Pazopanib
(advanced RCC)Bevacizumab + IFN-α
(metastatic RCC)
Temsirolimus(advanced RCC)
Immunotherapy withIFN-α or IL-2
201120102009200820072006200520042003200220012000 2012 2013 2014 2015
Everolimus(advanced RCC after failure
of sorafenib or sunitinib)
Axitinib(advanced RCC after failure of 1 systemic therapy)
VEG
F pa
thw
ay
inhi
bito
rs
mTO
R in
hibi
tors
Currently (2014) Approved RCC Therapies
Tumor cell membrane
VEGFR
P13K
AKT
mTOR
Raf
Mek
Ras
VEGFR
P P P P
Erk
Nucleus Transcription Factors
Cell adhesionCell survival
Cell proliferation
ApoptosisCell differentiation
Angiogenesis
Tumor blood vessel endothelial cell membrane
P P P
PDGFR
PP PP P
EGFR PDGFR
P P P PPP P P
Pericyte
BevacizumabVEGF-A
SunitinibAxitinibPazopanib
Sorafenib
TemsirolimusEverolimus
Modified from Rini BI, et al. J Clin Oncol. 2005;23:1028-1043.
Primary Endpoint: PFS (Independent Review)
N Median PFS, Mos (95% CI)
Pazopanib 557 8.4 (8.3-10.9)Sunitinib 553 9.5 (8.3-11.1)
HR: 1.047 (95% CI: 0.898-1.220)
Motzer RJ, et al. ESMO 2012. Abstract 2325.
Pts at Risk, n557553
361351
245249
136147
105111
6169
4648
1918
1310
13
PazopanibSunitinib
1.0
0.8
0.6
0.4
0.2
0
Prop
ortio
n of
Pts
Pro
gres
sion
Fre
e
0 4 8 12 16 20 24 28 32 36 40Mos
AXIS Trial: Axitinib Superior to Sorafenibin Second-line mRCC Therapy
Rini BI, et al. Lancet. 2011;378:1931-1939.
1.00.90.80.70.60.50.40.30.20.1
00 2 4 6 8 10 12 14 16 18 20
Prob
abili
ty o
f PFS
AxitinibSorafenib
Median PFS, Mos (95% CI)6.7 (6.3-8.6)4.7 (4.6-5.6)
Stratified HR: 0.665(95% CI: 0.544-0.812; P < .0001)
Pts at Risk, nAxitinib
Sorafenib256224
361362
202157
145100
9651
6428
3812
206
103
11
00
Months
Progression-Free Survival
Median PFS, MosEverolimus: 4.0
Placebo: 1.9
P < .0001
Motzer RJ, et al. Lancet. 2008;372:449-456.
100
80
60
40
20
00 2 4 6 8 10 12
Prob
abili
ty o
f PFS
(%)
EverolimusPlacebo
Pts at Risk, nEverolimus
Placebo13232
272138
474
81
20
00
00
Mos
PD-L2–mediated inhibition of TH2 T cells
Stromal PD-L1modulation of T cells
Reprinted from Clinical Cancer Research. 2013;19(5):1021-1034. Sznol M, et al. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. With permission from AACR.
Blockade of PD-1 Binding to PD-L1 (B7-H1) and PD-L2 (B7-DC) Revives T Cells
PD-L1 expression on tumor cells is induced by γ-interferon
In other words, activated T cells that could kill tumors are specifically disabled by those tumors
PD-1PD-L1PD-L2T-cell receptor MHC-1CD28Shp-2B7.1
IFN-γ–mediated upregulation of
tumor PD-L1 PD-L1/PD-1–mediated inhibition of tumor cell killing
Priming and activation of
T cells
Immune cell modulation of T cells
Tumor cell
IFN-γR
IFN-γ
Tumor-associated fibroblast M2
macrophage
Treg cell
Th2 T cell
Other NFκB P13K
CD8+ cytoxicT lymphocyte
T-cell polarizationTGF-β
IL-4/13
Can you generate tumor-killing T cells?
Dendritic cell
Antigen priming
Can the T cells get to the tumor?
T-cell trafficking
Can the T cells see the tumor?
Peptide-MHCexpression
Can the T cells be turned off?
Inhibitory cytokines
Can the T cells be turned off?
PD-L1 expression on tumor cells
Immunocompetent Mice Reject Tumors Originating in Immunodeficient Mice
Shankaran V, et al. Nature. 2001;410:1107-1111.
In other words, competent immune systems force the tumors to figure
out how to survive in hostile environments
Median OS for Patients With mRCC Treated With Nivolumab
1-yr OS: 70%
2-yr OS: 50%
Drake CG, et al. ASCO 2013. Abstract 4514.
100
80
60
40
20
0
OS
(%)
Mos Since Treatment Initiation 510 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Pts at Risk, n 034 33 28 28 23 19 14 12 8 8 8 8 8 5 2 0 0
Died/Treated15/34
Median, Mos (95% CI)> 22 (13.60 - NE)
CheckMate 025: A randomized, open-label, phase III
study of nivolumab versus everolimus in advanced renal cell carcinoma
Padmanee Sharma, Bernard Escudier, David F. McDermott, Saby George, Hans J. Hammers, Sandhya Srinivas, Scott S. Tykodi, Jeffrey A. Sosman,
Giuseppe Procopio, Elizabeth R. Plimack, Daniel Castellano, Howard Gurney, Frede Donskov, Petri Bono, John Wagstaff, Thomas C. Gauler, Takeshi Ueda,
Li-An Xu, Ian M. Waxman, Robert J. Motzer, on behalf of the CheckMate 025 investigators
Study design and endpoints
Disease assessments• Every 8 weeks from randomization through 12 months• Then every 12 weeks until progression or treatment discontinuationPrimary endpoint• Overall survival (OS)
Enrolled patients• Previously treated
advanced or metastatic clear-cell RCC
• 1 or 2 prior anti-angiogenic treatments R
ando
miz
e 1:
1Nivolumab
(N = 410) 3 mg/kg every 2 weeks
intravenous
Everolimus (N = 411)
10 mg/day oral
• Treat until progression or intolerable toxicity
• Treatment beyond progression was permitted if drug was tolerated and clinical benefit was noted
Randomized, open-labeled phase III study to compare nivolumab with everolimus in patients with advanced RCC after prior systemic
therapy (NCT01668784)
Overall survival
HR, hazard ratio; NE, not estimable.
Median OS, months (95% CI)
Nivolumab (N = 410) 25.0 (21.8–NE)
Everolimus (N = 411) 19.6 (17.6–23.1)
HR (98.5% CI), 0.73 (0.57–0.93)
P = 0.0018
0 3 6 129 15 18 21 24 27 30 330.0
0.3
0.1
0.2
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Ove
rall
Surv
ival
(Pro
babi
lity)
Nivolumab
Everolimus
The risk of death was reduced by 27% in patients in the nivolumab treatment group compared with those in the everolimus group
Study stopped after planned interim analysis (398 deaths) because assessment by an independent data monitoring committee concluded that the study met its primary endpoint, demonstrating superior OS for nivolumab
This means that patients are more likely to live when treated with nivolumab versus everolimus
Months
Nivolumab Everolimus0
8
15
23
30
25
5
Objective response rateO
bjec
tive
Res
pons
e R
ate
(%)
P < 0.0001
Patients on nivolumab treatment had a significantly better objective response rate than those on everolimus treatment
This means that more patients responded to treatment with nivolumab than to treatment with everolimus
▪ CheckMate 025 met its primary endpoint, demonstrating OS superiority with nivolumab versus everolimus
▪ This is the only phase III trial to demonstrate a survival advantage in previously-treated patients with mRCC versus standard therapy
▪ Nivolumab was associated with a greater number of objective responses than everolimus
▪ The survival improvement and favorable safety profile demonstrated in this phase III trial provides evidence for nivolumab as a potential new treatment option for previously treated patients with mRCC
▪ Based on the positive results of this trial, nivolumab was granted a breakthrough therapy designation from the FDA for advanced RCC, reinforcing the importance of these results in a patient population with large unmet medical need
Key conclusions
Cabozantinib in Relapsed or Refractory RCC: PFS
Choueiri TK, et al. ASCO 2012. Abstract 4504.
1.00
0.75
0.50
0.25
0
0 5 10 15 20
Prop
ortio
n Pr
ogre
ssio
n Fr
ee
Mos From First Dose
Median PFS, Mos 95% CIEvents, n
14.7 7.3, –8
Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma
Choueiri TK, NEJM, 2015
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Overall survival in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced renal
cell carcinoma
Choueiri TK, Proc ASCO 2016, Abstract 4506
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Long-term overall survival with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I
and II studies.
McDermott DF, Proc ASCO 2016, Abstract 4507
Fig 4. Probability of being the best treatment in terms of overall survival according to the four Bayesian models, as a function of time since the beginning of therapy.
Wiecek W, Karcher H (2016) Nivolumab versus Cabozantinib: Comparing Overall Survival in Metastatic Renal Cell Carcinoma. PLoS ONE 11(6): e0155389. doi:10.1371/journal.pone.0155389http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0155389
New agents and new targets in RCC
• Angiopoietins• ALK-1• IL-8• MDM2• HIF-2 alpha• Neurofibromin-2 (Merlin) and Hippo
Philips GK, ASCO Ed Book, 2014
ALK1: Activin Receptor-like Kinase IGupta S, Curr Oncol Rep, 2015
Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in ccRCC
Huang D, Cancer Res, 2010
Neurofibromin-2
A whole-genome sequencing study of a large cohort of primary RCC tumors and cell lines, found that a notable fraction (33%) of VHL wild-type clear cell RCCs contained inactivating mutations of the tumor suppressor gene NF2
Dalgliesh GL, Nature, 2010
Working hypothesis for the role of YAP and the Hippo pathway during tumor progression and metastasis.
John M. Lamar et al. PNAS 2012;109:14732-14733
©2012 by National Academy of Sciences
1st-line antiangiogenic TKI
2nd-line antiangiogenic TKI mTOR inhibitor
To be defined…
Today
1st-line antiangiogenic TKI
2nd-line antiangiogenic TKI Cabozantinib
mTOR inhibitor (?)
Tomorrow
Nivolumab
Sequence?