Ponencia en el primer simposio de la Asociación Colombiana de Hematología y Oncología (ACHO) de cáncer genitourinario, Bogotá, septiembre 23 y 24 de 2016.
Ahmedabad Call Girls CG Road 🔝9907093804 Short 1500 💋 Night 6000
El futuro del tratamiento del cáncer renal metastásico: inmunoterapia y terapias blanco dirigidas
1. 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
10. 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 with
IFN-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)
VEGFpathway
inhibitors
mTORinhibitors
11. 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 adhesion
Cell survival
Cell proliferation
Apoptosis
Cell differentiation
Angiogenesis
Tumor blood vessel
endothelial cell
membrane
P P P
PDGFR
PP PP P
EGFR PDGFR
P P P PPP P P
Pericyte
Bevacizumab VEGF-A
Sunitinib
Axitinib
Pazopanib
Sorafenib
Temsirolimus
Everolimus
Modified from Rini BI, et al. J Clin Oncol. 2005;23:1028-1043.
19. AXIS Trial: Axitinib Superior to Sorafenib
in Second-line mRCC Therapy
Rini BI, et al. Lancet. 2011;378:1931-1939.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 2 4 6 8 10 12 14 16 18 20
ProbabilityofPFS
Axitinib
Sorafenib
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, n
Axitinib
Sorafenib
256
224
361
362
202
157
145
100
96
51
64
28
38
12
20
6
10
3
1
1
0
0
Months
20. Progression-Free Survival
Median PFS, Mos
Everolimus: 4.0
Placebo: 1.9
P < .0001
Motzer RJ, et al. Lancet. 2008;372:449-456.
100
80
60
40
20
0
0 2 4 6 8 10 12
ProbabilityofPFS(%)
Everolimus
Placebo
Pts at Risk, n
Everolimus
Placebo
132
32
272
138
47
4
8
1
2
0
0
0
0
0
Mos
21.
22.
23.
24.
25. PD-L2–mediated
inhibition of TH2 T cells
Stromal PD-L1
modulation 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-1
PD-L1
PD-L2
T-cell receptor
MHC-1
CD28
Shp-2
B7.1
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+ cytoxic
T lymphocyte
T-cell polarization
TGF-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-MHC
expression
Can the T cells
be turned off?
Inhibitory cytokines
Can the T cells
be turned off?
PD-L1 expression
on tumor cells
26. 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
27. 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/Treated
15/34
Median, Mos (95% CI)
> 22 (13.60 - NE)
28. 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
29. 29
Study design and endpoints
Disease assessments
• Every 8 weeks from randomization through 12 months
• Then every 12 weeks until progression or treatment discontinuation
Primary endpoint
• Overall survival (OS)
Enrolled patients
• Previously treated
advanced or
metastatic clear-
cell RCC
• 1 or 2 prior anti-
angiogenic
treatments
Randomize1:1 Nivolumab
(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)
30. 30
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 33
0.0
0.3
0.1
0.2
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OverallSurvival(Probability)
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
31. 25
5
0
8
15
23
30
Nivolumab Everolimus
31
Objective response rate
ObjectiveResponseRate(%)
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
33. ▪ 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
33
Key conclusions
34.
35. 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
ProportionProgressionFree
Mos From First Dose
Median PFS, Mos 95% CIEvents, n
14.7 7.3, – 8
45. 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
46. 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
47. 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
48. 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
49. 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
50. 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
51. 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
52. 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
53. 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
54. 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
55. 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
56. 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
57. 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
58. 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
59. 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
60. 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
61. 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
62. 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
63. 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
64. 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
65. 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
66. 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
67. 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
68. 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
69. 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
70. 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
71. 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
72. 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
73. 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
74. 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
75. 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
76. 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.0155389
http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0155389
77.
78. 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
81. 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. The activation of the Hippo pathway by changes in cell density, cell shape, and cell adhesion leads to phosphorylation of the Hippo kinases (MST1/2 in mammals), which in combination with the adaptor protein Sav phosphorylate LATS1/2 kinases and their partner, MOB. The LATS/MOB complex then phosphorylates the transcriptional coactivator YAP and thereby represses YAP activity by promoting both cytoplasmic sequestration via 14-3-3 proteins and proteasomal degradation. Our results show that inhibiting the ability of the Hippo pathway to repress YAP results in increased YAP/TEAD-dependent gene expression, which influences both tumor growth and metastasis by enhancing processes that occur at both the primary tumor and at the metastatic site. A close homolog of YAP, TAZ, is regulated in a similar fashion by the Hippo pathway and likely plays a similar role.