1. Tratamiento antidiana
del Cáncer Renal
Santo Estevo, 14 de Junio de 2014
Martín Lázaro Quintela

3. Nuevas estrategias de tratamiento en cáncer renal: impacto en un
incremento en la supervivencia global
1. Motzer RJ, et al. J Clin Oncol 2009
Nueva EraNueva Era
La selección del tratamiento apropiado para cada
subgrupo de paciente y en cada una de las líneas es
clave en la SG del paciente
OS(años)
Numero de líneas de tratamiento en
secuencia (N>2)1

4. 1. Sunitinib SmPC, Jan 2014; 2. Sorafenib SmPC, Feb 2013; 3. Bevacizumab SmPC, Feb 2014; 4. Temsirolimus SmPC, Oct 2013;
5. Everolimus SmPC, Nov 2013; 6. Pazopanib SmPC, Dec 2013; 7. Axitinib SmPC, Oct 2013.
Targeted agents currently approved for mRCC in Europe

5. Clinical patterns of resistance to targeted therapy
Primary refractory
(2–3 months of treatment)
Adaptive (evasive) resistance
Early progressors
(6–12 months of treatment)
Late progressors
Changeintumour
measurements(%)
Changeintumour
measurements(%)
Changeintumour
measurements(%)Rini and Flaherty. Urol Oncol 2008.
Intrinsic resistance

6. Srinivas, ASCO 2011

8. Agent N ORR (%)
Median PFS
(months)
Median OS
(months)
Sunitinib vs IFN-α1
750 47 vs 12
P<0.001
11 vs 5
P<0.001
26.4 vs 21.8
P=0.051
Temsirolimus vs IFN-α2*
626 8.6 vs 4.8
NS
5.5 vs 3.1
P<0.001
10.9 vs 7.3
P=0.008
Bevacizumab + IFN-α vs
IFN-α3,4
649 31 vs 13
P=0.0001
10.2 vs 5.4
P<0.0001
23.3 vs 21.3
P=0.1291
Bevacizumab + IFN-α vs
IFN-α5,6
732 26 vs 13
P<0.0001
8.5 vs 5.2
P<0.0001
18.3 vs 17.4
P=0.069
Pazopanib vs placebo7,8
435
30 vs 3†
P<0.001
11.1 vs 2.8
P<0.0001
(9.2 vs 4.2†
P<0.0001)
22.9 vs 20.5†
P=0.224
Tivozanib9
517
33 vs 23†
P< 0,014
11.9 vs 9,1†
p= 0,042
NA
1. Motzer RJ, et al. J Clin Oncol 2009; 2. Hudes G, et al. N Engl J Med 2007; 3. Escudier B, et al. Lancet 2007; 4. Escudier B, et al. J Clin Oncol 2010; 5.
Rini BI, et al. J Clin Oncol 2008; 6. Rini B, et al. J Clin Oncol 2010; 7. Sternberg C, et al. J Clin Oncol 2010; 8. Sternberg C, et al. ESMO 2010; 9. Motzer, et
al. ASCO 2012
*Poor risk patients (modified MSKCC criteria); †
Treatment-naïve and cytokine refractory populations
Agentes frente a mRCC

9. Third-line Post-two VEGF-TKIs Everolimus IIA
Post-VEGFR-TKI
and mTOR inhibitor
VEGFR-TKI IIIB
ESMO 2012 guidelines for targeted treatment of mRCC
Post-cytokines Axitinib
Sorafenib
Pazopanib
Sunitinib
IA
IA
IIA
IIIA
Post-TKI Axitinib
Everolimus
IB
IIA
Favourable or
intermediate risk
Sunitinib
Bevacizumab + IFN-α
Pazopanib
IA
IA
IIB
Poor risk Temsirolimus IB
First-line
Second-line
Treatment
group
Standard
recommendation
Level of
evidence
Longer-termsurvival
IFN-α, interferon-alpha
Escudier et al. Ann Oncol 2012; Corrigendum Ann Oncol 2013.
Third-line

10. Less
potent
More
potent
Potency:IC50(nM)
VEGFR-1
VEGFR-2
VEGFR-3
Motesanib
AMG-706
Sunitinib ABT-869 Pazopanib Sorafenib Vatalanib
PTK787
Vandetanib
CediranibAxitinibTivozanibA
V-951
1,000
100
10
1
0.1
0.01
Figure modified using data from Chow LQM, Eckhardt SG. J Clin Oncol. 2007;
Eskens FALM, et al. AACR 2008. Abstract LB-201; Hu-Lowe DD, Clin Cancer Res 2008
Potency to Inhibit VEGF Receptors 1, 2, and 3

11. COMPARZ: PFS y OS

12. TIVO-1: PFS y OS
Motzer R J et al. JCO 2013;31:3791-3799
PFS OS
29,3 Tivo vs 28,8 Sora11,9 Tivo vs 9,1 Sora

13. RECORD3
Everolimus - sunitinib vs.
Sunitinib - everolimus
Primary endpoint of first-line PFS non-
inferiority was not met for everolimus
compared with sunitinib1
First-line study*
SWITCH
Sorafenib** - sunitinib vs.
sunitinib - sorafenib
Primary endpoint (Total PFS)
demonstrating superiority of sorafenib-
sunitinib over
sunitinib-sorafenib was not met2
Sequencing studies to date have been inconclusive
Limitations
•Insufficient patients in second-line to allow for robust analysis of sequencing
•Introduction of a number of potential areas of bias
1. Motzer at al. ASCO 2013; 2. Michel et al. ASCO GU 2014; 3. Everolimus SmPC, Nov 2013; 4. Sorafenib SmPC, Feb 2013.
*Everolimus is indicated for the treatment of patients with advanced RCC, whose disease has progressed on or after treatment with VEGF-targeted therapy3
;
**Sorafenib is indicated for advanced RCC after IFN α/IL-2 or if unsuitable for IFN-α/IL-2‑ 4
Please refer to prescribing information for each treatment option; DCR, disease control rate

14. SWITCH Phase III Study: Sorafenib → Sunitinib vs Sunitinib
→ Sorafenib in mRCC
• Primary endpoint: total PFS (from randomization to confirmed progression or death during
second-line therapy, or first line for pts who did not receive second-line treatment)
• Pts enrolled in Germany, Austria, and The Netherlands
• Efficacy assessed every 12 wks (per RECIST 1.0) and at end of treatment
Michel M, et al. ASCO GU 2014. Abstract 393.
Pts with mRCC,
unsuitable for
cytokines, no prior
systemic therapy,
ECOG PS 0-1, ≥ 1
lesion
Sorafenib
400 mg BID
Sunitinib
50 mg QD
Progression
or
intolerable
toxicity Sorafenib
400 mg BID
Sunitinib
50 mg QD
Stratified by MSKCC prognostic group
(favorable or intermediate)

15. SWITCH Study of Sorafenib → Sunitinib vs Sunitinib →
Sorafenib in mRCC: OS
Michel M, et al. ASCO GU 2014. Abstract 393.
100
80
60
40
20
0
0 5 10 15 20 25 30 35 40 45 50
Mos From Randomization
ProbabilityofOS(%)
Pts at Risk, n
So → Su
→ So
182
183
148
147
123
119
105
95
79
80
58
59
36
37
25
29
17
18
9
12
Median OS
So→ Su (n = 182): 31.5 mos (95% CI: 23.3-36.9)
Su → So (n = 183): 30.2 mos (95% CI: 23.6-50.1)
HR: 1.00; P = .49
55
6
7

16. Evolution in the first-line treatment of mRCC
Mediansurvival(months)
PFS OS
3–6
6–15*
13–22
18–32*
After AfterBefore Before
30
25
20
15
10
5
0
Median survival before and after the introduction of targeted agents (TKIs)1–11
1. Coppin et al. Cochrane Database Syst Rev 2005; 2. Gore et al. Lancet 2010; 3. Motzer et al. N Engl J Med 2007; 4. Escudier et al. Lancet 2007;
5. Rini et al. J Clin Oncol 2008; 6. Motzer et al. N Engl J Med 2013; 7. Motzer et al. J Clin Oncol 2009; 8. Escudier et al. J Clin Oncol 2010;
9. Rini et al. J Clin Oncol 2010; 10. Michel et al. ASCO GU 2014; 11. Motzer et al. ASCO 2013.
*With targeted agents as first-line mRCC therapy primarily in favourable/intermediate risk patients

17. Real world vs clinical trials
Real world
Purpose
Performance in
the real world Regulatory approval
Patient typeHeterogeneous Homogeneous
Control
Not placebo-controlled,
not blinded
Control arm provides
relative efficacy
Inclusion criteria
Strict (e.g. specific age group,
few co-morbidities)
Broad (e.g. elderly patients,
multiple co-morbidities)
Conditions
Real and diverse
clinical situations
Highly controlled,
stringent treatment delivery
Real world Pivotal clinical trials

18. Evolución de los pacientes que no cumplen criterios para ser
incluidos en ensayos clínicos
• 768 of 2210 (35%) patients in the International
Metastatic RCC Database Consortium (IMDC) were
deemed ineligible for clinical trials
• First-line results (ineligible patients vs eligible
patients)
– Response rate: 22% vs 29% (p=0.0005)
– mPFS: 5.2 vs 8.6 months (p<0.0001)
– mOS: 12.5 vs 28.4 months (p<0.0001)
• Second-line results (ineligible patients vs eligible
patients)
– PFS: 2.8 vs 4.3 months (p=0.0039)
Heng D Y C et al. Ann Oncol 2014;25:149-154

19. Progress in advanced kidney cancer, 2007–2014
Patient outcomes
Therapeutic options
Median PFS
4–5 months
Median PFS
9–11 months
Median PFS
4–5 months
? ?
~40–60%1,2
~100% <20%3–5
Eligible patients
1. Levy et al. Eur J Cancer 2013; 2. Sonpavde et al. Eur Urol 2012; 3. Iacovelli et al. Eur J Cancer 2013; 4. Pal et al. ASCO GU 2013;
5. Heng et al. ASCO 2013.
Adapted from Larkin. ASCO GU 2014
IFN-α, interferon-alpha
Sunitinib
Pazopanib
IFN-α + bevacizumab
Temsirolimus
Axitinib
(post-sunitinib/cytokine)
Everolimus
(post-VEGFR-TKI)
Sunitinib
(post-cytokine)
Pazopanib
(post-cytokine)
Sorafenib
(post-cytokine)
Everolimus
(post-VEGFR-TKI × 2)
Neoadjuvant Adjuvant First-line Second-line Third-line

20. Have we improved OS since 2007?
2007/20131,2
2010/20132,3
20134
20135
20146
20146
1. Motzer et al. J Clin Oncol 2009; 2. Motzer et al. N Engl J Med 2013; 3. Sternberg et al. Eur J Cancer 2013; 4. Motzer et al. J Clin Oncol 2013;
5. Motzer et al. ASCO 2013; 6. Michel et al. ASCO GU 2014.
MedianOS,months
Please refer to local prescribing information for each treatment option
Median OS for VEGF-targeted therapies in mRCC in clinical studies
Eve. Everolimus; Seq., sequence; Sor, sorafenib; Sun, sunitinib

21. ¿Podemos identificar a los largos
respondedores?

22. Complete responses to VEGF-TKIs
• Long-lasting CRs can occur after TKI treatment alone or when combined with local treatment
• Relapsing patients responded well to further therapy
• Median time to CR was 12.6 months in patients receiving TKIs alone, highlighting the
importance of maintaining therapy
Albiges et al. J Clin Oncol 2012.
Sunitinib-treated patients: n=59; sorafenib-treated patients: n=5
CR, complete response

23. CR, complete response; PD, disease progression; PR, partial response; SD, stable disease
*Six patients were not evaluable
Long-term responders to sunitinib
• Retrospective analysis of long-term responders to sunitinib (i.e. patients achieving durable CR or
remaining progression-free for >18 months)
• 186 patients treated with sunitinib monotherapy (n=89) or in combination (n=97) in 9 clinical trials
– Of 180 evaluable patients, 34 patients (19%) achieved long-term response
Variable All (N=186)*
Long-term responders (n=34)
Best objective response
CR 4 (2%) 3 (9%)
PR 74 (40%) 24 (71%)
SD 80 (43%) 7 (21%)
PD 22 (12%) 0
OS
Number of deaths 152 (82%) 24 (71%)
Molina et al. Clin Genitourin Cancer 2013.

24. Factors associated with long-term response
• Univariate analysis showed the following factors were associated with long-term response:
– Absence of bone or lung metastases
– Favourable MSKCC risk status
All
(N=186)
Long-term
responders (n=34)
Univariate logistic analysis
(Yes vs No) Odds Ratio (95%
CI)
p-value
Site of disease
Bone 50 (27%) 5 (51%) 0.41 (0.15–1.12) 0.08
Lung 131 (70%) 18 (53%) 0.39 (0.18–0.84) 0.02
Liver 41 (22%) 4 (12%) 0.41 (0.14–1.26) 0.12
> 2 metastatic sites 140 (75%) 22 (65%) 0.53 (0.24–1.19) 0.12
Previous treatment 72 (39%) 15 (44%) 1.32 (0.62–2.79) 0.48
Clear cell histologic
type
164 (88%) 31 (91%) 1.48 (0.41–5.30) 0.55
MSKCC risk group
Favourable 91 (49%) 22 (65%) 2.21 (1.02–4.78) 0.045
Intermediate/poor 95 (51%) 12 (35%) 1.0 (reference)
Molina et al. Clin Genitourin Cancer 2013.

25. Nuevos agentes dirigidosNuevos agentes dirigidos
Nuevas
aproximaciones
Nuevas
aproximaciones
Nuevos enfoques en el tratamiento del
Cáncer Renal metastásico

26. Nuevos agentes que no han cumplido las expectativas
Ang1/2, angiopoietin 1/2; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor
Ramucirumab Aflibercept
Dovitinib
BIBF 1120,
Lenvatanib
Tivozanib,
Cediranib
FGF receptor VEGF receptor PDGF receptor Tie2 receptor
AKT
MK-2206
FGF VEGF
PDGF
Ang1/2
AMG 386
Figlin et al. J Urol 2012
PI3K inhibitors

27. Nuevos agentes: c-MET
HGFHGF
PP
SRCSRC
PLCPLC
GAB1GAB1
RASRAS P13KP13K
MEKMEK
ERKERK
AKTAKT
mTORmTOR
PP
PP
PP
TKI no selectivo
Crizotinib
TKI no selectivo
Crizotinib
TKI selectivo MET
Tivantinib
Foretinib
Cabozantinib
TKI selectivo MET
Tivantinib
Foretinib
Cabozantinib
HGFHGF

28. Estudios con agentes frente a c-MET
Completed Phase I and II studies
Agent Study type Results
Foretinib
(XL 880)1
Phase II, 74 patients with pRCC PFS: 9.3 months
OS: NR
Tivantinib
(ARQ 197)2
One patient with RCC SD over 4 months
Ongoing Phase II and III studies3
Agent Study type Current status
CREATE study,
crizotinib
Phase II EORTC Type 1 pRCC type Ongoing
AcSé,
crizotinib
Phase II, pRCC Ongoing
METEOR study,
cabozantinib (XL 184)
Phase III, second-line vs everolimus,
ccRCC
Ongoing
Cabozantinib
(XL 184)
Phase II, pRCC Study opening
September 2013
Cabozantinib
(XL 184)
Phase II, first-line vs sunitinib, ccRCC Ongoing
1. Choueiri et al. JCO 2013; 2. Yap et al. JCO 2011; 3. www.clinicaltrials.gov

29. Cabozantinib
Fase II
25 pacientes
Más de una línea
SLP: 14.7 meses
RR 28%
Figlin, Int J Cancer 2013;133:788-796

30. Nuevos agentes
dirigidos
Nuevos agentes
dirigidos
Nuevos agentes de
inmunoterapia
Nuevos agentes de
inmunoterapia
Nuevas
aproximaciones
Nuevas
aproximaciones
Nuevos enfoques en el tratamiento del
Cáncer Renal metastásico

31. Nuevas dianas: Programmed death (PD)-1 pathway
PD-1 regula la función de los linfocitos T uniéndose con su ligando (PD-L1)
Ileana et al. Bul Cancer 2013

32. 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

33. Nuevas dianas: Programmed death
(PD)-1 pathway
• PD-L1 puede estar sobreexpresado en mRCC y asociado con:
– Patología desfavorable
– Comportamiento agresivo del tumor
– Pobre supervivencia
Thompson et al. Clin Cancer Res 2007; Thompson et al. PNAS 2004
A B
C D
Tumor PD-L1
Negative
Positive
0 1 2 3 4 5 6 7 8 9 10
0
20
40
60
80
100
Cancer-specificSurvival
N=306
Patients
Years from nephrectomy to last follow-up

34. Agentes Anti-PD1/anti-PD-L1 en desarrollo
Company Agent Structure Status
Amplimune/GSK AMP-224 Fc fusion protein
to PD-L2
Phase I
Bristol Myers
Squibb
Nivolumab Fully human,
IgG 4 Ab
Phase III RCC, others
solid tumours
Curetech/Teva CT-011
Humanized
monoclonal
Phase II melanoma,
RCC
Genentech/Roch
e
MPDL3280A PDL-1 Ab Phase I
Merck MK-3475
Humanized,
IgG 4 ab
Phase I
McDermott. ASCO GU 2012 (educational session)

35. Targeting PD-L1: MPDL3280A Phase Ia Efficacy
Summary in RCC
RECIST 1.1 ORR,
%
SD of ≥ 24 Wks,
%
24-Wk PFS,
%
Overall population
(N = 140)
21 16 45
RCC*
(n = 47)
13 32 53
Clear cell
(n = 40)
13 35 57
Nonclear cell
(n = 6)
17 0 20
Cho DC, et al. ASCO 2013. Abstract 4505.
Correlación entre status de PDL-1 y eficacia

36. MPDL3280A Phase Ia: Tumor Burden Over Time in
Patients With RCCChangeinSumofLongestDiameters
(SLD)FromBaseline(%)
Days on Study
100
50
-50
0 21 42 63 84 105
0
126 147 168 189 210 231 252 273 294 315 336 357 378 399 420
-100
441
New lesions
Discontinued study
20 mg/kg (n = 13)
10 mg/kg (n = 12)
3 mg/kg (n = 2)
15 mg/kg (n = 18)
Patients first dosed at 3-20 mg/kg prior to August 1, 2012, with at least 1 postbaseline evaluable tumor assessment;
data cutoff February 1, 2013.
Cho DC, et al. ASCO 2013. Abstract 4505.

37. Phase I Nivolumab Multidose Regimen
• Eligibility: advanced melanoma, NSCLC, RCC, CRC, or CRPC
with PD after 1-5 systemic therapies
Day 1* 15* 29* 43* 57
Follow-up q8w x 6
(48 wks)
Treat to confirmed
CR, worsening PD,
unacceptable
toxicity, or 12 cycles
(96 wks)
Off study
*Dose administered IV q2w.
Scans done at baseline and following each 8-wk treatment cycle.
Rapid PD or
clinical
deterioration
Unacceptable
toxicity
CR/PR/SD or PD
but clinically
stable
8-wk treatment cycle
Drake CG, et al. ASCO 2013. Abstract 4514.

38. Nivolumab: Outcomes in Patients With
Metastatic RCC
Dose, mg/kg Objective
Response Rate, %
(n/N)
Median DoR,
Wks (Range)
SD Rate,
% (n/N)
≥ 24 Wks ≥ 48 Wks
All doses 29.4 (10/34) 56.1
(36.6-126.7+)
26.5 (9/34) 5.9 (2/34)
1 27.8 (5/18) 56.1
(40.1-76.1+)
22.2 (4/18) 5.6 (1/18)
10 31.3 (5/16) 56.1
(36.6-126.7+)
31.3 (5/16) 6.3 (1/16)
Drake CG, et al. ASCO 2013. Abstract 4514.

39. 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)

40. Change in Target Lesions From Baseline After
Nivolumab Therapy
• Unconventional “immune-related” responses in patients with NSCLC,
Melanoma, and mRCC
Melanoma
First occurrence of new lesion
RCC
NSCLC
Wks Since Treatment Initiation
%ChangeFromBaselinein
TargetTumorLesion
Hodi FS, et al. 12th International Congress on Targeted Anticancer Therapies. Abstract O2.3.
100
80
60
40
20
0
-20
-40
-60
-80
-100
1600 10 20 30 40 50 60 70 80 90 100110120130140150

41. Nivolumab Phase II Dose-Ranging Study
• Pts with clear-cell mRCC (≥1 VEGF TKI; ≤ 3 previous systemic therapies)
– Randomized to receive nivolumab 0.3, 2, or 10 mg/kg IV every 3 wks
Motzer RJ, et al. ASCO 2014. Abstract 5009.
Outcome Nivolumab Dose
0.3 mg/kg
(n = 60)
2 mg/kg
(n = 54)
10 mg/kg
(n = 54)
ORR, % 20 22 20
Median PFS, mos 2.7 4.0 4.2
Median OS, mos 18.2 25.5 24.7
Tx-related AEs, % 75 67 78
Grade 3/4 AEs,* % 5 17 13
*No grade 3 or 4 pneumonitis reported.

42. Nuevos agentes: Ensayos fase III de vacunas + SOC versus SOC
AGS-003, autonomous dendritic cell product; IMA901, consists of multiple tumour-associated peptides
SOC, standard of care
Sunitinib + AGS-003Sunitinib + AGS-003
SunitinibSunitinib
Diagnosis of advanced
kidney cancer
Diagnosis of advanced
kidney cancer
Surgery
Tumour sample taken
Surgery
Tumour sample taken
Blood
donation
Blood
donation
Standard treatment with
sunitinib
Begins 6 weeks after
first dose of sunitinib
Standard treatment with
sunitinib
Begins 6 weeks after
first dose of sunitinib
Eligibility criteria:
 Metastatic and/or
locally advanced
ccRCC
 Favourable/intermediat
e risk HLA-A*02-
positive
 No prior systemic
therapy
Sunitinib
Sunitinib
+ IMA901 + GM-CSF
R
A
N
D
O
M
I
Z
E
D
ADAPT Study
IMPRINT trial
ADAPT study trial highlights. Available at: http://adaptkidneycancer.com. Accessed September 19,
2013;
www.clinicaltrials.gov (NCT01582672);
www.clinicaltrials.gov (NCT01265901)

43. Overnight
Shipment
Overnight
Shipment
1-2 Day Shipment
How is AGS-003 Produced for Each Patient?
•RNA that encodes autologous RCC antigens is isolated and amplified from a
small tumor specimen (~ 200mg) isolated during nephrectomy
•Monocytes isolated from a single leukapheresis are differentiated into DCs
•Within the central manufacturing facility in Durham NC, the DCs are
co-electroporated with RCC and CD40L RNA, vialed and cyropreserved for shipment
•One production run yields up to 5 years of treatment per patient(24 doses)

44. N=21

45. Figlin, 2011 Int KC Symp

47. ADAPT Study Design
Stratification based upon number
of risk factors (1, 2, 3, or 4)
Pre-treatment Induction Booster
• Open-label design, no placebo-control or requirement for leukapheresis on Arm B
• 80% power to detect ≥ 6 month OS improvement (HR: 0.708)
Diagnosis, Nephrectomy,
Screening
↓
Registration;
Leukapheresis (Arm A only)
Arm A: AGS-003 (8 doses) plus
Standard treatment*
for 48 weeks (N = 300)
≥ SD
Pre-treatment Induction Booster
Arm B: Standard treatment*
for 48 weeks
(N = 150)
AGS-003 quarterly +
Standard
treatment* until PD
Standard
treatment* until PD
≥ SD
* Standard treatment initiates with 6-week sunitinib cycles (50mg daily, 4 weeks on, 2 weeks rest.)
Other compatible agents may be substituted for intolerance and/or early PD prior to week 48.

48. ¿El futuro está en tratamientos guiados por
marcadores?
Setting Tumour markers Treatment choice
First-line
therapy
PDL1 expression Anti-PD1-based therapy
PDL1-/VHL null, BAP-1 WT Selective VEGF inhibitor
PDL1-/VHL null,
BAP-1 mutant
VEGF inhibitor + agent ‘X’
mTOR activation, high LDH TOR inhibitor
Other mutation Specific inhibitor
Second-line
therapy
Not necessary
BAP-1, BRCA1 associated protein-1; LDH, lactate dehydrogenase; mTOR, mammalian target of rapamycin;
PD1, programmed cell death 1; PDL1, programmed death ligand 1; TOR, target of rapamycin;
VEGF, vascular endothelial growth factor; VHL, Von Hippel–Lindau.
Atkins. IKCS 2012; Future leaders of RCC investigation

49. Estrategias de
combinación
Estrategias de
combinación
Nuevos agentes
dirigidos
Nuevos agentes
dirigidos
Nuevos agentes de
inmunoterapia
Nuevos agentes de
inmunoterapia
Nuevas
aproximaciones
Nuevas
aproximaciones
Nuevos enfoques en el tratamiento del
Cáncer Renal metastásico

50. Tratamiento de combinación: pasado,
presente y futuro
Pasado Presente Futuro
New studies combining
immunotherapies with existing
targeted agent
•CA209-016
BMS-936558 + sunitinib/
sunitinib/pazopanib/ipilimumab
4
Early combination therapy
slides were unsuccessful
•INTORACT
Bevacizumab + temsirolimus1
•BEST
Sorafenib + temsirolimus2
•RECORD 2
Bevacizumab + everolimus3
1. Rini et al. ESMO 2012; 2. McDermott et al. JCO 2013;
3. Hainsworth et al. JCO 2010; 4. www.clinicaltrials.gov (NCT01472081)

51. Estrategias de
combinación
Estrategias de
combinaciónNuevos escenariosNuevos escenarios
Nuevos agentes
dirigidos
Nuevos agentes
dirigidos
Nuevos agentes de
inmunoterapia
Nuevos agentes de
inmunoterapia
Nuevas
aproximaciones
Nuevas
aproximaciones
Nuevos enfoques en el tratamiento del
Cáncer Renal metastásico

52. Neoadyuvancia en cáncer renal
NCT01069770
Sunitinib
NCT01404104
Temsirolimus
NCT01263769
Axitinib
NCT000727532
Sorafenib
NCT01361113
Pazopanib

53. Adyuvancia en cáncer renal
SORCE
Sorafenib
PROTECT
Pazopanib
S-TRAC
Sunitinib
ASSURE
Sunitinib vs sorafenib
vs placebo
ATLAS
Axitinib
EVEREST
Everolimus

54. Nefrectomía en enfermedad metastásica
CARMENA
Nephrectomy + sunitinib
vs
nephrectomy alone
SURTIME
Surgery prior/after
sunitinib

55. PI: Arnaud Mejean (CCAFU, HEGP, Paris, France)
CARMENA: Estudio fase III sunitinib versus
nefrectomía + sunitinib
Objetivo primario: ¿Es sunitinib no inferior a la combinación
nefrectomía + sunitinib en supervivencia global?
Nephrectomy
Sunitinib
50 mg/day
(Schedule 4/2)
Sunitinib
50 mg/day
(Schedule 4/2)
R
A
N
D
O
M
I
Z
A
T
I
O
N
N=576
Metastatic
clear-cell RCC
www.clinicaltrials.gov (NCT00930033)

56. SURTIME: Estudio fase III comparando
nefectomía inmediata versus diferida
• Objetivo primario: PFS
• Objetivos secundarios: OS, association with prognostic gene and protein
expression profiles
Nephrectomy
Sunitinib
50 mg/day
(Schedule 4/2)
Nephrectomy
Sunitinib
50 mg/day
(Schedule 4/2)
N=458
Eligibility criteria
Synchronous
mRCC and
primary tumour
in situ
R
A
N
D
O
M
I
Z
A
T
I
O
N
www.clinicaltrials.gov (NCT01099423)
PI: Axel Bex (NCI, Amsterdam, Netherlands)

57. Conclusiones
• Los tratamientos antidiana han cambiado el tratamiento del
cáncer renal en los últimos años
• Los tratamientos antivegf permanecen con¡mo el SoC en primera
línea en pacientes de riesgo favorable o intermedio
• VEGFR- y mTOR-targeted son opciones en segunda línea
• Futuro
• Fármacos contra nuevas dianas
• Marcadores predictivos
• Combinaciones de los nuevos fármacos
• Nuevos escenarios