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?