Eleventh European International Kidney Cancer Symposium29-30 April 2016 Crowne Plaza Barcelona—Fira Center, Barcelona, Spain

Biomarkers for Targeted Therapy in RCC:

Any Progress?

James J. Hsieh, MD PhD

Medicine, GU Oncology

Memorial Sloan Kettering Cancer Center

Eleventh European International Kidney Cancer Symposium29-30 April 2016 Crowne Plaza Barcelona—Fira Center, Barcelona, Spain

Kidney Cancer Care

Before 2005, The Dark Age

Motzer RJ, et al. J Clin Oncol 2000;1928-35

Survival With Chemotherapy and Cytokines Retrospective

MSK Experience

Years Following Systemic Therapy

Tick mark (I) indicates last follow-up

Pro

po

rtio

n S

urv

ivin

g

Cytokine therapy (396 patients, 48 alive)

Interferon- 294 patients

Interleukin-2 68 patients

Both 34 patients

Chemotherapy (274 patients, 9 alive)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Interferon Response rate = 12%

Median PFS to Interferon= 4.7 months

Motzer RJ, et al. J Clin Oncol 2002;20:289–296

6

Current Signaling Targets in ccRCC (8 approved, 1 coming)

RAS

RAF

MEK

MAPK

HIF1/2

Target Genes

PI3K

AKT

mTORC1

Tumor Cell

Nucleus

HIF-1/2α

PTEN

Everolimus

Temsirolimus

Endothelial Cell

TIE2

Bevacizumab

FGF

PDGF

VEGF Sunitinib, Sorafenib,

Pazopanib, Axitinib

FGFR

PDGFR

VEGFR

Angiogenesis

mTORC2

TSC1/2

S6K

4EBP1

Rheb

HIF-1/2α

VHL

MET

Cabozantinib

Lenzatinib

1992-2005

Treatment for ccRCC(Past, Now & Future)

Sorafenib

Sunitinib

Temsirolimus

High dose interleukin-

2

2005 2006 2007 2008 2009

Bevacizumab + IFN

AxitinibInterferon- Everolimus

2010

Pazopanib

2012 2013-2015

Nivolumab

2016

Dark Age Modern Age Golden Age

• Lenvatinib

• Ipilimumab etc.

• Precision

• Combination Sequence

• Immunization

• Prevention

• DetectionHsieh, April, 2016

Cabozantinib

Targeted Therapy 2005-2015

Pan-Omics of Three Major Kidney Cancer Types

Creighton et al. Cell Reports 2016

A Clear Picture of Clear Cell Renal Cell Carcinoma

(Stage I ~ IV) (A Disease of Loss of 3p TSGs)

Hakimi et al. EU 2013, Nat Gen 2013

49%

29%

8%

6%

8%

MSKCC (n=185)

Swanton et al. NEJM 2012; NG 2014

Therapeutic Reponses & GenomicsCorrelations between Gene Mutations and Outcomes

of Targeted Therapy (VEGF & mTORC1 Inhibitors) of Patients

With Metastatic Clear Cell Renal Cell Carcinoma.

?

298 Cases:

128 Everolimus; 170 Temsirolimus

Treatment duration ≥20 months

14 cases: 7 Everolimus; 7 Temsirolimus

265 Cases

100 everolimus; 165 temsirolimus

6 cases

2 Everolimus; 4 Temsirolimus

13 Cases

6 Everolimus; 7 Temsirolimus

Remove patients receiving combination therapies

Remove patients without research consent to tissue procurement

Remove patients without tissue specimens available for analysis

The MSKCC mTOR Inhibitor Cohort

Voss et al. CCR 2014

R1

R2

R3

R4

R1

R49-

Voss et al. CCR 2014

Mutations in TSC1, TSC2, and MTOR are associated with response to

rapalogs in patients with metastatic Renal Cell Carcinoma.

Kwiatkowski DJ, Choueiri TK, Fay AP, Rini BI, Thorner AR, De Velasco G, Tyburczy M, Hamieh L, Albiges L,

Agarwal N, Ho TH, Song J, Pignon JC, Barrios PM, Michaelson MD, Van Allen EM, Krajewski KM, Porta C, Pal

SK, Bellmunt J, McDermott DF, Heng DY, Gray KP, Signoretti S.

Clin Cancer Res. 2016 Feb 1. pii: clincanres.2631.2015. [Epub ahead of print] PMID: 26831717

Voss et al. CCR 2014, Wei et al. NRU 2015

Now & Near Future:

Omics-Based Precision Therapy

Immunotherapy

Overcome Resistance (Multipharmacy)

Cancer Cell. 2014 Sep 8;26(3):309-17

PBRM1: The Second Most Commonly Mutated Gene in Human ccRCC

Loss of Vhl and Pbrm1 in mouse kidney causes

polycystic kidney disease and early mortality.

Ksp;Vhl-/-;Pbrm1-/- mice develop

multifocal clear cell kidney cancer

PBRM1 functions like an electrical resistor

in restraining the transcription of

HIF and STAT target genes when VHL is lost.

Convergence on the mTOR pathway activation

among ccRCC from mouse Ksp;VhlF/F;Pbrm1F/F mouse Hif1-TRACK,

and human VHL/PBRM1 mutants.

Three distinct genetic/epigenetic events in the development of ccRCC.

RECORD-3 (Whole 471 & NGS ccRCC 220)

OS, overall survival;

PFS, progression-free survival.

85% ccRCC

Primary endpoint analysis:

Median PFS first-line (mo)

Everolimus Sunitinib

7.9

(8.3 NGS)

10.7

(10.8 NGS)

Hazard Ratio = 1.4

2-Sided 95% CI [1.2–1.8]

Primary

• PFS – 1st-line noninferiority of everolimus to sunitinib

Key Secondary

• PFS – combined

• OS (E-S 22.4 months; S-E 29.5 months)

• Safety

Study endpoints

Motzer RJ et al. J Clin Oncol. 2014

1 : 1

R

A

N

D

O

M

I

Z

E

Everolimus

n=238

(109 NGS)

SC

RE

EN

Sunitinib

n=233

(111 NGS)

1st Line

Everolimus

n=99

(53 NGS)

Sunitinib

n=108

(59 NGS)Cro

sso

ver u

po

n

pro

gre

ss

ion

2nd Line

RECORD-3 vs. Published Datasets (Stage I-IV)

VHL PBRM1

BAP1

SETD2

KMD5C PTEN

49%

82%

52%

75% (n=164)

0% 50% 100%

Haikimi 2013 (n=185)

Sato 2013 (n=240)

TCGA (n=417)

RECORD-3 (n=220)

29%

41%

33%

46% (n=101)

0% 20% 40% 60% 80% 100%

Haikimi 2013 (n=185)

Sato 2013 (n=240)

TCGA (n=417)

RECORD-3 (n=220)

8%

11%

12%

30% (n=65)

0% 20% 40% 60% 80% 100%

Haikimi 2013 (n=185)

Sato 2013 (n=240)

TCGA (n=417)

RECORD-3 (n=220)

6%

10%

10%

19% (n=42)

0% 25% 50%

Haikimi 2013 (n=185)

Sato 2013 (n=240)

TCGA (n=417)

RECORD-3 (n=220)

8%

4%

7%

15% (n=32)

0% 25% 50%

Haikimi 2013 (n=185)

Sato 2013 (n=240)

TCGA (n=417)

RECORD-3 (n=220)

1.TCGA Nature. 2013; 2. Sato Y et al. Nat Genet. 2013; 3. Haikimi A et al. Eur Urol. 2013

2%

4%

12% (n=26)

0% 25% 50%

Sato 2013 (n=240)

TCGA (n=417)

RECORD-3 (n=220)

PFS1L and PBRM1 Mutation in ccRCC

PBRM1 Mutations: Comparable Benefit from Everolimus and Sunitinib

RED: Everolimus

Blue: Sunitinib

MT

WT

PFS1L and BAP1 Mutation in ccRCC

BAP1 Mutations: Worse on either

Everolimus or Sunitinib

RED: Everolimus

Blue: Sunitinib

MT

WT

Three Distinct ccRCC Molecular Subgroups

Differential Overall Survival on Targeted Therapies

(Treatment Sequence Matters)

BAP1 20%

PBRM1 46%

KDM5C 15%

Genetic Alteration Missense Mutation Truncating Mutation

BAP1

KDM5C

PBRM1

PFS1L and KDM5C Mutation in ccRCC

KDM5C Mutations with Exceptional Sunitinib Benefit

RED: Everolimus

Blue: Sunitinib

MT

WT

KDM5C MT Male Patients are

Long-term Responders to Sunitinib

RED: Sun-Eve

Green: Eve-Sun

MT

WT

BAP1 Gr (19%) PBRM1 Gr (35%) KDM5C Gr (14%) WT Gr (32%)

Proposed 2016 ccRCC Molecular Subgroups

For Precision Therapeutics

Hsieh et al. 2016

Currently Off

Treatment

Since Jan 2016

25yo

Saudi

Arabia

Male

Metastatic

Kidney

Cancer

Ipi+Nivo plus XRT in 2015

Kidney Cancer Evolution

& Therapeutic Opportunities

A Braided River Model

Wei & Hsieh, NRU 2015

Multipharmacy

Immuotherapy

Multipharmacy

MSKCC

TKCRP

4/2016

MSK Kidney Cancer

Core Lab

James HsiehDina Djesevic

Jianing Xu

Amrita Nargund

Toshinao Oyama

Jozefina Casucelli

Chelsea Ray

Maria Becerra

Yiyu Dong

Smrutiben Mehta

Yasin Senbabaoglu

Emily ChengToru Wakamatsu

Kwanghee Kim

Yogesh Ganesan

Song Han

Yuchen Xie

MetabolomicsMetabolon

Genomics

NYGC

Antibodies

Eureka

Cores

IGO/CMO

Metabolomics

ProteomicsSurgery

Paul Russo

Ari Hakimi

J. Coleman

Brandon Manley

Comp BioChris Sander

Nils WeinholdEdward ReznikJohn Chodera

Steven AlbaneseChristina Leslie

Hatice Osmangeyoglu

Radiology

Hedi Hricak

Kayvan Keshari

Evis Sala

Omer Aras

Jeremy Durack

Biostatistics

Mithat Gonen

Irina Ostrovnaya

Elli Papaemmanuil

Venkat Seshan

Emily Zabor

Medicine

Bob Motzer

James Hsieh

Martin Voss

Darren Feldman

Joe Lee

Maria Carlo

Pathology

Victor Reuter

Ying-Bei Chen

Satish Tickoo

Chris Iacobuzio

Mike Berger

Lu Wang

TCGA

& KCA

& ACKC

& Rare KCA

Immunology

Ming Li

NIH NCI

The Randy & Kathy MacDonald Fund

The Tuttle Fund

The Dahan TFE3 Fund

The Weiss Fund

The Bryan Fund

Rock Out For the Cure

Cycle for Survival

Functional Genomics Initiative

Pfizer Inc.

Novartis Inc.

CGI Inc.

Than

Thank You