Esophagogastric Cancer: CMET as a Novel Target

David H. Ilson, M.D., Ph.D.GI Oncology ServiceMemorial Sloan-Kettering Cancer CenterNew York, NY

DISCLOSURES

Grant/Research Support

– Amgen

– Bayer

– Bristol-Myers Squibb

Consultant

– Amgen

– Lilly

– Imclone

Speaker’s Bureau

– Genentech

Esophageal and Gastric CarcinomaUS Incidence in 2014

40,390 new cases

– Gastric: 22,220 (55%)

– Esophagus: 18,170 (45%)

Male > Female

Decline in Gastric Cancer Incidence

Increase in Esophageal , GE JX, cardia adeno

OS improvement, 1975-77, 1984-86, 1999-2006

– Gastric: 16% 18% 27%

– Esophageal: 5% 10% 19%

Siegel et al, CA 64: 9-29; 2014

Advanced Esophagogastric Cancer Chemotherapy: What Regimen to Use?

Advanced Esophagogastric Cancer Chemotherapy: What Regimen to Use?

Oxali:

EOX or EOF

Cape:

ECX or EOX XP FLO FUFIRI

S-1 Cis DCF ECF

Pts 489 513 160 109 170 305 221 126

%RR 44% 45% 41% 34% 32% 54% 36% 45%

TTP, months 6.7 6.5 5.6 5.5 5.0 6.0 5.6 7.4

OS, months 10.9 10.4 10.5 10.7 9.0 13.0 9.2 8.9

Cunningham NEJM 358:36;2008, Kang Annals Oncol 20:666;2009, Al-Batran JCO 26:1435;2008, Dank Annals Oncol 19:450;2008 Koizumi Lancet Oncol 9:215;2008, Van Cutsem JCO 24:4991;2006, Webb JCO 15:61;1997

Patient Selection for Chemotherapy

3 drug regimens (DCF, mDCF)

– High functional status, younger patients without comorbidities

– Willingness to tolerate side effects

– Access to frequent follow up and toxicity assessment

ECF: does epirubicin add anything but toxicity?

CALGB 80403 / ECOG 1206: Randomized Phase II Study of Standard Chemotherapy +

Cetuximab for Metastatic Esophageal Cancer

PC Enzinger, BA Burtness, DR Hollis, D Niedzwiecki, DH Ilson, AB Benson 3rd,

RJ Mayer, RM Goldberg

Does Epirubicin add benefit to Platinum/5-FU Chemo?

CALGB 80403 / ECOG E1206: ECF vs FOLFOX

Stratification:ECOG 0-1 vs 2ADC vs. SCC

ARM A: (ECF + cetuximab); 1 cycle = 21 days

Cetuximab 400 250mg/m2 IV, weeklyEpirubicin 50 mg/m2 IV, day 1Cisplatin 60mg/m2 IV, day 1Fluorouracil 200mg/m2/day, days 1-21

ARM B: (IC + cetuximab); 1 cycle = 21 days

Cetuximab 400 250mg/m2 IV, weeklyCisplatin 30 mg/m2 IV, days 1 and 8Irinotecan 65 mg/m2 IV, days 1 and 8

ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days

Cetuximab 400 250mg/m2 IV, weeklyOxaliplatin 85 mg/m2 IV, day 1Leucovorin 400 mg/m2, day 1Fluorouracil 400 mg/m2 IV bolus, day 1Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)

CALGB 80403/ECOG 1206: Phase II FOLFOX vs ECF vs Irino/Cis, + Cetuximab

*RECIST - confirmed; restaging every 6 weeksCI, confidence interval; CR, complete response; PD, progressive disease; SD, stable diseaseEnzinger PC, et al. J Clin Oncol. 2010;28 (15S): Abstract 4006.

ECF-C N=64

IC-C N=68

FOLFOX-C N=69

Response CR 0 1 ( 1%) 2 ( 3%)

PR 37 (58%) 30 (44%) 35 (51%)

SD 15 (23%) 23 (34%) 19 (28%)

PD 4 ( 6%) 10 (15%) 8 (12%)

Not eval / unknown 5 / 3 (8% /5%) 2 / 2 (3% /3%) 3 / 2 (4% /3%) Objective Response Rate*

(CR+PR)/total 57.8 45.6 53.6

(90% C.I.) 46.8 68.3 35.2 56.3 43.1 64.0

p vs. H0<0.25 <.0001 <.0001 <.0001 Response duration (mos) median 6.1 5.3 5.7

range 0.5 - 22.7 0.5 - 20.1 2.4 - 18.2

57.8 45.6 53.6

P vs H0≤0.25

(90% CI)

6.1 5.3 5.7

ECF-CN = 67

IC-CN = 71

FOLFOX-CN = 72

TotalN = 210

Mos 95% CI Mos 95% CI Mos 95% CI Mos 95% CI

OS Median # dead

11.551

(8.1, 12.5) 8.952

(6.2, 13.1) 12.451

(8.8, 13.9) 11.0154

(8.8, 12.3)

PFS Median # dead/pd

5.957

(4.5, 8.3) 5.064

(3.9, 6.0) 6.763

(5.5, 7.4) 5.8184

(5.1, 6.8)

TTF Median # dead/pd/ off for AE

5.5

58

(3.9, 7.2) 4.5

66

(3.6, 5.6) 6.7

64

(4.8, 7.2) 5.5

188

(4.5, 5.9)

CALGB 80403/ECOG 1206: Survival

FOLFOX = ECFAE, adverse event; PFS, progression-free survival; TTF, time to treatment failureEnzinger PC, et al. J Clin Oncol. 2010;28 (15S): Abstract 4006.

Second Line Chemo Gastric Cancer Phase III Trials Improved Survival

Docetaxel vs

BSC Docetaxel or

Irinotecan vs

BSC Paclitaxel vs

Irinotecan

Patients 84 84 133 69 111 112

RR % 7% -- 13%17%/10%

-- 21% 14%

PFS 12.2 wks NS NS NS 3.6 mo 2.3 mo

OS 5.2 mo 3.6 mo 5.3 mo(5.2-6.5)

3.8 mo 9.5 mo 8.4 mo

Significance HR 0.67P = 0.01

HR 0.657 P = 0.007

Ford H Lancet Oncol 15:78; 2014; Kang JH J Clin Oncol 30:1513; 2012 Ueda JCO 31: 4438; 2013

Gastric Cancer Second Line Chemo vs BSC: Survival

Docetaxel/Irinotecan vs BSC Docetaxel vs BSC

2009 Genentech USA, Inc. MBoC Program

The Hallmarks The Hallmarks of Cancerof Cancer

Evading growth suppressors

Enabling replicative immortality

Resisting cell death

Sustaining proliferative

signaling

Inducing angiogenesis

Activating invasion

and metastasis

The hallmarks of cancer:Emerging hallmarks

Adapted from Cell, 144, Hanahan D, Weinberg RA, The hallmarks of cancer: the next generation, 646-674, copyright © 2011, with permission from Elsevier.

Repro

gram

min

g

ener

gy

met

abol

ism

Evading imm

une

destruction

The Hallmarks The Hallmarks of Cancerof Cancer

Evading growth suppressors

Enabling replicative immortality

Resisting cell death

Sustaining proliferative

signaling

Inducing angiogenesis

Activating invasion

and metastasisRep

rogr

amm

ing

ener

gy

met

abol

ism

Evading imm

une

destruction

Gene Amplification more common in Esophagogastric Cancer

296 Esophageal / Gastric Cancers, 190 CRC

Amplified genes in 37% Gas / Eso tumors

– FGFR1-2

– HER2

– EGFR

– MET

Targetable Receptors and Receptor Tyrosine Kinases

KRAS also amplified

Similar data for a Chinese series

Dulak AM et al Can Res 72: 4383; 2012

Gastric Cancer Genomic Analysis: Singapore

193 primaries, 40 cell lines Common gene amplifications in 5

categories

KRAS: 9%

FGFR2: 9%

EGFR: 8%

ERBB2: 7%

MET: 4%

– Receptor Tyrosine Kinase pathways commonly affected

– All upstream from KRAS

– 37% targetable by RTK/Ras directed therapy

Deng et al Gut 61: 673; 2012

Molecular Targets: Esophageal and Gastric Cancer

Molecular Targets: Esophageal and Gastric Cancer

• Except for trastuzumab, there is no identified molecular target in gastric cancer

• Except for HER2, there is no identified biomarker for gastric cancer

• Recent Trials of EGFr, VEGFr Targeted Agents– Largely Failed

– Unselected patient population

VEGF Revisited?VEGF Revisited?

• Ramucirumab: Humanized moAb Targeting VEGr2 receptor

• REGARD: BSC vs Ramucirumab

• RAINBOW: 2nd Line Paclitaxel + / - Ramucirumab

Fuchs CS, et al. Lancet. 2014;383(9911):31-39. Wilke GI Symposium 2014 LBA 7

CMET Pathway

Goyal L, et al. Clin Cancer Res. 2013;19(9):2310-2318.

CMET Receptor Structure

CMET Downstream Signaling

Blumenschein JCO 30:3287;2012

CMET Downstream Signaling

22 2012 Genentech USA, Inc. All rights reserved.

Tyrosine kinase signaling results in a multitude of cellular effects: HER2-3 vs CMET

AK

T

PDK1

Cell cyclecontrol

Proliferation

↓Apoptosis

↑Survival

Angiogenesis

PI3K

Cyclin D1

p27

BAD

GSK3

NFκBmTOR

HER2=human epidermal growth factor receptor-2; HER3=human epidermal growth factor receptor-3; PI3K=phosphatidylinositol 3-kinase; GAB1=Grb2-associated binding protein 1; Grb2=growth factor receptor-bound protein 2; STAT3=signal transducer and activator of transcription 3; RAS=rat sarcoma; Sos=son of sevenless; PDK1=phosphoinositide-dependent kinase-1; PTEN=phosphatase and tensin homolog; RAF=rapidly accelerating fibrosarcoma; MEK=mitogen-activated protein kinase kinase; MAPK=mitogen-activated protein kinase; mTOR=mammalian target of rapamycin; BAD=Bcl-2–associated death promoter; NFκB=nuclear factor kappa–light-chain enhancer of activated B cells; GSK3β=glycogen synthase kinase 3 beta.Olayioye MA, et al. EMBO J. 2000;19:3159-3167. Rowinsky EK. Oncologist. 2003;8(3):5-17. Trusolino L, et al. Nat Rev Mol Cell Biol. 2010;11:834-848.

Sos Grb2 ShcRAS

RAF

MEK

MAPK

GAB1PI3K

Grb2

NFκB

MAPK

HER3HER2Met

CMET Prognostic in Esophageal Adeno

Tuynman et al BJC 98: 1102; 2008

145 consecutive patients undergoing surgeryCMET high (54%)by IHC had poorer OS, DSSHigher rates of local and metastatic recurrenceHigher CMET in higher T stage, N+, poorly differentiated tumorsIndependent Prognostic Factor, RR 2.3

CMET Gene amplification is relatively rare (5%)

– Rarer are activating TKI and other mutations

Over expression at the protein level is more common (IHC)

– Overcrowding of the cell surface with receptors engenders independence of ligand: constitutive activation

CMET activation: cell survival, proliferation, angiogenesis, and invasion and metastasis

– Protease activation and increase cell motility

– CMET and HGF signaling in vascular endothelium promote angiogenesis

– Hypoxia promotes HGF production and upregulates CMET expression

CMET

CMET amplified or over expressing tumors appear more aggressive with worse prognosis but appear more sensitive to CMET targeted agents

Paracrine, autocrine activation: Ligand Hepatocyte Growth Factor Receptor dimerization Activation of receptor associated tyrosine kinase

Downstream: PIK3CA Kinase, RAS, STAT, RAC

CMET Receptor Cross Talk Interaction with CMET with other receptors and intra

cellular Tyrosine Kinases

Surface Integrin proteins

– MET down regulates surface e-Cadherin (tumor suppressor) which increases TCF/Beta catenin nuclear signaling, increases proliferation

HER1 (EGFR): activates CMET by generation of reactive oxygen species

HER2: Trastuzumab may upregulate CMET, interacts with HER3

RON: shares homology with MET, and the ligand Macrophage Stimulating protein shares homology with HGF

How can we inhibit MET?

Targeting HGF ligand, preventing receptor binding

Blockade of ligand binding to the CMET receptor

Inhibition of C-MET receptor trans phosphoyrlation and activation

Inhibition of activated kinase activity and phosphorylation of the signal transducer docking site

Interference with the docking site and signal transducers

Prominent cMET / HGF InhibitorsProminent cMET / HGF Inhibitors

Agent Structure Target

Rilotumumab Human monoclonal antibody

HGF

Onartuzumab Humanized monovalent antibody

c-MET

Tivantinib (ARQ 197)

Small molecule c-MET kinase

Cabozantinib (XL184)

Small molecule c-MET kinase

Other CMET Agents in Development

Rilotumumab

Humanized monoclonal antibody against HGF

Binds to the HGF ligand light chain

Inhibits binding of HGF to the CMET receptor

AE’s specific to rilotumumab include nausea, fatigue, constipation, and peripheral edema

Toxicities in phase II + ECF, at 7.5 and 15 mg/kg dosing

– Peripheral edema, greater hematologic toxicity, more thromboembolic events

CMET: Rilotumumab: Anti HGF Ligand Antibody, First Line

Phase II

RANDOMIZE

ARM ARilotumumab (15 mg/kg) + ECX

Q3W (n = 40)

ARM BRilotumumab (7.5 mg/kg) + ECX

Q3W (n = 40)

ARM CPlacebo + ECXQ3W (n = 40)

Stratification factors:ECOG PS 0 vs 1LA vs Metastatic

E: Epirubicin: 50 mg/m2 IV, day 1C: Cisplatin: 60 mg/m2 IV, day 1

X: Capecitabine: 625 mg/m2 BID orally, days 1-2

Rilotumumab: IV over 60 ± 10 minutes prior to chemotherapyClinicalTrials.gov identifier: NCT00719550Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535.

Patientsb, n 118

Acceptable tumor sample available, n (%) 90 (76)

c-Met assay failed, n 0

c-MetHigh, n (%) 38 (42)

c-MetLow, n (%) 52 (58)

Evaluable patients in treatment arms

Arms A + B: All rilotumumab + ECX, n (%)

62 (78)

Arm C: Placebo + ECX, n (%) 28 (74)

Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535.

Analysis of c-Met Expression by IHCa

a c-MetHigh defined as >50% of tumor cells express c-Metb Per protocol analysis set

PFS and OS in c-MetHigh PatientsMedian Months

(80% CI) HR (80% CI)

6.9 (5.1, 7.5) 0.53 (0.25, 1.13)

4.6 (3.7, 5.2)

Median Months (80% CI) HR (80% CI)

11.1 (9.2, 13.3) 0.29 (0.11, 0.76)

5.7 (4.5, 10.4)

Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535.

Ongoing Trials: Met Inhibitors Targeting CMET, + IHC

RILOMET-1: Phase III

– ECX + / - Rilotumumab (targeting ligand HGF)

MetGastric: Phase III

– FOLFOX + / - Onartuzumab monovalent anti MET receptor antibody

– Blocking ligand binding

Tyrosine Kinase Inhibitors

– Promising phase I activity in CMET amplified (AMG 337)

– Negative trials of earlier agents

MET TKI’s Type I: drug targets the ATP binding site receptor in the active

confirmation

– After tyrosyl residues in the activation loop have been phosphorylated

– Majority of agents

Type II: target a binding site immediately adjacent to the region occupied by ATP characteristic of inactive kinase

Foretinib, Tivantinib (neither Type I or II), Cabozantinib, Crizotinib

AMG 337: a selective inhibitor which inhibits multiple mechanisms of MET activation

– Single Agent Phase II

– Phase II + FOLFOX (ECOG)

MSKCC: Foretinib (CMET, VEGFr2)

Foretinib: muti targeted TKI

Targets MET, RON, RON, AXL, TIE-2

Two doses evaluated

– 240 mg/d for 5 days every 2 weeks

– 80 mg/d

74 patients, 10 with stable disease (23%) median 3.2 months

3 with MET amplification: one with stable disease

Shah et al PLoS One 8: Epub 2013

Tivantinib

Selective, non ATP competitive small molecule inhibitor of CMET

Asian trial, daily Tivantinib, phase II

30 patients with gastric cancer, 1-2 prior regimens

PFS 43 days

No responses

No correlation with activity and CMET expression or gene amplification, or HGF

Kang YK Invest New Drugs 32: 355; 2014

Crizotinib

Multi national trial

ALK, MET tyrosine kinase inhibitor

489 pts with EG cancer screened for MET, EGFR, and HER2 amplification

– 10 (2%) CMET+, 23 (4.7%) EFGR+, 45 (8.9%) HER2+

2 of 4 CMET amplified patients treated had brief responses (30% tumor reduction for 3.7 months, 16% reduction for 3.5 months)

More aggressive clinical course in CMET + patients

Lennerz et al JCO 29: 4803; 2011

Resistance to MET Activation Mutation of the CMET Tyrosine Kinase

Activation of the EGFr pathway

– Bypasses CMET by similar downstream signaling via PIK3CA Kinase and RAS

KRAS amplification

– Constitutive downstream pathway activation

Therapeutic strategies to overcome resistance to CMET inhibitors

– Target ligand, receptor, and TK

– Target downstream pathways

– Target rescue pathways (EGFr, HER2)

Esophagogastric Cancer: CMET Targeted Agents

Esophagogastric Cancer: CMET Targeted Agents

• Chemo:– Two-drug regimens

- FOLFOX, Cape-Ox, Cape-Cis

• Targeted therapies– Biomarkers to identify patients– Gene amplification > mutation in esophagogastric

cancer

• Trastuzumab: HER2+ / amplified esophagogastric cancers

• VEGFR2: Ramucirumab, active single agent with improved disease control, PFS, OS

– + Paclitaxel: Second line all outcomes improved

Esophagogastric Cancer: Targeted Agents

Esophagogastric Cancer: Targeted Agents

• MET Pathway key driver in esophagogastric cancer• Amplification in some, increased protein expression in

many– Poor prognosis

• Drugs that target the ligand and receptor– Rilotumumab: binds HGF– Onartuzumab: blocks ligand binding

• Drugs that target the TK– Negative results for foretinib, tivantinib, crizotinib– Rare patients with CMET gene amplification

• Phase III trials of ECX + Rilotumumab, FOLFOX + Onartuzumab are ongoing in CMET high ICH pts

• Further trials of TKI’s, CMET gene amplified patients