Novel Targets and Therapies for GI Malignancies: What does the future hold?

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

GI Cancers: US Incidence in 2013

292,200 new cases and 144,570 deaths (49%)

Case Fatality Rate:

– Colorectal: 48%

– Esophagogastric: 66%

– Pancreatic: 85%

– HCC: 70%

Male > Female

Ongoing rise in Esophageal and GEJ Adenocarcinoma, HCC

Siegel et al, CA 63: 11-30; 2013

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

Molecular Targets: Esophageal and Gastric Cancer

Molecular Targets: Esophageal and Gastric Cancer

• KRAS mutation: <5%

• BRAF mutation: <5%

• EGFr mutation: <5%

• HER2 over expression / amplification: 10% to 25%– Trastuzumab + chemo improves OS in HER2+ disease

• CMET amplification: 10%– IHC over expression 40%

Dulak AM, et al. Cancer Res. 2012;72(17):4383-4393. Dulak AM, et al. Nat Genet. 2013;45(5):478-486. Lordick F, et al. Lancet Oncol. 2013;14(6):490-499. Bang YJ, et al. Lancet. 2010;376(9742):687-697.

ToGA Trial Design

HER2-positiveadvanced GC

(n = 584)

5FU or capecitabine + cisplatin(n = 290)

R

5FU or capecitabine + cisplatin

+ trastuzumab(n = 294)

Phase III, randomized, open-label, international, multicenter study

3807 patients screened 810 HER2-positive (22.1%)

• Stratification factors─ Advanced vs metastatic ─ GC vs GEJ─ Measurable vs nonmeasurable─ ECOG PS 0-1 vs 2─ Capecitabine vs 5-FU

Bang Y, et al. Lancet. 2010;376(9742):687-697

ToGA: Efficacy OutcomeToGA: Efficacy Outcome

• Preplanned subgroup analysis indicated improved OS benefit with increasing HER2 expression by IHC

• Exploratory analysis of IHC 2+/FISH+ and IHC 3+ cohort demonstrated a 4-month increase in OS with trastuzumab

− HR: 0.65 (95% CI: 0.51-0.83)

Chemotherapy + Trastuzumab

(n = 294)

Chemotherapy Alone

(n = 290) HR (95% CI) P Value

Primary endpoint

Median OS, months 13.8 11.1 0.74 (0.60-0.91) .0046

Secondary endpoints

Median PFS, months 6.7 5.5 0.71 (0.59-0.85) .0002

ORR, % 47.3 34.6 - .0017

• CR 5.4 2.4 - .0599

• PR 41.8 32.1 - .0145

ORR, overall response rateBang Y, et al. Lancet. 2010;376(9742):687-697.

Targeted Agents Phase III: HER2: Met Disease

LOGIC: Cape-Ox + / - Lapatinib (HER2+)

– First line

– Negative trial for OS

– Benefit in Asian pts

TYTAN: Paclitaxel + / - Lapatinib (HER2+)

– Second Line: Negative Trial

– PFS and Survival Benefit in subset of patients IHC 3+ for lapatinib

Hecht JR, et al. J Clin Oncol. 2013;31(Suppl):Abstract LBA4001 Bang et al GI Cancers Symposium 2013 Abstract 11

RTOG 1010: Phase III Study of Neoadjuvant Trastuzumab and Chemoradiation for

Esophageal Adenocarcinoma (Siewert I, II)

RTOG 1010: Phase III Study of Neoadjuvant Trastuzumab and Chemoradiation for

Esophageal Adenocarcinoma (Siewert I, II)

‘

CHEMORADIATIONCHEMORADIATION

HER-2 (+)(FISH)

HER-2 (+)(FISH)

TRASTUZUMAB+

CHEMORADIATION

TRASTUZUMAB+

CHEMORADIATION

SURGERYSURGERY

SURGERY+

TRASTUZUMAB (1 YR)

SURGERY+

TRASTUZUMAB (1 YR)

HER-2 (-)(FISH)

HER-2 (-)(FISH)

ALTERNATIVE STUDIES

ALTERNATIVE STUDIES

Chemoradiation: Carboplatin, Paclitaxel + RT 5040 cGy SurgeryMaintenance trastuzumab post opOS Primary Endpoint

HER2-Directed Therapy TrialsHER2-Directed Therapy Trials

• Ongoing HER2 Trials– First-line

- JACOB: Cape-Cis-Trastuzumab + / - Pertuzumab, 780 patients

- HELOISE: Cape-Cis + 2 dose levels of Trastuzumab, 400 patients

– Second-line:- GATSBY: Paclitaxel vs TDM-1

VEGF-A

VEGF-R1(Flt-1)

MigrationInvasionSurvival

VEGF-R3(Flt-4)

Lymphangio-genesis

VEGF-R2(KDR/Flk-1)Proliferation

SurvivalPermeability

PlGFVEGF-B

VEGF-C, VEGF-D

Fu

nct

ion

s

Large molecule VEGF inhibitors

Bevacizumab

Ramucirumab

Aflibercept (VEGF Trap)

Targeted Agents Phase III: Negative Trials for VEGF, mTOR, and EGFr

AVAGAST: Cape-Cisplatin + / - Bevacizumab

– Negative trial for OS

mTOR GRANITE: BSC vs Everolimus – Negative trial for OS

REAL 3: ECX + / - Panitumumab (U.K.)

– Negative: Panitumumab had inferior outcomes

EXPAND: Cape-Cis + / Cetuximab (E.U.)

– Negative: Cetuximab trended inferior

COG: BSC vs Gefitinib (U.K.): Negative

Ohtsu A, et al. J Clin Oncol. 2011;29(30):3968-3976 Ohtsu A, et al. J Clin Oncol. 2013;31(31):3935-3943 Waddell T Lance Oncol 14: 481; 2013 Lordick F et al Lancet 14:490; 2013 Sutton JCO 30: 2012 (suppl 34 abstr 6)

EGFr: Definitive Cetuximab + Chemo RT SCOPE-1

Cape-Cis Cape-Cis-RT + / - RT

258 pts (65 AC,188 SCC)

RTOG 0436

Pac-Cis-RT + / - Cetuximab

328 pts (203 AC,125 SCC)

Crosby Lancet 14: 627; 2013 Suntha JCO 32: 2014 (suppl 3; abstr LBA6

VEGF Revisited?VEGF Revisited?

• Apatinib– Small-molecule multitargeted TKI with activity against VEGFR– China– 144 patients, placebo vs 850 mg/d or 425 mg BID– OS 2.5 months 4.0 months, 4.5 months– RR 10%

• Phase III Trial Planned

• Ramucirumab: Humanized moAb Targeting VEGr2 receptor

TKI, tyrosine kinase inhibitor; VEGFR, VEGF receptorLi J, et al. J Clin Oncol. 2013;31(26):3219-3225. Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

VEGFr: Ramucirumab in Gastric Cancer: REGARD Trial

RANDOMIZATION, 355 patients

BSC + Placebo

Fuchs CS, et al. Lancet. 2014;383(9911):31-39

Gastric/GEJ Cancer with POD on FU or Platinum Based Chemo

BSC + Ramucirumab 8 mg/kg q 2 weeks

VEGF Revisited? Ramucirumab: REGARD Trial

VEGF Revisited? Ramucirumab: REGARD Trial

• PFS improved 2.1 months 3.8 months (HR 0.483, P<.0001)

• OS improved 3.8 months 5.2 months (HR 0.776, P = .047)

• Disease control improved from 23% to 49% (P<.0001)

• Essentially no toxicity (rare grade ≥3 hypertension 8%)

Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

REGARD Trial: ResultsREGARD Trial: Results

27

HR (95% CI) = 0.776 (0.603-0.998)Log-rank P value (stratified) =.047

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 28

0

20

40

60

80

100

238 117

Number at riskRamucirumab

Placebo

15466

9234

4920

177

74

32

00

01

Ramucirumab (n = 238)Placebo (n = 117)Censored

Time Since Randomization, Months

Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

20

HR (95% CI) = 0.483 (0.376-0.620)Log-rank P value (stratified) <.0001

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

0

40

60

80

100

238 117

Number at riskRamucirumab

Placebo21392

52

00

11327

6511

617

454

302

182

182

112

41

21

10

10

10

10

Time Since Randomization, Months

Ramucirumab (n = 238)Placebo (n = 117)Censored

OS PFS

Treat until disease

progression or

intolerable toxicity

• Important inclusion criteria:

- Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma

- Progression after 1st line platinum/fluoropyrimidine based chemotherapy

•Stratification factors:

- Geographic region,

- Measurable vs non-measurable disease,

- Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)

Ramucirumab 8 mg/kg day 1&15+ Paclitaxel 80 mg/m2 day 1,8 &15

of a 28-day cycleN = 330

Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15

N = 335

SCREEN

RANDOMIZE

Survival and safety

follow-up

VEGFr: RAINBOW: Study Design

1:1

Wilke GI Symposium 2014 LBA 7

RAINBOW: Ramucirumab + Paclitaxel for Metastatic Gastric Cancer

RAINBOW: Ramucirumab + Paclitaxel for Metastatic Gastric Cancer

• 665 pts with POD on fluorinated pyrimidine + platinum

• Weekly paclitaxel 80 mg/m2 + /- Ram 8 mg/kg

• PFS improved 2.9 months 4.4 months (HR 0.635, P<.0001)

• OS improved 7.4 months 9.6 months (HR 0.807, P = .0169)

• RR improved from 16% to 28% (p = 0.0010 (P<.0001)

• Increased toxicity neutropenia and hypertension

Wilke GI Symposium 2014 LBA 7

RamucirumabRamucirumab

• First-line: FOLFOX + / - Ramucirumab

– Randomized phase II

• Other VEGF agents

– FOLFOX + / - Pazopanib (TKI)

VEGF Adjuvant Trials Gastric Cancer

VEGF Adjuvant Trials Gastric Cancer

• MAGIC 2 Trial: EOX + / - Bevacizumab– Amended for HER2 + patients– Randomized to + / - Lapatinib (HER1-2 TKI)

CMET Pathway

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

CMET: Rilotumumab: Gastric Cancer 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.

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

– ECX + / - Rilotumumab (targeting ligand HGF)

MetGastric

– FOLFOX + / - MetMab (targeting receptor)

Tyrosine Kinase Inhibitors

– Promising phase I activity in CMET amplified

Fibroblast growth factor receptor

Ligand activated trans membrane growth factor receptor

Signals via RAS Map kinase and PI3K-AKT but also via Hedgehog and Notch pathways, and WNT

Phase II Trials

– Dovitinib (TKI) in FGFR gene amplified gastric cancer

– Dovitinib + Docetaxel in gastric cancer

PARP Inhibitors: Olaparib in Gastric Cancer

RANDOMIZATION:

Paclitaxel

Bang YJ, et al. J Clin Oncol. 2013;31(suppl): Abstract 4013

Gastric/GEJ Cancer with POD on FP

Paclitaxel + Olaparinib

PARP Inhibition in Gastric Cancer: Olaparib

Patients randomized to Paclitaxel + / OlaparibTissue testing for ATM protein

Negative in13% = In vitro sensitivity to olaparib 124 patients randomized, ATM + / -OS benefit in ATM + / -, Greater in ATM –Phase III Trial planned

Bang YJ, et al. J Clin Oncol. 2013;31(suppl): Abstract 4013

Trials of Targeted Agents1st Line

Target Agent Trial Regimen Number Status

HER2 Pertuzumab JACOB XP + T +/- Pertuzumab

780 Ongoing

HER2 Trastuzumab HELOISE XP + T (2 doses) 400 Ongoing

CMET Rilotumumab Rilomet-1 ECX + / - Rilo 650 Ongoing

CMET Onartuzumab MetGastric FOLFOX + /- O 800 Ongoing

EGFr Panitumumab NCT01627379 5-FU-Cis + / - Pan

300 Ongoing

VEGFr Pazopanib PaFLO FLO + / - Pazop 75 Ongoing

2nd Line

mTOR Everolimus AIOST00111 Pac + / - Evero 665 Ongoing

HER2 TDM-1 GATSBY Pac vs TDM-1 412 Ongoing

EGFr Nimotuzumab NCT01813253 Irino + / - Nimo 400 Ongoing

PARP Olaparib Pac + / - Olap Planned

Esophagogastric Cancer: ImmunotherapiesEsophagogastric Cancer: Immunotherapies• Agents that deregulate immune suppression

• Anti PD-1 phase I:

– PD-1: T cell programmed cell death receptor, blockade may enhance immune responses

– Active in NSCLC, RCC

– 7 gastric cancers, no activity

• Anti PDL-1 phase I– MPDL3280A: Blocks ligand

– PR in 1/1 Gastric Cancer, 26/29 responses ongoing

– Enhanced activity in PDL-1 + patients

• Ipilimumab

– Anti CTLA-4 antibody

– Phase II

– FOLFOX capecitabine maintenance vs ipilumimab

Ribas A, et al. N Eng J Med. 2012;366:2443 Herbst R et al. JCO 31 (supp): Abstract 3000

HCC: Sorafenib is the Standard for Advanced Disease

SHARP TRIAL ASIA PACIFIC TRIAL

Llovet NEJM 359: 378; 2008 Chang Lancet Oncol 10:25; 2009

OS 4.5 6.2 months, HR 0.68OS 7.9 10.7 months, HR 0.69

Sorafenib in HCC

Modest single agent activity in Child’s A pts with HCC

Toxicity monitoring and dose reduction are key

Outcomes vary depending on geographic region, etiology and severity of cirrhosis

No biomarker has been identified

Failed Phase III TrialsAgent Target Number Overall Survival

First Line

Sunitinib vs Sorafenib

VEGFr, PDGFr, C-KIT, FLT3

1074 8.1 vs 10 months, HR 1.31

Brivanib vs Sorafenib

VEGFr, FGFr 1155 9.5 vs 9.9 months, HR 1.07

Erlotinib/Placebo vs E/Sorafenib

EGFR 720 9.5 vs 8.5 months, HR 0.929

Linifanib vs Sorafenib

VEGFr, PDGFr 1035 9.1 vs 9.8 months, HR 1.046

Second Line

Brivanib vs BSC VEGFr, FGFr 395 9.4 vs 8.2 months, HR 0.89

Sorafenib OS consistently 8.5-10 months

Ongoing Single Agent Studies

Angiogenesis:

– Ramucirumab, TSU-68, Cedirinab, Pazopanib, lenvatinib, Axitinib

CMET:

– Tivantinib, cabozantinib, foretinib, METmab, IMC-280, LY2875358

EGFR:

– Lapatinib, cetuximab

mTOR:

– Everolimus, temsirolimus, sirolimus, CC-23

Ongoing Single Agent Studies

MEK

– Selumetinib, rafametinib

HDAC

– Belinostat, resminostat

HSP-90

– Genetespib

Oncolytic viruses

– JX-594

Immunotherapy

– Tremelimumab, PD-1, PD-L1

CMET Targeted Therapy in HCC Tivantinib vs Placebo in HCC

– CMET TKI

107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib

– 160 mg tivantinib vs placebo

– Cross over permitted at POD

TTP HR 0.64, p = 0.04

– OS not different, given cross over (6.2-6.6 months)

CMET IHC low, better prognosis, no benefit from tivantinib

CMET IHC high, OS 3.8 to 7.2 months (HR 0.38, p = 0.01) with tivantinib

Phase III Trial planned in CMET high pts

Santoro Lancet Oncol 14: 55; 2013

OS CMET High

CMET Targeted Therapy in HCC Cabozantinib vs Placebo in HCC (4007)

– CMET and VEGR2 TKI, most patients failed sorafenib

107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib

– 100 mg cabozantinib, stable disease randomized to placebo or continuation

– Cross over permitted at POD

41 treated

PFS 4.4 mos, OS 15 mos in all pts

RR 5%, Stable disease 78%

Larger phase II trial planned

Verslype et alJ Clin Oncol 30: 2012 (suppl Abst 4007)

Promising Signals

Ramucirumab

– Anti VEGFr2

– RR 10%, PFS 4 months, OS 12 months

Lenvatinib

– VEGFr1-3, FGFr1-4, RET, KIT, PDGFrβ TKI

– 37% modified RECIST response rate

– TTP 12.8 months, OS 18.7 months

Immunotherapy

– Anti CTLA-4

– RR 17%, PFS 6 months

Ongoing Trials First Line

– Sorafenib vs Sorafenib + Doxorubicin (CALGB 80802)

– Lenvantinib vs Sorafenib

Sorafenib + Local Regional Therapy

– Sorafenib + / - SBRT (RTOG 1112)

– Sorafenib + / - TACE (ECOG)

– Sorafenib vs Y90

Second Line

– Ramucirumab vs BSC

– ADI-PEG 20 vs BSC

– Tivantinib and Cabozantinib vs BSC

– Regorafenib vs BSC

Pancreatic Cancer

Improvements in Chemotherapy

Gemcitabine G + Nab-Paclitaxel FOLFIRINOX

OS 6 months 8.5 months 11.1 months

Response: 6% 23% 32%

Targeted Agents

– Only approved agent is EGFr TKI Erlotinib

Moore, et al. J Clin Oncol, 2007

NCI PA.3 Phase III TrialUntreated Advanced Pancreas Ca

Stratify N= 569

•LA vs M1•Center•PS 0-1 vs 2

Primary Enpoint OS80% power, 33% increase

Gemcitabine +

Placebo

RANDOMIZE

Gemcitabine +

Erlotinib

Moore, et al. J Clin Oncol, 2007

Months

Su

rviv

al D

istr

ibu

tio

n F

un

cti

on 1.00

0.75

0.50

0.25

00 6 12 18 24

PA.3 Overall SurvivalG + Erlotinib

(N= 261)G + Placebo

(N= 260)

Med. Survival (mths) 6.24 mths 5.9 mths

1-Year Survival 23% 17%

CR + PR 8.6% 8%

CR + PR + SD 57% 49%

HR= 0.82 (0.69-0.99) p= 0.038

*Adjusted for PS and extent of disease at baseline† From Cox regression model‡ From 2-sided log-rank test

Molecular CorrelatesGemcitabine +/- Erlotinib PA.3

• N= 569 pts – 117 samples (21%)

– EGFR (+) or (–) no correlation with outcome– Post-hoc K-ras mutational status analysis

Trend to OS benefit in the pts with wild-type K-ras

Gem Gem + E HR P-value

K-ras mutant 7.4 mths 6.0 mths 1.07 0.78

K-ras WT 4.5 mths 6.1 mths 0.66 0.34

Moore, et al. ASCO, 2007 (Abst #4521)

Genetic Alterations in Pancreatic CaGene Mutation/ Deletion• p16 80% • K-ras (B-raf) 90%+• p53 70%• SMAD4/ TGFβR1+2 55%• BRCA 1, 2, PALB2 5-8%• Mismatch repair genes 4%• STK11 (Peutz-Jeghers) 5%• MKK4 5-13%• FANCC/ FANCG 5% Amplification/ Overexpression• PI3K/ Akt, c-myc, Shh/ Gli, Notch, etc (10-30%)

Infiltrating pancreatic ca

Other Genetic Changes• Telomere shortening• Widespread allelic loss

Courtesy, M. Goggins (JHCC)

NegativePhase III Anti-Vascular Trials in PC

Drug N RR Med OS Reference

Gemcitabine + Bevacizumab590

13% 5.8 mths KindlerCALGB 80303Gemcitabine + Placebo 10% 6.1 mths

Gemcitabine + Erlotinib + Bevaciz.607

13.5% 7.1 mths Van CutsemAViTAGemcitabine + Erlotinib 8.6% 6 mths

Gemcitabine + Axitinib593

NR 8.5 mthsKindler

Gemcitabine + Placebo NR 8.3 mths

Gemcitabine + Aflibercept594

NR 7.7 mthsRougier

Gemcitabine + Placebo NR 6.5 mths

Kindler, HJ. J Clin Oncol, 2010. Van Cutsem, E. J Clin Oncol, 2009. Kindler, HJ. Lancet Oncology, 2011. Rougier, P. ESMO, GI, 2010

New Targets, New DrugsTarget Class of Drug Example of Drug

IGF-1R Antibody to IGF-1RTyrosine kinase inhibitor

AMG 479, MK-0646, IMC-A12OSI-906

RAS Farnesyl transf. inhibitorOncolytic viral agents

Tipifarnib, SalarasibReovirus

mTOR/ P13K/ AKT/MEK

mTOR inhibitorAKT, P13K

Everolimus, temsirolimusMK-2206, XL-765, BKM-120, Selumetinib

Hedgehog (Hh)Notch

Small molecule Hh inhibitorGamma-secretase inhibitor

GDC-0449, IPI-926, LDE-225R04929097

PMSCA Antibody to PSCA AGS-1C4D4

SRC SRC, bcr-abl inhibitor Dasatinib, AZD 0530

TRAIL Antibody to DR4, DR5 MapatumumabAMG 655

Integrin Antibody to α5β1 integrin Volociximab

PARP PARP inhibitor AZD 2281, ABT-888, BSI-201

Vaccines/ Immunotherapy Checkpoint inhibitors, vaccines Ipilumimab, nivolumab,

GVAX/CRS207

Phase II: GVAX + / - CRS-207 GVAX: Irradiated, GM-CSF secreting allogeneic

pancreatic cancer cell lines given intradermally, preceded by Cytoxan to reduce T regs

CRS-207: Live-attenuated Listeria monocytogenes which expresses mesothelin immune stimulant

90 pts previous treated randomized 2: 1 to

C/GVAX + CRS-207 or C/GVAX alone

OS 6.1 vs 3.9 months (HR 0.54, p = 0.011)

More CA 19-9 stabilization with combination

Le J Clin Oncol 32: 2014 (suppl 3; abstr 177)

Recent Negative Phase II-III Targeted TherapyDrug Trial Med PFS or OS Reference

Gem + AMG-479 (IGF-1R) Phase III GAMMA No ChangePress Release

Gem + Placebo

Gem + Sorafenib Phase III BAYPAN PFS 5.7 mosGoncalves Ann Oncol 2012Gem + Placebo 3.8 mos

Gem Phase II LEAP OS 6.0 mos Poplin ASCO 2013CO-1.01 (hENT1) 6.0 mos

Gem + Masitinib (CKIT, PDGF, FGF)

Phase III 7.7 mos Deplanqa GI

Symposium 2013Gem + Placebo 6.0 mos

Gem + IPI-926 (Shh) Phase II6.0 mos

Press Release

Gem 5.9 mos

Gem + Vismodegib Phase II6.3 mos

Catenacci ASCO 2012

Gem (Shh) 5.4 mos

Novel Targets Stroma and Microenvironment

– PEGPH20: degrades hyaluronic acic, may increase drug delivery

– Onoing phase II:

Nab-P + / - PEGPH20

FOLFIRINOX + / - PEGPH20

BRCA mutant pancreatic cancers (5%)

– Deficient homologous DS DNA repair

– Results in genomic instability, chromosomal deletion and exchange

– PARP inhibition

Cis-Gem + / Veliparib, randomized phase II

Ongoing Randomized Phase II-III Trials

Number Target

Phase III

Gem + / - TH302 (alkylating agent)

660 Hypoxic Environment

Phase II

Gem-Nab-P + / - PEGPH20

M402OMP59R5OGX-427

132148140132

Hyaluronic acidStromaNotchHSP27

Gem + / -MSC193698

AfatinibTL-118

17411780

MEKEGFR, HER2Angiogenesis

Gem-Cis + / - Veliparib 70 PARP

Approved Targeted Agents in CRC Growth factor receptor inhibitors:

– VEGFr/ VEGF

Anti VEGF A ligand antibody: Bevacizumab

Soluble VEGF receptor: Aflibercept

VEGFr TKI: Regorafenib

– EGFr:

Anti EGFr antibodies:

Cetuximab

Panitumumab

Integration of VEGF Targeted Agents into Chemotherapy

Bevacizumab can be used with first line FOLFIRI, 5-FU/capecitabine, FOLFOX

Bevacizumab can be continued into second line chemotherapy, with FOLFOX or FOLFIRI

Alfibercept can be used second line with FOLFIRI after POD on FOLFOX/Bev

Regorafenib: Late line therapy after POD on all conventional lines of therapy

Intracellular

Extracellular

Src PLC GAP Grb2 Shc Nck Vav Grb7 Crk

Ras

PKC

Survival, Growth, Proliferation, Adhesion, Migration, Angiogenesis, Metastasis

PI3K MAPK JNK

Abl

HER1/EGFR Signaling Pathways

P P

Data from Sedlacek. Drugs. 2000;59:435.

Integration of EGFR Agents in Colorectal Cancer: KRAS WT tumors

First Line:

– Cetuximab, Panitumumab approved to combine with FOLFIRI or FOLFOX

– Capecitabine based trials with Cetuximab failed toxicity

Second, Third Line

– Cetuximab, Panitumumab approved as monotherapy

– Suggested added benefit when combined with irinotecan or FOLFIRI second line

BRAF mutant patients are eligible for EGFR therapy

All KRAS Mutant Patients Should Not Get Cetuximab

Current testing looks at KRAS exon 2 mutations

Trial of FOLFOX + / - Cetuximab

An additional 17% had KRAS exon 3/4, NRAS exon 2/3/4

Douillard NEJM 369:11;2013

Primary endpointPrimary endpoint: OS: OS Secondary endpointsSecondary endpoints: ORR, PFS, TTF, DOR, and safety: ORR, PFS, TTF, DOR, and safety

CALGB 80405: Bevacizumab vs Cetuximab in First-line KRAS WT mCRC

Untreated Untreated KRAS WT KRAS WT mCRCmCRC(n=1500)(n=1500)

BevacizumabBevacizumab+ FOLFOX+ FOLFOXor FOLFIRIor FOLFIRI

CetuximabCetuximab+ FOLFOX+ FOLFOXor FOLFIRIor FOLFIRI

PDPD

PDPD

RR

NCT identifier: NCT00265850. 5757

• Key inclusion criteria– Patients ≥18 years with histologically confirmed diagnosis of mCRC– ECOG PS 0-2– prior adjuvant chemotherapy allowed if completed >6 month before inclusion

• Amendment in October 2008 to include only KRAS wildtype patients

• 150 active centers in Germany and Austria

Phase III study design

FOLFIRI + CetuximabCetuximab: 400 mg/m2 i.v. 120min initial dose

250 mg/m2 i.v. 60min q 1w

FOLFIRI + CetuximabCetuximab: 400 mg/m2 i.v. 120min initial dose

250 mg/m2 i.v. 60min q 1w

FOLFIRI + BevacizumabBevacizumab: 5 mg/kg i.v. 30-90min q 2w

FOLFIRI + BevacizumabBevacizumab: 5 mg/kg i.v. 30-90min q 2w

mCRC1st-line therapyKRAS wild-type

N= 592

Randomize 1:1

FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2 irinotecan: 180 mg/m2

5-FU: 2,400 mg/m2 (i.v. 46h)

Evaluation of ORR

p = Fisher´s exact test (one-sided) p = Fisher´s exact test (one-sided)

FOLFIRI + Cetuximab FOLFIRI + BevacizumabOdds ratio

pORR % 95%-CI % 95%-CI

ITT population

(N= 592)62.0 56.2 – 67.5 58.0 52.1 – 63.7

1.180.85-1.64 0.183

Assessable for response

(N= 526)72.2 66.2 – 77.6 63.1 57.1 – 68.9

1.521.05-2.19 0.017

Progression-free survival

0.75

1.0

0.50

0.25

12 24 36 48 60 72

months since start of treatment

297295

numbers at risk

10099

1915

106

54

3

0.0

Pro

ba

bil

ity

of

su

rviv

al

Eventsn/N (%)

Median(months)

95% CI

― FOLFIRI + Cetuximab 250/297(84.2%)

10.0 8.8 – 10.8

― FOLFIRI + Bevacizumab 242/295(82.0%)

10.3 9.8 – 11.3

HR 1.06 (95% CI 0.88 – 1.26)Log-rank p= 0.547

Overall survival

Eventsn/N (%)

Median(months)

95% CI

― FOLFIRI + Cetuximab 158/297(53.2%)

28.7 24.0 – 36.6

― FOLFIRI + Bevacizumab 185/295(62.7%)

25.0 22.7 – 27.6

HR 0.77 (95% CI: 0.62 – 0.96)Log-rank p= 0.017

0.012 24 36 48 60 72

months since start of treatment

297295

numbers at risk

218214

111111

6047

2918

92

0.75

1.0

0.50

0.25

0.0

Pro

ba

bil

ity

of

su

rviv

al

I4T-MC-JVBBPhase III Trial 2nd Line FOLFIRI +/- Ramucirumab (RAISE)I4T-MC-JVBBPhase III Trial 2nd Line FOLFIRI +/- Ramucirumab (RAISE)

Stratification factors:•Region•KRAS status•First-line TTP (<>6 mos)

1:1

mCRC afterfailure

FP/oxaliplatin+ BEV regimen

R

525 pts Ramucirumab IV+ FOLFIRI q 2 weeks

525 pts Placebo + FOLFIRIq 2 weeks

62

Primary EP: OSAccrual completedPIs: Tabernero

Anti-CTLA4 in CRCAnti-CTLA4 in CRC

1/45 crc: PR

(response duration 15m)

Median PFS 2.3m

45% alive >6months

Chung et al. JCO 2010

0/18 crc0/18 crc

RESPONSE RATE

1/14 crc: CRRESPONSE RATE

BMS-936559 BMS-936558

RESPONSE RATE0/19 crc

MPDL3280A

1/4 crc

RESPONSE RATE

Anti-PDL1 Anti-PD1

Net N =55 CRC patients

Study Design (CA209-142 trial)to open January 2014: anti PD-1Study Design (CA209-142 trial)

to open January 2014: anti PD-1

BRAF V600E Inhibitor: PLX4032 (Vemurafenib)BRAF V600E Inhibitor: PLX4032 (Vemurafenib)

78% Response Rate

-100

-75

-50

-25

0

25

50

75

100

%C

han

ge

Fro

m B

asel

ine

(Su

m o

f L

esio

n S

ize)

-100

-75

-50

-25

0

25

50

75

100

%C

han

ge

Fro

m B

asel

ine

(Su

m o

f L

esio

n S

ize)

5% Response Rate

Refractory Melanoma Refractory Colorectal

Oncogene mutation does not imply oncogene dependence

Flaherty et al NEJM ‘10 Kopetz et al ASCO ‘10

Understand the biological context in which particular mutations occur

Low AKT activation

Minimal hypermethylation

High AKT activation

Extensive hypermethylation

Kopetz, CTPM Jan 2011

Randomized Phase II of Dual BRAF + EGFR Inhibition in BRAFmut mCRC

Primary endpoint: PFSArm B design pending outcomes from ongoing Phase 1 studies

N=42 ~800 screened

Eligibility:1) BRAF V600

mutation2) Prior treatment for

metastatic disease3) No more than 2

prior progression on chemotherapy

4) No prior cetuximab

Stratified:1) Prior treatment

with irinotecan

R

Cetuximab + Irinotecan

Vemurafenib + Cetuximab +Irinotecan

PFS

Arm A

Arm B

Courtesy: Scott Kopetz

Prominent cMET / HGF InhibitorsProminent cMET / HGF Inhibitors

Agent Structure Target

Rilotumumab Human monoclonal antibody

HGF

Onartuzumab (metMab)

Humanized monovalent antibody

c-MET

Tivantinib (ARQ 197)

Small molecule c-MET kinase

Cabozantinib (XL184)

Small molecule c-MET kinase

Phase 2 Study DesignPhase 2 Study Design

Eligibility• Age ≥ 18 years• Inoperable, locally

advanced or metastatic disease

• KRAS WT• 1 line of prior systemic

Tx• ECOG PS 0-1• No prior anti-EGFR

therapy

RANDOMIZE

N = 1501:1

DOUBLE

BLIND

Tivantinib(ARQ 197)360 mg PO BID

Cetuximab 500 mg/m2 IV q14 days

+

PlaceboPO BID

Irinotecan 180 mg/m2 IV q14 days

Cetuximab 500 mg/m2 IV q14 days

+ Irinotecan 180 mg/m2 IV q14 days

Primary Endpoint:PFSSecondary Endpoints:OS, ORR, safety

Stratification Factors:1) ECOG PS (0 vs 1)2) Best response to 1st-line therapy (CR/PR/SD vs PD) Eng et al., ASCO 2013

Progression-Free SurvivalFull Analysis Set (median follow-up: 15.9 mo)

Progression-Free SurvivalFull Analysis Set (median follow-up: 15.9 mo)

HR = 0.85 (95% CI, 0.55 - 1.33)Stratified log-rank P = 0.38

Pro

gre

ssio

n-F

ree S

urv

ival,

%

0 3 9 156 12 18 21

Time Since Randomization, mo

100

75

50

25

0Placebo (n = 57)Tivantinib (n = 60)

Events Median, mo 95% CI

T 44 8.3 5.6 - 10.8

P 37 7.3 5.3 - 9.0

Eng et al., ASCO 2013

PFS and OS by MET ExpressionPFS and OS by MET ExpressionMET-High MET-Low

Pro

gre

ssio

n-F

ree S

urv

ival,

%

0 3 6 9 12 15 18

100

50

75

25

0

Tivantinib(n = 24)Placebo(n = 20)

Overa

ll S

urv

ival,

%

0 4 8 12 16 20 24 28 32Time Since Randomization, mo

100

50

75

25

0

0 3 6 9 12 15 2118

100

50

75

25

0

Pro

gre

ssio

n-F

ree S

urv

ival,

%

Time Since Randomization, mo

100

50

75

25

0

Overa

ll S

urv

ival,

%

21

HR = 0.78 (95% CI, 0.24 - 2.47)Log-rank P = 0.67

HR = 0.22 (95% CI, 0.06 - 0.80)Log-rank P = 0.01

HR = 0.74 (95% CI, 0.36 - 1.52)Log-rank P = 0.41

HR = 0.58 (95% CI, 0.25 - 1.36)Log-rank P = 0.20

Tivantinib(n = 11)Placebo(n = 12)

PFS

OS

0 4 8 12 16 20 24 28 32

ORR: T = 54.2%; P = 30.0% ORR: T = 27.3%; P = 41.7%

Eng et al., ASCO 2013