1. Novel Targets and Therapies for GI Malignancies: What does the future hold?
David H. Ilson, M.D., Ph.D.
GI Oncology Service
Memorial Sloan-Kettering Cancer Center
New York, NY

2. 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: ; 2013

3. 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

4. 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): Dulak AM, et al. Nat Genet. 2013;45(5): Lordick F, et al. Lancet Oncol. 2013;14(6): Bang YJ, et al. Lancet. 2010;376(9742):

5. ToGA Trial Design
Phase III, randomized, open-label, international, multicenter study
5FU or capecitabine + cisplatin
(n = 290)
3807 patients screened
810 HER2-positive (22.1%)
HER2-positive advanced GC (n = 584) R
5FU or capecitabine + cisplatin
+ trastuzumab
(n = 294)
Stratification factors
Advanced vs metastatic
GC vs GEJ
Measurable vs nonmeasurable
ECOG PS 0-1 vs 2
Capecitabine vs 5-FU
Eligibility criteria for the ToGA trial include: >18 years of age, HER2-positive histologically confirmed gastric cancer or gastro-oesophageal adenocarcinoma, with inoperable, locally advanced or recurrent and/or metastatic disease.
The ToGA trial planned to recruit 584 patients. An additional 10 patients, who had already signed the informed consent form when the screening cut-off was reached, were allowed to enter the trial, resulting in a total of 594 patients recruited.
The primary end point is overall survival in the two treatment arms. Secondary end points include progression-free survival, overall response rate, clinical benefit rate, duration of response and safety profile.
Bang Y, et al. Lancet. 2010;376(9742):

6. ToGA: Efficacy Outcome
Chemotherapy + Trastuzumab
(n = 294)
Chemotherapy Alone
(n = 290)
HR (95% CI)
P Value
Primary endpoint
Median OS, months
13.8
11.1
0.74 ( )
.0046
Secondary endpoints
Median PFS, months
6.7
5.5
0.71 ( )
.0002
ORR, %
47.3
34.6 -
.0017 CR
5.4
2.4
.0599 PR
41.8
32.1
.0145
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: )
ORR, overall response rate
Bang Y, et al. Lancet. 2010;376(9742):

7. 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

8. RTOG 1010: Phase III Study of Neoadjuvant Trastuzumab and Chemoradiation for Esophageal Adenocarcinoma (Siewert I, II) ‘
CHEMORADIATION
SURGERY
HER-2 (+)
(FISH)
TRASTUZUMAB +
CHEMORADIATION
SURGERY +
TRASTUZUMAB (1 YR)
HER-2 (-)
(FISH)
ALTERNATIVE STUDIES
Chemoradiation: Carboplatin, Paclitaxel + RT 5040 cGy  Surgery
Maintenance trastuzumab post op
OS Primary Endpoint

9. HER2-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

10. Large molecule VEGF inhibitors
VEGF-A
VEGF-R1
(Flt-1)
Migration
Invasion
Survival
VEGF-R3
(Flt-4)
Lymphangio-
genesis
VEGF-R2
(KDR/Flk-1)
Proliferation
Permeability
PlGF
VEGF-B
VEGF-C,
VEGF-D
Functions Y
Bevacizumab Y
Ramucirumab
Aflibercept
(VEGF Trap)

11. Targeted Agents Phase III: Negative Trials for VEGF, mTOR, and EGFr
AVAGAST: Cape-Cisplatin + / - Bevacizumab
Negative trial for OS
mTOR GRANITE: BSC vs Everolimus
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): Ohtsu A, et al. J Clin Oncol. 2013;31(31):
Waddell T Lance Oncol 14: 481; Lordick F et al Lancet 14:490; Sutton JCO 30: 2012 (suppl 34 abstr 6)

12. 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

13. VEGF Revisited? Apatinib Phase III Trial Planned
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 receptor
Li J, et al. J Clin Oncol. 2013;31(26): Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

14. VEGFr: Ramucirumab in Gastric Cancer: REGARD Trial
Gastric/GEJ Cancer with POD on FU or Platinum Based Chemo
RANDOMIZATION, 355 patients
Patients with advanced gastric cancer refractory to prior FP were randomly assigned into weekly paclitaxel or irinotecan group. Stratification factors were institution, performance status and target lesion. Paclitaxel 80mg/m2 was administered weekly for consecutive three weeks with one-week rest. And irinotecan 150mg/m2 was administered bi-weekly.
BSC + Placebo
BSC + Ramucirumab 8 mg/kg q 2 weeks
Fuchs CS, et al. Lancet. 2014;383(9911):31-39

15. 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.

16. Time Since Randomization, Months Time Since Randomization, Months
REGARD Trial: Results OS
PFS 20
HR (95% CI) = ( )
Log-rank P value (stratified) <.0001 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 40 60 80
100
PFS, %
238
117
Number at risk
Ramucirumab
Placebo
213 92
113 27 65 61 45 30 18
Time Since Randomization, Months
Ramucirumab (n = 238)
Placebo (n = 117)
Censored 27
HR (95% CI) = ( )
Log-rank P value (stratified) =.047 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 28 40 60 80
100
OS, %
238
117
Number at risk
Ramucirumab
Placebo
154 66 92 34 49
Ramucirumab (n = 238)
Placebo (n = 117)
Censored
Time Since Randomization, Months
Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

17. VEGFr: RAINBOW: Study Design
1:1
Ramucirumab 8 mg/kg day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
of a 28-day cycle
N = 330 R A N D O M I Z E
Treat until disease progression or intolerable toxicity
Survival and safety follow-up S C R E EN
Placebo day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
N = 335
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)
Wilke GI Symposium 2014 LBA 7

18. 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 = (P<.0001)
Increased toxicity neutropenia and hypertension
Wilke GI Symposium 2014 LBA 7

21. Ramucirumab First-line: FOLFOX + / - Ramucirumab Other VEGF agents
Randomized phase II
Other VEGF agents
FOLFOX + / - Pazopanib (TKI)

22. VEGF Adjuvant Trials Gastric Cancer
MAGIC 2 Trial: EOX + / - Bevacizumab
Amended for HER2 + patients
Randomized to + / - Lapatinib (HER1-2 TKI)

23. CMET Pathway
Goyal L, et al. Clin Cancer Res. 2013;19(9):

24. CMET: Rilotumumab: Gastric Cancer First Line
Phase II
ARM A
Rilotumumab (15 mg/kg) + ECX
Q3W (n = 40)
RANDOM I ZE
ARM B
Rilotumumab (7.5 mg/kg) + ECX
Q3W (n = 40)
ARM C
Placebo + ECX
Q3W (n = 40)
Stratification factors:
ECOG PS 0 vs 1
LA vs Metastatic
E: Epirubicin: 50 mg/m2 IV, day 1
C: 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 chemotherapy
ClinicalTrials.gov identifier: NCT Zhu M, et al. J Clin Oncol. 2012;30(Suppl): Abstract 2535.

25. PFS and OS in c-MetHigh Patients
Median 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.

26. 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

27. 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

28. PARP Inhibitors: Olaparib in Gastric Cancer
Gastric/GEJ Cancer with POD on FP
RANDOMIZATION:
Paclitaxel
Paclitaxel + Olaparinib
Bang YJ, et al. J Clin Oncol. 2013;31(suppl): Abstract 4013

29. PARP Inhibition in Gastric Cancer: Olaparib
Patients randomized to Paclitaxel + / Olaparib
Tissue 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

30. Trials of Targeted Agents
1st Line
Target
Agent
Trial
Regimen
Number
Status
HER2
Pertuzumab
JACOB
XP + T +/- Pertuzumab
780
Ongoing
Trastuzumab
HELOISE
XP + T (2 doses)
400
CMET
Rilotumumab
Rilomet-1
ECX + / - Rilo
650
Onartuzumab
MetGastric
FOLFOX + /- O
800
EGFr
Panitumumab
NCT
5-FU-Cis + / - Pan
300
VEGFr
Pazopanib
PaFLO
FLO + / - Pazop 75
2nd Line
mTOR
Everolimus
AIOST00111
Pac + / - Evero
665
TDM-1
GATSBY
Pac vs TDM-1
412
Nimotuzumab
NCT
Irino + / - Nimo
PARP
Olaparib
Pac + / - Olap
Planned

31. Esophagogastric 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

32. HCC: Sorafenib is the Standard for Advanced Disease
SHARP TRIAL
ASIA PACIFIC TRIAL
OS 7.9  10.7 months, HR 0.69
OS 4.5  6.2 months, HR 0.68
Llovet NEJM 359: 378; Chang Lancet Oncol 10:25; 2009

33. 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

34. Failed Phase III Trials
Agent
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
395
9.4 vs 8.2 months, HR 0.89
Sorafenib OS consistently months

35. Ongoing Single Agent Studies
Angiogenesis:
Ramucirumab, TSU-68, Cedirinab, Pazopanib, lenvatinib, Axitinib
CMET:
Tivantinib, cabozantinib, foretinib, METmab, IMC-280, LY
EGFR:
Lapatinib, cetuximab
mTOR:
Everolimus, temsirolimus, sirolimus, CC-23

36. Ongoing Single Agent Studies
MEK
Selumetinib, rafametinib
HDAC
Belinostat, resminostat
HSP-90
Genetespib
Oncolytic viruses
JX-594
Immunotherapy
Tremelimumab, PD-1, PD-L1

37. 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 ( 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
OS CMET High
Santoro Lancet Oncol 14: 55; 2013

38. 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)

39. Promising Signals Ramucirumab Lenvatinib Immunotherapy 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

40. 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

41. 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

42. NCI PA.3 Phase III Trial Untreated Advanced Pancreas Ca
Gemcitabine +
Placebo R A N D O M I Z E
Erlotinib
Stratify N= 569
LA vs M1
Center
PS 0-1 vs 2
Primary Enpoint OS
80% power, 33% increase
Moore, et al. J Clin Oncol, 2007

43. Survival Distribution Function
PA.3 Overall Survival
Months
Survival Distribution Function
1.00
0.75
0.50
0.25 6 12 18 24
G + 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 ( ) p= 0.038
*Adjusted for PS and extent of disease at baseline
† From Cox regression model
‡ From 2-sided log-rank test
Moore, et al. J Clin Oncol, 2007

44. Molecular Correlates Gemcitabine +/- 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)

45. Genetic Alterations in Pancreatic Ca
Gene Mutation/ Deletion
p %
K-ras (B-raf) 90%+
p %
SMAD4/ TGFβR %
BRCA 1, 2, PALB2 5-8%
Mismatch repair genes 4%
STK11 (Peutz-Jeghers) 5%
MKK %
FANCC/ FANCG 5%
Amplification/ Overexpression
PI3K/ Akt, c-myc, Shh/ Gli, Notch, etc (10-30%)
Other Genetic Changes
Telomere shortening
Widespread allelic loss
Infiltrating pancreatic ca
Courtesy, M. Goggins (JHCC)

46. NegativePhase III Anti-Vascular Trials in PC
Drug N RR
Med OS
Reference
Gemcitabine + Bevacizumab
590
13%
5.8 mths
Kindler
CALGB 80303
Gemcitabine + Placebo
10%
6.1 mths
Gemcitabine + Erlotinib + Bevaciz.
607
13.5%
7.1 mths
Van Cutsem
AViTA
Gemcitabine + Erlotinib
8.6%
6 mths
Gemcitabine + Axitinib
593 NR
8.5 mths
8.3 mths
Gemcitabine + Aflibercept
594
7.7 mths
Rougier
6.5 mths
Kindler, HJ. J Clin Oncol, Van Cutsem, E. J Clin Oncol, Kindler, HJ. Lancet Oncology, Rougier, P. ESMO, GI, 2010

47. New Targets, New Drugs Target Class of Drug Example of Drug IGF-1R
Antibody to IGF-1R
Tyrosine kinase inhibitor
AMG 479, MK-0646, IMC-A12
OSI-906
RAS
Farnesyl transf. inhibitor
Oncolytic viral agents
Tipifarnib, Salarasib
Reovirus
mTOR/ P13K/ AKT/MEK
mTOR inhibitor
AKT, P13K
Everolimus, temsirolimus
MK-2206, XL-765, BKM-120, Selumetinib
Hedgehog (Hh)
Notch
Small molecule Hh inhibitor
Gamma-secretase inhibitor
GDC-0449, IPI-926, LDE-225 R
PMSCA
Antibody to PSCA
AGS-1C4D4
SRC
SRC, bcr-abl inhibitor
Dasatinib, AZD 0530
TRAIL
Antibody to DR4, DR5
Mapatumumab
AMG 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

48. 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)

49. Recent Negative Phase II-III Targeted Therapy
Drug
Trial
Med PFS or OS
Reference
Gem + AMG-479 (IGF-1R)
Phase III GAMMA
No Change
Press Release
Gem + Placebo
Gem + Sorafenib
Phase III BAYPAN
PFS 5.7 mos
Goncalves Ann Oncol 2012
3.8 mos
Gem
Phase II LEAP
OS 6.0 mos
Poplin ASCO 2013
CO-1.01 (hENT1)
6.0 mos
Gem + Masitinib (CKIT, PDGF, FGF)
Phase III
7.7 mos
Deplanqa GI Symposium 2013
Gem + IPI-926 (Shh)
Phase II
5.9 mos
Gem + Vismodegib
6.3 mos
Catenacci ASCO 2012
Gem (Shh)
5.4 mos

50. 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

51. Ongoing Randomized Phase II-III Trials
Number
Target
Phase III
Gem + / - TH302 (alkylating agent)
660
Hypoxic Environment
Phase II
Gem-Nab-P + / - PEGPH20
M402
OMP59R5
OGX-427
132
148
140
Hyaluronic acid
Stroma
Notch
HSP27
Gem + / -
MSC193698
Afatinib
TL-118
174
117 80
MEK
EGFR, HER2
Angiogenesis
Gem-Cis + / - Veliparib 70
PARP

52. 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

53. 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

54. HER1/EGFR Signaling Pathways
Extracellular
Intracellular P P
Src
PLC
GAP
Grb2
Shc
Nck
Vav
Grb7
Crk
Ras
Abl
PKC
PI3K
MAPK
JNK
Survival, Growth, Proliferation, Adhesion, Migration, Angiogenesis, Metastasis
Data from Sedlacek. Drugs. 2000;59:435.
Sedlacek Drugs. 2000;59:435.

55. 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

56. 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

57. CALGB 80405: Bevacizumab vs Cetuximab in First-line KRAS WT mCRC
Untreated
KRAS WT mCRC
(n=1500)
Bevacizumab + FOLFOX or FOLFIRI
Cetuximab + FOLFOX or FOLFIRI PD R
Primary endpoint: OS
Secondary endpoints: ORR, PFS, TTF, DOR, and safety
NCT identifier: NCT 57

58. Phase III study design FOLFIRI + Cetuximab FOLFIRI + Bevacizumab
Cetuximab: 400 mg/m2 i.v. 120min initial dose
250 mg/m2 i.v. 60min q 1w
mCRC
1st-line therapy
KRAS wild-type
N= 592
Randomize 1:1
FOLFIRI + Bevacizumab
Bevacizumab: 5 mg/kg i.v min q 2w
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)
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 58 58

59. Assessable for response
Evaluation of ORR
FOLFIRI + Cetuximab
FOLFIRI + Bevacizumab
Odds ratio p
ORR %
95%-CI
ITT population
(N= 592)
62.0
56.2 – 67.5
58.0
52.1 – 63.7
1.18
0.183
Assessable for response
(N= 526)
72.2
66.2 – 77.6
63.1
57.1 – 68.9
1.52
0.017
p = Fisher´s exact test (one-sided)

60. Probability of survival months since start of treatment
Progression-free survival
Events
n/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
1.0
0.75
Probability of survival
0.50
0.25
0.0 12 24 36 48 60 72
months since start of treatment
numbers
at risk
297
295
100 99 19 15 10 6 5 4 3

61. Probability of survival months since start of treatment
Overall survival
Events
n/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
1.0
0.75
Probability of survival
0.50
0.25
0.0
0.0 12 24 36 48 60 72
months since start of treatment
numbers
at risk
297
295
218
214
111 60 47 29 18 9 2

62. I4T-MC-JVBBPhase III Trial 2nd Line FOLFIRI +/- Ramucirumab (RAISE)62
I4T-MC-JVBBPhase III Trial 2nd Line FOLFIRI +/- Ramucirumab (RAISE)
Ramucirumab IV + FOLFIRI q 2 weeks
525 pts
mCRC after failure FP/oxaliplatin + BEV regimen R
1:1
Placebo + FOLFIRI q 2 weeks
525 pts
Stratification factors:
Region
KRAS status
First-line TTP (<>6 mos)
Primary EP: OS
Accrual completed
PIs: Tabernero 62

63. Anti-CTLA4 in CRC 1/45 crc: PR (response duration 15m) Median PFS 2.3m
45% alive >6months
Chung et al. JCO 2010

64. Anti-PDL1 Anti-PD1 BMS-936559 BMS-936558 MPDL3280A RESPONSE RATE
0/18 crc
1/14 crc: CR
MPDL3280A
RESPONSE RATE
RESPONSE RATE
1/4 crc
0/19 crc
Net N =55 CRC patients

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

66. BRAF V600E Inhibitor: PLX4032 (Vemurafenib)
Refractory Melanoma
Refractory Colorectal
100
100
78% Response Rate
5% Response Rate 75 75 50 50 25 25
Low AKT activation
Minimal hypermethylation
High AKT activation
Extensive hypermethylation
%Change From Baseline
(Sum of Lesion Size)
%Change From Baseline
(Sum of Lesion Size)
-25
-25
-50
-50
-75
-75
Flaherty et al NEJM ‘10
Kopetz et al ASCO ‘10
-100
-100
Oncogene mutation does not imply oncogene dependence
Understand the biological context in which particular mutations occur
Kopetz, CTPM Jan 2011

67. Randomized Phase II of Dual BRAF + EGFR Inhibition in BRAFmut mCRC
Primary endpoint: PFS
Arm B design pending outcomes from ongoing Phase 1 studies
N=42
~800 screened
Courtesy: Scott Kopetz

68. Prominent 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)

69. Phase 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
DOUBLE
BLIND
Cetuximab mg/m2 IV q14 days
Tivantinib (ARQ 197) 360 mg PO BID +
Irinotecan mg/m2 IV q14 days
Cetuximab mg/m2 IV q14 days
Placebo PO BID +
Irinotecan mg/m2 IV q14 days
N = 150
1:1
Primary Endpoint:
PFS
Stratification Factors:
1) ECOG PS (0 vs 1)
2) Best response to 1st-line therapy (CR/PR/SD vs PD)
Secondary Endpoints:
OS, ORR, safety
Eng et al., ASCO 2013

70. Progression-Free Survival, % Time Since Randomization, mo
Progression-Free Survival Full Analysis Set (median follow-up: 15.9 mo)
HR = 0.85 (95% CI, )
Stratified log-rank P = 0.38
Progression-Free Survival, % 3 9 15 6 12 18 21
Time Since Randomization, mo
100 75 50 25
Placebo (n = 57)
Tivantinib (n = 60)
Events
Median, mo
95% CI T 44
8.3 P 37
7.3
Eng et al., ASCO 2013

71. PFS and OS by MET Expression
MET-High
MET-Low
PFS
ORR: T = 54.2%; P = 30.0%
ORR: T = 27.3%; P = 41.7%
100
100
HR = 0.74 (95% CI, )
Log-rank P = 0.41
HR = 0.22 (95% CI, )
Log-rank P = 0.01 75 75
Progression-Free Survival, % 50
Progression-Free Survival, % 50
Tivantinib
(n = 24)
Tivantinib
(n = 11) 25 25
Placebo
(n = 20)
Placebo
(n = 12) OS 3 6 9 12 15 18 21 3 6 9 12 15 18 21
100
HR = 0.58 (95% CI, )
Log-rank P = 0.20
100
HR = 0.78 (95% CI, )
Log-rank P = 0.67 75 75
Overall Survival, % 50
Overall Survival, % 50 25 25 4 8 12 16 20 24 28 32 4 8 12 16 20 24 28 32
Time Since Randomization, mo
Time Since Randomization, mo
Eng et al., ASCO 2013