1. The Gastrointestinal Malignancy Pipeline -What does the future hold for GI Cancers? Targeting the HER-family Receptors
David H. Ilson, M.D., Ph.D.
GI Oncology Service
Memorial Sloan-Kettering Cancer Center
New York, NY

2. DISCLOSURES Grant/Research Support Consultant Speaker’s Bureau Amgen
Bayer
Bristol-Myers Squibb
Consultant
Lilly
Imclone
Speaker’s Bureau
Genentech

3. GI Cancers: US Incidence in 2013
292,200 new cases and 144,570 deaths (49%)
Case Fatality Rate:
Colorectal: 36%
Esophagogastric: 66%
Pancreatic: 85%
HCC: 70%
Male > Female
Ongoing rise in Esophageal and GEJ Adenocarcinoma, HCC
Siegel et al, CA 63: ; 2013

4. HER signaling: The network begins with the 4 HER receptors
Extracellular ligand-binding domain
HER1/EGFR
HER2
HER3
HER4
Transmembrane
domain
Intracellular tyrosine kinase domain
HER=human epidermal growth factor receptor; EGFR=epidermal growth factor receptor.
Rowinsky EK. Oncologist. 2003;8:5-17. Yarden Y, Sliwkowski MX. Nat Rev Mol Cell Biol. 2001;2:

5. 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.

6. 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

7. All RAS 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

8. 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 8

9. 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

10. 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

11. S0205 Overall Survival Gemcitabine N = 369 Gem + Cetuximab N = 366 PFS
100%
Gemcitabine
N = 369
Gem + Cetuximab
N = 366
PFS
3.0 months
3.5 months OS
5.9 months
6.4 months
80%
60%
40%
HR= 1.09 (95% CI: 0.93, 1.27)
20% 0% 12 24 36
Months After Registration
Philip et al. J Clin Oncol 2010; 28:

12. HER2 in Pancreatic Cancer
Capecitabine + Trastuzumab: 17 pts with IHC 3+
OS 6.9 months, PFS at 12 weeks 23.5%
Gemcitabine + Trastuzumab: 34 pts, 30 IHC 2+, 4 IHC 3+
PR in 6%, OS 7 months, 1 yr OS 19%.
Harder et al Br J Cancer 106:1033;2012, Safran et al Cancer Invest 22: 706; 2004

13. 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

14. HCC: 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/Sorafenib vs Placebo/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

15. Gene Amplification: The Driver 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
Similar data for a Chinese series
Dulak AM et al Can Res 72: 4383; 2012

16. Targeted Agents Phase III: Negative Trials for EGFr
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
Trials conducted with no biomarker selection of patients
No biomarker identified in EG Cancer
Waddell T Lance Oncol 14: 481; Lordick F et al Lancet 14:490; Sutton JCO 30: 2012 (suppl 34 abstr 6)

17. EGFr: Cetuximab in Gastric Cancer: EXPAND Trial
Untreated Gastric/GEJ Cancer
RANDOMIZATION:904pts
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.
Cape-Cis
Cape-Cis + Cetuximab
Lordick F et al Lancet 14:490; 2013

18. EXPAND Trial: Cetuximab in Gastric CancerOS
PFS

19. R REAL3 Trial Design Arm A: EOC Arm B: mEOC-P EOC (Arm A):
Untreated advanced adenocarcinoma or undifferentiated carcinoma of the oesophagus, OGJ or stomach
EOC (Arm A):
Epirubicin 50mg/m2 IV D1
Oxaliplatin 130mg/m2 IV D1
Capecitabine 1250mg/m2/day PO in two divided doses D1-21
mEOC-P (Arm B)1:
Epirubicin 50mg/m2 IV D1
Oxaliplatin 100mg/m2 IV D1
Capecitabine 1000mg/m2/day PO in two divided doses D1-21
Panitumumab 9mg/kg IV D1
Okines et al, JCO Presented at ASCO 2012

20. Primary Endpoint – OS Based on 251 OS events
100
Median OS
(95% CI)
% alive at 1 year
11.3m (9.6 – 13.0)
46% (38% - 54%)
8.8m (7.7 – 9.8)
33% (26% - 41%)
HR 1.37, p = 0.013 80 60
Probability of Survival (%) 40
EOC
HR 1.37 (95% CI: 1.07 – 1.76) 20
EOC-P 6 12 18 24 30 36
Months from Randomisation
Number at risk
EOC
275 49 3
EOC-P
278 38 2
Presented at ASCO 2012
Based on 251 OS events

21. Trial Results - PFS Based on 333 PFS events
100
Median PFS
(95% CI)
% alive and progression-free at 1 year
7.4m (6.3 – 8.5)
21% (14% - 27%)
6.0m (5.5 – 6.5)
20% (14% - 26%)
HR 1.22, p = 0.068 80 60
Probability of Survival (%) 40
EOC 20
EOC-P
HR 1.22 (95% CI: 0.98 – 1.52) 6 12 18 24 30
Months from Randomisation
Number at risk
EOC
275 25 2
EOC-P
278 24
Presented at ASCO 2012
Based on 333 PFS events

22. 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)

23. EGFr: Gefitinib vs BSC, COG Trial
766 pts
Esophageal and GEJ Adeno pts refractory to chemotherapy
Placebo vs Gefitinib
No difference in OS
Sutton JCO 30: 2012 (suppl 34 abstr 6)

24. ToGA Trial Design
Phase III, randomized, open-label, international, multicenter study: Trastuzumab
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
Bang Y, et al. Lancet. 2010;376(9742):

25. 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):

26. 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
Novel HER2 targeted agents, Phase III:
Second line: TDM-1 vs paclitaxel
First line: Trastuzumab + / - pertuzumab
Hecht JR, et al. J Clin Oncol. 2013;31(Suppl):Abstract LBA4001
Bang et al GI Cancers Symposium 2013 Abstract 11

27. 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
EGFr
Panitumumab
NCT
5-FU-Cis + / - Pan
300
2nd Line
TDM-1
GATSBY
Pac vs TDM-1
412
Nimotuzumab
NCT
Irino + / - Nimo
mTOR
Everolimus
AIOST00111
Pac + / - Evero
665

28. GI Cancers: HER Family Targeted Agents
Biomarkers to identify responding patients
Colorectal Cancer
EGFr blocking antibodies active as monotherapy, and + chemotherapy first and second line
Benefit limited to RAS type wild type
Testing beyond exon 2 KRAS required
Pancreatic Cancer
Marginal benefit for erlotinib + gemcitabine
Negative trial for cetuximab + gemcitabine
Negative phase II trials of trastuzumab

29. GI Cancers: HER Family Targeted Agents
HCC: Large phase III trial of erlotinib + sorafenib negative
Gene amplification > mutation in esophagogastric cancer
EGFR
Negative trials in EG Cancer
No Biomarker
Trastuzumab: improves outcome in HER2+ / amplified esophagogastric cancers
Lapatinib + chemo: failed to improve OS
Newer HER2 agents, TDM-1 and pertuzumab, will be studied