Jordan%20D.%20Berlin,%20MD

1
Current and Future Directions in the Treatment of
GI Cancers Optimizing Treatment by Genetic
Features of Disease
In association with Translational Research in
Oncology

• Jordan D. Berlin, MD
• Professor of MedicineVanderbilt
  UniversityClinical Director, GI OncologyThe
  Vanderbilt-Ingram Cancer CenterNashville,
  Tennessee

This program is supported by educational grants
from
2
About These Slides

• Our thanks to the presenters who gave permission
  to include their original data
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• These slides may not be published or posted
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  Options

DisclaimerThe materials published on the
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of the authors of the CCO material, not those of
Clinical Care Options, LLC, the CME providers, or
the companies providing educational grants. The
materials may discuss uses and dosages for
therapeutic products that have not been approved
by the United States Food and Drug
Administration. A qualified healthcare
professional should be consulted before using any
therapeutic product discussed. Readers should
verify all information and data before treating
patients or using any therapies described in
these materials.
3
Program Faculty

• Program Director
• Dennis J. Slamon, MD, PhD
• TRIO ChairmanChief, Division of
  Hematology/OncologyDavid Geffen School of
  Medicine at UCLALos Angeles, California

• Faculty
• Jordan D. Berlin, MD
• Professor of MedicineVanderbilt
  UniversityClinical Director, GI OncologyThe
  Vanderbilt-Ingram Cancer CenterNashville,
  Tennessee

4
Faculty Disclosures

• Jordan D. Berlin, MD, has disclosed that he has
  received consulting fees from Amgen, AstraZeneca,
  Bristol Myers-Squibb, Celgene, Clovis, Roche, and
  sanofi-aventis and has received fees for non-CME
  services from Lilly and Incyte.
• Dennis J. Slamon, MD, PhD, has disclosed that he
  has received consulting fees from Genentech,
  GlaxoSmithKline, and Roche.

5
What Will We Discuss?

• Colorectal cancer
• Actionable items EGFR inhibitors
• Future directions
• Gastric cancer
• Actionable items HER2 inhibitors
• Future directions

6
Colorectal Cancer Current Agents

• 5-FU/capecitabine
• Thymidylate synthase
• Thymidine phosphorylase
• Irinotecan
• UGT1A1
• Oxaliplatin
• ERCC1

• Bevacizumab
• Biomarkers under investigation
• Panitumumab/cetuximab
• Ras
• Raf?

7
EGF Receptor A Rational Target for CRC Therapy
Ligand
Target for EGFR-cetuximab
EGFR-TK
Target for EGFT-TK inhibitor
pY
GRB2
pY
SOS
P13K
RAS
RAF
pY
STAT
MEK
AKT
PTEN
MAPK
Gene transcriptionCell-cycle progression
P
P
Cyclin D1
MYC
FOS
JUN
MYC
Cyclin D1
Proliferation/maturation
Survival (antiapoptosis)
Chemotherapy/radiotherapy resistance
Invasion andmetastasis
Angiogenesis
Meyerhardt JA, et al. N Engl J Med.
2005352476-487. Venook A. Oncologist.
200510250-261.
8
CRC Adenoma-Carcinoma Sequence
Normal colon
Hyperproliferative epithelium
Adenoma
Carcinoma
APChMSH2hMLH1abnormalities (hereditary)
Methylationabnormalities
APChMSH2hMLH1inactivation
KRAS mutation
18q deletion
p53 deletion
Further accumulation of genetic abnormalities
32 to 57KRAS mutant
9
Detecting Tumor KRAS Mutations
Single base substitutions that render GTPase
domain insensitive to inactivation by GAP

• Gly 12 Asp
• Gly 12 Ala
• Gly 12 Val
• Gly 12 Ser

• Gly 12 Arg
• Gly 12 Cys
• Gly 13 Asp

• DNA extracted from tumor (FFPE, cell-free DNA)
• Mutational analysis by sequencing (various
  methods) or mutant allele-specific amplification
• Detection threshold
• 1 of mutant DNA in a background of wild-type
  genomic DNA
• Mutations in other areas occur but are not
  studied well yet (eg, codon 61

10
EGFR Inhibitors

• Antibodies are effective
• But they clearly dont work for everybody
• Tyrosine kinase inhibitors are not effective
• Is the lack of EGFR-activating mutations in CRC
  the only reason they dont work?
• When we started, we didnt know what would
  predict efficacy or inefficacy
• First biomarker was skin toxicity

11
Panitumumab vs BSC in CRC PFS
1.0
Panitumumab BSC
0.8
HR 0.54 (95 CI 0.44-0.66 stratified log-rank
testP lt .000000001)
0.6
Event-Free Probability
0.4
0.2
0
0
8
16
24
32
40
48
56
Wks From Randomization

• Rate of disease progression was 46 lower in the
  panitumumab arm

Van Cutsem E, et al. J Clin Oncol.
2007251658-1664.
12
Panitumumab vs BSC OS
1.0
PanitumumabBSCHR 1.00(95 CI 0.82-1.22)
0.8
OS (primary analysis), all randomized patients
0.6
Survival Probability
0.4
0.2
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
Mos From Random Assignment
Patients at Risk, nPanitumumabBSC
231232
198194
158144
122115
8686
5765
4041
2421
1015
47
44
24
01
1.0
Events, n/N ()121/144 (84)53/56 (95)
Grade 2-4Grade 1HR 0.59(95 CI 0.42-0.85)
0.8
0.6
Survival Probability
OS by worst severity of skin-related toxicity
0.4
0.2
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
Patients at Risk, nGrade 2-4Grade 1
Mos From Random Assignment
14950
13844
11830
9621
6913
477
343
212
81
31
31
20
00
Van Cutsem E, et al. J Clin Oncol.
2007251658-1664.
13
Mutant KRAS Subgroup PFS by Treatment
1.0
0.9
0.8
Medianin Wks
Meanin Wks
Events, n/N ()
0.7
0.6
76/84 (90)
7.4
9.9
Pmab BSC
Proportion With PFS
0.5
95/100 (95)
7.3
10.2
BSC alone
HR 0.99 (95 CI 0.73-1.36)
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
50
52
Patients at Risk, n
Wks
Pmab BSC
78
76
72
26
10
8
6
5
5
5
5
4
4
4
4
2
2
2
2
2
2
2
1
1
1
84
91
77
61
37
22
19
10
9
8
6
5
5
4
4
4
4
4
4
3
3
3
2
2
2
2
100
BSC alone
Amado RG, et al. J Clin Oncol. 2008261626-1634.
14
Wild-Type KRAS Subgroup PFS by Treatment
P lt .0001 for quantitative-interaction test
comparing PFS log-HR (Pmab/BSC) between WT and
mutant KRAS groups
1.0
0.9
Medianin Wks
Meanin Wks
0.8
Events, n/N ()
0.7
115/124 (93)
12.3
19.0
Pmab BSC
0.6
9.3
114/119 (96)
7.3
BSC alone
Proportion Progression Free
0.5
HR 0.45 (95 CI 0.34-0.59stratified log-rank
test, P lt .0001)
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
50
52
Patients at Risk, n
Wks
7
7
6
5
5
124
119
112
106
80
69
63
58
50
45
44
44
33
25
21
20
17
13
13
13
10
Pmab BSC
10
9
9
6
6
6
5
4
3
3
2
2
2
2
1
119
109
91
81
38
20
15
15
14
11
6
BSC Alone
Amado RG, et al. J Clin Oncol. 2008261626-1634.
15
NCIC CTG CO.17 Progression-Free Survival
Study Arm Median PFS, Mos 95 CI
Cetuximab BSC 1.9 1.8-2.1
BSC alone 1.8 1.8-1.9
1.0
0.9
0.8
0.7
0.6
Proportion Progression Free
0.5
HR 0.68 (95 CI 0.57-0.80) Stratified
log-rank P lt .001
0.4
0.3
0.2
0.1
0
0
3
6
9
12
15
Mos
Cetuximab BSC
BSC
Censored
Censored
Jonker DJ, et al. N Engl J Med.
20073572040-2048.
16
NCIC CTG CO.17 Overall Survival
Study Arm Median OS, Mos 95 CI
Cetuximab BSC 6.1 5.4-6.7
BSC alone 4.6 4.2-4.9
1.0
0.9
0.8
0.7
0.6
HR 0.77 (95 CI 0.64-0.92) Stratified
log-rank P .005
Proportion Alive
0.5
0.4
0.3
0.2
0.1
0
0
3
6
9
12
15
18
21
24
27
Mos
Patients at Risk, n
Cet BSC
287
217
136
78
37
14
4
0
0
0
BSC
285
197
85
44
26
12
8
2
1
0
Cetuximab BSC
BSC
Censored
Censored
Jonker DJ, et al. N Engl J Med.
20073572040-2048.
17
NCIC CTG C0.17 OS in KRAS Wild-Type Patients
Study Arm Median OS, Mos 95 CI
Cetuximab BSC 9.5 7.7-10.3
BSC alone 4.8 4.2-5.5
1.0
0.8
HR 0.55 (95 CI 0.41-0.74) Log-rank P lt .001
0.6
Proportion Alive
0.4
0.2
CetuximabBSC
0
0
2
4
6
8
10
12
14
16
18
Mos From Randomization
Karapetis CS, et al. N Engl J Med.
20083591757-1785.
18
NCIC CTG C0.17 Overall Survival in KRAS Mutant
Patients
Study Arm MS, Mos 95 CI
Cetuximab BSC 4.5 3.8-5.6
BSC alone 4.6 3.6-5.5
1.0
0.8
HR 0.98 (95 CI 0.70-1.37) Log rank P .89
0.6
Proportion Alive
0.4
0.2
CetuximabBSC
0
0
2
4
6
8
10
12
14
16
18
Mos From Randomization
Karapetis CS, et al. N Engl J Med.
20083591757-1785.
19
CRYSTAL Phase III Trial of First-line FOLFIRI
Cetuximab in mCRC
Stratified by ECOG score (0-1 vs 2) and
geographic region (Western Europe vs Eastern
Europe vs outside Europe)
FOLFIRI Cetuximab IV 400 mg/m2 on Day 1,
then 250 mg/m2/wk (n 599)
Patients with EGFR-positive mCRC(N 1198)
PD
FOLFIRI (n 599)

• Populations
• Randomized patients n 1217
• Safety population n 1202
• ITT population n 1198

FOLFIRI irinotecan 180 mg 5-fluorouracil 400
mg/m2 bolus and 2400 mg/m2 as 46-hr continuous
infusion folinic acid every 2 wks.
Van Cutsem E, et al. N Engl J Med.
20093601408-1417.
20
CRYSTAL Phase III Trial of First-line FOLFIRI
Cetuximab in mCRC PFS (ITT)
1.0
0.9
Cetuximab FOLFIRI (n 599)
FOLFIRI (n 599)
0.8
HR 0.851 (95 CI 0.726-0.998)
0.7
Stratified log-rank P .0479
0.6
8.9 mos
Proportion Progression Free
1-yr PFS rate23 vs 34
0.5
8.0 mos
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
12
14
16
18
20
Mos
Van Cutsem E, et al. ASCO 2007. Abstract 4000.
21
CRYSTAL Trial of First-line FOLFIRI Cetuximab
PFS in KRAS Wild-Type Pts
1.0
KRAS wild-type (n 348) HR 0.68 P .02
mPFS cetuximab FOLFIRI 9.9 mos mPFS FOLFIRI
8.7 mos
0.9
0.8
0.7
0.6
1-yr PFS rate25 vs 43
Proportion Progression Free
0.5
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
12
14
16
18
Mos
Cetuximab FOLFIRI
FOLFIRI
Van Cutsem E, et al. N Engl J Med.
20093601408-1417.
22
CRYSTAL Trial of First-line FOLFIRI Cetuximab
PFS in KRAS-Mutant Pts
1.0
KRAS-mutant patients (n 192) HR 1.07 P .47
mPFS cetuximab FOLFIRI 7.6 mos mPFS
FOLFIRI 8.1 mos
0.9
0.8
0.7
0.6
Proportion Progression Free
0.5
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
12
14
16
Mos
Cetuximab FOLFIRI
FOLFIRI
Van Cutsem E, et al. N Engl J Med.
20093601408-1417.
23
CRYSTAL Updated Survival Analysis Efficacy
Results

• Significant interactions between KRAS status and
  treatment outcome observed with PFS, OS, and ORR
  efficacy outcomes
• Survival and response benefits with addition of
  cetuximab only achieved in KRAS wild-type pts

Outcome Cetuximab FOLFIRI FOLFIRI Hazard Ratio P value
Wild-type KRAS Median PFS, mos Median OS, mos ORR, 9.9 23.5 57.3 8.4 20.0 39.7 0.696 0.796 2.069 .0012 .0093 lt .001
Mutated KRAS Median PFS Median OS ORR, 7.4 16.7 31.3 7.7 16.2 36.1 1.171 1.035 0.822 .26 .75 .35
Odds ratio
Van Cutsem E, et al. J Clin Oncol.
2011292011-2019.
24
OPUS Phase II Study of FOLFOX Cetuximab in mCRC
MutantKRAS (n 47)
Oxaliplatin 85 mg/m2 5-FU/LV q2w
Wild-type KRAS(n 73)
Patients with EGFR-positive mCRC andECOG
performance score 2(N 337)
Stratified by ECOG PS 0/1 vs 2
Cetuximab 400 mg/m2 on Day 1,thereafter 250
mg/m2 once wkly Oxaliplatin 85 mg/m2 5-FU/LV
q2w
MutantKRAS(n 52)
Wild-type KRAS(n 61)
233 patients evaluable for KRAS.

• Primary endpoint ORRSecondary endpoints PFS,
  OS, rate of curative surgery for metastases,
  safety

Bokemeyer C, et al. ASCO 2008. Abstract 4000.
25
OPUS Biomarker Analysis OS Results
Bokemeyer C, et al. Ann Oncol. 2011221535-1546.
26
PRIME KRAS Status in Response to Panitumumab

• Randomized, global, open-label, phase III trial

Stratified by ECOG PS (0-1 vs 2) and geographic
region (Western Europe, Canada, and Australia vs
all other locations)
Panitumumab 6.0 mg/kg q2w FOLFOX4 q2w(n 593)
Patients with previously untreated mCRC (N
1183)
FOLFOX4 q2w(n 590)
Douillard JY, et al. J Clin Oncol.
2010284697-4705.
27
PRIME Efficacy Results

• Mutated KRAS patients
• Worse PFS outcome with panitumumab addition
• HR 1.27 95 CI 1.04-1.55P .02

• Wild-type KRAS patients
• PFS significantly improved with FOLFOX4
  panitumumab
• HR 0.80, 95 CI 0.67-0.96P .01

Outcome, mos Panitumumab FOLFOX4 FOLFOX4 P value
Wild-type KRAS Median PFS Median OS 10.0 23.9 8.6 19.7 .01 .17
Mutated KRAS Median PFS Median OS 7.4 15.5 9.2 19.2 .02 .15
Douillard JY, et al. J Clin Oncol.
2010284697-4705.
28
KRAS Are All Mutations Equal?

• Mutation pattern1
• 79 of CRC tumors have mutations in codon 12
• 17.6 of CRC tumors have mutations in codon 13
• Anecdotal reports suggest lt 10 of KRAS-mutated
  CRC patients can respond to anti-EGFR
  therapy2,3
• Codon 13 mutations overrepresented in these
  tumors
• Codon 13 mutations show weaker transforming
  activity in vitro4
• KRAS G13D mutation associated with longer OS and
  PFS vs other KRAS mutations1
• These data are not compelling enough to suggest
  using cetuximab or panitumumab in patients with
  codon 13 mutations

1. De Roock W, et al. JAMA. 20103041812-1820.
2. Benvenuti S, et al. Cancer Res.
2007672643-2648.3. Moroni M, et al. Lancet
Oncol. 20056279-286. 4. Guerrero S, et al.
Cancer Res. 2000606750-6756.
29
Impact of BRAF Mutations on Anti-EGFR Therapy

• 5 to 9 of CRC tumors have specific BRAF V600E
  mutation1,2
• Results in constitutive activation of BRAF
  protein
• Typically do not occur in tumors with KRAS exon 2
  mutations2
• Outcomes with BRAF V600E mutation
• Non-first-line setting BRAF V600E mutation
  associated with resistance to EGFR-targeted
  agents3-5
• First-line setting BRAF V600E mutation
  associated with poorer prognosis, but some
  patients may still benefit from addition of
  cetuximab to chemotherapy6-7

1. Van Cutsem E, et al. ASCO 2010. Abstract 3570.
2. Tol J, et al. NEJM. 200936198-99. 3. Di
Nicolantonio F, et al. J Clin Oncol.
2008265705-5712. 4. Laurent-Puig P, et al. J
Clin Oncol. 2009275924-5930. 5. Loupakis F, et
al. Br J Cancer. 2009101715-721. 6. Van Cutsem
E, et al. J Clin Oncol. 2011292011-2019. 7.
Bokemeyer C, et al. ASCO 2010. Abstract 3506.
30
BRAF Mutations in First-Line Setting

• CRYSTAL and OPUS combined analysis
• Patients with wild-type KRAS/mutated BRAF
• Worse outcomes vs wild-type KRAS/wild-type BRAF
• Still experienced non-significant improvements
  (small N)

Outcome Wild-type KRAS/Mutated BRAF Wild-type KRAS/Mutated BRAF Wild-type KRAS/Mutated BRAF Wild-type KRAS/Wild-type BRAF Wild-type KRAS/Wild-type BRAF Wild-type KRAS/Wild-type BRAF
Outcome Cetuximab CT CT Only P Value Cetuximab CT CT Only P Value
Median PFS, mos 7.1 3.7 .267 10.9 7.7 lt .001
Median OS, mos 14.1 9.9 .079 24.8 21.1 .041
Median ORR, 21.9 13.2 .4606 60.7 40.9 lt .0001
Bokemeyer C, et al. ASCO 2010. Abstract 3506.
31
KRAS Mutations and EGFR Inhibition

• What we know
• Consistently, patients with common KRAS mutations
  do not benefit from EGFR inhibitors
• What we strongly suspect
• Patients with BRAF mutations and/or NRAS
  mutations will have a similar lack of benefit for
  EGFR inhibitors
• What we dont know at all
• What other KRAS mutations may exist (eg, codon
  61) and their effects on EGFR inhibition

32
Other Potential Biomarkers in CRC

• PI3K 391
• Associated with significantly decreased PFS in
  patients treated with FOLFIRI plus cetuximab1
• NRAS 22
• Prognostic/predictive value unclear2
• EGFR ligands
• Surrogate markers for EGFR inhibition with
  cetuximab3

• DNA hypermethylation 304
• Associated with poor prognosis5
• Defective mismatch repair 156
• Improved prognosis and stage-dependent
  survival7
• Predictive for lack of efficacy of 5-FU-based
  adjuvant therapy8
• VEGF receptors and ligand
• VEGF expression may be associated with poorer
  prognosis9

1. Linot B, et al. ASCO 2010. Abstract 365. 2.
Irahara N, et al. Diagn Mol Pathol.
201019157-163. 3. Cremolini C, et al. ASCO
2010. Abstract 99. 4. Kulendran M, et al.
Cancers. 201131622-1638. 5. Barault L, et al.
Cancer Res. 2008688541-8546. 6. Kerr DJ. J Clin
Oncol. 2010283210-3212. 7. Popat S, et al. J
Clin Oncol. 200523609-618. 8. Sargent D, et al.
J Clin Oncol. 2010283219-3227. 9. Bendardaf R,
et al. Anticancer Res. 2008283865-3870.
33
CORRECT Phase III Study of Regorafenib vs BSC in
mCRC PFS
1.00
Regorafenib Placebo
Median, mos 1.9 1.795 CI
1.9-2.1 1.7-1.7
0.75
HR 0.49 (95 CI 0.42-0.581-sided P lt .000001)
Proportion Alive
0.50
Placebo (n 255)
0.25
Regorafenib (n 505)
0
200
100
50
0
150
300
250
350
Days From Randomization
Grothey A, et al. ASCO GI 2012. Abstract LBA385.
34
PFS Curves for Regorafenib Look Strangely Familiar
1.0
PanitumumabBSC
0.8
HR 0.54 (95 CI 0.44-0.66 stratified log-rank
testP lt .000000001)
0.6
Event Free Probability
0.4
0.2
0
0
8
16
24
32
40
48
56
Wks From Randomization
Van Cutsem E, et al. J Clin Oncol.
2007251658-1664.
35
Regorafenib

• Simply put, a drug in need of a biomarker
• Biomarkers are under analysis for both
  bevacizumab and regorafenib
• It works, but it would be ideal if we knew the
  biomarkers for efficacy sooner than we did for
  KRAS and EGFR inhibition

36
Gastric Cancer

• EGFR is part of a family of proteins
• Also known as HER1
• Other members include HER2, HER3, HER4
• EGFR is overexpressed in gastric cancers
• Ras mutations are not common in gastric cancers
  (2.8)
• However, EGFR inhibition has shown little, if
  any, activity in gastric cancer
• Raf mutations are rare in gastric cancer (2.2)

Lee, et al Oncogene 2003 226942-5
37
Rationale for Targeting HER2 in Gastric Cancer

• 10 to 25 tumors overexpress HER21
• HER2 overexpression associated with poor
  prognosis2
• Poor survival
• Serosal invasion
• Lymph node metastases
• Disease stage
• Distant metastases

1. Yano T, et al. Oncol Rep. 20061565-71. 2.
Jorgensen JT, et al. J Cancer. 20123137-144.
38
HER2 and Trastuzumab Mechanism of Action
Trastuzumab
HER2 receptor

• Trastuzumab
• Inhibits HER2-mediated signalling in
  HER2-positive tumors
• Prevents HER2 activation by blocking
  extracellular domain cleavage
• Activates antibody-dependent cellular
  cytotoxicity
• Trastuzumab is effective against
  HER2-overexpressing gastric cancer cell lines

39
Phase III ToGA Study of Trastuzumab Chemo in
Advanced HER2 Gastric Cancer

• Rationale a subpopulation of gastric cancers
  overexpress HER2

Stratified by ECOG PS, advanced vs metastatic,
gastric vs GEJ, measurable disease, capecitabine
vs 5-FU
5-FU or Capecitabine Cisplatin 80 mg/m2 q3w x
6 Trastuzumab 6 mg/kg q3w until PD (8-mg/kg
loading dose) (n 294)
Patients with advanced gastric cancer screened
for HER2 status(N 3803)
Patients with HER2 advanced gastric cancer(n
810 22 of successful screenings)
R
5-FU or Capecitabine Cisplatin 80 mg/m2 q3w x
6 (n 290)
(n 584)
Selected at investigators discretion 5-FU 800
mg/m2/day infusional on Days 1-5 q3w x 6
capecitabine 1000 mg/m2 BID on Days 1-14 q3w x 6.
Bang YJ, et al. Lancet. 2010376687-697.
40
ToGA Study of Trastuzumab Chemo in HER2
Gastric Cancer Analysis

• Primary endpoint OS
• Secondary endpoints
• PFS, TTP, ORR, clinical benefit rate, duration of
  response, QoL, safety, pain intensity, analgesic
  consumption, weight change, pharmacokinetics
• Sample size assumptions
• Median OS improvement from 10 to 13 mos (HR
  0.77)
• a-level 0.05, 80 power
• Required sample size 584 patients randomized 11
• Analyses
• First preplanned interim analysis after 230
  events (50)
• Second interim analysis after 345 events (75)
  considered final by independent data and safety
  monitoring committee

Bang YJ, et al. Lancet. 2010376687-697.
41
ToGA Primary Endpoint OS
1.0
MedianOS 13.811.1
Events, n 167182
HR 0.74
95 CI 0.60-0.91
P Value .0046
0.9
FC T
0.8
FC
0.7
0.6
0.5
Survival Probability
0.4
0.3
0.2
11.1
13.8
0.1
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
Mos
Pts at Risk, n
FC T
294 290
277 266
246 223
209 185
173 143
147 117
113 90
90 64
71 47
56 32
43 24
30 16
21 14
13 7
12 6
6 5
4 0
1 0
0 0
FC
Bang YJ, et al. Lancet. 2010376687-697.
42
ToGA Efficacy Outcomes
Outcome Chemotherapy Trastuzumab (n 294) Chemotherapy Alone (n 290) HR (95 CI) P Value
Median OS, mos 13.8 11.1 0.74 (0.60-0.91) .0046
Median PFS, mos 6.7 5.5 0.71 (0.59-0.85) .0002
ORR, 47 35 - .0017
CR 5 2 - .0599
PR 42 32 - .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-mo increase in OS with
  trastuzumab
• HR 0.65 (95 CI 0.51-0.83)

Bang YJ, et al. Lancet. 2010376687-697.
43
ToGA Efficacy OS by HER2 Status
Subgroup
Median OS, Mos
HR
95 CI
N
All
11.1
13.8
vs
0.74
0.60-0.91
584
Preplanned analysis

IHC0/FISH IHC1/FISH IHC2/FISH IHC3/FISH IHC
3/FISH-
7.2 10.2 10.8 12.3 17.7
10.6 8.7 12.3 17.9 17.5
vs vs vs vs vs
0.92 1.24 0.75 0.58 0.83
0.48-1.76 0.70-2.20 0.51-1.11 0.41-0.81 0.20-3.38
61 70 159 256 15
Exploratory analysis

IHC0 or 1/FISH IHC2/FISH or IHC3
8.7 11.8
10.0 16.0
vs vs
1.07 0.65
0.70-1.62 0.51-0.83
131 446
0.2
0.4
0.6
1
2
3
4
5
Risk Ratio
Favors T
Favors no T
Van Cutsem E, et al. ASCO 2009. Abstract LBA4509.
44
ToGA Efficacy OS in Pts With HER2 IHC2/FISH or
IHC3
1.0
MedianOS 16.011.8
Events, n 120136
HR 0.65
95 CI 0.51-0.83
0.9
FC T
0.8
FC
0.7
0.6
0.5
Event
0.4
0.3
0.2
11.8
16.0
0.1
0
36
34
32
30
28
26
24
22
20
18
16
14
12
10
8
6
4
2
0
Mos
Pts at Risk, n
113
218 198
40
53
124
2011
228 218
196 170
170 141
142 112
12296
10075
8453
6539
5128
10
00
3920
2813
FC T
FC
Bang YJ, et al. Lancet. 2010376687-697.
45
Future of Gastric Cancer

• HER2 inhibition
• Trastuzumab may be evaluated in combination with
  other regimens
• Introducing trastuzumab into adjuvant and
  neoadjuvant therapy is already starting
• Lapatinib and other inhibitors of HER2 need to be
  assessed
• Other potential markers for efficacy
• c-Met

46
RTOG 1010 Neoadjuvant Phase III Trial in
Esophageal/GEJ Adenocarcinoma
Stratified by presence of adenopathy and involved
celiac nodes
Radiation (50.4 Gy) Paclitaxel Carboplatin
Trastuzumab
Surgery 5-8 wks after radiation completion
Maintenance Trastuzumab q3w x 13
Patients with confirmed HER2-overexpressing
esophageal or GEJ adenocarcinoma(planned N 160)
Radiation (50.4 Gy) Paclitaxel Carboplatin
Surgery 5-8 wks after radiation completion

• Primary endpoint DFS (15 ? 27 mos HR 0.56)

Principal investigator H. Safran, Providence,
RI. ClinicalTrials.gov. NCT01196390.
47
c-Met

• Overexpressed in both gastric and esophageal
  cancers
• In esophageal cancer, expression increases in the
  pathway from metaplasia to adenocarcinoma
• Can confer poor prognosis
• Preclinical studies show some cell lines
  susceptible to Met inhibition
• c-Met can activate HER signaling through
  cross-talk with HER family receptors

Anderson MR, et al Clin Cancer Res.
2006125936-5943. Arkenau H-T. J Cancer Res
Clin Oncol. 2009135855-866.
48
c-Met Pathway
49
c-Met Inhibition

• c-Met inhibition has worked in both gastric and
  esophageal cell lines
• c-Met inhibition in esophageal cancer
• In at least 1cell line (Flo-1), Met increased
  PI3K/AKT and PI3K inhibition mimicked the effects
  of Met inhibition
• That means that in Flo-1 cells, PI3K mediates Met
  activity
• Annotating the cell lines may help us better
  understand what works and when

Watson GA, et al. Neoplasia. 20068949-955.
50
c-Met Pathway

• c-Met, like HER family, has complex interactions
  with other signaling pathways
• HER family activation may confer resistance
• Upregulation of c-Met doesnt always mean c-Met
  sensitivity
• There are many mechanisms of resistance to c-Met
• Mutations in another pathway,
• Upregulation of pathway proteins
• Gene overexpression
• Stimulation by ligand of another, complimentary
  (HER) pathway
• In turn, c-Met activation can confer resistance
  to inhibition of another pathway

51
Early Clinical Results

• In a randomized phase II of AMG 102 (rilotumumab)
  chemotherapy vs chemotherapy alone (ECX) with
  apparent benefit for AMG 102 (ESMO 2011)
• Split patients into high and low expression of
  cMet
• High c-Met OS better (HR 0.29, P .012) for AMG
  102 arms
• Low c-Met OS trended towards worse (HR 1.84, P
  NS) for AMG 102 arms

Oliner KS, et al. ASCO 2012. Abstract 4005.
52
Gastric Cancer Conclusions

• HER2 is the start for gastric cancer
• Trastuzumab now
• Other HER2 inhibitors in the future
• Other targets are there
• c-Met
• VEGF?
• IGF1R?

53
Personalized Medicine in GI Cancers?

• We have already started
• CRC and EGFR inhibitors
• Gastric cancer and HER2
• GIST and cKIT mutational status
• We can do more as we may have biomarkers for the
  chemotherapy agents we use
• What about tumor heterogeneity?
• How did this become a new concept?
• We have been living with this since the start of
  cancer therapy

54
Slide Acknowledgments

• Scott Kopetz
• Heinz Josef Lenz
• Eric van Cutsem
• Jean Yves Douilliard
• Axel Grothey

• Jonker
• Bang YJ
• Bokemeyer C

55
Go Online for More CCO Coverage of Chicago 2012!

• Capsule Summaries of all the key data, plus
  CME-certified Slidesets exploring the clinical
  implications of these findings
• Downloadable slides for use as a study resource
  or in your noncommericial presentations

• clinicaloptions.com/oncology