Overview of Targeted Therapies for Esophageal and Gastric Cancers

Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Unit Sarah Cannon Research Institute Nashville, TN

Basic Numbers

Esophageal cancer – 17,460 new cases in the U. S. 2012 – 15,070 deaths Gastric cancer – 21,320 new cases in the U. S. 2012 – 10,540 deaths 5 year survival rate <5% for patients with metastatic disease

Why targeted therapy?

Going after what makes the cancer a cancer Our drug development is catching up with the lab Identification of certain pathways that are key in cancer development and survival We are still learning – One set of targets does not fit all – All of the pathways talk to each other – Side effect profiles are different, but can be just as toxic to the patient – Chronic cancer treatment?

Can Targeted Therapies Improve Outcomes?

Pathways with targeted therapies where we have data or are currently under later stage study – HER2 – VEGF – EGF – mTOR – Met

ToGA trial – HER2 + gastric cancer

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

3807 patients screened 1 810 HER2-positive (22.1%) HER2-positive advanced GC (n=584) R  Stratification factors − advanced vs metastatic − GC vs GEJ − − − measurable vs non-measurable ECOG PS 0-1 vs 2 capecitabine vs 5-FU a Chosen at investigator’s discretion GEJ, gastroesophageal junction 5-FU or capecitabine a + cisplatin (n=290) 5-FU or capecitabine a + cisplatin + trastuzumab (n=294) Bang, Y., et al. Lancet, 2010

Primary end point: OS

Event 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 2 4 11.1

FC + T FC

13.8

Events 167 182 Median OS 13.8

11.1

HR 95% CI 0.74

0.60, 0.91

6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months)

p value 0.0046

No. at risk T, trastuzumab 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 Van Cutsem ASCO 2009

Secondary end point: PFS

Event 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 5.5

2 4 6.7

FC + T FC Events Median PFS HR 226 235 6.7

5.5

95% CI 0.71

0.59, 0.85

6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time (months)

p value 0.0002

No. at risk 294 290 258 238 201 182 141 99 95 62 60 33 41 17 28 7 21 5 13 3 9 3 8 2 6 2 6 1 6 1 4 0 2 0 0 0 Van Cutsem ASCO 2009

ToGA: Overall Survival (FISH+ or IHC3+)

Bang, Y. Lancet, 2010

ToGA Survival: IHC 2+/FISH+ or IHC 3+ (Post-hoc Exploratory Analysis)

Bang, Y. Lancet, 2010

Patients (%)

Secondary end point: tumor response rate

Intent to treat

p=0.0145

p=0.0017

F+C + trastuzumab F+C

32.1% 41.8% 34.5% 47.3% p=0.0599

2.4% 5.4%

CR ORR= CR + PR CR, complete response; PR, partial response PR ORR Van Cutsem ASCO 2009

LOGiC Trial: Gastric Cancer Randomized Phase III

Adenocarcinoma of the stomach, GEJ, or esophagus HER2 positive (FISH+, IHC 3+) No previous treatment for advanced disease N = 545 R A N D O M I Z E CapOx (Oxaliplatin 130 mg/m 2 IV Day 1 for up to 8 cycles + Capecitabine 850 mg/m 2 BID Days 1-14) + Lapatinib 1250 PO daily CapOx (as above) + Placebo daily Stratification ₋ Region of the world ₋ Prior neoadjuvant and/or adjuvant chemotherapy

TYTAN Trial: Second Line Gastric Cancer Randomized Phase

III

Adenocarcinoma of the stomach, GEJ, or esophagus HER2 positive Second Line China, Korea, Japan, Taiwan N = 261 R A N D O M I Z E Paclitaxel 80 mg/m 2 IV D1, 8, 15 of 28 day cycle + Lapatinib 1500 PO daily N = 130 Paclitaxel 80 mg/m 2 IV D1, 8, 15 of 28 day cycle N = 131 Stratification ₋ Prior gastrectomy ₋ Prior anti HER2 therapy Bang GI ASCO 2013

TYTAN

ITT Population T + L

OS (mo) PFS (mo) 11.0

HR 0.84

[0.64,1.11] 5.4

HR 0.85

[0.63,1.13]

T

8.9

4.4

OS (mo) PFS (mo)

HER2 IHC 3+ T + L

14.0

HR 0.59 [0.37,0.93] 5.6

HR 0.54

[0.33,0.90]

T

7.6

4.2

Bang GI ASCO 2013

Trastuzumab Target expression : HER2 Monoclonal antibody: Trastuzumab Cytotoxic agent: DM1 Highly potent cytotoxic agent Linker: MCC Systemically stable

T-DM1 structure

T-DM1 is a novel ADC T-DM1 Average drug: antibody ratio ≅ 3.5:1

Trastuzumab Emtansine: Phase II Study of 2L treatment for HER2+ Metastatic Gastric Cancer Phase II n=100 2L Her2 positive mGC PS: 0 -1 IHC 3+ or IHC 2+/ISH+ Prior Ctx + prior HER2 N=412 Stratified by: region, PS, prior gastrectomy, prior HER2-targeted tx 2 T-DM1 3.6 mg/kg q3 wk 2 1 T-DM1 2.4 mg/kg/wk Chemotherapy ** • Phase II: 3 arm; 2:2:1 randomization; endpoints: safety, PK, PFS, ORR; n=100 * Dose selection based on PK/safety/efficacy ** Investigator’s choice between paclitaxel 80 mg/m 2 /wk and docetaxel 75 mg/m 2 q 3 wk

HER2 blockade for gastric cancers

TOGA trial shows survival benefit using trastuzumab for patients with advanced gastric cancer – We should be testing patients early – What is the definition of HER2 positivity?

IHC 3+ and/or FISH + But do FISH+ with IHC 0/1+ benefit?

What are the next steps (follow breast cancer)?

– Lapatinib – TDM-1 – Trastuzumab plus lapatinib?

– Pertuzumab combinations?

– Neoadjuvant use?

AVAGAST:

A Randomized Double-Blind Placebo- Controlled Phase III Study

Capecitabine*/Cisplatin (XP) + Placebo q3w Locally advanced or metastatic gastric cancer R Capecitabine*/Cisplatin (XP) + Bevacizumab q3w Stratification factors: 1. Geographic region 2. Fluoropirimidine backbone 3. Disease status *5-FU also allowed if cape contraindicated Cape 1000 mg/m 2 oral bid, d1 –14, 1-week rest Cisplatin 80 mg/m 2 d1 Bevacizumab 7.5 mg/kg d1 Maximum of 6 cycles of cisplatin Cape and bevacizumab/placebo until PD

Survival rate 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 Number at risk XP + Placebo XP + Bev 387 387 3 343 355

Overall Survival

6 271 291 10.1

12.1

9 204 232 12 Study month 146 178 15 98 104 18 54 50 XP + Placebo XP + Bev HR = 0.87

95% CI 0.73–1.03 p = 0.1002

21 15 19 24 0 0

Kang ASCO 2010

Progression-Free Survival

Progression-free survival rate 1.0

0.9

0.8

0.7

0.6

6.7

0.5

0.4

0.3

5.3

0.2

0.1

0.0

XP + Placebo XP + Bev HR = 0.80

95% CI 0.68–0.93 p = 0.0037

0 Number at risk XP + Placebo XP + Bev 387 387 3 279 306 6 145 201 9 86 123 12 Study month 55 71 15 32 38 18 15 11 21 3 3 24 0 0

Kang ASCO 2010

Best Overall Response:

Measurable Disease Population

Patients with measurable disease Overall response 95% CI Difference 95% CI P value (



2 ) Complete response Partial response Stable disease Progressive disease Not assessable XP + Placebo N=387 XP + Bev N=387 297 111 (37%) 31.9

–43.1

9% 0.6

–16.6

311 143 (46%) 40.3

–51.7

0.0315

3 (1%) 108 (36%) 5 (2%) 138 (44%) 90 (30%) 63 (21%) 33 (11%) 93 (30%) 44 (14%) 31 (10%)

Kang ASCO 2010

Regional Differences in Efficacy

OS Region Asia Europe America PFS Asia Europe America XP + Placebo Median, mo XP + Bev Median, mo 12.1

13.9

8.6

6.8

5.6

4.4

4.4

11.1

11.5

6.7

6.9

5.9

Delta, mo Hazard Ratio 1.8

0.97

95% CI 0.75

–1.25

2.5

4.7

1.1

0.85

0.63

0.92

0.63

–1.14

0.43

–0.94

0.74

–1.14

2.5

1.5

0.71

0.65

0.54

–0.93

0.46

–0.93

Kang ASCO 2010

Patient Characteristics by

% of patients Age ECOG PS Primary site Extent of disease

Region

Asia <65 ≥65 0 –1 2 Stomach GEJ Metastatic Locally advanced 72 28 97 3* 94 6 99 1 Europe 68 32 91 9 78 22 95 5 Pan-America 77 23 96 4 84 16 92 8 Prior gastrectomy Measurable lesion Liver metastasis yes no yes no yes no 32 68 73 27 27 73 23 77 88 12 37 63 27 73 77 23 42 58

Gastric cancer types

Intestinal type – Well-differentiated – Related to gastritis, gastric atrophy, intestinal metaplasia – More common in in older men, East Asia, Eastern Europe, Central and South America – Decreasing incidence Diffuse type – Undifferentiated – Related to pangastritis – More common in younger patients, M = F – Increasing incidence – Worse prognosis

Gastric cancer by location

Gastric cardia tumors – Rapidly increasing incidence in the West – Correlates with the increasing incidence of esophageal and GE junction adenocarcinoma – Poorer prognosis than distal stomach – Shares demographic and pathologic features of Barrett’s-associated esophageal cancer – Not associated with atrophic gastritis and intestinal metaplasia – Different genetic polymorphisms seen between cardia and non-cardia tumors, suggesting they have different biology El-Serag 2002, Powell 1992

AVAGAST Conclusions

Overall the study was negative for survival benefit However, looking at the Americas patients there appears to be a benefit to using bevacizumab Highlights the difference in gastric cancers in different parts of the world – different epidemiology, different survivals, different responses to treatment

REGARD: Randomized Phase III Trial 2

nd

Line Ramicirumab vs. Placebo

26

Ramucirumab IV q 2 weeks Second line metastatic gastric and GEJ adenocarcinoma

R 1:1

Placebo q 2 weeks Press release 10/12: met primary endpoint of OS and secondary endpoint of PFS Press release 1/23/13: OS 5.2 vs. 2.6 mo PFS 2.1 vs. 1.3 mo Primary EP: OS N = 355

RAINBOW: Randomized Phase III Trial 2

nd

Line Paclitaxel +/-

27

Ramicirumab

Paclitaxel 80 mg/m2 d1, 8, 15 + Ramucirumab IV q 2 weeks Second line metastatic gastric and GEJ adenocarcinoma

R 1:1

Paclitaxel 80 mg/m2 d1, 8, 15 + Placebo q 2 weeks Primary EP: OS N = 665

Randomized Phase II Trial 1

st

Line FOLFOX +/- Ramucirumab

28

Ramucirumab IV + FOLFOX q 2 weeks First line metastatic esophagogastric adenocarcinoma

R 1:1

Placebo + FOLFOX q 2 weeks Primary EP: PFS

REAL-3

Waddell ASCO 2012

Waddell ASCO 2012

Waddell ASCO 2012

Waddell ASCO 2012

Waddell ASCO 2012

Waddell ASCO 2012

EXPAND: Randomized Phase III Trial 1

st

Line Capecitabine/Cisplatin +/- Cetuximab

Cetuximab IV + Capecitabine/Cisplatin q 3 weeks First line metastatic gastric and GEJ adenocarcinoma

R 1:1

N = 455 N = 904 Capecitabine/Cisplatin q 3 weeks

35

N = 449 Primary EP: PFS Lordick ESMO 2012

PFS (months) OS (months) RR

EXPAND

Cape/Cis + Cetuximab (n = 455) 4.4

HR 1.091 [0.92,1.29] P = 0.316

9.4

29% Cape/Cis (n = 449) 5.6

10.7

30%

Lordick ESMO 2012

Gefitinib in advanced esophageal cancer progressing after chemotherapy Gefitinib 500mg od (n=225)

Patients progressing following chemotherapy Simple randomisation

Placebo (n=225) Planned:

18 months to recruit 450 patients

Primary endpoint:

Overall survival - powered to detect an increase in 1 year survival from 10 to 18%, 82.5% power, 5% significance level.

Secondary endpoints:

PFS, toxicity & PROs • • • • Multi-centre Double-blind – patients, clinicians and trial office staff blinded to trial treatment Treated until progression Regular CT scans

1.00

0.75

0.50

0.25

Overall Survival

By treatment Placebo - median OS=3.60m

Gefitinib - median OS=3.73m

1.00

By performance status PS0 - median OS=6.03m PS1 - median OS=3.93m PS2 - median OS=1.97m

0.75

Treatment HR= 0.90 (0.74 to 1.09) Log rank test p=0.285

0.50

0.25

PS0 - HR=1.00

PS1 - HR=1.40 (1.10, 1.78) PS2 - HR=2.98 (2.22, 3.98) Log rank test p<0.0001

0.00

0 3 6 12 18 Months from randomisation COG 2012 ESMO 29th Sept 2012 24 0.00

0 3 6 12 18 Months from randomisation 24

1.00

0.75

0.50

Progression free survival

Kaplan-Meier survival estimates Placebo - Median PFS=1.17mths

Gefitinib - Median PFS=1.60mths

HR= 0.795 (95%CI, 0.657 to 0.962) Log rank test p=0.017

Days on protocol therapy Placebo: median 35; IQR 27 to 62; range 0 to 372 Gefitinib: median 42; IQR 27 to 91; range 0 to 680 0.25

0.00

0 Number at risk Gefitinib Placebo COG 2012 223 222 ESMO 29th Sept 2012 3 62 51 6 9 12 Months from randomisation 25 21 15 6 7 3 15 4 0 18 2 0

EGFR Inhibition for Gastric Cancers

Three negative randomized trials Anything to biomarkers?

– REAL-3 does not show anything predictive, only prognostic, but numbers are low – EXPAND – 97% tumor sample acquisition – will this help us learn anything?

– Gefitinib – biomarker studies also pending – are TKI’s different than antibodies?

Squamous vs. adenocarcinomas?

– Small randomized phase II of cetuximab for SCC showed potential benefit – like head and neck?

Lordick, et al, ASCO 2008, n = 66, RR 19 vs. 13%, PFS 5.7 vs. 3.6 mo, OS 9.5 vs. 5.5 mo

PI3K/Akt/mTOR Pathway in Gastric Cancer

The PI3K/Akt/mTOR pathway, a key regulator of cell proliferation, growth, survival, metabolism, and angiogenesis, is dysregulated in 50%-60% of gastric cancers 1-3 Everolimus, an oral mTOR inhibitor, showed efficacy in preclinical models of gastric cancer 1,4-6 •

In a phase 2 study of 53 patients with previously treated advanced gastric cancer, everolimus showed promising efficacy and acceptable tolerability 7

mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

1 Xu DZ et al.

BMC Cancer

. 2010;10:536; 2 Lang SA et al.

Cancer

. 2007;120:1803-10; 3 Yu G et al.

Clin Cancer Res

. 2009;15:1821-29; 4 Taguchi F et al.

Invest New Drugs

. 2011;29:1198-205; 5 Cejka D et al.

Anticancer Res

. 2008;28:3901-08; 6 Jaeger-Lansky A et al.

Cancer Biol Ther

. 2010;9:919-27; 7 Doi T et al.

J Clin Oncol

41

Phase 3 GRANITE-1 Study Design

2 1

Everolimus 10 mg PO daily + BSC* (n = 439) Treatment until disease progression or intolerable toxicity Placebo PO daily + BSC (n = 217) Safety follow-up: EOT + 28 d Survival follow-up: every 3 mo

• •

Stratification by region: Asia vs rest of world Stratification by number of lines of previous systemic chemotherapy (1 vs 2)

BSC, best supportive care; EOT, end of treatment; PO, orally.

ClinicalTrials.gov identifier: NCT00879333.

Van Cutsem GI ASCO 2012

Overall Survival (FAS)

100 80 60 Censoring Times Everolimus + BSC (n/N = 352/439) Placebo + BSC (n/N = 180/217) Kaplan-Meier medians Everolimus + BSC: 5.39 months Placebo + BSC: 4.34 months Hazard ratio: 0.90 (95% CI, 0.75-1.08) Log-rank P value = 0.1244

40 20 0 0 2 4 6 8 No. of patients still at risk Time (months) Everolimus Placebo 0 439 217 2 355 172 4 253 117 6 195 82 8 139 60 10 12 14 Time (months) 10 87 35 12 52 28 14 30 16 16 16 13 12 18 20 22 24 18 6 8 20 3 4 22 1 1 24 0 0

Van Cutsem GI ASCO 2012

Overall Survival by Stratification Factors (FAS)

Hazard Ratio (95% CI) All (N = 656) 0.90 (0.75-1.08) Prior chemotherapy 1 (n = 313) 2 (n = 343) Region Asia (n = 363) ROW (n = 293) Cross-class.

of strata 1 prior chemo & Asia (n = 146) 2 prior chemo & Asia (n = 217) 1 prior chemo & ROW (n = 167) 2 prior chemo & ROW (n = 126) 0.6

Everolimus 10 mg/d 0.8

1.0

In favor of 1.2

1.4

Placebo 0.94 (0.73-1.23) 0.90 (0.70-1.15) 0.96 (0.75-1.23) 0.85 (0.65-1.10) 0.94 (0.63-1.39) 0.98 (0.71-1.35) 0.91 (0.64-1.31) 0.74 (0.50-1.09) ROW, rest of world.

Van Cutsem GI ASCO 2012

Progression-Free Survival (FAS)

100 80 60 Censoring Times Everolimus + BSC (n/N = 386/439) Placebo + BSC (n/N = 206/217) Kaplan-Meier medians Everolimus + BSC: 1.68 months Placebo + BSC: 1.41 months Hazard ratio: 0.66 (95% CI, 0.56-0.78) Log-rank P value < 0.0001

40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (months) 13 14 15 16 17 18 19 20 21 No. of patients still at risk Time (months) 0 1 2 3 Everolimus Placebo 439 217 367 168 179 55 117 28 4 92 23 5 60 17 6 44 8 7 37 7 8 27 6 9 20 3 10 13 2 11 10 2 12 6 2 13 5 2 14 3 2 15 3 2 16 2 2 17 1 2 18 1 2 19 0 2 20 0 1 21 0 0

Van Cutsem GI ASCO 2012

Rationale for Targeting MET

 Met is a receptor tyrosine kinase.

 Following binding to its only known ligand, hepatic growth factor (HGF), Met receptors dimerize, leading to growth, migration and survival signals  Met is amplified, mutated, overexpressed in many tumors  Met expression is associated with a worse prognosis in many cancers including NSCLC, colorectal, gastric, and breast cancers  Met pathway also implicated in resistance to bevacizumab in colorectal cancer patients and resistance to EGFR inhibitors

Activation of Met in Cancer

MUTANT MET Paracrine HGF INCREASED MET Paracrine HGF AUTOCRINE HGF LUNG HCC (Childhood) PAPIL. RENAL (Hereditary & Sporadic ) Other Focal Amp BREAST COLORECTAL ESOPHAGEAL GASTRIC GLIOMA HNSCC LUNG MELANOMA MESOTHELIOMA OVARIAN PANCREATIC RENAL GASTRIC LUNG Met CRC GLIOMA OSTEOSARCOMA PANCREATIC GASTRIC

Met Pathway and Targeted Agents

Appleman (2011) JCO ePub

1+

Development of Met IHC as a Diagnostic

 Intensity of Met staining on tumor cells scored on 0 –3+ scale 2+ 3+ 1+ 2+ 3+

‘Met High’ is defined as: ≥50% tumor cells with a staining intensity of 2 + or 3 +

AMG-102 for gastric cancer

Met receptor overexpression is associated with poor prognosis for gastric cancer patients Update on randomized phase II trial – ECX plus AMG-102 (rilotumumab) at 7.5 or 15 mg/kg (n = 82) vs. ECX plus placebo (n = 39) Met high defined as > 50% tumor cells positive for Met expression (n = 27 vs. 11) Oliner ASCO 2012

Clinical Efficacy in the Intent-to-Treat Population*

100 80 60 40

Progression-Free Survival

Rilotumumab + ECX (n = 82) Placebo + ECX (n = 39) 20 HR 0.64

0 0 1 2 3 4 5 6 7 8 9 Time (months) 10 11 12 13 14 15 16 Median Months (80% CI) 5.6 (4.9

–6.9) 4.2 (3.7

–4.6) HR † (80% CI) 0.64 (0.48

–0.85) P Value 0.045

100 80 60 40

Overall Survival

Rilotumumab + ECX (n = 82) Placebo + ECX (n = 39) Median Months (80% CI) 11.1 (9.5

–12.1) 8.9 (5.7

–10.6) HR † (80% CI) 0.73 (0.53

–1.01) 20 0 HR 0.73

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

*Results based on the updated analysis with data cutoff of April 1, 2011. Stockholm, Sweden; abstract #6504.

† Adjusted for baseline randomization stratification variables (ECOG status [0 or 1] and disease extent [locally advanced or metastatic]).

Iveson T, et al. European Multidisciplinary Cancer Congress, September 23-27, 2011,

P Value 0.215

Oliner ASCO 2012

Improved PFS and OS in MET

High

Patients

100 80

Progression-Free Survival

60 40 20 Rilotumumab + ECX (n = 27) Placebo + ECX (n = 11) 0 HR 0.51

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time (Months) Median Months (80% CI) 6.9 (5.1

–7.5) 4.6 (3.7

–5.2) HR * (95% CI) 0.51 (0.24

–1.10) P Value 0.085

100 80 60 40 20 0 HR 0.29

Overall Survival

Rilotumumab + ECX (n = 27) Placebo + ECX (n = 11) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time (Months) Median Months (80% CI) 11.1 (9.2

–13.3) 5.7 (4.5

–10.4) HR + (95% CI) 0.29 (0.11

–0.76) P Value 0.012

•

MET-evaluable OS HR, 0.95

•

ITT OS HR, 0.73

*HR adjusted for baseline disease extent and ECOG PS.

Oliner ASCO 2012

Targeted Agents for Gastric and Esophageal Cancers

They are in testing, and some look promising We are going to have to come to terms with the epidemiology of this disease to target the right populations in trials Biomarkers are essential, though we do not quite know what we are doing yet But we are continuing to move forward!