Treatment of Advanced HER2-Negative Gastroesophageal Carcinomas

David Malka, MD, PhDHead of Gastrointestinal Tumor GroupDepartment of Oncologic MedicineInstitut Gustave RoussyVillejuif, France

Treatment of Advanced HER2-NegativeGastroesophageal Carcinomas

This program is supported by an educational donation from

clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy

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Program Faculty

Program Director:Manish A. Shah, MDDirector, Gastrointestinal OncologyWeill Cornell Medical CollegeNewYork-Presbyterian HospitalNew York, New York

Faculty:David Malka, MD, PhDHead of Gastrointestinal Tumor GroupDepartment of Oncologic MedicineInstitut Gustave RoussyVillejuif, France


Faculty Disclosures

David Malka, MD, PhD, has disclosed that he has received consulting fees from Roche and contracted research support from Amgen, Merck Serono, and Roche.

Manish A. Shah, MD, has disclosed that he has received consulting fees and contracted research support from Genentech and sanofi-aventis.


Reference Trial Chemo, n BSC, n HR for OS 95% CI

Murad

Cancer 1993FAMTX 30 10 0.33 0.17-0.64

Pyrhönen

BJC 1995FEMTX 21 20 0.25 0.25-0.47

Scheithauer

Ann Hematol 1996ELF 52 51 0.49 0.33-0.74

Total 103 81 0.37 0.24-0.55

Effective: 11 vs 4.3 mos; P < .00001

Palliative CT: OS

Wagner AD, et al. Cochrane Database Syst Rev. 2010;3:CD004064.


Palliative CT

5-FU/antimetabolite

Anthracyclines

Cisplatin

« modern »

Taxanes

Oxaliplatin

Oral 5-FU

Irinotecan

+ targeted therapies

« old »


« old »

5-FU/antimetabolite

Anthracyclines

Cisplatin

FAMTX (5-FU + doxo + HD MTX)

FUP (5-FU + cisplatin)

ECF (epirubicin + cisplatin + 5-FU)

ELF (etoposide + leucovorin + 5-FU)

EAP (etoposide + doxo + cisplatin)

Palliative CT

=


Palliative CT

« old »

5-FU/antimetabolite

Anthracyclines

Cisplatin

=





EAP (etoposide + doxo + cisplatin)


Meta-analysis of Chemotherapy in Advanced Gastric Cancer

PolyCT > single-agent CT

Combination 5-FU/CDDP/anthra > 5-FU/CDDP

Combination 5-FU/CDDP/anthra > 5-FU/anthra

Wagner AD, et al. J Clin Oncol. 2006;24:2903-2909. Wagner AD, et al. Cochrane Database Syst Rev. 2010;3:CD004064.


Meta-analysis GASTRIC (Individual Data)

Bouché O, et al. JFHOD 2009. Abstract.

Results

49 eligible randomized studies

(7120 patients) identified

Individual data available for 18 studies (3226

patients): 45%

Median survival: 8.1 mos

CT Without vs With Anthracyclines7 studies = 1195 patients

HR: 1.03 (95% CI: 0.91-1.17; P = .66)

3% ± 6increase

4.0 2.0CT-anthra

better

1.0 0.5CT+anthra

better

0.25

Total 559/603(92.7%)

553/592(93.4%)

Test for heterogeneityChi-square = 3.73. df = 7; P > .1

Events/Patients HR & CICT-anthra CT+anthra CT-anthra CT+ anthra

A06A13A15A17A20A24A26A29

RothYamamuraCullinanNioCullinanThuss-Pat.VanhoferCoombes

71/7932/3560/8013/2753/5344/45

235/25131/33

30/4137/39

176/17616/30

103/10340/43

115/12530/35


Palliative CT

LV/5-FU2-P[2]Cap-P[1]

1. Kang Y, et al. ASCO 2006. Abstract LBA4018. 2. Taieb J, et al. Ann Oncol. 2002;13:1192-1196.

« old »

5-FU/antimetabolite

Anthracyclines

Cisplatin

=





EAP (etoposide + doxo.+ cisplatin)


Noninferiority Trial: XP vs FP (ML17032)

PFS (Primary Endpoint)XP (n = 139)

FP (n = 137)

Medians

5.6 mos (95%CI: 4.9-7.3)

5.0 mos (95% CI: 4.2-6.3)

N = 316

Cisplatin: 80 mg/m² on Day 1Capecitabine: 2 g/m² on Days 1-14 or 5-FU: 800 mg/m² on Days 1-5Every 3 wks

OS, Mos (95% CI)

10.5

(9.3-11.2)

9.3

(7.4-10.6)

Kang YK, et al. Ann Oncol. 2009;20:666-673.

0

Mos

2 4 6 8 10 12 14 16 18 20 22 24 26

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n W

ith

PF

S

Grade 3/4 Treatment-Related AEs, %

XP(n = 156)

FP(n = 155)

Neutropenia 16 19

Vomiting 7 8

Diarrhea 5 5

Stomatitis 2 6

Hand-foot syndrome

4 0


« old »

5-FU/antimetabolite

Anthracyclines

Cisplatin

Palliative CT

ECF(ECX)

FUP(XP)

RegimensRegimens


« old »

5-FU/antimetabolite

Anthracyclines

Cisplatin

Palliative CT

« modern »

Taxanes

Oxaliplatin

Oral 5-FU

Irinotecan

ECF(ECX)

FUP(XP)


« old »

5-FU/antimetabolite

Anthracyclines

Cisplatin

« modern »

Taxanes

Oxaliplatin

Oral 5-FU

Irinotecan

Palliative CT

ECF(ECX)

FUP(XP)


Tax325 Trial: Phase III Study in First-line Advanced Gastric Cancer

Docetaxel 75 mg/m2 on Day 1CDDP 75 mg/m2 on Day 15-FU 750 mg/m2 on Days 1-5q3w

CDDP 100 mg/m2 on Day 1 5-FU 1000 mg/m2 on Days 1-5q4w

N = 457

Primary endpoint: TTP

R

Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.



HR: 1.47 (95% CI: 1.19-1.82)Risk reduction: 32%

TAX325: TTP Final Analysis

90

100

80

70

60

50

40

30

20

10

00 3

Pro

bab

ilit

y (%

)

6 9 12 15 18 21Mos

148119

7142

4018

1710

105

7 6DCFCF

Pts at Risk, n

DCFMedian: 5.6 mos

CFMedian: 3.7 mos

Log-rank P ≤ .001


n OR, %TTP, mos

OS, mos

Grade 3/4 Adverse Events

DCF

CF

221/227

P value

224/230

37

.01

25

5.6

≤ .001

3.7

9.2

.02

8.6

Nonhematol: 49% GI events Hematol: 82% neutropenia; 29% all-grade febrile neutropenia

Nonhematol: 47% GI eventsHematol: 57% neutropenia; 12% all-grade febrile neutropenia


TAX325: Phase III DCF vs CF for Advanced Gastric Cancer


Alternatives to DCF: Less Toxic and as Effective? Some Examples . . .

Randomized phase II study (GATE study) of docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer.Van Cutsem E, Boni C, Tabernero J, et al. ASCO 2011. Abstract 4018.


« old »

5-FU/antimetabolite

Anthracyclines

Cisplatin

ECF(ECX)

Regimens

FUP(XP)

Palliative CT

DCFmDCF

« modern »

Taxanes

Oxaliplatin

Oral 5-FU

Irinotecan


Palliative CT

« old »

5-FU/antimetabolite

Anthracyclines

Cisplatin

ECF(ECX)

Regimens

FUP(XP)

DCFmDCF

« modern »

Taxanes

Oxaliplatin

Oral 5-FU

Irinotecan


ECF EOF

X: Capecitabine 1250 mg/m2/day

O: Oxaliplatin 130 mg/ m2/3 wks 5-FU

vsX

Cisplatin vs Oxaliplatin

REAL2 Trial in Advanced Gastric Cancer

E: Epirubicin 50 mg/m2 +C: Cisplatin 60 mg/m2 +F: 5-FUc 200 mg/m2/day

Noninferiority

Primary endpoint = OS

N = 1002

Cunningham D, et al. N Engl J Med. 2008;358:36-46.

EOXECX


Cunningham D, et al. ASCO 2006. Abstract LBA4017. Cunningham D, et al. N Engl J Med. 2008;358:36-46.

REAL2: Survival

Survival by Regimen (ITT)

Arm OS, Mos

1-Yr Survival, % (95% CI)

P Value HR (95% CI)

ECF 9.9 37.7 (31.8-43.6) 1.00

EOF 9.3 40.4 (34.2-46.5) .612 0.96 (0.79-1.15)

ECX 9.9 40.8 (34.7-46.9) .389 0.92 (0.76-1.11)

EOX 11.2 46.8 (40.4-52.9) .020 0.80 (0.66-0.97)

ECFEOFECXEOX

100

80

60

40

20

0

Pro

bab

ility

of

Su

rviv

al (

%)

Yrs Since Randomization0 1 2 3


Palliative CT

EOXFOLFOX

FLO

« old »

5-FU/antimetabolite

Anthracyclines

Cisplatin

ECF(ECX)

Regimens

FUP(XP)

DCFmDCF

« modern »

Taxanes

Oxaliplatin

Oral 5-FU

Irinotecan


Palliative CT

EOXFOLFOX

FLO

« old »

5-FU/antimetabolite

Anthracyclines

Cisplatin

ECF(ECX)

Regimens

FUP(XP)

DCFmDCF

« modern »

Taxanes

Oxaliplatin

Oral 5-FU

Irinotecan


Phase III Strategic Trial: FFCD 03-07

Primary endpoint: time to first-line treatment failure (TTF1)

Secondary endpoints

– PFS, OS (TTF second line)

– Toxicity

– ORR, QoL

– QLQC30 and STO-22

A: ECX until progression ; FOLFIRI 2d line

B: FOLFIRI until progression ; ECX 2d line

Time from randomization to:1/progression or 2/treatment interruptionor 3/death

Time from randomization to:1/progression or 2/treatment interruptionor 3/death

ECX : D1 = epirubicin 50 mg/m² (15 min), cisplatin 60 mg/m² (1 hr); D2-15 : capecitabine 1 g/m² x 2/day; D1 = D21Cumulated dose of epirubicin < 900 mg/m² (max 18 cures)

FOLFIRI: D1 = irinotecan 180 mg/m² (90 min) + LV 400 mg/m² (2 hrs), 5-FU b 400 mg/m², 5-FU ci 2400 mg/m² (46 hr). D1 = D14

Guimbaud R, et al. ESMO 2010. Abstract 8010.

Stratified by: Mesurable or not WHO PS 0-1 or 2 Adj (R)CT or not Linitis or not Cardial or gastric Center

R


1.0

0.8

0.6

0.4

0.2

0

TT

F

Mos

0 4 8 12 16 20 24 28 32

Log-rank P = .008 HR (ECX vs FOLFIRI): 0.77

(95% CI: 0.63-0.94)

ECX first line: 4.24 mos (95% CI: 3.48-4.65) FOLFIRI first line : 5.09 mos (95% CI: 4.53-5.68)

ECX 209 108 33 8 4 2 1 1 1FOLFIRI 207 123 50 19 6 3 2 1 0

OS:ECX first line: 9.49 mos

FOLFIRI first line: 9.72 mos

Less toxicity with FOLFIRI

==

Guimbaud R, et al. ESMO 2010. Abstract 8010.

FFCD 03-07: TTF1


Palliative CT

IF

FOLFIRI

EOXFOLFOX

FLO

« old »

5-FU/antimetabolite

Anthracyclines

Cisplatin

ECF(ECX)

Regimens

FUP(XP)

DCFmDCF

« modern »

Taxanes

Oxaliplatin

Oral 5-FU

Irinotecan

Targeted Agents for First-line Treatment of Advanced Disease


Targeting VEGF in Gastric Cancer

VEGF is a key mediator of angiogenesis[1]

VEGF expression is associated with more aggressive disease and poor prognosis in gastric Ca[2,3]

Bevacizumab:– Antibody against VEGF

1. Neufeld G, et al. FASEB J. 1999;13:9-22. 2. Kim SE, et al. Gut Liver. 2009;3:88-94. 3. Lieto E, et al. Ann Surg Oncol. 2008;15:69-79.


AVAGAST

Subgroup analyses (planned): Americas > Europe > Asia No unexpected toxicity Benefit

– PFS (6.7 vs 5.3 mos; HR: 0.80; 95% CI: 0.68-0.93; P = .004)

– ORR (46.0% vs 37.4%; P = .03)

Bevacizumab: active, but variable according to region – cancer biology? biomarker?

International, phase III, advanced gastric ADK, first line (n = 774) CDDP (x6)–capecitabine (or FU) + bevacizumab or placebo

Ohtsu A, et al. J Clin Oncol. 2011;30:3968-3976.

1.00.90.80.70.60.50.40.30.20.1

0

Su

rviv

al

(pro

ba

bil

ity

)

0 3 6 9 12 15 21 2418Mos Since Start of Study

10.1

12.1HR: 0.87(95% CI: 0.73-1.03;P = .100)

Fluoropyrimidine/cisplatin + placeboFluoropyrimidine/cisplatin + bevacizumab

Patients at Risk, nFluoropyrimidine/cisplatin + placeboFluoropyrimidine/cisplatin + bevacizumab

387387

343355

271291

204232

146178

98104

5450

1519

00


AVAGAST

Nonasiatic patients, diffuse or distal gastric adenocarcinomaO

S (

%)

Mos

Placebo + chemotherapyBevacizumab + chemotherapy

Shah MA, et al. ASCO GI 2012. Abstract 5.

1.00.90.80.70.60.50.40.30.20.1

00 3 6 9 12 18 21 2415

HR: 0.67(95% CI: 0.52-0.88)

163159

Patients at Risk, nPlacebo + chemotherapy

Bevacizumab + chemotherapy134144

94119

6394

4363

2528

910

13

00


AVAGAST: Potential Predictive Markers for Efficacy of Bevacizumab in Gastric Cancer High baseline plasma VEGF-A and low baseline neuropilin-1

expression each associated with trend toward improved OS with bevacizumab

– Significant benefit observed in pts from non-Asian geographic regions

Van Cutsem E, et al. J Clin Oncol. 2012;[Epub ahead of print].

*High indicates > median value; low indicates l≤ median.†PFS during first-line therapy.‡For bevacizumab + chemotherapy vs placebo + chemotherapy.§Interaction of treatment effect using likelihood ratio test.

Biomarker Subgroup*Patients,

N

OS PFS†

HR‡ 95% CI P§ HR‡ 95% CI P§

All patients 774 0.87 0.73-1.03 0.75 0.64-0.89

VEGF-A LowHigh

357355

1.010.72

0.77-1.310.57-0.93

.07 0.860.66

0.67-1.100.52-0.85

.11

Neuropilin-1 LowHigh

350329

0.751.07

0.59-0.970.81-1.40

.06 0.680.80

0.53-0.870.62-1.05

.37


Overexpression: > 50%KRAS/BRAF mutations: rare

EGFR

Targeting EGFR in Gastric Cancer


Anti-EGFR

30% to 90% of gastric cancers: EGFR overexpression

1. Lordick F, et al. Br J Cancer. 2010;102:500-505. 2. Moehler M, et al. Ann Oncol. 2011;22:1358-1366. 3. Pinto C, et al. Br J Cancer. 2009;101:1261-1268. 4. Pinto C, et al. Ann Oncol. 2007;18:510-517. 5. Kim C, et al. Invest New Drugs. 2011;29:366-373. 6. Han SW, et al. Br J Cancer. 2009;100:298-304. 7. Richards DA, et al. ASCO 2011. Abstract 4015. 8. Woell E, et al. ASCO 2009. Abstract 4538. 9. Chan JA, et al. Ann Oncol. 2011;22:1367-1373. 10. Li J, et al. ASCO 2010. Abstract 4107.

Author Treatment N ORR, % PFS or TTP, Mos OS, Mos

First line

Lordick (AIO)[1] FUFOX/cetuximab 52 65.0 7.6 9.5

Moehler[2] IF/cetuximab 49 46.0 9.0 16.5

Pinto (DOCETUX)[3] DC/cetuximab 72 41.2 5.0 9.0

Pinto (FOLCETUX)[4] FOLFIRI/cetuximab 38 44.1 8.0 16.0 (expected)

Kim[5] XELOX/cetuximab 44 52.3 6.5 11.8

Han[6] mFOLFOX6/cetuximab 38 50.0 5.5 9.9

Richards[7] DOCOX ± cetuximab 150 29.0 5.1 8.5

Woell[8] OXALI/IRI/cetuximab 51 63.0 5.7 8.8

Second line

Chan[9] Cetuximab 35 3.0 1.6 3.1

Li[10] FOLFIRI/cetuximab 61 51.0 4.9 8.1


Targeting EGFR in Gastric Cancer

Cetuximab: EXPAND[1]

XP vs XP + cetuximab Completed, n = 870

(endpoint: PFS)

Panitumumab: REAL3[2]

EOX vs EOX + panitumumab

EGFR

1. ClinicalTrials.gov. NCT00678535. 2. Waddell TS, et al. ASCO 2012. Abstract LBA4000.


REAL3: Trial Design

Waddell TS, et al. ASCO 2012. Abstract LBA4000.

Untreated advanced adenocarcinoma or

undifferentiated carcinoma of the esophagus, OGJ,

or stomach(N = 553)

R

EOCE 50 mg/m2, O 130 mg/m2

+ C 1250 mg/m2/day(n = 275)

mEOC + PE 50 mg/m2, O 100 mg/m2

+ C 1000 mg/m2/day + P 9 mg/kg(n = 278)

1:1


REAL3: Outcomes

Measure EOC (n = 275) mEOC + P (n = 278) P Value

Median OS, mos 11.3 8.8 .013

Median PFS, mos 7.4 6.0 .068

RR, % 42 46 .467

Waddell TS, et al. ASCO 2012. Abstract LBA4000.

In the mEOC arm, grade 1-3 rash was associated with:– Improvement in median OS 10.2 vs 4.3 mos (P < .001)– Similar significant improvements seen in RR and PFS

– Multivariate analysis for OS in the first 200 patients has not revealed other predictive markers associated with panitumumab

– Multivariate analysis for OS showed a negatively prognostic role for KRAS mutation (P = .025) and PI3KCA mutation (P = .048)


Targeting HGF/c-Met Pathway

HGF/c-Met pathway: mediates mitogenesis, morphogenesis, and motogenesis[1]

Over or aberrant expression of HGF or c-Met reported in various human cancers, including gastric[2]

Rilotumumab[3]

– Human IgG2 monoclonal antibody directed against human HGF

– Blocks HGF binding to its receptor c-Met

– Inhibits cell activities mediated via HGF/c-Met path (cell proliferation, survival, migration, and invasion)

1. Birchmeier C, et al. Nat Rev Mol Cell Biol. 2003;4:915-925. 2. Peruzzi B, et al. Clin Cancer Res. 2006;12:3657-3660. 3. Giordano S. Curr Opin Mol Ther. 2009;11:448-455.


First-line CT: Rilotumumab

Iveson T, et al. ESMO 2011. Abstract 6504.

ECX + Rilotumumab7.5 mg/kg/3 wks

(n = 42)

ECX + Rilotumumab15 mg/kg/3 wks

(n = 40)Phase IILA/M+

Gastric/GEJPS 0-1

(N = 121)

➔ primary endpoint: PFS➔ secondary endpoints: ORR, OS, toxicity, biomarkers

ECX + Placebo(n = 39)

R



Outcome ECX +Rilotumumab

15 mg/kg(n = 40)

ECX +Rilotumumab

7.5 mg/kg(n = 42)

ECX +Placebo(n = 39)

PFS, mos HR 95% CI

5.30.69

0.48-0.98

6.80.57

0.41-0.79

4.2

OS, mos 11.1 11.1 8.9

ORR, % 28 48 21




In ECX + placebo arm, high c-Met associated with shorter OS vs low c-Met

– HR: 3.22 (95% CI: 1.08-9.63)

Median OS by c-MET Status, Mos

ECX +Rilotumumab

ECX +Placebo

HR (95% CI) P Value

IHC c-Met > 50% tumor cells(n = 38/90)

11.1 5.7 0.29(0.11-0.76)

.012

IHC c-MET ≤ 50% tumor cells(n = 52/90)

NR NR 1.84 (0.78-4.34)

.166

Biomarker population (n = 90)

Oliner KS, et al. ASCO 2012. Abstract 4005.



All Grades ECX + Rilotumumab(n = 82)


Neutropenia 54 33

Thrombocytopenia 11 0

Edema 27 8

Alopecia 41 26

Nausea 51 41

Grade 3+ ECX + Rilotumumab(n = 82)


Neutropenia 44 33

Deep vein thrombosis 7 0

Thrombocytopenia 6 0



MEGA: Ongoing Trial

Endpoints Primary: 4-mo PFS rate (RECIST 1.1) Secondary: toxicity (NCI CTC AE V4), objective response rate, disease control rate, TTP, PFS, OS Exploratory

– Pharmacogenetic analyses– EGFR/RAS/RAF and HGF/c-Met pathway analyses– Circulating tumor/immune cell levels

Malka D, et al. ASCO 2011. Abstract TPS178.

AGEC (n = 165)First linePS 0-1Stratified by:Stage (LA vs M+)Type (signet-ring cell/diffuse vs intestinal/mixed)Center (n ~ 30)

*Oxaliplatin 85 mg/m2 in 2 hrs, folinic acid 400 mg/m2 in 2 hrs, fluorouracil 400 mg/m2 bolus then 2400 mg/m2 in 46 hrs, every 2 wks.†6 mg/kg IV in 1 hr, every 2 wks.‡10 mg/kg IV in 1 hr, every 2 wks.

PRODIGE 17 ACCORD 20/0904 MEGAFrench, multicenter, open-label, randomized phase II trial

Eudract N°: 2009-012797-12

mFOLFOLX6* + Panitumumab†

(n = 55)

mFOLFOLX6*(n = 55)

mFOLFOLX6* + Rilotumumab‡

(n = 55)

R

Until disease progression or limiting toxicity


CT + BSC(n = 133)

BSC(n = 69)Phase III

1 or 2 CT lines(5-FU/platinum)

PS 0-1(N = 202)

2:1Docetaxel 60 mg/m2/3 wksOr Irinotecan 150 mg/m2/2 wks

R

➔ Primary endpoint: OS

Second-line CT: First Phase III Trial

Kang JH, et al. J Clin Oncol. 2012;30:1513-1518.



Median age: 56 yrs 1 line: 73%; 2 lines: 27% PS 0: 54% > 1 M+ site: 65% < 3-mo treatment-free interval: 74%

Further CT, ≥ 3rd line: 40% vs 22%; P = .011 No QoL data

CT + BSC(n = 133)

BSC(n = 69)

OS, mos 5.3 3.8HR: 0.66

(95% CI: 0.48-0.89;P = .007)





1.0

0.8

0.6

0.4

0.2

00 3

Su

rviv

al P

rob

abil

ity

6 9 12 15 18 21Mos

10145

6415

3611

267

185

CT + BSCBSC

Pts at Risk, n13369

CT + BSCBSC


Palliative CT

Targeted therapies

IF

FOLFIRI

EOXFOLFOX

FLO

« old »

5-FU/antimetabolite

Anthracyclines

Cisplatin

ECF(ECX)

Regimens

FUP(XP)

DCFmDCF

« modern »

Taxanes

Oxaliplatin

Oral 5-FU

Irinotecan

Targeted Agents for Second/Third-line Treatment of

Advanced Disease


Targeting PI3K/mTOR Pathway in Gastric Cancer PI3K/mTOR pathway: important regulator of cell growth,

survival, proliferation, angiogenesis, and metabolism

50% to 60% of gastric cancers demonstrate dysregulation of the pathway[1-3]

mTOR inhibitors demonstrated preclinical and early clinical efficacy in gastric cancer[1,4-7]

1. Xu DZ, et al. BMC Cancer. 2010;10:536. 2. Lang SA, et al. Cancer. 2007;120:1803-1810. 3. Yu G, et al. Clin Cancer Res. 2009;15:1821-1829. 4. Taguchi F, et al. Invest New Drugs. 2011;29:1198-1205. 5. Cejka D, et al. Anticancer Res. 2008;28:3901-3908. 6. Jaeger-Lansky A, et al. Cancer Biol Ther. 2010;9:919-927. 7. Doi T, et al. J Clin Oncol. 2010;28:1904-1910.


Second- to Third-line CT: Everolimus

GRANITE-1

Van Cutsem E, et al. ASCO GI 2012. Abstract LBA3.

Placebo + BSC(n = 217)

Everolimus 10 mg/day + BSC(n = 439)Phase III

M+1 or 2 CT lines

PS 0-1(N = 656)

2:1R

➔ Primary endpoint: OS


Pts at Risk, n



100

80

60

40

20

00 1

PF

S (

%)

6 9 12 15 18 21Mos

367168

448

203

62

32

EverolimusPlacebo

439217

Censoring timesEverolimus + BSC (n/N = 386/439)Placebo + BSC (n/N = 206/217)

Kaplan-Meier MediansEverolimus + BSC: 1.68 mosPlacebo + BSC: 1.41 mos

HR: 0.66 (95% CI: 0.56-0.78;log-rank P < .0001)

00

2

17955

3

11728

4

9223

5

6017

7

377

8

276

10

132

11

102

13

52

14

32

16

22

17

12

19

02

20

01

12


Pts at Risk, n



100

80

60

40

20

00

OS

(%

)

6 12 18 24Mos

19582

5228

EverolimusPlacebo

439217

Censoring timesEverolimus + BSC (n/N = 352/439)Placebo + BSC (n/N = 180/217)

Kaplan-Meier mediansEverolimus + BSC: 5.39 mosPlacebo + BSC: 4.34 mos

HR: 0.90 (95% CI: 0.75-1.08;log-rank P = .1244)

00

2

355172

4

253117

8

13960

10

8735

14

3016

16

1312

20

34

22

11

68


Targeting VEGF in Gastric Cancer

VEGF is a key mediator of angiogenesis[1]

VEGF expression is associated with more aggressive disease and poor prognosis in gastric Ca[2,3]

Ramucirumab

– Fully humanized antibody directed against VEGFR-2

Apatinib

– Small-molecule multitargeted TKI with activity against VEGFR

1. Neufeld G, et al. FASEB J. 1999;13:9-22. 2. Kim SE, et al. Gut Liver. 2009;3:88-94. 3. Lieto E, et al. Ann Surg Oncol. 2008;15:69-79.


RAINBOW: Ramucirumab + Paclitaxel for Metastatic Gastric Cancer

ClinicalTrials.gov. NCT01170663.

Paclitaxel + Placebo

Paclitaxel + Ramucirumab

Phase III

Patients with metastatic gastric or GEJ

adenocarcinoma withPD after ≥ 1 cycle of

first-line treatment with platinum/fluoropyrimidine doublet ± anthracycline

(estimated N = 663)

R

➔ primary endpoint: OS


Apatinib vs Placebo as Third-line Tx for Advanced/Metastatic Gastric Cancer

ClinicalTrials.gov. NCT00970138.

Apatinib 425 mg BID

Apatinib 850 mg QDPhase II/III

Patients with metastatic gastric adenocarcinoma who experienced tx failure with

≥ 2 lines of CT(N = 141)

➔ primary endpoint: PFS

Placebo

R


Summary: Targeted Agents in Late-Phase DevelopmentPhase III

Phase II HGF/c-MET Sorafenib Sunitinib

Target Agent Trials Results

VEGF

Bevacizumab AVAGAST Negative

Apatinib NCT00970138 Ongoing

Ramucirumab RAINBOW Ongoing

EGFRCetuximab EXPAND Ongoing

Panitumumab REAL3 ASCO 2012

HER2Trastuzumab ToGA Positive

Lapatinib LOGiC Ongoing

mTOR Everolimus Granite-1 Negative


Summary

Gastroesophageal carcinomas are relatively chemosensitive tumors; however, responses are short lived

– Quest for ideal chemotherapy backbone is similar to search for the holy grail: best regimen may be fluoropyrimidine/platinum doublet?

Targeted therapies are much needed in HER2-negative gastroesophageal carcinomas to improve patient outcomes

– Results with bevacizumab and everolimus did not meet primary endpoint

– Other investigational targeted agents may lead to improved outcomes in ongoing and future trials

– Predictive markers needed to identify patients most likely to benefit from each targeted agent

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 noncommercial presentations

clinicaloptions.com/oncology

http://www.clinicaloptions.com/oncology

Documents

Treatment of Advanced HER2-Negative Gastroesophageal Carcinomas