Novel Biologic Therapies for Second-Line Gastric Cancer

Charles S. Fuchs, MD

Dana-Farber Cancer Institute

Harvard Medical School

Boston, MA

Second-Line Therapy in Gastric Cancer

• No approved 2nd-line chemotherapy

• 20-40% patients receiving 1st-line therapy receive 2nd-line

• Taxanes and irinotecan most commonly used 2nd-line therapy

Phase II Studies of Taxanes as Second-Line Therapy for Gastric Cancer

Drug Author No. of Pts RR PFS (mos)

OS (mos)

Docetaxel Graziano 21 5% -- 3.5

Docetaxel Giuliani 30 17% -- 6.0

Docetaxel Jo (S. Korea) 154 14% 2.6 7.2

Paclitaxel Hironka (Japan) 38 24% -- 5.0

Vinorelbine Kulke 29 7% 1.9 7.8

Second-Line Therapy in Gastric Cancer

Historically, few randomized phase III trials compared to BSC

Numerous phase II trials: Variability in response to 1st-line therapy Variability in prior 1st-line therapy Publication bias Small number of patients

Second-Line Therapy in Gastric Cancer

• 625 pts who received 1st-line therapy at 3 centers in Italy

• 28% (175) received 2nd-line therapy

• RR = 16%

• Median OS = 6 months

• Predictors of poor survival:• ECOG PS 2• Hgb 11.5 g/l• CEA > 50 ng/ml• >3 to 4 metastatic sites• TTP for 1st-line 6 months

Catalano et al. 2008

Second-Line Therapy in Gastric Cancer

1,080 patients in three 1st-line phase III trials• 20% received 2nd line therapy• RR for 2nd-line therapy = 13%• Median OS = 5.6 months

• Independent poor prognostic factors:• ECOG PS ≥ 2• Liver mets• Peritoneal mets• Serum alkaline phosphatase ≥ 100 U/L

Chau et al J Clin Oncol 2004

Chau et al J Clin Oncol 2004

Irinotecan vs. Best Supportive Care in Second-line Gastric Cancer

Thuss-Patience et al. ASCO 2009

Irinotecan 250 mg/m2 q 3weeks

Best Supportive Care

Median Survival

4.1 mos

2.4 mos

P = 0.02

HR = 0.48 (95% CI, 0.25-0.92)

N

21

19

Cougar-02: Randomized Trial of Docetaxel vs. BSC in Relapsed Esophagogastric Adenocarcinoma

R

A

N

D

O

M

I

Z

E

Docetaxel 75 mg/m2 q 3 weeks

Best supportive care

168 patients :

Primary Endpoint: Overall Survival

Cougar-02: Randomized Trial of Docetaxel vs. BSC in Relapsed Esophagogastric Adenocarcinoma

Docetaxel BSC P value

Response rate 7% NR

Overall survival 5.2 months 3.6 months 0.01

Cook et al. ASCO 2013

MetastasisProliferation/MaturationSurvival/Apoptosis Angiogenesis

MAPK

MEK

Gene transcriptionCell-cycle progression

PI3-K

RAS RAF

SOS

GRB2

PTEN AKTSTAT

pY

pYK K

pY

EGFR Signal Transduction

M

G1S

G2

Ongoing Randomized Trials in Advanced Esophagogastric Adenocarcinoma

RANDOMIZE

730 patients

EOX

EOXPanitumumab

REAL-3 Trial

RANDOMIZE

870 patients

CapecitabineCisplatinEXPAND Trial

CapecitabineCisplatinCetuximab

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 cancers1-3

• Everolimus, an oral mTOR inhibitor, showed efficacy in preclinical models of gastric cancer1,4-6

13

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

1Xu DZ et al. BMC Cancer. 2010;10:536; 2Lang SA et al. Cancer. 2007;120:1803-10; 3Yu G et al. Clin Cancer Res. 2009;15:1821-29; 4Taguchi F et al. Invest New Drugs. 2011;29:1198-205; 5Cejka D et al. Anticancer Res. 2008;28:3901-08; 6Jaeger-Lansky A et al. Cancer Biol Ther. 2010;9:919-27; 7Doi T et al. J Clin Oncol. 2010;28:1904-1910.

• In a phase 2 study of 53 patients with previously treated advanced gastric cancer, everolimus showed promising efficacy and acceptable tolerability7

Phase 3 GRANITE-1 Study Design

14

Everolimus 10 mg PO daily

+ BSC*(n = 439)

Placebo PO daily+

BSC(n = 217)

SC

RE

EN

Treatment until

disease progression

or intolerable

toxicity

• Stratification by region: Asia vs rest of world• Stratification by number of lines of previous

systemic chemotherapy (1 vs 2)

Safety follow-up: EOT + 28 d

Survival follow-up: every 3 mo

RA

ND

OM

IZE

(N =

656

)

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

ClinicalTrials.gov identifier: NCT00879333.

2

1

Overall Survival (FAS)

15

Pro

bab

ilit

y o

f o

vera

ll s

urv

ival

(%

) 100

80

60

40

20

00 2 4 6 8 10 12

Time (months)

14

Censoring TimesEverolimus + 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

No. of patients still at riskTime (months)EverolimusPlacebo

16 18 20 22 24

0 2 4 6 8 10 12 14 16 18 20 22 24

217 172 117 82 60 35 28 16 12 8 4 1 0439 355 253 195 139 87 52 30 13 6 3 1 0

AngiogenesisTumor growth

VEGF-A

VEGFR2

VEGF-A

VEGFR2

Ligand binding activates VEGFR2 andp44/p42 MAP kinases

Ramucirumab

No signaling

Inhibit new blood vesselformation and tumor growth

Ramucirumab binds to VEGFR2, blocks VEGFligand binding

VEGF binds toVEGFR2 receptor;VEGF-C, -D competefor binding toVEGFR2

¨ Ramucirumab (IMC-1121B; RAM) is a recombinant human IgG1 monoclonal antibody receptor antagonist designed to bind the extracellular domain of VEGF Receptor-2, thereby blocking the binding of VEGF ligands and inhibiting receptor activation.

Role of VEGF Pathway in Tumor Growth

Endothelial cell membrane

VEGF-CVEGF-D

VEGF-CVEGF-D

Ramucirumab 8 mg/kg q2wk

+ BSC (n = 238)

RANDOMIZE

Placebo q2wk +

BSC (n = 117)

SCREEN

Treatment until disease progression

or intolerable

toxicity

Tumor assessment,

survival, and safety follow-up

N = 355

• Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial• Gastric or GEJ adenocarcinoma• Stratification factors: region, weight loss (≥10% vs. <10% over 3 months),

location of primary tumor (gastric vs. GEJ)• Global: 6 continents, 30 countries, 120 study centers

REGARD Study Design

2:1

Abbreviations: BSC=best supportive care; GEJ= gastroesophageal junction

Fuchs et al. Lancet 2013

Months

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28

Ove

rall

Su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0

RamucirumabPlaceboCensoredCensored

Ram 238 154 92 49 17 7 3 0 0

Plcb 117 66 34 20 7 4 2 1 0

No. at Risk

HR (95% CI) = 0.776 (0.603, 0.998)

Log rank P-value (stratified) = 0.0473

Ramucirumab Placebo

Patients / Events 238 / 179 117 / 99

Median (mos) (95% CI) 5.2 (4.4, 5.7) 3.8 (2.8, 4.7)

6-month OS 42% 32%

12-month OS 18% 11%

REGARD: Overall Survival

Fuchs et al. Lancet 2013

Tumor Response

RamucirumabN=238

PlaceboN=117

P-value

n (%) n (%)

Best Overall Response

Complete response (CR) 1 (0.4) 0

Partial response (PR) 7 (2.9) 3 (2.6)

Stable disease (SD) 108 (45.4) 24 (20.5)

Progressive disease 78 (32.8) 63 (53.8)

Not evaluable / Not assessed 44 (18.5) 27 (23.1)

Response rate: CR + PR 8 (3.4) 3 (2.6) 0.756

Disease control rate: CR + PR + SD 116 (48.7) 27 (23.1) <0.0001

Months

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

Pro

gre

ss

ion

-fre

e S

urv

iva

l

0.0

0.2

0.4

0.6

0.8

1.0

RamucirumabPlaceboCensored

Censored

Ram 238 213 113 65 61 45 30 18 18 11 5 4 2 1 1 1 1 0

Plcb 117 92 27 11 7 4 2 2 2 2 2 1 1 0 0 0 0 0

No. at Risk

HR (95% CI) = 0.483 (0.376, 0.620)

Log rank P-value (stratified) = ≤0.0001

Ramucirumab Placebo

Patients / Events 238 / 199 117 / 108

Median (mos) (95% CI) 2.1 (1.5, 2.7) 1.3 (1.3, 1.4)

12-week PFS 40% 16%

REGARD: Progression-free Survival

Fuchs et al. Lancet 2013

Ramucirumab (N=236) Placebo (N=115)

TEAEs*Any Grade

(%)Grade ≥3

(%) Any Grade

(%)Grade ≥3

(%)

Fatigue 36 6 40 10

Abdominal pain 29 6 28 3

Decreased appetite 24 3 23 3

Vomiting 20 3 25 4

Constipation 15 <1 23 3

Anemia 15 6 15 8

Dysphagia 11 2 10 4

Dyspnea 9 2 13 6

Treatment Emergent Adverse Events *

Adverse Events of Special InterestRamucirumab (N=236) Placebo (N=115)

Category of event Any Grade Grade ≥3  Any Grade Grade ≥3

(%) (%) (%) (%)

Hypertension * † 16 8 8 3

Bleeding/Hemorrhage 13 3 11 3

Arteriothromboembolic 2 1 0 0

Venous thromboembolic 4 1 7 4

Proteinuria 3 <1 <1 <1

GI perforation <1 <1 <1 <1

Fistula (GI and non-GI) <1 <1 <1 <1

Infusion-related reaction <1 0 2 0

Cardiac failure <1 0 0 0

† No Grade 4 hypertension was observed among ramucirumab-treated patientsFuchs et al. Lancet 2013

REGARD: Time to Performance Status Deterioration*

Ramucirumab Placebo

Median 5.1 mos 2.4 mos

*Time to deterioration in ECOG PS score of 2 or worse Fuchs et al. Lancet 2013

Median OS in randomized 2nd-line gastric cancer studies presented/published in 2009-2013

Irinotecan vs BSC (n=40)

CTX [Docetaxel or Irinotecan] vs BSC (n=202)

Docetaxel vs ASC (n=131)

Ramucirumab vs BSC (n=355)

0 1 2 3 4 5 6

Median OS (months) by study arm

Active Treatment BSC

3.8

4.02.4

5.23.8

5.23.6

Ramucirumab vs PBO (BSC) 1 (n=355)

Docetaxel vs ASC2 (n=131)

CTX [Docetaxel or Irinotecan] vs BSC3 (n=202)

Irinotecan vs BSC4 (n=40)

5.3

1. Fuchs et al. Lancet 20132. Ford et al. Proc Gastrointestinal Cancer Symp 2013. LBA4.3. Kang et al. J Clin Oncol 30:1513-1518, 20124. Thuss-Patience et al. EUR J CANCER 47: (2011) 2306-2314.

Response Rates in randomized 2nd-line gastric cancer studies presented/published in 2009-2013

Series1 0%

9%

7%

3%Ramucirumab vs PBO (BSC)1

(n=355)

Docetaxel vs ASC2 (n=131)

CTX [Docetaxel or Irinotecan] vs BSC3 (n=202)

Irinotecan vs BSC4 (n=40)

1. Fuchs et al. Lancet 20132. Ford et al. Proc Gastrointestinal Cancer Symp 2013. LBA4.3. Kang et al. J Clin Oncol 30:1513-1518, 20124. Thuss-Patience et al. EUR J CANCER 47: (2011) 2306-2314.

Treat until disease

progression or

intolerable toxicity

• 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)

Ramucirumab 8 mg/kg day 1&15+ Paclitaxel 80 mg/m2 day 1,8 &15

of a 28-day cycleN = 330

Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15

N = 335

SCREEN

RANDOMIZE

Survival and safety

follow-up

RAINBOW: Study Design

* GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC

1:1

ToGA: A Randomized, Open Label Multicenter Phase III Study

27

HER2-positive* advanced

gastric or GEJ cancer

(n=584)

Capecitabine1 or iv 5-FU2† + cisplatin3

(n=290)

R

*IHC 3+ or FISH+5-FU=5-fluorouracil; GEJ=gastroesophageal junction; R=randomization; ECOG PS =Eastern Cooperative Oncology Group performance score.

Capecitabine or iv 5-FU2† + cisplatin3 + trastuzumab

(n=294)

3807 patients screened810 HER2-positive

(22.1%)

Bang YJ, et al. Lancet. 2010;376:687-697.

• Stratification factors

• Advanced vs. metastatic disease

• GC vs. GEJ

• Measurable vs. non-measureable

• ECOG PS 0-1 vs. 2

• Capecitabine vs. 5-FU

†Chosen at investigator’s discretion1 1000 mg/m2 bid d1-14 q3w x 6 cycles2 800 mg/m2/day continuous iv infusion d1-5 q3w x 6 cycles3 80 mg/m2 q3w x 6 cycles4 8 mg/kg loading dose followed by 6 mg/kg q3w until disease progression

ToGA Primary Endpoint: Overall Survival

28Bang YJ, et al. Lancet. 2010;376:687-697.

EventsMedian

OS (mo)

HR 95% CI p-value

FC + Trastuzumab

167 13.8 0.74 0.60, 0.91 0.0046

FC 182 11.1

Time (months)

11.1 13.8

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

0.00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ilit

y

294290

277266

246223

209185

173143

147117

11390

9064

7147

5632

4324

3016

2114

137

126

65

40

10

00

No. at risk

F+C+TrastuzumabF+C

F=fluoropyrimidine (either fluorouracil or capecitabine); C=cisplatin.

T-DM1 structure

T-DM1 is a novel ADC

Average drug:antibody ratio 3.5:1≅

Highly potent cytotoxic agent

Monoclonal antibody: Trastuzumab

Systemically stable

Target expression: HER2

Cytotoxic agent: DM1

Linker: MCC

T-DM1

Trastuzumab

Phase III Study of T-DM1 Versus Taxane in Patients With HER-2 Gastric Cancer

R

A

N

D

O

M

I

Z

E

T-DM1

q 3 weeks

Paclitaxel or Docetaxel

412 HER-2 pts following first-line therapy:

Primary endpoint:

Overall SurvivalT-DM1

weekly

MET Amplification as a Predictor of Drug Sensitivity in Gastric and Esophageal Adenocarcinoma

Graziano et al J Clin Onc 2011:

230 pts: 10% MET amplifications

Worse prognosis

Smollen et al PNAS, 2006

Yapp et al J Clin Onc 2011:

Phase I trial of ARQ197

Minor regression in gastric cancer

Second-Line Therapy for Gastric Cancer: 2014

• For all patients, 2nd-line ramucirumab significantly improves overall survival

• Survival benefit for ramucirumab appears comparable to 2nd-line docetaxel or irinotecan

• Addition of ramucirumab to 2nd-line paclitaxel significantly improves overall survival

• Other novel targeted approaches that may emerge:

• HER-2 directed therapy

• C-MET pathway directed therapy

• Ongoing mining of genomic data may generate the next generation of targets

Back-up Slides

Post-discontinuation Treatment

Ramucirumab (N=238) Placebo (N=117)

n (%) n %

Patients with any PDT* 75 (31.5) 46 (39.3)

Chemotherapy 69 (29.0) 44 (37.6)

Biologic therapy 6 (2.5) 1 (0.9)

Radiotherapy 4 (1.7) 6 (5.1)

Surgery 2 (0.8) 0 0

*Each patient may have received more than one regimen.PDT = Post-discontinuation Treatment

0.1 0.5 1 1.5 2 3 4 5

0.776 (0.603, 0.998)

0.846 (0.611, 1.171)0.722 (0.471, 1.106)

0.676 (0.499, 0.916)1.431 (0.852, 2.405)

0.784 (0.590, 1.042)0.636 (0.306, 1.321)

0.883 (0.425, 1.834)0.728 (0.554, 0.957)

0.823 (0.608, 1.114)0.756 (0.472, 1.211)

0.896 (0.667, 1.205)0.464 (0.265, 0.813)0.694 (0.265, 1.818)

0.871 (0.556, 1.366)0.800 (0.582, 1.101)

0.876 (0.631, 1.216)0.660 (0.389, 1.119)

0.751 (0.541, 1.042)0.795 (0.516, 1.225)

0.793 (0.605, 1.041)0.784 (0.372, 1.654)

0.756 (0.517, 1.105)0.790 (0.510, 1.224)

0.560 (0.366, 0.857)1.009 (0.583, 1.745)0.908 (0.579, 1.423)

1.075 (0.638, 1.810)0.682 (0.508, 0.915)

0.808 (0.620, 1.054)0.434 (0.143, 1.313)

0.563 (0.296, 1.072)0.814 (0.617, 1.072)

1.426 (0.448, 4.539)

HR (95% CI)

Favors Ramucirumab Favors Placebo

238

15682

16969

1813918

21820

19939

9992

37201

17959

1655518

41197

67171

965290

16375

64174

13265

N(Ram)

<65≥65

MaleFemale

WhiteAsianOther

YesNo

First-LineAdjuvant/Neo

DoubletsTriplets

≥10%<10%

GastricGEJ

NALAAsia

HispanicNot Hispanic

0≥1

DiffuseIntestinalUnknown

0-2≥3

YesNo

<6 months≥6 months

Subgroup

Age Group

Sex

Overall

Race

Ethnicity

ECOG PS

Measurable Tumor

Prior Therapy

First-Line Type

Hist. Subtype

# Metastatic Sites

Peritoneal

Progression-free Interval

Weight Loss

Primary Tumor

Geo Region

Category

117

7146

7938

91179

10611

10314

6336

17100

8532

80298

1998

3186

443538

7146

4572

7428

N(Plcb)

REGARD: Subgroup Analysis for OS

238

15682

16969

1813918

21820

19939

9992

37201

17959

1655518

41197

67171

965290

16375

64174

13265

N(Ram)

<65≥65

MaleFemale

WhiteAsianOther

YesNo

First-LineAdjuvant/Neo

DoubletsTriplets

≥10%<10%

GastricGEJ

NALAAsia

HispanicNot Hispanic

0≥1

DiffuseIntestinalUnknown

0-2≥3

YesNo

<6 months≥6 months

Subgroup

Age Group

Sex

Overall

Race

Ethnicity

ECOG PS

Measurable Tumor

Prior Therapy

First-Line Type

Hist. Subtype

# Metastatic Sites

Peritoneal

Progression-free Interval

Weight Loss

Primary Tumor

Geo Region

Category

117

7146

7938

91179

10611

10314

6336

17100

8532

80298

1998

3186

443538

7146

4572

7428

N(Plcb)

0.1 0.5 1 1.5 2 2.5

0.483 (0.376, 0.620)

0.450 (0.327, 0.620)0.490 (0.319, 0.752)

0.377 (0.277,0.515)0.805 (0.504,1.288)

0.450 (0.338, 0.599)0.735 (0.356, 1.517)

0.421 (0.199, 0.893)0.480 (0.367, 0.629)

0.513 (0.384, 0.685)0.386 (0.229, 0.649)

0.474 (0.352, 0.639)0.456 (0.270, 0.771)0.690 (0.268, 1.773)

0.695 (0.438, 1.103)0.423 (0.308, 0.580)

0.535 (0.385, 0.743)0.465 (0.282, 0.769)

0.460 (0.334, 0.635)0.599 (0.386, 0.927)

0.531 (0.406, 0.694)0.431 (0.194, 0.958)

0.479 (0.331, 0.694)0.531 (0.337, 0.837)

0.487 (0.318, 0.746)0.456 (0.267, 0.778)0.550 (0.347, 0.870)

0.571 (0.338, 0.965)0.423 (0.315, 0.569)

0.484 (0.371, 0.631)0.277 (0.081, 0.948)

0.335 (0.174, 0.648)0.502 (0.381, 0.661)

0.651 (0.209, 2.030)

HR (95% CI)

Favors Ramucirumab Favors Placebo

REGARD: Subgroup Analysis for PFS