Esophagogastric Cancer

Barbara Burtness, MDFox Chase Cancer Center

June 3, 2013

Lapatinib in combination with capecitabine plus oxaliplatin in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: The TRIO-013/LOGiC Trial

JR Hecht, Y Bang, S Qin, H Chung, J Xu, J Park, K Jeziorski, Y Shparyk, PM Hoff, AF Sobrero, P Salman, J Li, S Protsenko,

ME Buyse, K Afenjar, T Kaneko, A Kemner, S Santillana, MF Press, DJ Slamon

Translational Research In Oncology

HER2 in Gastric Cancer• Amplified in 7-34%1

• Amplification may predict resistance to conventional modalities2

OS INT0116 According to Treatment Arm

1.

1. Gravalos and Jimeno. Ann Oncol 2008; 19:15832. Gordon M A et al. Ann Oncol 2013;annonc.mdt106

HER2 Directed Therapy in Gastric Cancer

ToGA Trial demonstrated survival advantage for addition of trastuzumab in HER2 + gastric cancer1

1. Bang et al. Lancet 2010; 376:687

Comparing Lapatinib and Trastuzumab

• Antibody may also exert anticancer activity via recruitment of immune effectors

• Interpatient variation in lapatinib drug metabolism and bioavailability is significant– Pharmacogenomic predictors, role of smoking

undefined• Markers of resistance

– MET associated with lapatinib resistance in HER2 activated gastric cancer cell lines1

– Secondary HER2 mutations described in acquired lapatinib resistance in BrCa2

• Downstream signaling intermediaries– Kras mutation 6%, PTEN loss 15%3

1. Chen CT et al. Mol Cancer Ther. 2012 Mar;11(3):660-9.2. Kancha RK, et al. PLoS One. 2011;6(10):e26760.3. Okines et al. Eur J Can 2013; S0959:115

Lapatinib in Gastric Cancer

• Lapatinib administered to 47 chemonaive metastatic gastric cancer patients at 1500 mg orally daily1

– PR =9%– Median TTF 1.9 months– OS 4.8 months

• Gene expression of HER2, IL-8 and genomic polymorphisms IL-8, and vascular endothelial growth factor correlated with OS

1. Iqbal S, et al. Ann Oncol. 2011;22:2610.

OS by gene expressionMarker RECIST

ResponseOS median

months

p

EGFR > median

11% 3.3 0.24

EGFR <median

0% 5.7

HER2>

median

13% 6.8 0.0031

HER2

<median

0% 3.0

IL-8> median

0% 3.0 0.016

IL8< median

17% 5.6Iqbal S, et al. Ann Oncol. 2011;22:2610-5

TRIO-013/LOGiC Study Design

1. Confirmed histology

2. Local/central

HER-2+

3. Confirmed eligibility Stratification factors

•Prior (neo)Adjuvant therapy

•Region (Asia, North America,

Rest of the World)

R

Day 1: Oxaliplatin 130 mg/m2

Day 1−14: Capecitabine 850 mg/m2, bid

Day 1−21: Lapatinib 1250 mg, qd

(one cycle = 21 days)

Tumor tissue sent to central lab

Day 1: Oxaliplatin 130 mg/m2

Day 1−14: Capecitabine 850 mg/m2, bid

Day 1−21: Placebo, qd

(one cycle = 21 days)

Primary Efficacy Population (PEP)

(HER-2 status confirmed by FISH)

Primary Endpoint: Overall Survival (PEP)

CapeOx+L

CapeOx+P

1.0

0.8

0.6

0.4

0.2

0.0

Cu

mu

lati

ve s

urv

ival

p

rob

ab

ilit

y

0 5 10 15 20 25 30 35 40 45

Time since randomization (months)

PEP CapeOx+L

N=249

CapeOx+P

N=238

Median (95% CI) (mo)

12.2 (10.6, 14.2) 10.5 (9.0, 11.3)

HR (95% CI) 0.91 (0.73, 1.12)

Subjects at risk CapeOx+L 249 199 133 83 47 24 9 3 3CapeOx+P 238 189 106 53 34 17 11 7 2 2

ITT analysis HR 0.91

Overall Survival: Subgroup Analysis Primary efficacy population (N=487)

Region Asia (n=193)North America (n=17)Rest of World (n=277)

Prior adjuvant use Yes (n=38)No (n=449)

Age (years) <60 (n=236)≥60 (n=251)

Baseline ECOG status 0−1 (n=444)2 (n=43)

Primary site Esophagus (n=20)GE Junction (n=43)

Gastric (n=424)

Histological type Diffuse (n=19)Intestinal (n=436)

Other (n=32)

Pylorus intact Yes (n=373)No (n=114)

HER2 status (all FISH+) IHC 0 (n=27)IHC 1+ (n=54)

IHC 2+ (n=108)IHC 3+ (n=297)

IHC 0−1+ (n=81)IHC 2−3+ (n=405)

1 2 3 4 5Hazard Ratio (CapeOx+L / CapeOx+P)

Favors CapeOx+PFavors CapeOx+L

0

Hazard ratio (95% CI)0.91 (0.73, 1.12)

0.68 (0.48, 0.96)1.61 (0.53, 4.83)1.04 (0.79, 1.37)

1.52 (0.68, 3.41)0.83 (0.67, 1.04)

0.69 (0.51, 0.94)1.08 (0.81, 1.45)

0.88 (0.70, 1.10)0.76 (0.41, 1.44)

0.87 (0.32, 2.35)0.90 (0.44, 1.85)0.89 (0.71, 1.11)

0.64 (0.25, 1.65)0.93 (0.75, 1.17)0.58 (0.26, 1.29)

0.80 (0.63, 1.01)1.06 (0.67, 1.68)

0.56 (0.24, 1.31)1.16 (0.61, 2.20)0.79 (0.50, 1.25)0.90 (0.69, 1.18)

0.91 (0.55, 1.51)0.86 (0.68, 1.09)

TRIO/LOGIC Vs. ToGATRIO/LOGIC ToGA

Chemo Duration Fluoropyrimidine not fixed

6 cycles

% from Asia 40% 50%

RR 40 -> 53% 35 -> 47%

PFS 5.4 -> 6.0 mo 5.5 -> 6.7 mo

OS 10.5 -> 12.2 mo 11.1 -> 13.8 mo

HR for HER2 high .86 .65

Conclusions Lapatinib Trial

• Lapatinib and capecitabine/oxaliplatin did not lead to a significant survival advantage over capecitabine/oxaliplatin

• Impact on RR comparable to trastuzumab • Source of regional differences not clear• Role of markers of resistance

– c-MET, EGFR, IL-8– Can acquired HER2 mutations be identified?

• Studies ongoing to assess role of pertuzumab, TDM-1

A phase III randomized clinical trial of adjuvant paclitaxel followed by oral

fluorinated pyrimidines for locally advanced gastric cancer –SAMIT Study-

K. Yoshida, A. Tsuburaya, M. Kobayashi, S. Yoshino, M. Takahashi, N. Takiguchi, K. Tanabe, N. Takahashi,

H. Imamura, N. Tatsumoto, A. Hara, K. Nishikawa, R. Fukushima, A. Kurita, H. Kojima, Y. Miyashita,

K. Oba, ME Buyse, S. Morita, J. Sakamoto,

Stomach Cancer Adjuvant Multi-institutional Trial, SAMIT, Group

Adjuvant Therapy in Gastric Cancer

JAMA. 2010;303(17):1729-1737.

Adjuvant Systemic Therapy• CA80101 randomized 546 patients to Macdonald

(bolus 5-FU/LV, infusional 5-FU RT, bolus 5-FU/LV) vs. ECF-> 5FU/RT -> ECF– ECF did not improve OS [HR 1.03, P = .80]– Toxicity profile favored ECF over bolus 5-FU/LV1

• CLASSIC trial randomized 1035 patients with D2 lymph node dissection to observation or adjuvant capecitabine/oxaliplatin– 3-year DFS 74% on cape/ox vs. 60% for observation [HR

0.56, P<.001] 1. Fuchs CS et al. Proc ASCO 20112. Bang et al. Proc ASCO 2011

Study schemeRandomized phase III, two-by-two factorial design

UFT S-1

Monotherapyoral FUs

Arm A Arm B: Control

SequentialPTXoral FUs

Arm C Arm D

S-1 80 mg/m2UFT 267 mg/m2

48wks 48wks

X 3 36wks

PTX 80 mg/m2

X 3 36wks

DFS: Sequential, CD vs Monotherapy, AB

AB, Mono: 54.0% (95%CI: 50.2-57.6)CD, Seq. : 57.2% (95%CI: 53.4-60.8)

3yr DFS

Superiority of SequentialHR: 0.92 (95%CI: 0.80-1.07; p=0.273)

AC, UFT base: 53.0% (95%CI: 49.2-56.6)BD, S-1 base : 58.2% (95%CI: 54.4-61.8)

3yr DFS

Non-inferiority of UFTHR:1.23 (95%CI:1.07-1.43), p = 0.151Superiority of S-1HR: 0.81, p = 0.0057

DFS: UFT base vs S-1 base

DFS in Each Arms

Months

SAMIT Conclusions• Sequential taxane -> fluoropyrimidine not superior

to fluoropyrimidine monotherapy• 2 x 2 factorial design not optimal for assessing the

2nd component of a sequential regimen– May alter PK, toxicity profile, select for resistance

pathways, early progressors are not evaluated• Did not exclude HER2 amplified• Biomarkers of taxane sensitivity should be

explored

COUGAR-02: Randomised phase III study of docetaxel versus active symptom control in patients with relapsed esophago-gastric adenocarcinoma

N Cook, A Marshall, JM Blazeby, JA Bridgewater, J Wadsley, FY Coxon, W Mansoor, S Madhusudan, S Falk,

GW Middleton, D Swinson, I Chau, J Thompson, D Cunningham, P Kareclas, JA Dunn, HER Ford

On behalf of COUGAR 02 investigators and NCRI Upper GI Clinical Studies Group

Trial funded by Cancer Research UK grant CRUK/07/013

EudraCT Number: 2006-005046-37ISRCTN 13366390

Second Line Therapy of Advanced Gastric Cancer

• N=40 compared IRI to BSC1

– PS 0-2– OS 4 vs. 2.4 m [HR 0.48, p=.012]1

• Phase III of 2nd line chemo (N=133)vs. BSC (N=69)2

– PS 0-1– OS 5.3 vs. 3.8 m [HR 0.67, p=.007]– No difference between IRI and docetaxel

• GRANITE: 439 randomized to everolimus, 217 to placebo3

– Median OS everolimus 5.4 m vs 4.3 m [NS]

1. Thuss-Patience et al. Eu J Cancer 2011; 47:23062. Kang et al. J Clin Oncol 2012; 13:1513. 3. Van Cutsem et al. J Clin Oncol 30, 2012 (suppl 4; abstr LBA3)

Overall Survival: WJOGP

rob

abili

ty (

%)

(Months)

108111

8075

3629

1010

23

01

wPTXCPT-11

Number at risk

01

CPT-11

wPTX

n

111

108

Median

8.4M

9.5M

p

0.38

HR (95% CI)

1.13 (0.86-1.49)

Trial Design

Adenocarcinoma of esophagus,

esophagus-gastric junction or

stomach refractory to platinum and fluoropyrimide

Arm A (n=84): Docetaxel 75mg/m2 IV every 3

weeks for up to 6 cycles+ ASC

Arm B (n=84): Active symptom control

May include: Radiotherapy, analgesia, anti-emetics,

steroids

Assess every 3 weeks for 18 weeks, then

every 6 weeks

RANDOMISE1:1

n=168

Stratified by:

1.Disease status (Locally advanced vs metastatic); 2. Site of disease (Esophagus vs GEJ vs Stomach); 3. Time to progression after previous chemotherapy ( 0 vs 0-3 vs 3-6 months); 4. ECOG PS ( 0/1 vs 2)

0

25

50

75

100

0 2 4 6 8 10 12 14 16 18

Perc

enta

ge s

urvi

ving

Months from randomisation

DocetaxelASC

No. at Risk:Docetaxel 84 69 53 33 25 17 10 8 5 4 ASC 84 70 38 19 13 9 6 2 1 1

Overall survivalMedian survival: 5.2 months (95% CI 4.1-5.9) for Docetaxel 3.6 months (95% CI 3.3-4.4) for ASC

Hazard ratio 0.67 (95% CI 0.49-0.92), p=0.01

Conclusions

• Second line therapy extends survival in advanced gastric cancer and is an appropriate standard of care

• Docetaxel is an appropriate choice, although toxic in this population

• Patient selection based on performance status and peritoneal carcinomatosis may be useful in identifying group of patients in whom this strategy will also be clinically meaningful

• Future studies may identify biomarkers to aid selection between taxanes and irinotecan