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 medianmonths

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, bidDay 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, bidDay 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

Cum

ulat

ive

surv

ival

pr

obab

ility

0 5 10 15 20 25 30 35 40 45Time since randomization (months)

PEP CapeOx+LN=249

CapeOx+PN=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 36wksPTX 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: WJOGPr

obab

ility

(%)

(Months)

108111

8075

3629

1010

23

01

wPTXCPT-11

Number at risk01

CPT-11wPTX

n

111108

Median

8.4M9.5M

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 su

rviv

ing

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