JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Author affiliations appear at the end of this

article.

Published online ahead of print at

www.jco.org on November 30, 2015.

Supported by GlaxoSmithKline as clinical

collaboration with Translational Research

in Oncology (TRIO). Lapatinib (Tykerb/

Tyverb) is an asset of Novartis Pharma AG

as of March 2, 2015. TRIO provided

statistical analyses and translational

studies, and Fishawack Indicia, Ltd

provided editorial assistance, funded by

GlaxoSmithKline and Novartis Pharma

AG.

Terms in blue are defined in the glossary,

found at the end of this article and online

at www.jco.org.

Authors’ disclosures of potential conflicts

of interest are found in the article online at

www.jco.org. Author contributions are

found at the end of this article.

Clinical trial information: NCT00680901.

Corresponding author: J. Randolph Hecht,

MD, David Geffen School of Medicine at

UCLA, 2825 Santa Monica Blvd, Santa

Monica, CA 90404; e-mail: jrhecht@

mednet.ucla.edu.

© 2015 by American Society of Clinical

Oncology

0732-183X/16/3405w-443w/$20.00

DOI: 10.1200/JCO.2015.62.6598

Lapatinib in Combination With Capecitabine PlusOxaliplatin in Human Epidermal Growth Factor Receptor2–Positive Advanced or Metastatic Gastric, Esophageal, orGastroesophageal Adenocarcinoma: TRIO-013/LOGiC—A Randomized Phase III TrialJ. Randolph Hecht, Yung-Jue Bang, Shukui K. Qin, Hyun C. Chung, Jianming M. Xu, Joon O. Park,Krzysztof Jeziorski, Yaroslav Shparyk, Paulo M. Hoff, Alberto Sobrero, Pamela Salman, Jin Li,Svetlana A. Protsenko, Zev A. Wainberg, Marc Buyse, Karen Afenjar, Vincent Houe, Agathe Garcia,Tomomi Kaneko, Yingjie Huang, Saba Khan-Wasti, Sergio Santillana, Michael F. Press, and Dennis Slamon

See accompanying editorial on page 401

A B S T R A C T

PurposeTo evaluate the efficacy of adding lapatinib to capecitabine and oxaliplatin (CapeOx) in patients withpreviously untreated human epidermal growth factor receptor 2 (HER2) –amplified advancedgastroesophageal adenocarcinoma.

Patients and MethodsPatients with HER2-positive advanced gastroesophageal adenocarcinoma were randomly assignedat a one-to-one ratio to CapeOx plus lapatinib 1,250mg or placebo daily. Primary end point was overallsurvival (OS) in patients with centrally confirmedHER2 amplification in the primary efficacy population.

ResultsA total of 545 patients were randomly assigned, and 487 patients comprised the primary efficacypopulation. Median OS in the lapatinib and placebo arms was 12.2 (95% CI, 10.6 to 14.2) and10.5 months (95% CI, 9.0 to 11.3), respectively, which was not significantly different (hazard ratio,0.91; 95% CI, 0.73 to 1.12). Median progression-free survival in the lapatinib and placebo arms was6.0 (95%CI, 5.6 to 7.0) and 5.4 months (95%CI, 4.4 to 5.7), respectively (hazard ratio, 0.82; 95%CI,0.68 to 1.00; P = .0381). Response rate was significantly higher in the lapatinib arm: 53% (95% CI,46.4 to 58.8) compared with 39% (95% CI, 32.9 to 45.3) in the placebo arm (P = .0031). Preplannedexploratory subgroup analyses showed OS in the lapatinib arm was prolonged in Asian and youngerpatients. No correlation was observed between HER2 immunohistochemistry status and survival.There were increased toxicities in the lapatinib arm, particularly diarrhea.

ConclusionAddition of lapatinib to CapeOx did not increase OS in patients with HER2-amplified gastro-esophageal adenocarcinoma. There were clear differences in the effect of lapatinib depending onregion and age. Future studies could examine this correlation.

J Clin Oncol 34:443-451. © 2015 by American Society of Clinical Oncology

INTRODUCTION

Gastric cancer is the third most common cause ofcancer-related death worldwide.1 There is nostandard first-line chemotherapy for this disease,but current treatment options include a combi-nation of a fluoropyrimidine and platin, such ascisplatin or oxaliplatin.2 Despite advances in cyto-toxic therapies, survival for patients with metastatic

disease remains poor, with few patients remainingalive 2 years after initiation of treatment.3-5

Human epidermal growth factor receptor 2(HER2) is associated with approximately 20% of

gastroesophageal adenocarcinomas,6,7 and targetedinhibition of HER2 has been shown to significantlyimprove outcomes in patients with breast canceroverexpressing or amplifying HER2.8,9 Lapatinib isa small-molecule tyrosine kinase inhibitor of

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epidermal growth factor receptor and HER2, approved for thetreatment of HER2-positive breast cancer.10 In vitro and in vivostudies with lapatinib in HER2-amplified upper GI cell lines havedemonstrated significant antitumor effects.11

A 9% response rate was seen with lapatinib monotherapy inpatients with gastroesophageal adenocarcinoma.12 At the outset ofthis study, no anti-HER2 agent had demonstrated improvedsurvival in this disease. Therefore, the TRIO-013 (TranslationalResearch in Oncology)/LOGiC (Lapatinib Optimization Study inthe HER2-Positive Gastric Cancer) trial was conducted to assessthe clinical benefit and safety of adding lapatinib to capecitabineand oxaliplatin (CapeOx) as first-line chemotherapy.

PATIENTS AND METHODS

Study Design and TreatmentTRIO-013/LOGiC was a multicenter, double-blind, randomized

phase III study conducted at 186 centers in 22 countries in Asia, Europe,North America, and South America. The study was conducted inaccordance with the current ethical principles outlined in the Declarationof Helsinki and Good Clinical Practice (GCP) guidelines.13,14 Writteninformed consent was obtained from each patient before the performanceof any study-specific procedures. When deviations from GCP weredetected, corrective and preventative actions were implemented, and theappropriate regulatory authorities and ethics committees were notified.

Patients were randomly assigned at a one-to-one ratio to CapeOx(capecitabine 1,700 mg/m2 and oxaliplatin 130 mg/m2) plus lapatinib1,250 mg (lapatinib arm) or to CapeOx plus placebo (placebo arm).Treatment was administered in 21-day cycles, consisting of intravenousoxaliplatin on day 1 (for up to eight cycles) and oral capecitabine in twodaily doses (morning and evening) from day 1 to 14. Oral lapatinib orplacebo were administered continuously and treated until progressivedisease, unacceptable toxicity, or withdrawal; safety and disease assess-ments were performed throughout the study. If any study drugs werestopped, patients could continue receiving the remaining drugs. Randomassignment was performed centrally and stratified by prior adjuvant and/or

neoadjuvant chemotherapy (yes v no) and by geographic region (NorthAmerica, Asia, or rest of world [ROW]).

PatientsEligible patients were age$ 18 years and had histologically confirmed

unresectable adenocarcinoma of the stomach, esophagus, or gastro-esophageal junction with radiologically evaluable disease according toRECIST,15 Eastern Cooperative Oncology Group performance status # 2,and adequate organ function. No prior palliative chemotherapy wasallowed, and prior treatment with oxaliplatin-based neoadjuvant oradjuvant chemotherapy could not have been completed , 12 monthsbefore study entry. Tumors had to have HER2 amplification by fluo-rescence in situ hybridization (FISH) assessed by local or designated centrallaboratory. If unavailable, immunohistochemistry (IHC; 3+) or HER2amplification by chromogenic or silver in situ hybridization was permitted.The Appendix (online only) provides full inclusion and exclusion criteria.

End Points and AssessmentsThe primary end point was overall survival (OS), defined as the time

from random assignment until death resulting from any cause. Previousanalyses of studies with lapatinib in patients with breast cancer showedbenefit only in patients with HER2 amplification, regardless of IHCstatus.16 Therefore, efficacy analyses were performed in the primaryefficacy population (PEP), consisting of patients with disease confirmedforHER2 amplification as determined by FISH in the central laboratories(Appendix).

Secondary end points included progression-free survival (PFS),defined as the time from random assignment until the earliest date ofdisease progression or death resulting from any cause; best overall responserate, defined as the percentage of patients experiencing a confirmedcomplete response or partial response; duration of response (DoR); qualityof life (QoL); and safety assessments (including drug exposure). Earlydeaths (ie, death , 30 days after first dose of study drug) were assessed inthe safety population as post hoc analyses. Preplanned exploratory efficacyanalyses included subgroup analysis of OS based on geographic region(Asia, North America, or ROW), prior adjuvant use, age, baseline EasternCooperative Oncology Group status, primary disease site, histologic cancertype, whether pylorus was intact, and HER2 FISH or IHC status.

Assessed for eligibility(N = 4,674)

Randomly assignedto ITT population

(n = 545)

Assigned to receive CapeOxplus lapatinib 1,250 mg

(n = 272; 100%)

Assigned to receive CapeOx plus placebo(n = 273; 100%)

Included in the primary efficacy population(n = 249; 92%)

Included in the primary efficacy population(n = 238; 87%)

)%27;081=n(detelpmoC)%5;21=n(werdhtiW

Lost to follow-up (n = 8; 3%) Decided to withdraw (n = 4; 2%)

)%32;75=n(gniognO

)%17;071=n(detelpmoC)%8;91=n(werdhtiW

Lost to follow-up (n = 7; 3%) Decided to withdraw (n = 11; 5%) Due to investigator decision (n = 1; < 1%)

)%12;94=n(gniognO

HER2 eligible for testing Central (n = 212; 39%) Local (n = 333; 61%)HER2 eligible but (n = 14; 3%) failed at least one entry criteria

Fig 1. CONSORT diagram. CapeOx,capecitabine and oxaliplatin; HER2, humanepidermal growth factor receptor 2; ITT,intent to treat.

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Treatment responses were evaluated by the investigator using RECIST(version 1.0).15 Severity of adverse events (AEs) was graded according toNational Cancer Institute Common Terminology Criteria for Adverse Events(version 3.0).17 Change in health-related QoL was also assessed usingpatient questionnaires. An independent data safety monitoring committeeregularly reviewed study data for safety and efficacy.

Sample Size and Statistical AnalysisInitially, the planned sample size was 410 patients, with PFS as the

primary end point. After the ToGA (Trastuzumab for Gastric Cancer) trialresults were released, the primary end point was changed to OS, and thestudy was powered to test the hypothesis that addition of lapatinib to CapeOxwould improve median OS from 11.1 to 13.1 months (hazard ratio [HR],0.74).18 To ensure 80%power for a two-sided log-rank test at ana of 0.05, 337events were necessary. On the basis of these assumptions, 454 patients wererequired in the PEP. Assuming discordance between local and central FISHtesting of approximately 15%, a sample size of 535 patients was planned.

OS and PFS were compared between the two treatment arms using atwo-sided stratified log-rank test, stratifying for prior adjuvant or neo-adjuvant chemotherapy and region. Kaplan-Meier estimates were calcu-lated for median OS, PFS, and DoR (Appendix). A sensitivity analysis wasperformed for PFS, with censoring of the patients who were switched tononprotocol therapies before disease progression. Additional sensitivityanalyses to assess OS, PFS, and safety were conducted after significantdeviations from GCP at three study sites in Poland; these analyses excluded atotal of 27 patients (lapatinib arm, n = 13; placebo arm, n = 14) from the PEP.

RESULTS

PatientsA total of 545 patients were randomly assigned between June

2008 and January 2012 and comprised the intent-to-treat (ITT)population. The PEP included all randomly assigned patients withcentrally confirmed HER2-positive status (lapatinib arm, n = 249;placebo arm, n = 238). There were 537 patients in the safetypopulation (lapatinib arm, n = 270; placebo arm, n = 267). Patientflow is summarized in Figure 1.

Patient demographic and baseline characteristics in the PEPwere similar between treatment arms (Table 1). In the lapatiniband placebo arms, respectively, 7% and 8% of patients had receivedprior adjuvant or neoadjuvant treatment, 40% and 39% patientswere from Asia (majority from China or South Korea), and 57%(both treatment arms) were from the ROW (excluding NorthAmerica). There were no major differences in baseline charac-teristics between the PEP and ITT population (data not shown).

Overall, 5% and 8% patients received trastuzumab as follow-up therapy (Asia, 9% and 12%; ROW, 1% and 4%) in the lapatiniband placebo arms, respectively. A majority of Asian patientsreceiving post-study trastuzumab were South Korean.

EfficacyThe cutoff date for primary efficacy analysis was September 24,

2012, after 350 deaths had occurred. Median follow-up was23 months. The primary end point (ie, median OS in PEP) was12.2 months (95% CI, 10.6 to 14.2) in the lapatinib arm and10.5 months (95% CI, 9.0 to 11.3) in the placebo arm (Fig 2A), whichwas not statistically significant (HR, 0.91; 95% CI, 0.73 to 1.12; P =.3492). ITT analysis of OS was consistent with the results in the PEP,with anHRof 0.91 (95%CI, 0.74 to 1.10;P= .3244). SimilarOS valueswere observed in the sensitivity analyses after excluding 27 patientsfrom three sites with significant protocol deviations (HR, 0.90; 95%

CI, 0.73 to 1.12; P = .3252). Because the trial missed its primary endpoint of OS, all other analyses are reported with a descriptive intent.

A significant difference between the lapatinib and placeboarms was observed for PFS in the PEP (HR, 0.82; 95% CI, 0.68to 1.00; P = .0381). Median PFS values were 6.0 months (95%CI, 5.6 to 7.0) in the lapatinib arm and 5.4 months (95% CI, 4.4to 5.7) in the placebo arm (Fig 2B). Similar PFS values wereobserved in the sensitivity analyses (HR, 0.82; 95% CI, 0.67 to1.00; P = .0381). In the sensitivity analysis with censoring atthe time a patient received nonprotocol therapy, median PFSvalues in the lapatinib and placebo arms were 6.0 (95% CI,5.6 to 6.9) and 5.3 months (95% CI, 4.4 to 5.7), respectively;

Table 1. Patient Demographic and Baseline Clinical Characteristics at InitialDiagnosis (Primary Efficacy Population)

Characteristic

No. (%)

CapeOx PlusLapatinib(n = 249)

CapeOx PlusPlacebo(n = 238)

Age, yearsMedian 61.0 59.0Range 19-86 27-84

Male sex 189 (76) 176 (74)HER2 IHC status0 13 (5) 14 (6)1+ 34 (14) 20 (8)2+ 58 (23) 50 (21)3+ 143 (57) 154 (65)Unknown 1 (, 1) 0

ECOG performance status0 79 (32) 63 (26)1 149 (60) 153 (64)2 21 (8) 22 (9)

Pylorus intactYes 193 (78) 180 (76)No 56 (22) 58 (24)

Prior adjuvant or neoadjuvant treatmentYes 18 (7) 20 (8)No 231 (93) 218 (92)

RegionNorth America 8 (3) 9 (4)Asia 100 (40) 93 (39)Rest of world 141 (57) 136 (57)

Primary siteEsophageal 12 (5) 8 (3)Gastric 214 (86) 210 (88)Gastroesophageal junction 23 (9) 20 (8)

Adenocarcinoma histology 249 (100) 238 (100)Gastric cancer typeDiffuse 9 (4) 10 (4)Intestinal 225 (90) 211 (89)Other 15 (6) 17 (7)

Extent of diseaseUnresectable locally advanced 10 (4) 10 (4)Metastatic 236 (95) 227 (95)Locally recurrent 3 (1) 1 (, 1)

No. of metastatic sites0 2 (, 1) 1 (, 1)1 77 (31) 65 (27)2 92 (37) 85 (36)$ 3 78 (31) 87 (37)

Abbreviations: CapeOx, capecitabine and oxaliplatin; ECOG, Eastern Cooper-ative Oncology Group; HER2, human epidermal growth factor receptor 2; IHC,immunohistochemistry.

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with such censoring, the difference was not statistically sig-nificant (HR, 0.84; 95% CI, 0.69 to 1.03; P = .0773).

A significant difference was observed in overall response ratebetween treatment arms: 53% (95% CI, 46.4 to 58.8) in the lapatinib

arm and 39% (95% CI, 32.9 to 45.3) in the placebo arm (P = .0031[Data Supplement]). Median DoR was 7.3 months (95% CI, 6.4to 8.5) in the lapatinib arm and 5.6 months (95% CI, 4.6 to 6.0) inthe placebo arm (Data Supplement). No significant difference was

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Time From Random Assignment (months)No. at riskCapeOx+L 249 199 133 83 47 24 9 3 3CapeOx+P 238 189 106 53 34 17 11 7 2 2

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Time From Random Assignment (months)No. at riskCapeOx+L 249 143 59 29 8 3 3 1 1CapeOx+P 238 119 32 18 10 6 5 3 1 1

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P+xOepaC L+xOepaC PEP (n = 249) (n = 238)Median (95% CI; mo) 12.2 (10.6 to 14.2) 10.5 (9.0 to 11.3)HR (95% CI) 0.91 (0.73 to 1.12)P 2943.

Without censoring CapeOx+L CapeOx+PPEP (n = 249) (n = 238)Median (95% CI; mo) 6.0 (5.6 to 7.0) 5.4 (4.4 to 5.7)HR (95% CI) 0.82 (0.68 to 1.00)P 1830.

With censoring CapeOx+L CapeOx+PPEP (n = 249) (n = 238)Median (95% CI; mo) 6.0 (5.6 to 6.9) 5.3 (4.4 to 5.7)HR (95% CI) 0.84 (0.69 to 1.03)P 3770.

Fig 2. (A) Overall and (B) progression-free survival in primary efficacy population. CapeOx, capecitabine and oxaliplatin; HR, hazard ratio; L, lapatinib; P, placebo; PEP,primary efficacy population.

Favors CapeOx+L Favors CapeOx+P

5430 1 2

)IC %59( oitar drazaH oitar drazaH n P

2943. )21.1 ot 37.0( 19.0 784 ycaciffe yramirP population

Region1620. )69.0 ot 84.0( 86.0 391 aisA 1563. )38.4 ot 35.0( 16.1 71 aciremA htroN 1877. )73.1 ot 97.0( 40.1 772 dlroW fo tseR

Prior adjuvant use8492. )14.3 ot 86.0( 25.1 83 seY 0590. )40.1 ot 76.0( 38.0 944 oN

Age, years1410. )49.0 ot 15.0( 96.0 632 06 <

≥ 3295. )54.1 ot 18.0( 80.1 152 06

Baseline ECOG status9542. )01.1 ot 07.0( 88.0 444 1-0 8773. )44.1 ot 14.0( 67.0 34 2

Primary site0277. )53.2 ot 23.0( 78.0 02 sugahposE 9867. )58.1 ot 44.0( 09.0 34 noitcnuJ EG 4203. )11.1 ot 17.0( 98.0 424 cirtsaG

Histological type1003. )56.1 ot 52.0( 46.0 91 esuffiD 5845. )71.1 ot 57.0( 39.0 634 lanitsetnI 2751. )92.1 ot 62.0( 85.0 23 rehtO

Pylorus intact3450. )10.1 ot 36.0( 08.0 373 seY 4497. )86.1 ot 76.0( 60.1 411 oN

HER2 status (all FISH+)7461. )13.1 ot 42.0( 65.0 72 0 CHI 0946. )02.2 ot 16.0( 61.1 45 +1 CHI 3113. )52.1 ot 05.0( 97.0 801 +2 CHI 3064. )81.1 ot 96.0( 09.0 792 +3 CHI 2807. )15.1 ot 55.0( 19.0 18 +1–0 CHI 5012. )90.1 ot 86.0( 68.0 504 +3–2 CHI

Fig 3. Forest plot for overall survival:subgroup analysis. CapeOx, capecitabineand oxaliplatin; ECOG, Eastern Coopera-tive Oncology Group; FISH, fluorescencein situ hybridization; GE, gastro-esophageal; HER2, human epidermalgrowth factor receptor 2; IHC, immuno-histochemistry; L, lapatinib; P, placebo.

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observed between the lapatinib and placebo arms in health-related QoL (Appendix).

Preplanned exploratory analyses included OS by geographicregion and age. In the Asian subgroup, median OS was16.5 months (95% CI, 13.3 to 20.2) in the lapatinib arm and10.9 months (95% CI, 9.0 to 14.9) in the placebo arm (HR, 0.68;95% CI, 0.48 to 0.96; P = .0261; Figs 3 and 4). In the ROWsubgroup, however, median OS was 10.0 months (95% CI, 8.0 to12.0) in the lapatinib arm and 9.1 months (95% CI, 8.3 to 10.9) inthe placebo arm (HR, 1.04; 95% CI, 0.79 to 1.37; P = .7781; Figs 3and 4A). In patients age , 60 years, median OS was 12.9 months(95% CI, 11.1 to 16.0) in the lapatinib arm and 9.0 months (95%CI, 7.8 to 11.3) in the placebo arm (HR, 0.69; 95% CI, 0.51 to 0.94;P = .0141; Figs 3 and 4B). In patients age $ 60 years, median OSwas 11.3 months (95% CI, 8.4 to 13.8) in the lapatinib arm and10.9 months (95% CI, 9.6 to 14.1) in the placebo arm (HR, 1.08;95% CI, 0.81 to 1.45; P = .5923; Figs 3 and 4B).

Post hoc analysis of the OS data by region and age showed thatpatients age, and$ 60 years from Asia had HRs of 0.60 (95% CI,0.38 to 0.94) and 0.80 (95% CI, 0.47 to 1.36), respectively. Outsideof Asia, patients age, 60 years had an HR of 0.74 (95% CI, 0.49 to

1.11), whereas those age $ 60 years had an HR of 1.32 (95% CI,0.91 to 1.90; Fig 5 [results of similar analyses for North Americanpatients are shown in the Data Supplement]).

Multivariable Cox regression analysis of PFS and OS revealedstatistically significant effects of region (favoring Asian patients),age (favoring younger patients), pylorus status (favoring pylorusintact), histology (favoring nondiffuse histology), and treatment(favoring lapatinib), as well as an interaction between age and treat-ment (larger effect of lapatinib in younger patients [Data Supple-ment]). In thesemultivariable analyses, the effect of lapatinib treatmenton PFS had anHR of 0.176 (95%CI, 0.062 to 0.495; P= .0010) and onOS had an HR of 0.304 (95% CI, 0.099 to 0.936; P = .0379).

No correlation was observed between IHC status and OSbenefit from lapatinib in this FISH-positive population. OS HR forIHC 0 to 1+ was 0.91 (95%CI, 0.55 to 1.51; P = .7082) and for IHC2 to 3+ was 0.86 (95% CI, 0.68 to 1.09; P = .2105; Fig 3).

SafetyIn the lapatinib arm, 255 patients (94%) experienced AEs, and

72 patients (27%) experienced serious AEs, comparedwith 236 (88%)

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Time From Random Assignment (months)No. at riskCapeOx+L 100 93 70 49 25 16 7 3 3CapeOx+P 93 77 47 28 19 11 7 5 1 1

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Time From Random Assignment (months)No. at riskCapeOx+L 141 101 59 30 19 6 2CapeOx+P 136 104 53 21 12 4 2 1

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P+xOepaC L+xOepaC )832 = n( )942 = n(

Median (95% CI; mo) 16.5 (13.3 to 20.2) 10.9 (9.0 to 14.9)HR (95% CI) 0.68 (0.48 to 0.96)P 1620.

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Time From Random Assignment (months)No. at riskCapeOx+L 113 102 85 53 38 20 11 5 3 2 2CapeOx+P 123 96 61 32 17 13 7 3 1 1 1 1

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Time From Random Assignment (months)No. at riskCapeOx+L 136 108 78 59 35 21 16 9 4 1 1CapeOx+P 115 100 75 42 31 21 13 10 8 4 1 1

124 8 20 28 4840 4416 24 3632

P+xOepaC L+xOepaC )321 = n( )311 = n(

Median (95% CI; mo) 12.9 (11.1 to 16.0) 9.0 (7.8 to 11.3)HR (95% CI) 0.69 (0.51 to 0.94)P 1410.

P+xOepaC L+xOepaC )832 = n( )942 = n(

Median (95% CI; mo) 10.0 (8.0 to 12.0) 9.1 (8.3 to 10.9)HR (95% CI) 1.04 (0.79 to 1.37)P 1877.

P+xOepaC L+xOepaC )511 = n( )631 = n(

Median (95% CI; mo) 11.3 (8.4 to 13.8) 10.9 (9.6 to 14.1)HR (95% CI) 1.08 (0.81 to 1.45)P 3295.

0 124 8 20 28 4840 4416 24 3632

Fig 4. Overall survival in primary efficacy population by (A) region (left, Asia; right, rest of world) and (B) age (left,, 60 years; right,$ 60 years). CapeOx, capecitabine andoxaliplatin; HR, hazard ratio; L, lapatinib; P, placebo.

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and 52 patients (19%) experiencing AEs and serious AEs, respectively,in the placebo arm (Table 2). Fifty-seven patients (21%) experiencedan AE leading to study drug discontinuation in the lapatinib arm,compared with 50 (19%) in the placebo arm (Table 2). Overallincidence of AEs observed in the sensitivity analyses was similar.

The most common AEs in both arms were diarrhea, nausea,vomiting, and decreased appetite (Table 2). A majority of these AEswere grade 1 to 2 in severity. More patients experienced grade 1 to 2and grade$ 3 AEs in the lapatinib arm. Diarrhea, in particular, wasincreased, with overall diarrhea experienced in 58% of patients inthe lapatinib arm, compared with 29% of patients in the placeboarm. Grade$ 3 diarrhea was experienced by 12% of patients in thelapatinib arm and 3% in the placebo arm (Table 2).

Fifteen patients (6%) experienced fatal serious AEs in thelapatinib arm (Table 2), four of which were attributed to studytreatment, whereas nine (3%) experienced serious AEs in theplacebo arm, one of which was attributed to study treatment(Appendix). Post hoc analysis seemed to show numeric differencesin early deaths (, 30 days) between the lapatinib and placebo armsin patients in the ROW (12% v 5%), particularly in patients age$60 years (7% v 1% [Data Supplement]). Relative drug exposure was

slightly lower in the lapatinib arm but was similar overall betweentreatments (Data Supplement).

DISCUSSION

Both lapatinib- and trastuzumab-based regimens improve out-comes in patients with HER2-positive breast cancer. Preclinical andearly clinical studies also showed lapatinib to have activity in upperGI cancers with HER2 amplification.11 Although the addition ofthe anti-HER2 antibody trastuzumab to cisplatin-based therapy inthe ToGA trial resulted in a significant improvement in OS,18

adding lapatinib to CapeOx in the first-line treatment of patientswith advanced gastroesophageal adenocarcinoma in our study didnot significantly improve OS, and a higher incidence of AEs wasobserved in the lapatinib arm. However, lapatinib treatment wasnot without effect, and preplanned subgroup and additional posthoc multivariable analyses revealed striking differences in out-comes in some populations, especially patients from Asia andyounger patients (age , 60 years).

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Time From Random Assignment (months)No. at riskCapeOx+L 53 50 39 28 11 6 3 2 2CapeOx+P 54 43 24 13 8 5 1 1 1

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0

Time From Random Assignment (months)No. at riskCapeOx+L 47 43 31 21 14 10 4 1 1CapeOx+P 39 34 23 15 11 6 6 4

105 20 30 454015 25 35

0 105 20 30 454015 25 35

P+xOepaC L+xOepaC PEP (n = 53) (n = 54)Median (95% CI; mo) 15.7 (11.9 to 19.4) 10.5 (7.8 to 12.6)HR (95% CI) 0.60 (0.38 to 0.94)

Cum

ulat

ive

Surv

ival

(pro

babi

lity)

1.0

0.8

0.6

0.4

0.2

B

Time From Random Assignment (months)No. at riskCapeOx+L 57 45 30 16 9 4 1CapeOx+P 68 47 22 7 4 1

Cum

ulat

ive

Surv

ival

(pro

babi

lity)

1.0

0.8

0.6

0.4

0.2

Time From Random Assignment (months)No. at riskCapeOx+L 84 56 29 14 10 2 1CapeOx+P 68 57 31 14 8 3 2 1

P+xOepaC L+xOepaC )86 = n( )75 = n(

Median (95% CI; mo) 11.2 (9.7 to 15.6) 8.4 (7.4 to 11.3)HR (95% CI) 0.74 (0.49 to 1.11)

P+xOepaC L+xOepaC PEP (n = 47) (n = 39)Median (95% CI; mo) 19.7 (13.8 to 26.0) 11.1 (9.4 to 20.9)HR (95% CI) 0.80 (0.47 to 1.36)

P+xOepaC L+xOepaC )86 = n( )48 = n(

Median (95% CI; mo) 8.2 (6.6 to 11.3) 10.4 (8.5 to 11.9)HR (95% CI) 1.32 (0.91 to 1.90)

0 155 10 25 3520 30

Fig 5. Overall survival by region, stratified by age (left,, 60 years; right,$ 60 years): (A) Asia and (B) rest of world. CapeOx, capecitabine and oxaliplatin; HR, hazard ratio;L, lapatinib; P, placebo; PEP, primary efficacy population.

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There are several possible explanations for these results.Trastuzumab may have superior efficacy against HER2-positivecancers compared with lapatinib. Although the addition of lapa-tinib to capecitabine in patients with HER2-positive breast cancer,for whom trastuzumab-containing therapy had failed, was shownto improve survival,9 a recent breast cancer study showed lapatinib tobe inferior to trastuzumab in combination with chemotherapy in themetastatic setting.19 There also may be biologic differences betweenHER2-positive breast and gastroesophageal cancers. Even withtrastuzumab treatment, patients with HER2-positive gastric cancerhave a relatively short survival, with few patients living . 3 years.18

Lapatinib and trastuzumab have distinct toxicity profiles, andthe addition of lapatinib to chemotherapy in the TRIO-013/LOGiCtrial increased some specific toxicities, particularly diarrhea, whichwas not experienced frequently with the addition of trastuzumab.Patients with gastroesophageal cancer may be less able to tolerateGI toxicities than patients with breast cancer, leading to decreasedefficacy or reduced patient compliance.

Despite the advantages of patient convenience with oralagents, concerns exist about absorption of such agents. Feedingalone has been shown to significantly change lapatinib absorp-tion.20 Twenty-three percent of patients had their pylorus removedin this study, which could have affected emptying, and in thissubgroup, there was no benefit in terms of OS (HR, 1.06; 95% CI,0.67 to 1.68), as opposed to patients with an intact pylorus (HR,0.80; 95% CI, 0.63 to 1.01). No pharmacokinetics were per-formed in this trial, but in the recently published second-linephase III TyTan (Tykerb With Taxol in Asian HER2-PositiveGastric Cancer) trial of paclitaxel with or without lapatinib, ina small subset of patients, those with an intact pylorus had higherplasma levels of lapatinib.21

There was also significant variability of effect of lapatinib andpatient location. In the 40% of patients from Asia, a clear benefitwas observed in OS with the addition of lapatinib (HR, 0.68; 95%CI, 0.48 to 0.96), which was not seen in other patients (Fig 3). This

difference between Asian and non-Asian patients was not observedin the ToGA trial, in which Asian patients had an HR of 0.82 (95%CI, 0.61 to 1.11), which was similar to the overall improvement(HR, 0.74; 95% CI, 0.60 to 0.91) and less than the improvementseen in Latin American and European patients.18 The TyTan trial,conducted only in Asian patients, showed a trend toward improvedsurvival with the addition of lapatinib (especially in non-JapaneseAsians) but did not reach statistical significance.21 Other trials withbiologic agents, such as the AVAGAST (Avastin in Gastric Cancer)trial with bevacizumab, have also found differences between Asianand non-Asian patients, although in these cases, Asian patients didnot benefit from the targeted therapy.4

Gastric cancers in Asian populations differ from those in theWest and, in some populations (including Chinese and Japanesepatients), are more likely to occur in younger patients, be moredistal, and have intestinal histology.22 There may be additionalmolecular differences, with recent studies showing lack of corre-lation between Lauren histologic classification and genetic alter-ations and the presence of multiple molecular subtypes.23 Otherpotential differences between Asian and non-Asian patients mayinclude body mass, more frequent use of second- or third-linetherapy, surgery type, toxicity tolerance, and physicians’ experiencewith patients with gastric cancer.

Another observation was the difference in the effect oflapatinib between older and younger patients. In lapatinib-treated patients age , 60 years, there was a significantimprovement in OS (HR, 0.69; 95% CI, 0.51 to 0.94), which wasnot seen in older patients (HR, 1.08; 95% CI, 0.81 to 1.45). In apost hoc subgroup analysis, both younger and older Asian patientsbenefited, whereas there was a major difference in outcome betweenolder and younger non-Asian patients. Possible explanations for thisinclude differing biology between older and younger patients andtolerance of toxicities. However, a different effect onOSwith age wasobserved in the ToGA trial (age, 60 years: HR, 0.84; 95%CI, 0.62 to1.14; age $ 60 years: HR, 0.66; 95% CI, 0.49 to 0.88),18 with older

Table 2. AEs (Safety Population)

AE Summary

No. (%)

CapeOx Plus Lapatinib (n = 270) CapeOx Plus Placebo (n = 267)

Any on-treatment AE 255 (94) 236 (88)Any serious AE 72 (27) 52 (19)AE leading to study drug discontinuation 57 (21) 50 (19)Fatal serious AE 15 (6) 9 (3)

AE by MaximumGrade*

No. (%)

Any Grade Grade 3 Grade 4 Grade 5 Any Grade Grade 3 Grade 4 Grade 5

Diarrhea 156 (58) 32 (12) 1 (, 1) 2 (, 1) 77 (29) 9 (3) 0 0Nausea 132 (49) 15 (6) 0 0 114 (43) 6 (2) 0 0Vomiting 118 (44) 17 (6) 0 1 (, 1) 96 (36) 12 (4) 0 0Decreased appetite 111 (41) 12 (4) 1 (, 1) 0 86 (32) 7 (3) 0 0Fatigue 64 (24) 13 (5) 1 (, 1) 0 57 (21) 10 (4) 1 (, 1) 0Peripheral neuropathy 51 (19) 2 (, 1) 0 0 54 (20) 5 (2) 0 0Asthenia 47 (17) 10 (4) 0 0 38 (14) 16 (6) 0 0Neutropenia 12 (4) 6 (2) 3 (1) 0 3 (1) 1 (, 1) 0 0Dehydration 11 (4) 5 (2) 1 (, 1) 0 6 (2) 4 (1) 0 0Anemia 9 (3) 5 (2) 3 (1) 0 8 (3) 2 (, 1) 3 (1) 1 (, 1)Ascites 2 (, 1) 0 0 0 6 (2) 5 (2) 0 0

Abbreviations: AE, adverse event; CapeOx, capecitabine and oxaliplatin.*$ 2% in either treatment arm.

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patients (age . 60 years) experiencing an improved OS comparedwith younger patients after treatment with lapatinib.

The use of lapatinib in combination with CapeOx in patientswith HER2-positive gastric cancer cannot be recommended.Future research may identify a subgroup of patients who benefitfrom such treatment, although there are several new anti-HER2agents, such as pertuzumab and ado-trastuzumab, that are beingtested in HER2-positive gastric cancer. Recently published CancerGenome Atlas data revealed additional molecular subgroups in apopulation ofWestern and Asian gastric cancers.24 In breast cancer,lapatinib in combination with trastuzumab has activity superior tothat of either single agent, which was also seen in preclinical gastriccancer models and may be worth examining in the future.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Disclosures provided by the authors are available with this article atwww.jco.org.

AUTHOR CONTRIBUTIONS

Conception and design: J. Randolph Hecht, Yung-Jue Bang, Paulo M.Hoff, Alberto Sobrero, Jin Li, Marc Buyse, Tomomi Kaneko, Michael F.Press, Dennis SlamonFinancial support: Dennis SlamonAdministrative support: Dennis SlamonProvision of study materials or patients: J. Randolph Hecht, Yung-JueBang, Yaroslav Shparyk, Paulo M. Hoff, Alberto SobreroCollection and assembly of data: J. Randolph Hecht, Yung-Jue Bang,Shukui K. Qin, Hyun C. Chung, Jianming M. Xu, Joon O. Park, KrzysztofJeziorski, Yaroslav Shparyk, Paulo M. Hoff, Pamela Salman, Jin Li, SvetlanaA. Protsenko, Karen Afenjar, Agathe Garcia, Tomomi Kaneko, YingjieHuang, Sergio Santillana, Michael F. PressData analysis and interpretation: J. Randolph Hecht, Yung-Jue Bang,Shukui K. Qin, Hyun C. Chung, Jianming M. Xu, Alberto Sobrero, Zev A.Wainberg, Marc Buyse, Karen Afenjar, Vincent Houe, Tomomi Kaneko,Yingjie Huang, Saba Khan-Wasti, Sergio Santillana, Michael F. Press,Dennis SlamonManuscript writing: All authorsFinal approval of manuscript: All authors

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1. Ferlay J, Soerjomataram I, Dikshit R, et al:Cancer incidence and mortality worldwide: Sources,methods andmajor patterns in GLOBOCAN 2012. IntJ Cancer 136:E359-E386, 2015

2. Wagner AD, Unverzagt S, Grothe W, et al:Chemotherapy for advanced gastric cancer. CochraneDatabase of Syst Rev 3:CD004064, 2010

3. Van Cutsem E, Moiseyenko VM, Tjulandin S,et al: Phase III study of docetaxel and cisplatin plusfluorouracil compared with cisplatin and fluorouracilas first-line therapy for advanced gastric cancer: Areport of the V325 Study Group. J Clin Oncol 24:4991-4997, 2006

4. Ohtsu A, Shah MA, Van Cutsem E, et al:Bevacizumab in combination with chemotherapy asfirst-line therapy in advanced gastric cancer: Arandomized, double-blind, placebo-controlled phaseIII study. J Clin Oncol 29:3968-3976, 2011

5. Cunningham D, Okines AF, Ashley S: Cape-citabine and oxaliplatin for advanced esophagogastriccancer. N Engl J Med 362:858-859, 2010

6. Allgayer H, Babic R, Gruetzner KU, et al: C-erbB-2 is of independent prognostic relevance ingastric cancer and is associated with the expressionof tumor-associated protease systems. J Clin Oncol18:2201-2209, 2000

7. Deng N, Goh LK, Wang H, et al: A compre-hensive survey of genomic alterations in gastriccancer reveals systematic patterns of molecularexclusivity and co-occurrence among distinct ther-apeutic targets. Gut 61:673-684, 2012

8. Slamon DJ, Leyland-Jones B, Shak S, et al:Use of chemotherapy plus a monoclonal antibodyagainst HER2 for metastatic breast cancer thatoverexpresses HER2. N Engl J Med 344:783-792,2001

9. Geyer CE, Forster J, Lindquist D, et al: Lapa-tinib plus capecitabine for HER2-positive advancedbreast cancer. N Engl J Med 355:2733-2743, 2006

10. Zheng J, de Guia T, Wang-Jairaj J, et al: Effi-cacy and safety of fluticasone furoate/vilanterol (50/25 mcg; 100/25 mcg; 200/25 mcg) in Asian patientswith chronic obstructive pulmonary disease: Arandomised placebo-controlled trial. Curr Med ResOpin 31:1191-1200, 2015

11. Wainberg ZA, Anghel A, Desai AJ, et al:Lapatinib, a dual EGFR and HER2 kinase inhibitor,selectively inhibits HER2-amplified human gastriccancer cells and is synergistic with trastuzumabin vitro and in vivo. Clin Cancer Res 16:1509-1519,2010

12. Iqbal S, Goldman B, Fenoglio-Preiser CM, et al:Southwest Oncology Group study S0413: A phase IItrial of lapatinib (GW572016) as first-line therapy inpatients with advanced or metastatic gastric cancer.Ann Oncol 22:2610-2615, 2011

13. Wielders PL, Ludwig-Sengpiel A, Locantore N,et al: A new class of bronchodilator improves lungfunction in COPD: A trial with GSK961081. Eur RespirJ 42:972-981, 2013

14. Celli BR, MacNee W: Standards for the diag-nosis and treatment of patients with COPD: Asummary of the ATS/ERS position paper. Eur Respir J23:932-946, 2004

15. Therasse P, Arbuck SG, Eisenhauer EA, et al:New guidelines to evaluate the response to treatmentin solid tumors: European Organisation for Researchand Treatment of Cancer, National Cancer Institute ofthe United States, National Cancer Institute of Canada.J Natl Cancer Inst 92:205-216, 2000

16. Press MF, Finn RS, Cameron D, et al: HER-2gene amplification, HER-2 and epidermal growthfactor receptor mRNA and protein expression, andlapatinib efficacy in women with metastatic breastcancer. Clin Cancer Res 14:7861-7870, 2008

17. Common Terminology Criteria for Adverse Eventsv3.0 (CTCAE): http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf

18. Bang YJ, Van Cutsem E, Feyereislova A, et al:Trastuzumab in combination with chemotherapyversus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophagealjunction cancer (ToGA): A phase 3, open-label,randomised controlled trial. Lancet 376:687-697,2010

19. Gelmon KA, Boyle F, Kaufman B, et al: Open-label phase III randomized controlled trial comparingtaxane-based chemotherapy (Tax) with lapatinib (L) ortrastuzumab (T) as first-line therapy for women withHER2+metastatic breast cancer: Interim analysis (IA)of NCIC CTG MA.31/GSK EGF 108919. J Clin Oncol30, 2012 (suppl; abstr LBA671)

20. Koch KM, Reddy NJ, Cohen RB, et al:Effects of food on the relative bioavailability oflapatinib in cancer patients. J Clin Oncol 27:1191-1196, 2009

21. Satoh T, Rui-Hua X, Chung HC, et al: Lapa-tinib plus paclitaxel versus paclitaxel alone in thesecond-line treatment of HER2-amplified advancedgastric cancer in Asian populations: TyTAN, arandomized, phase III study. J Clin Oncol 32:2039-2049, 2014

22. Gill S, Shah A, Le N, et al: Asian ethnicity-related differences in gastric cancer presentation andoutcome among patients treated at a Canadiancancer center. J Clin Oncol 21:2070-2976, 2003

23. Tan IB, Ivanova T, Lim KH, et al: Intrinsicsubtypes of gastric cancer, based on gene expres-sion pattern, predict survival and respond differentlyto chemotherapy. Gastroenterology 141:476-485,485.e1-485.e11, 2011

24. Cancer Genome Atlas Research Network:Comprehensive molecular characterization of gastricadenocarcinoma. Nature 513:202-209, 2014

AffiliationsJ. Randolph Hecht, Zev A. Wainberg, and Dennis Slamon, David Geffen School of Medicine, University of California Los Angeles,

SantaMonica;Michael F. Press, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Yung-Jue Bang, SeoulNational University College of Medicine; Hyun C. Chung, Yonsei Cancer Center, Yonsei Cancer Research Institute, Yonsei University College ofMedicine; Joon O. Park, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Shukui K.

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Qin, People’s Liberation Army Cancer Center, Nanjing Bayi Hospital, Jiangsu; Jianming M. Xu, Affiliated Hospital of the MilitaryMedical Science Academy, Beijing; Jin Li, Cancer Hospital of Shanghai Fudan University, Shanghai, People’s Republic of China;Krzysztof Jeziorski, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Yaroslav Shparyk,Lviv State Regional Oncology Medical and Diagnostic Center, Lviv, Ukraine; Paulo M. Hoff, Sociedade Beneficente deSenhoras–Hospital Sirio Libanĕs, Sao Paolo, Brazil; Alberto Sobrero, Istituto di Ricovero e Cura a Carattere Scientifico SanMartino Istituto Scientifico Tumori, Genova, Italy; Pamela Salman, Fundacion Arturo Lopez Perez, Santiago, Chile; SvetlanaA. Protsenko, Petrov Research Institute of Oncology, St Petersburg, Russia; Marc Buyse, International Drug Development Institute,Leuven, Belgium; Karen Afenjar, Vincent Houe, and Agathe Garcia, Translational Research in Oncology, Paris, France; TomomiKaneko and Saba Khan-Wasti, GlaxoSmithKline, Brentford, United Kingdom; and Yingjie Huang and Sergio Santillana,GlaxoSmithKline, Philadelphia, PA.

n n n

GLOSSARY TERMS

HER2neu (human epidermal growth factor receptor 2):also called ErbB2. HER2neu belongs to the epidermal growth factorreceptor (EGFR) family and is overexpressed in several solid tumors. LikeEGFR, it is a tyrosine kinase receptor whose activation leads to pro-liferative signals within the cells. On activation, the human epidermalgrowth factor family of receptors are known to form homodimers andheterodimers, each with a distinct signaling activity. Because HER2 is thepreferred dimerization partner when heterodimers are formed, it is

important for signaling through ligands specific for any members of thefamily. It is typically overexpressed in several epithelial tumors.

lapatinib: a dual tyrosine kinase inhibitor. Lapatinib has beendeveloped as an inhibitor of the tyrosine kinase activities of ErbB1(EGFR) and ErbB2. Like other tyrosine kinase inhibitors, it competeswith ATP binding to the intracellular regions of the receptors that areactivated after tyrosine phosphorylation.

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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2–Positive Advanced or MetastaticGastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC— A Randomized Phase III Trial

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships areself-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For moreinformation about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.

J. Randolph HechtConsulting or Advisory Role: Amgen, Roche/GenentechResearch Funding: GlaxoSmithKline (Inst), Amgen (Inst), Pfizer (Inst),Immunomedics (Inst), Gilead Sciences (Inst), Celgene (Inst), OncoMed(Inst)

Yung-Jue BangConsulting or Advisory Role: GlaxoSmithKlineResearch Funding: GlaxoSmithKline (Inst)

Shukui K. QinNo relationship to disclose

Hyun C. ChungConsulting or Advisory Role: Celltrione, Eli Lilly, Taiho Pharmaceutical,MerckResearch Funding: Eli Lilly (Inst)

Jianming M. XuNo relationship to disclose

Joon O. ParkResearch Funding: GlaxoSmithKline

Krzysztof JeziorskiNo relationship to disclose

Yaroslav ShparykNo relationship to disclose

Paulo M. HoffHonoraria: AstraZeneca (I)Research Funding: GlaxoSmithKline, AstraZeneca, Roche

Alberto SobreroHonoraria: Amgen, Bayer, Merck Serono, Roche, Sanofi

Pamela SalmanNo relationship to disclose

Jin LiHonoraria: Roche, PfizerResearch Funding: Merck

Svetlana A. ProtsenkoNo relationship to disclose

Zev A. WainbergConsulting or Advisory Role: Taiho Pharmaceutical, SirtexSpeakers’ Bureau: GenentechResearch Funding: Novartis (Inst), Plexxikon (Inst), Pfizer (Inst),Biomarin (Inst)Travel, Accommodations, Expenses: Genentech, Eli Lilly

Marc BuyseEmployment: IDDIStock or Other Ownership: IDDI

Karen AfenjarTravel, Accommodations, Expenses: Roche

Vincent HoueNo relationship to disclose

Agathe GarciaNo relationship to disclose

Tomomi KanekoEmployment: GlaxoSmithKline, Novartis PharmaStock or Other Ownership: GlaxoSmithKline

Yingjie HuangEmployment: GlaxoSmithKlineStock or Other Ownership: GlaxoSmithKline

Saba Khan-WastiEmployment: GlaxoSmithKlineStock or Other Ownership: GlaxoSmithKlineResearch Funding: GlaxoSmithKline

Sergio SantillanaEmployment: GlaxoSmithKline, Takeda PharmaceuticalsStock or Other Ownership: GlaxoSmithKline, Takeda PharmaceuticalsTravel, Accommodations, Expenses: GlaxoSmithKline, TakedaPharmaceuticals

Michael F. PressHonoraria: GlaxoSmithKlineConsulting or Advisory Role: GlaxoSmithKlineResearch Funding: GlaxoSmithKline (Inst)

Dennis SlamonLeadership: BiomarinStock or Other Ownership: PfizerTravel, Accommodations, Expenses: Biomarin, Novartis, Pfizer

© 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

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Acknowledgment

We thank the patients who participated in this study, the study site staff for study management oversight, and David Griffiths, PhD,Fishawack Indicia, Ltd, for editorial assistance (funded by GlaxoSmithKline and Novartis Pharma AG).

Appendix

Methods

PatientsInclusion criteria: elapsed time period of $ 3 weeks since any major surgery and . 5 years since prior chemotherapy for

malignancy (other than gastric carcinoma); unresectable gastric carcinoma or esophageal cancer resulting from locally advanced orlocally recurrent disease; and elapsed time period of$ 3 weeks since any major surgery and. 5 years since prior chemotherapy formalignancy (other than gastric carcinoma).

Exclusion criteria: planned concurrent anticancer therapy; gastric carcinoid, epidermoid, sarcoma, or squamous cell car-cinoma; known history of active CNS disease; malabsorption syndrome or uncontrolled inflammatory GI disease; known history ofuncontrolled or symptomatic angina, arrhythmias, or congestive heart failure; current active hepatic or biliary disease; history ofother malignancy during the last 5 years; and unresolved or unstable serious toxicity from prior administration of anotherinvestigational drug and/or prior cancer treatment.

All patients provided written informed consent before study participation.

AssessmentsHuman epidermal growth factor receptor 2 fluorescence in situ hybridization assay. Both biopsy and resection specimens were used

for central human epidermal growth factor receptor 2 (HER2) fluorescence in situ hybridization (FISH) testing. The PathVysionHER2 FISH assay was used, with average HER2 gene copy number and chromosome 17 centromere copy number determined.HER2 amplification was defined as a ratio of HER2 gene copy number to chromosome 17 copy number of $ 2.0, as discussedelsewhere.16

Tumor assessments. Tumor assessments were performed within 28 days before study entry and repeated every 6 weeks for36 weeks and every 12 weeks thereafter using computed tomography scans of the chest, abdomen, and pelvis (or computedtomography of chest and magnetic resonance imaging of abdomen and pelvis).

Safety. Serious adverse events (SAEs) monitored included cardiac dysfunction, signs and symptoms of pneumonitis (grade $3), any clinically or medically relevant grade 4 laboratory abnormality, increased ALT, and any new primary cancer. Cardiac, liver,and dermatologic assessments were also performed during the study.

Health outcomes. Patient questionnaires included: European Organisation for Research and Treatment of Cancer (EORTC)Health-Related Quality of Life Questionnaire Core 30 (QLQ C-30; version 3), the EORTC gastric cancer module (QLQ STO-22), orthe EORTC esophageal cancer module (QLQ OES-18).

Treatment exposure. Treatment exposure was analyzed separately for each treatment (lapatinib or placebo, capecitabine, andoxaliplatin).

Sample Size and Statistical AnalysisThe randomization code was created by the GlaxoSmithKline internal randomization system named Randall (block size, 6). A

randomization code was generated, stratifying prior adjuvant or neoadjuvant use and region (North America, Asia, or rest ofworld), blinded to all project members and investigators and locked until unblinding in February 2013.

The Pike estimator of the hazard ratio was calculated based on the log-rank method and presented with an approximate 95%CI. Greenwood’s formula was used to calculate the SE of the overall and progression-free survival estimates.

ACox proportional regression model was used for additional multivariable analyses. Type I error was fully allocated to primaryanalysis of overall survival only, and no adjustment was performed in the study.

Results

SafetyFatal SAEs in the capecitabine and oxaliplatin (CapeOx) plus lapatinib arm included death (cause unknown; n = 2 [, 1%]),

diarrhea and pneumonia aspiration (both n = 2 [, 1%]), and abdominal pain, impaired gastric emptying, gastric obstruction,vomiting, sepsis, abdominal infection, multiorgan failure, sudden death, cerebrovascular accident, epilepsy, acute myocardial

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infarction, and cardiorespiratory arrest (all n = 1 [, 1%]). Fatal SAEs in the CapeOx plus placebo arm included sepsis, anemia,cellulitis, coma, drowning, infectious enterocolitis, hematemisis, large intestine perforation, and anemia (all n = 1 [, 1%]).

Health OutcomesFor the EORTC QLQ-C30 questionnaire, there was a difference in the attrition rate by week 36, with approximately 53% (102

of 192) of patients in the CapeOx plus lapatinib arm having discontinued and approximately 73% (143 of 195) in the CapeOx plusplacebo arm having discontinued.

Few significant differences were observed between the CapeOx plus lapatinib arm and the CapeOx plus placebo arm regardingchanges in EORTC QLQ-C30 results over time, except for role functioning and cognitive functioning scores at week 30 (better forCapeOx plus lapatinib), role functioning, nausea and vomiting, and constipation scores at week 36 (better for CapeOx pluslapatinib), and diarrhea over the first 30 weeks (worse for CapeOx plus lapatinib).

Study ManagementThe following study site staff provided study management oversight: Kaen Diego, Luis Fein, Juan A. Lacava, Guillermo L. Lerzo,

Guillermo Mendez, Mirta Susana Varela, and Juan J. Zarba (Argentina); Kathia Abdalla, Mariangela Correa, Daniel de IracemaGomes Cubero, Andre Murad, Yeni Veronica Neron do Nascimento, Jose Getulio Martins Segalla, Guilherme Luiz Stelko Pereira,Fernando Meton de Alencar Camara Viera, Alberto Wainstein, and Juliana Yorimi Yamaguchi (Brazil); Neil Sun Chua, RichardHeng-Fu Shao, Wilson H. Miller, and Stephen Welch (Canada); Osvaldo Giannini and Eduardo Yañez (Chile); Yi Ba, Li Bai, YuxianBai, Zhendong Chen, Ying Cheng, Bi Feng, Jun Liang, Rongcheng Luo, Xuenong Ouyang, Hongming Pan, Yihong Sun, JinwanWang, and Liwei Wang (China); Anneli Elme and Krista Leppik (Estonia); Frank Wong and Thomas Chung Cheung Yau (HongKong); Laszlo Budi, Cs}oszi, Eva Somogyine Ezer, Laszlo Mangel, and Gabor Pajkos (Hungary); Baruch Brenner, Efraim Idelevich,Einat Shacham-Shmueli, and Ido Wolf (Israel); Jaydip Biswas, Goswami Chanchal, Ajay Mehta, K. Pavithran, ArumughamRajkumar, Mehta Shaesta, Atul Sharma, and Choondal Devan Sivanandan (India); Dino Amadori, Giuseppe Aprile, AndreaArdizzoni, Sandro Barni, Carlo Barone, Vincenzo Catalano, Luigi Cavanna, Francesco Di Costanzo, Marina Faedi, RobertoLabianca, Luciano Latini, Gabriele Luppi, Cora N. Sternberg, and Emiliano Tamburini (Italy); Ik-Joo Chung, Seok Yun Kang, HoonKyo Kim, Yeul Hong Kim, Seong-Hoon Shin, and Hong Suk Song (Korea); German Calderillo-Ruiz and Carlos Alberto Hernandez-Hernandez (Mexico); Marco B. Polee and Dirk J. Richel (the Netherlands); Krzysztof Krzemieniecki, Pawel Murawa, Joanna Pikiel,Pawel Rozanowski, Piotr Sawrycki, Magdalena Sikorska, and Zoran Stojcev (Poland); Fernando Hurtado de Mendoza, PaolaMontenegro, and Patricia Pimentel (Peru); Svetlana Vladimirovna Averyanova, Oleg Aleksandrovich Gladkov, Vera AndreevnaGorbunova, Igor Leonidovich Kiselev, Nadezhda Vitalievana Kovalenko, Natalia Levchenko, Georgy Moiseyevich Manikhas,Vladimir Mikhailovich Moiseyenko. Dina Damirovna Sakaeva, Nailya Zagidovna Sherman, Marina Vasilievna Shomova, DmitriyPetrovich Udovitsa, and Dmitry Mikhailovich Vyushkov (Russia); Patrapim Sunpaweravong (Thailand); Alper Sevinc (Turkey);Wen-Liang Fang, Yan-Shen Shan, and Ming-Chin Yu (Taiwan); Igor N. Bondarenko, Yuriy Dumanskiy, Lurii S. Golovko, Yevhen S.Hotko, Volodymyr L. Komisarenko, Olexiy O. Kovalyov, Nataliya V. Martsynkovska, Viktor V. Paramonov, Tetiana M. Popovska,Alexander Y. Popovych, Roman V. Senyutovich, Vitaliy M. Sorkin, and Nataliia L. Voitko (Ukraine); David P. Chan, SheldonJ. Davidson, Eddie H. Hu, and David Park (United States).

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