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

Rationale for Lapatinib in UGI Adenocarcinoma

• Amplification of HER-2 is common in gastroesophageal adenocarcinomas

• Lapatinib is a small molecule tyrosine kinase inhibitor of EGFR and HER-2, approved in HER-2+ breast cancer

• Lapatinib showed activity in in vitro and in vivo studies with HER-2 amplified UGI cell lines (Wainberg 2010)

• Modest single agent activity was noted in UGI cancers (Hecht 2008, Iqbal 2011)

• No anti-HER-2 agent had been demonstrated to improve outcomes in this disease at the time of study design and initiation

TRIO/GSK Collaboration

• TRIO (Translational Research in Oncology) is an international nonprofit academic research group based in Canada, France and South America created by the merger of BCIRG and the UCLA-affiliated TORI network in conjunction with UCLA translational oncology laboratories

• TRIO-013/LOGiC is a clinical collaboration between TRIO and GSK

• Statistical analyses and translational studies presented were performed by TRIO

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 amplification confirmed by FISH centrally)

Endpoints and Statistical Considerations

• Primary Endpoint– Overall Survival in the Primary Efficacy Population (PEP)

• Secondary Endpoints– PFS, RR, duration of response, clinical benefit, safety and toxicity,

HRQOL, molecular and pharmacogenetic analyses

• Statistical Assumptions– Hypothesis: Hazard ratio: 0.735– Median OS of 14 months vs 10.3 months– 80% power, 2-sided alpha of 5% – 337 OS events required for final analysis– 350 events included in this final analysis

Eligibility Criteria

• Histologically confirmed adenocarcinoma of the stomach, esophagus or gastro-esophageal junction

• Locally advanced unresectable or metastatic disease• Measurable or evaluable disease according to RECIST • HER-2 amplification by FISH assessed by local or designated

central laboratory– IHC (IHC3+), CISH amplification, or SISH amplification permitted– Tissue available for central testing

• ECOG Performance status ≤ 2• No prior palliative chemotherapy

Trial Conduct

• 545 patients were enrolled from June 2008 to January 2012

• 186 centers in 22 countries participated

• Initial study design had PFS as the primary endpoint with a sample size of 410 patients

• In September 2009, the study was amended to change the primary endpoint to OS and increase sample size to 535 patients

Study Populations

Population CapeOx + LapatinibN

CapeOx + PlaceboN

TotalN

Intent-to-Treat (ITT) 272 273 545

Primary Efficacy Population (PEP) 249 238 487

Safety Population 270 267 537

Patient CharacteristicsCapeOx + Lapatinib

N=249CapeOx + Placebo

N=238

Gender M : F 189 (76%) : 60 (24%) 176 (74%) : 62 (26%)

Age (Median [min, max]) 61.0 (19, 86) 59.0 (27, 84)

ECOG Performance Status 0 79 (32%) 63 (26%)

1 149 (60%) 153 (64%)

2 21 (8%) 22 (9%)

Primary Site Esophageal 12 (5%) 8 (3%)

GE Junction 23 (9%) 20 (8%)

Gastric 214 (86%) 210 (88%)

Gastric Cancer Type Diffuse 9 (4%) 10 (4%)

Intestinal 225 (90%) 211 (89%)

Other 15 (6%) 17 (7%)

Pylorus Intact 193 (78%) 180 (76%)

Prior Neo/adjuvant therapy 18 (7%) 20 (8%)

Region North America (NA) 8 (3%) 9 (4%)

Asia 100 (40%) 93 (39%)

Rest of World (ROW) 141 (57%) 136 (57%)

Primary Endpoint: Overall Survival (PEP)

CapeOx+L

CapeOx+P

1.0

0.8

0.6

0.4

0.2

0.0

Cum

ula

tive

sur

viva

l pro

babi

lity

0 5 10 15 20 25 30 35 40 45

Time 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) = 0.3492

Subjects at risk CapeOx+L 249 199 133 83 47 24 9 3 3

CapeOx+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)

OS by Region

CapeOx+L

CapeOx+P

1.0

0.8

0.6

0.4

0.2

0.0

Cum

ula

tive

sur

viva

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babi

lity

0 5 10 15 20 25 30 35 40 45

Time since randomization (months)

ASIA ROW

Subjects at riskCapeOx+L 100 93 70 49 25 16 7 3 3 141 101 59 30 19 6 2 CapeOx+P 93 77 47 28 19 11 7 5 1 136 104 53 21 12 4 2 1

CapeOx+LN=100

CapeOx+PN=93

Median (95% CI) (mo)

16.5 (13.3,20.2)

10.9 (9.0,14.9)

HR (95% CI) 0.68 (0.48,0.96)

CapeOx+LN=141

CapeOx+PN=136

Median (95% CI) (mo)

10.0 (8.0,12.0)

9.1 (8.3,10.9)

HR (95% CI) 1.04 (0.79,1.37)

1.0

0.8

0.6

0.4

0.2

0.0

Cum

ula

tive

sur

viva

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babi

lity

0 5 10 15 20 25 30 35 40 45

Time since randomization (months)

CapeOx+L

CapeOx+P

OS by Age

Presented by:

Subjects at riskCapeOx+L 113 102 85 53 38 20 11 5 3 2 2 136 108 78 59 35 21 16 9 4 1 1 CapeOx+P 123 96 61 32 17 13 7 3 1 1 1 1 115 100 75 42 31 21 13 10 8 4 1 1

CapeOx+LN=113

CapeOx+PN=123

Median (95% CI) (mo)

12.9 (10.6-16.0)

9.0( 7.8-11.3)

HR (95% CI) 0.69 (0.51, 0.94)

CapeOx+LN=136

CapeOx+PN=115

Median (95% CI) (mo)

11.3 (8.4-13.8)

10.9 (9.4-14.1)

HR (95% CI) 1.08 (0.81, 1.45)

Time since randomization (months)

1.0

0.8

0.6

0.4

0.2

0 4 8 12 16 20 24 28 32 36 40 44 480.0

Cum

ula

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sur

viva

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babi

lity

Time since randomization (months)

<60 years ≥60 years

Cum

ula

tive

sur

viva

l pro

babi

lity

1.0

0.8

0.6

0.4

0.2

0 4 8 12 16 20 24 28 32 36 40 44 480.0

CapeOx+L

CapeOx+P

CapeOx+L

CapeOx+P

Progression Free Survival (PEP)

CapeOx+LN=249

CapeOx+PN=238

Median (95% CI) (mo) 6.0 (5.6, 7.0) 5.4 (4.4, 5.7)

HR (95% CI) 0.86 (0.71, 1.04) p= 0.1026

Subjects at riskCapeOx+L 249 212 180 121 95 63 43 35 27 17 9 9 5 4 4 3 2 1 1 1 1 0 0 0 0CapeOx+P 238 205 157 91 54 36 25 20 18 15 11 9 7 6 6 6 5 4 3 2 1 1 1 1 0

Without Censoring

CapeOx+LN=249

CapeOx+PN=238

Median (95% CI) (mo) 6.0 (5.6, 7.0) 5.4 (4.4, 5.7)

HR (95% CI) 0.82 (0.68, 1.00) p=0.0381

With Censoring

CapeOx+L

CapeOx+P

1.0

0.8

0.6

0.4

0.2

0.0

Cum

ula

tive

sur

viva

l pro

babi

lity

0 4 10 14 18 26 30 34 38 46

Time since randomization (months)

2 6 8 22 42

Note: The curve displayed represents data without censoring

Best Overall ResponseCapeOx + Lapatinib

N=249CapeOx + Placebo

N=238

Complete response 6 (2%) 5 (2%)

Partial response 126 (51%) 90 (38%)

Stable Disease 70 (28%) 94 (39%)

Disease Progression 20 (8%) 22 (9%)

Not evaluable/unknown 27 (11%) 27 (11%)

Overall RR 53% (95%CI : 46.6−59.3) 40% (95% CI : 33.6−46.4)

Median Duration of Response (month) 7.3 (95%CI : 6.4–8.4) 5.6 (95%CI : 4.8–6.0)

ORR by region

North America 63 % 56 %

Asia 65 % 39 %

ROW 44 % 40 %

Relative Drug Exposure

Treatment Group CapeOx + Lapatinib CapeOx + Placebo

N Median, % (min, max) N Median, % (min, max)

Lapatinib/Placebo

Overall 270 95 (44, 112) 267 97 (55, 102)

Asia 111 91 (44, 100) 108 95 (70, 102)

ROW 151 98 (44, 112) 151 100 (55, 100)

Oxaliplatin

Overall 270 92 (46, 103) 267 96 (43, 109)

Asia 111 88 (56, 103) 108 90 (56, 104)

ROW 151 95 (46, 103) 151 97 (66, 109)

Capecitabine

Overall 270 82 (10, 119) 267 89 (30, 112)

Asia 111 75 (25, 99) 108 85 (30, 102)

ROW 151 88 (10, 119) 151 91 (40, 112)

Summary of Adverse Events

Safety (Number of Subjects)

CapeOx + Lapatinib N=270

CapeOx + PlaceboN=267

AEs 255 (94%) 236 (88%)

SAEs 72 (27%) 52 (19%)

AEs leading to study drug discontinuation 57 (21%) 48 (18%)

Fatal AEs 15 (6%) 9 (3%)

Summary of On-Therapy AEs by Maximum Grade (>20% in either treatment arm)

Safety Population

CapeOx + Lapatinib (N=270)

CapeOx + Placebo (N=267)

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

Any 255 (94%) 91 (34%) 17 (6%) 15 (6%) 236 (88%) 69 (26%) 25 (9%) 9 (3%)

Diarrhea 156 (58%) 32 (12%) 1 (<1%) 2(<1%) 77 (29%) 9 (3%) 0 0

Nausea 132 (49%) 15 (6%) 0 0 114 (43%) 6 (2%) 0 0

Vomiting 118 (44%) 17 (6%) 0 1 (<1%) 96 (36%) 12 (4%) 0 0

Decreased appetite 111 (41%) 12 (4%) 1 (<1%) 0 86 (32%) 7 (3%) 0 0

Fatigue 64 (24%) 13 (5%) 1 (<1%) 0 57 (21%) 10 (4%) 1 (<1%) 0

Rash 57 (21%) 0 0 0 20 (7%) 0 0 0

Palmar-plantar erythrodysesthesia syndrome

53 (20%) 2 (<1%) 0 0 34 (13%) 2 (<1%) 0 0

TRIO-013/LOGiC Summary

• Primary endpoint of improving OS was not met• Secondary efficacy endpoints of PFS, RR, duration of response

were improved with addition of lapatinib• Improved OS was seen in Asian patients and patients under 60• No new safety signal was identified, but increased toxicity was

seen with the addition of lapatinib to CapeOx, particularly diarrhea and skin toxicity

• There was no significant correlation between HER-2 IHC and overall survival in PEP

• Further biomarker analyses are ongoing

Acknowledgements

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Patients Investigators TRIO and GSK Study Teams