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
Day 1: Oxaliplatin 130 mg/m2
Day 1−14: Capecitabine 850 mg/m2, bid
1. Confirmed
histology
2. Local/central
HER-2+
3. Confirmed
eligibility
Day 1−21: Lapatinib 1250 mg, qd
(one cycle = 21 days)
R
Day 1: Oxaliplatin 130 mg/m2
Day 1−14: Capecitabine 850 mg/m2, bid
Stratification factors
• Prior (neo)Adjuvant
therapy
Day 1−21: Placebo, qd
(one cycle = 21 days)
• Region (Asia,
North America,
Rest of the World)
Tumor tissue sent
to central lab
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 + Lapatinib
N
CapeOx + Placebo
N
Total
N
Intent-to-Treat (ITT)
272
273
545
Primary Efficacy
Population (PEP)
249
238
487
Safety Population
270
267
537
Patient Characteristics
CapeOx + Lapatinib
N=249
CapeOx + Placebo
N=238
M:F
189 (76%) : 60 (24%)
176 (74%) : 62 (26%)
Age (Median [min, max])
61.0 (19, 86)
59.0 (27, 84)
0
79 (32%)
63 (26%)
1
149 (60%)
153 (64%)
2
21 (8%)
22 (9%)
Esophageal
12 (5%)
8 (3%)
GE Junction
23 (9%)
20 (8%)
Gastric
214 (86%)
210 (88%)
Diffuse
9 (4%)
10 (4%)
225 (90%)
211 (89%)
15 (6%)
17 (7%)
193 (78%)
180 (76%)
18 (7%)
20 (8%)
8 (3%)
9 (4%)
Asia
100 (40%)
93 (39%)
Rest of World (ROW)
141 (57%)
136 (57%)
Gender
ECOG Performance Status
Primary Site
Gastric Cancer Type
Intestinal
Other
Pylorus Intact
Prior Neo/adjuvant therapy
Region
North America (NA)
Cumulative survival probability
Primary Endpoint: Overall Survival
(PEP)
1.0
PEP
0.8
Median (95% CI)
(mo)
0.6
HR (95% CI)
CapeOx+L
N=249
CapeOx+P
N=238
12.2 (10.6, 14.2)
10.5 (9.0, 11.3)
0.91 (0.73, 1.12) = 0.3492
0.4
0.2
CapeOx+L
CapeOx+P
0.0
Subjects at risk
CapeOx+L
CapeOx+P
0
5
10
249
238
199
189
133
106
15
20
25
30
Time since randomization (months)
83
53
47
34
24
17
9
11
ITT analysis HR 0.91
35
40
45
3
7
3
2
2
Overall Survival: Subgroup Analysis
Hazard ratio (95% CI)
Primary efficacy population (N=487)
0.91 (0.73, 1.12)
Region
Asia (n=193)
North America (n=17)
Rest of World (n=277)
0.68 (0.48, 0.96)
1.61 (0.53, 4.83)
1.04 (0.79, 1.37)
Yes (n=38)
No (n=449)
1.52 (0.68, 3.41)
0.83 (0.67, 1.04)
Age (years)
<60 (n=236)
≥60 (n=251)
0.69 (0.51, 0.94)
1.08 (0.81, 1.45)
Baseline ECOG status
0−1 (n=444)
2 (n=43)
0.88 (0.70, 1.10)
0.76 (0.41, 1.44)
Esophagus (n=20)
GE Junction (n=43)
Gastric (n=424)
0.87 (0.32, 2.35)
0.90 (0.44, 1.85)
0.89 (0.71, 1.11)
Diffuse (n=19)
Intestinal (n=436)
Other (n=32)
0.64 (0.25, 1.65)
0.93 (0.75, 1.17)
0.58 (0.26, 1.29)
Yes (n=373)
No (n=114)
0.80 (0.63, 1.01)
1.06 (0.67, 1.68)
Prior adjuvant use
Primary site
Histological type
Pylorus intact
HER2 status (all FISH+)
IHC 0 (n=27)
IHC 1+ (n=54)
IHC 2+ (n=108)
IHC 3+ (n=297)
0.56 (0.24, 1.31)
1.16 (0.61, 2.20)
0.79 (0.50, 1.25)
0.90 (0.69, 1.18)
IHC 0−1+ (n=81)
IHC 2−3+ (n=405)
0.91 (0.55, 1.51)
0.86 (0.68, 1.09)
0
Favors CapeOx+L
1
2
5
4
3
Hazard Ratio (CapeOx+L / CapeOx+P)
Favors CapeOx+P
OS by Region
ROW
1.0
Median
(95% CI) (mo)
0.8
CapeOx+L
N=100
CapeOx+P
N=93
16.5
(13.3,20.2)
10.9
(9.0,14.9)
HR (95% CI)
0.68 (0.48,0.96)
0.6
0.4
0.2
CapeOx+L
CapeOx+P
5
10
15
20
25
30
35
40
Time since randomization (months)
Subjects at risk
CapeOx+L 100
CapeOx+P 93
93
77
70
47
1.0
Median
(95% CI) (mo)
0.8
49
28
25
19
16
11
7
7
3
5
3
1
45
CapeOx+L
N=141
CapeOx+P
N=136
10.0
(8.0,12.0)
9.1
(8.3,10.9)
HR (95% CI)
1.04 (0.79,1.37)
0.6
0.4
0.2
CapeOx+L
CapeOx+P
0.0
0.0
0
Cumulative survival probability
Cumulative survival probability
ASIA
0
5
10
15
20
25
30
35
40
Time since randomization (months)
141 101
136 104
59
53
30
21
19
12
6
4
2
2
1
45
OS by Age
≥60 years
<60 years
Median
(95% CI) (mo)
0.8
CapeOx+L
N=113
CapeOx+P
N=123
12.9
(10.6-16.0)
9.0
( 7.8-11.3)
HR (95% CI)
0.69 (0.51, 0.94)
0.6
0.4
0.2
CapeOx+L
CapeOx+P
Cumulative survival probability
Cumulative survival probability
1.0
1.0
Median
(95% CI) (mo)
0.8
CapeOx+L
N=136
CapeOx+P
N=115
11.3
(8.4-13.8)
10.9
(9.4-14.1)
HR (95% CI)
1.08 (0.81, 1.45)
0.6
0.4
0.2
CapeOx+L
CapeOx+P
0.0
0.0
0
4
8
12 16 20 24 28 32 36 40 44 48
Time since randomization (months)
Subjects at risk
CapeOx+L 113 102 85 53
CapeOx+P 123 96 61 32
Presented by:
38 20 11
17 13 7
5
3
3
1
2
1
2
1
1
0
4
8
12 16 20 24 28 32 36 40 44 48
Time since randomization (months)
136 108 78 59 35 21 16 9
115 100 75 42 31 21 13 10
4
8
1
4
1
1
1
Progression Free Survival (PEP)
Cumulative survival probability
1.0
Without Censoring
Median (95% CI) (mo)
0.8
Median (95% CI) (mo)
0.4
5.4 (4.4, 5.7)
CapeOx+L
N=249
CapeOx+P
N=238
6.0 (5.6, 7.0)
5.4 (4.4, 5.7)
HR (95% CI)
0.82 (0.68, 1.00) p=0.0381
CapeOx+L
CapeOx+P
0 2 4
Subjects at risk
CapeOx+L
CapeOx+P
6.0 (5.6, 7.0)
0.86 (0.71, 1.04) p= 0.1026
With Censoring
0.0
CapeOx+P
N=238
HR (95% CI)
0.6
0.2
CapeOx+L
N=249
6
8 10
14
18
22
26
30
34
38
42
46
Time since randomization (months)
249 212 180 121
238 205 157 91
95
54
63 43 35 27 17 9
36 25 20 18 15 11
9
9
5
7
4
6
Note: The curve displayed represents data without censoring
4
6
3
6
2
5
1
4
1
3
1
2
1
1
0
1
0
1
0
1
0
0
Best Overall Response
CapeOx + Lapatinib
CapeOx + Placebo
N=249
N=238
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%)
53% (95%CI : 46.6−59.3)
40% (95% CI : 33.6−46.4)
7.3 (95%CI : 6.4–8.4)
5.6 (95%CI : 4.8–6.0)
North America
63 %
56 %
Asia
65 %
39 %
ROW
44 %
40 %
Complete response
Overall RR
Median Duration of
Response (month)
ORR by region
Relative Drug Exposure
Treatment
Lapatinib/Placebo
Oxaliplatin
Capecitabine
Group
CapeOx + Lapatinib
CapeOx + Placebo
N
Median, % (min, max)
N
Median, % (min, max)
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)
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)
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
CapeOx + Placebo
N=270
N=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)
CapeOx + Lapatinib
(N=270)
Safety Population
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
Canada
Netherlands Estonia
Poland Ukraine
Hungary
Italy Turkey
Israel
USA
China
India
Mexico
Peru
Chile
Patients
Russia
Korea
Taiwan
Hong Kong
Thailand
Brazil
Argentina
Investigators TRIO and GSK Study Teams