Trial Outcomes & Findings for LOGiC - Lapatinib Optimization Study in ErbB2 (HER2) Positive Gastric Cancer: A Phase III Global, Blinded Study Designed to Evaluate Clinical Endpoints and Safety of Chemotherapy Plus Lapatinib (NCT NCT00680901)

Last Updated: 2025-08-07

Results Overview

Overall Survival was defined as the time from randomization to death from any cause. Participants who had not died were censored at their follow-up visit, either because follow-up had ended or was still ongoing.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

545 participants

Primary outcome timeframe

From date of randomization till death due to any cause, assessed up the cut-off date for Primary Analysis (24-Sep-2012) (average of 4 years)

Results posted on

2025-08-07

Participant Flow

This study was conducted at 186 centers in 21 countries in North America (Canada and US), Asia (China, Hong Kong, Korea and Taiwan), and Rest of World (ROW) (Argentina, Brazil, Chile, Estonia, Hungary, India, Israel, Italy, Mexico, Netherlands, Peru, Poland, Russian Federation, Turkey, and Ukraine).

Participants were randomized into one of two treatment arms: CapeOx plus lapatinib (the experimental arm) or CapeOx plus placebo (the control arm) using a 1:1 randomization.

Participant milestones

Participant milestones
Measure	CapeOx Plus Lapatinib Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Overall Study STARTED	272	273
Overall Study Primary Efficacy (PE) Population	249	238
Overall Study Safety Population	270	267
Overall Study Ongoing: On Study Treatment	1	0
Overall Study Ongoing: In Follow Up	1	0
Overall Study COMPLETED	243	233
Overall Study NOT COMPLETED	29	40

Reasons for withdrawal

Reasons for withdrawal
Measure	CapeOx Plus Lapatinib Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Overall Study Ongoing: On Study Treatment	1	0
Overall Study Ongoing: In Follow Up	1	0
Overall Study Adverse Event	1	1
Overall Study Lost to Follow-up	3	5
Overall Study Subject decided to withdraw from the study	4	15
Overall Study Sponsor decision	1	0
Overall Study Physician Decision	0	2
Overall Study Subject reached protocol defined stopping criteria	1	0
Overall Study Other protocol defined stopping criteria	17	17

Baseline Characteristics

LOGiC - Lapatinib Optimization Study in ErbB2 (HER2) Positive Gastric Cancer: A Phase III Global, Blinded Study Designed to Evaluate Clinical Endpoints and Safety of Chemotherapy Plus Lapatinib

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CapeOx Plus Lapatinib n=272 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=273 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	Total n=545 Participants Total of all reporting groups
Age, Continuous	59.4 Years STANDARD_DEVIATION 11.20 • n=5 Participants	58.5 Years STANDARD_DEVIATION 11.23 • n=7 Participants	58.9 Years STANDARD_DEVIATION 11.21 • n=5 Participants
Sex: Female, Male Female	66 Participants n=5 Participants	73 Participants n=7 Participants	139 Participants n=5 Participants
Sex: Female, Male Male	206 Participants n=5 Participants	200 Participants n=7 Participants	406 Participants n=5 Participants
Race/Ethnicity, Customized African American/African Heritage (Hrtg)	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Race/Ethnicity, Customized Central/South Asian Hrtg	11 Participants n=5 Participants	3 Participants n=7 Participants	14 Participants n=5 Participants
Race/Ethnicity, Customized Japanese/East Asian Hrtg/South East Asian Hrtg	112 Participants n=5 Participants	114 Participants n=7 Participants	226 Participants n=5 Participants
Race/Ethnicity, Customized White	144 Participants n=5 Participants	150 Participants n=7 Participants	294 Participants n=5 Participants

PRIMARY outcome

Timeframe: From date of randomization till death due to any cause, assessed up the cut-off date for Primary Analysis (24-Sep-2012) (average of 4 years)

Population: Primary Efficacy (PE) population

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=249 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=238 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Overall Survival at the Time of Primary Analysis	12.2 Months Interval 10.6 to 14.2	10.5 Months Interval 9.0 to 11.3

PRIMARY outcome

Timeframe: From date of randomization till death due to any cause, assessed up the cut-off date for Primary Analysis (24-Sep-2012) (average of 4 years)

Population: Intent-to-Treat (ITT) Population

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=272 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=273 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Overall Survival in All Randomized Participants at the Time of Primary Analysis	11.9 Months Interval 10.4 to 13.8	10.4 Months Interval 9.1 to 11.3

SECONDARY outcome

Timeframe: From date of randomization till death due to any cause, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Primary Efficacy (PE) population

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=249 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=238 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Overall Survival at the Time of Final Analysis	12.0 Months Interval 10.4 to 13.8	10.4 Months Interval 9.0 to 11.3

SECONDARY outcome

Timeframe: From date of randomization till the earliest date of disease progression or death due to any cause, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Primary Efficacy (PE) population

Progression-Free Survival (PFS) was defined as the time from randomization to the earliest occurrence of disease progression or death from any cause. Per RECIST v1.0, progression was defined as at least a 20% increase in the sum of diameters of target lesions from the smallest recorded sum or the appearance of one or more new lesions. Participants with symptomatic progression, even without radiological confirmation, were also counted. Those who had neither progressed nor died were censored at their follow-up visit, either because follow-up had ended or was ongoing. Participants who received non-study anti-cancer therapies before progression were also censored.

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=249 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=238 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Progression Free Survival (PFS)	6.2 Months Interval 5.6 to 7.0	5.4 Months Interval 4.4 to 5.7

SECONDARY outcome

Timeframe: From date of randomization till the date of the first documented response of CR or PR, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Primary Efficacy (PE) population

A participant was considered a responder if they had achieved either a complete response (CR), defined as the disappearance of all target and non-target lesions, or a partial response (PR), defined as at least a 30% reduction in the sum of the longest diameters of target lesions from baseline, as assessed by the investigator and confirmed by radiographic imaging within four weeks of the initial observation.

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=249 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=238 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Percentage of Participants With a Confirmed Complete Response (CR) or a Partial Response (PR)	131 Participants	94 Participants

SECONDARY outcome

Timeframe: From date of randomization till date of disease progression (PD) or death due to any cause, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Primary Efficacy (PE) population

Clinical Benefit (CB) was defined as evidence of a complete response (CR), partial response (PR), or stable disease (SD). CR referred to the disappearance of all target and non-target lesions, PR to at least a 30% reduction in the sum of the longest diameters of target lesions from baseline, and SD to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progression, based on the smallest sum of diameters recorded since treatment initiation. All assessments were made by the investigator.

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=249 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=238 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Percentage of Participants With Clinical Benefit (CB)	199 Participants	188 Participants

SECONDARY outcome

Timeframe: From date of randomization till the first documented evidence of confirmed CR or PR, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Primary Efficacy (PE) population. Only those participants who had a confirmed CR or PR were analyzed for time to response.

Time to Response (TTR) was defined as the duration from randomization to the first documented evidence of either a complete response (CR) (the disappearance of all target and non-target lesions) or a partial response (PR) (at least a 30% reduction in the sum of the longest diameters of target lesions from baseline) as assessed by the investigator.

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=131 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=94 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Time to Response (TTR)	1.4 Months Interval 1.4 to 1.5	1.4 Months Interval 1.4 to 1.6

SECONDARY outcome

Timeframe: From the time of the first documented evidence of a confirmed CR or PR until the earliest date of disease progression or death due to any cause, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Primary Efficacy (PE) population. Only those participants who had a confirmed CR or PR were analyzed for duration of response.

Duration of Response (DOR) was defined as the time from the first documented evidence of a complete response (CR) or partial response (PR) until the first recorded sign of disease progression or death from any cause. According to RECIST, progression was defined as at least a 20% increase in the sum of diameters of target lesions from the smallest recorded sum or the appearance of one or more new lesions. Participants who had neither progressed nor died were censored at their follow-up visit, either because follow-up had ended or was ongoing. Those who received non-study anti-cancer therapies before progression were also censored.

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=131 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=94 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Duration of Response (DOR)	7.3 Months Interval 6.4 to 8.5	5.6 Months Interval 4.6 to 6.0

SECONDARY outcome

Timeframe: From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Safety population

An Adverse Event (AE) was defined as any untoward medical occurrence in a participant that was temporally associated with the use of a medicinal product, regardless of its causal relationship. This included any unfavorable or unintended sign (such as abnormal lab findings), symptom, or disease, whether new or worsened. A Serious Adverse Event (SAE) was defined as any such occurrence that, at any dose, resulted in death, was life-threatening, required hospitalization or its prolongation, caused disability or incapacity, led to a congenital anomaly or birth defect, or was a potential case of drug-induced liver injury.

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=270 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=267 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Percentage of Participants With Any On-therapy Adverse Event (AE) and Serious Adverse Event (SAE) On-Therapy Adverse Events (Any AE regardless of seriousness)	255 Participants	237 Participants
Percentage of Participants With Any On-therapy Adverse Event (AE) and Serious Adverse Event (SAE) On-Therapy Serious Adverse Events	73 Participants	54 Participants

SECONDARY outcome

Timeframe: From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Safety population. Only participants with On-therapy AEs

An Adverse Event (AE) was defined as any untoward medical occurrence in a participant that was temporally associated with the use of a medicinal product, regardless of its relationship to the product. This included any unfavorable or unintended sign (such as abnormal lab results), symptom, or disease, whether new or worsened. The severity of AEs was graded according to NCI CTCAE version 3.0: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), and Grade 5 (death related to toxicity).

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=255 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=237 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Percentage of Participants With On-therapy Adverse Event (AE) by Maximum Grade Grade 1	43 Participants	56 Participants
Percentage of Participants With On-therapy Adverse Event (AE) by Maximum Grade Grade 2	85 Participants	78 Participants
Percentage of Participants With On-therapy Adverse Event (AE) by Maximum Grade Grade 3	94 Participants	69 Participants
Percentage of Participants With On-therapy Adverse Event (AE) by Maximum Grade Grade 4	17 Participants	25 Participants
Percentage of Participants With On-therapy Adverse Event (AE) by Maximum Grade Grade 5	16 Participants	9 Participants

SECONDARY outcome

Timeframe: From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Safety population. Only participants with on-therapy Serious Adverse Events (SAEs)

A Serious Adverse Event (SAE) was defined as any such occurrence that resulted in death, was life-threatening, required hospitalization or its prolongation, caused disability or incapacity, led to a congenital anomaly or birth defect, or was a potential case of drug-induced liver injury. The severity of SAEs was graded according to NCI CTCAE version 3.0: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), and Grade 5 (death related to toxicity).

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=73 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=54 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Percentage of Participants With On-therapy Serious Adverse Event (SAE) by Maximum Grade Grade 1	3 Participants	3 Participants
Percentage of Participants With On-therapy Serious Adverse Event (SAE) by Maximum Grade Grade 2	6 Participants	4 Participants
Percentage of Participants With On-therapy Serious Adverse Event (SAE) by Maximum Grade Grade 3	37 Participants	21 Participants
Percentage of Participants With On-therapy Serious Adverse Event (SAE) by Maximum Grade Grade 4	13 Participants	18 Participants
Percentage of Participants With On-therapy Serious Adverse Event (SAE) by Maximum Grade Grade 5	14 Participants	8 Participants

SECONDARY outcome

Timeframe: From Baseline up to disease progression (PD), assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Primary Efficacy (PE) population. Only those participants contributing data at the indicated time point were analyzed.

The EORTC QLQ-C30 is a comprehensive questionnaire developed for assessing the quality of life of cancer patients across different aspects including function scales namely physical, role, cognitive, emotional and social; symptom scales such as fatigue, pain, nausea and vomiting; and a global scale pronouncing overall health status. Its scoring method involves a 4-point Likert scale (ranging from 1 'Not at all' to 4 'Very Much'). Domain scores are calculated by averaging the items within the respective domain and then linearly transforming the score to fit within a 0-100 scale to finalize the scores. In terms of interpretation, a high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.

Outcome measures

SECONDARY outcome

Timeframe: From Baseline up to disease progression (PD), assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Primary Efficacy (PE) population. Only those participants contributing data at the indicated time point were analyzed.

The QLQ-STO22 consists of 22 items divided into five subscales: dysphagia, pain, reflux, eating restrictions and anxiety, as well as single items addressing dry mouth, body image, taste, and hair loss. Each item is answered on a 4-point scale, ranging from 1 (not at all) to 4 (very much). Raw scores for each subscale or single item are calculated by averaging the scores of the individual items that make up the scale. These scores are then linearly transformed to range from 0 to 100. In terms of interpretation, a higher score indicates a worse quality of life concerning the specific symptoms assessed.

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=60 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=54 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Mean Change From Baseline in the EORTC Quality of Life (QOL) Questionnaire of Stomach 22 (QLQ-STO22) Scales/Items Score Scale Reflux scale	-1.4 Scores on a scale Standard Deviation 21.86	-4.1 Scores on a scale Standard Deviation 18.48
Mean Change From Baseline in the EORTC Quality of Life (QOL) Questionnaire of Stomach 22 (QLQ-STO22) Scales/Items Score Scale Eating restrictions scale	1.2 Scores on a scale Standard Deviation 27.83	-3.2 Scores on a scale Standard Deviation 22.11
Mean Change From Baseline in the EORTC Quality of Life (QOL) Questionnaire of Stomach 22 (QLQ-STO22) Scales/Items Score Scale Dysphagia scale	3.4 Scores on a scale Standard Deviation 22.99	-3.1 Scores on a scale Standard Deviation 16.92
Mean Change From Baseline in the EORTC Quality of Life (QOL) Questionnaire of Stomach 22 (QLQ-STO22) Scales/Items Score Scale Pain scale	-1.5 Scores on a scale Standard Deviation 22.20	-0.6 Scores on a scale Standard Deviation 18.71
Mean Change From Baseline in the EORTC Quality of Life (QOL) Questionnaire of Stomach 22 (QLQ-STO22) Scales/Items Score Scale Anxiety scale	-2.9 Scores on a scale Standard Deviation 27.42	-7.5 Scores on a scale Standard Deviation 24.38
Mean Change From Baseline in the EORTC Quality of Life (QOL) Questionnaire of Stomach 22 (QLQ-STO22) Scales/Items Score Scale Dry mouth scale	2.8 Scores on a scale Standard Deviation 31.13	1.9 Scores on a scale Standard Deviation 32.00
Mean Change From Baseline in the EORTC Quality of Life (QOL) Questionnaire of Stomach 22 (QLQ-STO22) Scales/Items Score Scale Taste scale	4.5 Scores on a scale Standard Deviation 37.37	9.2 Scores on a scale Standard Deviation 32.03
Mean Change From Baseline in the EORTC Quality of Life (QOL) Questionnaire of Stomach 22 (QLQ-STO22) Scales/Items Score Scale Body image scale	-3.3 Scores on a scale Standard Deviation 37.68	-1.9 Scores on a scale Standard Deviation 30.66
Mean Change From Baseline in the EORTC Quality of Life (QOL) Questionnaire of Stomach 22 (QLQ-STO22) Scales/Items Score Scale Hair loss scale	-16.7 Scores on a scale Standard Deviation 23.57	0.0 Scores on a scale Standard Deviation 33.33

SECONDARY outcome

Timeframe: From Baseline up to disease progression (PD), assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Primary Efficacy (PE) population. Only those participants contributing data at the indicated time point were analyzed.

The EQ-5D is a standardized instrument developed by the EuroQoL Group to measure health-related quality of life. It includes a descriptive system covering five dimensions and a Visual Analogue Scale (VAS), often referred to as the Thermometer Score. The Utility Score (Health Utility Index) is derived from the five dimensions of the EQ-5D descriptive system (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has levels indicating severity (e.g., 1 = no problems, 2 = some problems, 3 = extreme problems). These combinations form a health state, which is then converted into a single index value using a country-specific value set. In the UK-based value set, the possible EQ-5D index utility values range from -0.594 to 1.0, where: 1.0 = perfect health, 0 = death and \< 0 = health states considered worse than death.

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=59 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=57 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Mean Change From Baseline in Utility Score (Health Utility Index) in the EuroQoL-5 Dimensions (EQ-5D) Questionnaire	-0.17 Scores on a scale Standard Deviation 0.347	-0.07 Scores on a scale Standard Deviation 0.328

SECONDARY outcome

Timeframe: From Baseline up to disease progression (PD), assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Primary Efficacy (PE) population. Only those participants contributing data at the indicated time point were analyzed.

The EQ-5D is a standardized instrument developed by the EuroQol Group to measure health-related quality of life. It includes a descriptive system covering five dimensions and a Visual Analogue Scale (VAS), often referred to as the Thermometer Score. The Thermometer Score is a self-rated health score using a vertical visual analogue scale , where respondents rate their overall health on a scale from 0 (worst imaginable health) to 100 (best imaginable health).

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=61 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=60 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Mean Change From Baseline in Thermometer Score (EQ VAS) in the EuroQoL-5 Dimensions (EQ-5D) Questionnaire	-4.61 Scores on a scale Standard Deviation 23.054	-7.90 Scores on a scale Standard Deviation 17.349

SECONDARY outcome

Timeframe: From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Safety Population. Only those participants contributing data at the indicated time point were analyzed.

The severity of chemistry parameters was graded according to NCI CTCAE version 3.0: Grade 0 (No adverse event or within normal limits), Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (life-threatening). Chemistry data included: Alanine aminotransferase (ALT), Albumin, Alkaline phosphatases (ALP), Aspartate aminotransferase (AST), Calcium (hypercalcemia), Calcium (hypocalcemia), Creatine Kinase (CK), Creatine, Glucose (hyperglycemia), Glucose (hypoglycemia), Magnesium (hypermagnesemia), Magnesium (hypomagnesemia), Potassium (hyperkalemia), Potassium (hypokalemia), Sodium (hypernatremia), Sodium (hyponatremia) and Total Bilirubin.

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=260 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=262 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Alanine aminotransferase (ALT) · Grade 0	163 Participants	153 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Alanine aminotransferase (ALT) · Grade 1	87 Participants	94 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Alanine aminotransferase (ALT) · Grade 2	8 Participants	11 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Alanine aminotransferase (ALT) · Grade 3	2 Participants	4 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Alanine aminotransferase (ALT) · Grade 4	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Albumin · Grade 0	123 Participants	140 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Albumin · Grade 1	72 Participants	66 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Albumin · Grade 2	59 Participants	48 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Albumin · Grade 3	3 Participants	4 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Albumin · Grade 4	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Alkaline phosphatases (ALP) · Grade 0	120 Participants	114 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Alkaline phosphatases (ALP) · Grade 1	113 Participants	109 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Alkaline phosphatases (ALP) · Grade 2	22 Participants	25 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Alkaline phosphatases (ALP) · Grade 3	5 Participants	12 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Alkaline phosphatases (ALP) · Grade 4	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Aspartate aminotransferase (AST) · Grade 0	108 Participants	93 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Aspartate aminotransferase (AST) · Grade 1	133 Participants	142 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Aspartate aminotransferase (AST) · Grade 2	16 Participants	21 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Aspartate aminotransferase (AST) · Grade 3	3 Participants	6 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Aspartate aminotransferase (AST) · Grade 4	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Calcium (hypercalcemia) · Grade 0	237 Participants	242 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Calcium (hypercalcemia) · Grade 1	17 Participants	19 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Calcium (hypercalcemia) · Grade 2	2 Participants	1 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Calcium (hypercalcemia) · Grade 3	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Calcium (hypercalcemia) · Grade 4	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Calcium (hypocalcemia) · Grade 0	129 Participants	134 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Calcium (hypocalcemia) · Grade 1	74 Participants	81 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Calcium (hypocalcemia) · Grade 2	50 Participants	43 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Calcium (hypocalcemia) · Grade 3	3 Participants	4 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Calcium (hypocalcemia) · Grade 4	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Creatine Kinase (CK) · Grade 0	1 Participants	3 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Creatine Kinase (CK) · Grade 1	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Creatine Kinase (CK) · Grade 2	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Creatine Kinase (CK) · Grade 3	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Creatine Kinase (CK) · Grade 4	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Creatinine · Grade 0	230 Participants	228 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Creatinine · Grade 1	21 Participants	33 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Creatinine · Grade 2	7 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Creatinine · Grade 3	2 Participants	1 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Creatinine · Grade 4	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Glucose (hyperglycemia) · Grade 0	107 Participants	119 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Glucose (hyperglycemia) · Grade 1	115 Participants	103 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Glucose (hyperglycemia) · Grade 2	30 Participants	32 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Glucose (hyperglycemia) · Grade 3	6 Participants	8 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Glucose (hyperglycemia) · Grade 4	1 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Glucose (hypoglycemia) · Grade 0	223 Participants	237 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Glucose (hypoglycemia) · Grade 1	32 Participants	20 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Glucose (hypoglycemia) · Grade 2	3 Participants	2 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Glucose (hypoglycemia) · Grade 3	1 Participants	1 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Glucose (hypoglycemia) · Grade 4	0 Participants	2 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Magnesium (hypermagnesemia) · Grade 0	229 Participants	234 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Magnesium (hypermagnesemia) · Grade 1	20 Participants	17 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Magnesium (hypermagnesemia) · Grade 2	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Magnesium (hypermagnesemia) · Grade 3	5 Participants	5 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Magnesium (hypermagnesemia) · Grade 4	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Magnesium (hypomagnesemia) · Grade 0	189 Participants	199 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Magnesium (hypomagnesemia) · Grade 1	59 Participants	52 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Magnesium (hypomagnesemia) · Grade 2	5 Participants	5 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Magnesium (hypomagnesemia) · Grade 3	1 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Magnesium (hypomagnesemia) · Grade 4	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Potassium (hyperkalemia) · Grade 0	228 Participants	234 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Potassium (hyperkalemia) · Grade 1	20 Participants	14 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Potassium (hyperkalemia) · Grade 2	8 Participants	11 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Potassium (hyperkalemia) · Grade 3	2 Participants	2 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Potassium (hyperkalemia) · Grade 4	1 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Potassium (hypokalemia) · Grade 0	160 Participants	195 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Potassium (hypokalemia) · Grade 1	75 Participants	54 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Potassium (hypokalemia) · Grade 2	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Potassium (hypokalemia) · Grade 3	21 Participants	11 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Potassium (hypokalemia) · Grade 4	3 Participants	1 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Sodium (hypernatremia) · Grade 0	234 Participants	234 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Sodium (hypernatremia) · Grade 1	18 Participants	20 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Sodium (hypernatremia) · Grade 2	2 Participants	5 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Sodium (hypernatremia) · Grade 3	3 Participants	2 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Sodium (hypernatremia) · Grade 4	2 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Sodium (hyponatremia) · Grade 0	186 Participants	199 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Sodium (hyponatremia) · Grade 1	52 Participants	42 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Sodium (hyponatremia) · Grade 2	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Sodium (hyponatremia) · Grade 3	19 Participants	16 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Sodium (hyponatremia) · Grade 4	2 Participants	4 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Total Bilirubin · Grade 0	153 Participants	178 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Total Bilirubin · Grade 1	55 Participants	42 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Total Bilirubin · Grade 2	43 Participants	33 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Total Bilirubin · Grade 3	7 Participants	3 Participants
Percentage of Participants With Worst-case On-therapy Chemistry Toxicities Total Bilirubin · Grade 4	2 Participants	5 Participants

SECONDARY outcome

Timeframe: From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)

Population: Safety Population. Only those participants contributing data at the indicated time point were analyzed.

The severity of hematologic parameters was graded according to NCI CTCAE version 3.0: Grade 0 (No adverse event or within normal limits), Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (life-threatening). Hematology data included: Hemoglobin, Platelet count, Total Neutrophils (Total ANC - Total Absolute Neutrophil Count) and White Blood Cell count.

Outcome measures

Outcome measures
Measure	CapeOx Plus Lapatinib n=261 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=263 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Hemoglobin · Grade 0	18 Participants	22 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Hemoglobin · Grade 1	104 Participants	121 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Hemoglobin · Grade 2	104 Participants	93 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Hemoglobin · Grade 3	35 Participants	27 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Hemoglobin · Grade 4	0 Participants	0 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Platelet count · Grade 0	97 Participants	116 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Platelet count · Grade 1	95 Participants	86 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Platelet count · Grade 2	43 Participants	27 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Platelet count · Grade 3	21 Participants	30 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Platelet count · Grade 4	5 Participants	2 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Total Neutrophils (Total ANC - Total Absolute Neutrophil Count) · Grade 0	112 Participants	127 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Total Neutrophils (Total ANC - Total Absolute Neutrophil Count) · Grade 1	42 Participants	45 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Total Neutrophils (Total ANC - Total Absolute Neutrophil Count) · Grade 2	58 Participants	48 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Total Neutrophils (Total ANC - Total Absolute Neutrophil Count) · Grade 3	22 Participants	27 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities Total Neutrophils (Total ANC - Total Absolute Neutrophil Count) · Grade 4	6 Participants	2 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities White Blood Cell count · Grade 0	126 Participants	136 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities White Blood Cell count · Grade 1	71 Participants	74 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities White Blood Cell count · Grade 2	50 Participants	47 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities White Blood Cell count · Grade 3	12 Participants	4 Participants
Percentage of Participants With Worst-case On-therapy Hematologic Toxicities White Blood Cell count · Grade 4	2 Participants	1 Participants

Adverse Events

CapeOx Plus Lapatinib

Serious events: 73 serious events

Other events: 243 other events

Deaths: 42 deaths

CapeOx Plus Placebo

Serious events: 54 serious events

Other events: 214 other events

Deaths: 40 deaths

CapeOx Plus Lapatinib (Long Term Follow-up (LTFU))

Serious events: 0 serious events

Other events: 0 other events

Deaths: 199 deaths

CapeOx Plus Placebo (Long Term Follow-up (LTFU))

Serious events: 0 serious events

Other events: 0 other events

Deaths: 189 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: + 1 862 778 8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	CapeOx Plus Lapatinib n=61 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.	CapeOx Plus Placebo n=61 Participants Participants received a combination therapy consisting of: 1. Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2. Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator's discretion. 3. Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Global health status/QoL	-6.6 Scores on a scale Standard Deviation 24.63	-5.1 Scores on a scale Standard Deviation 23.97
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Physical functioning	-9.4 Scores on a scale Standard Deviation 25.61	-9.6 Scores on a scale Standard Deviation 22.33
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Role functioning	-8.9 Scores on a scale Standard Deviation 34.64	-11.7 Scores on a scale Standard Deviation 31.67
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Emotional functioning	-3.8 Scores on a scale Standard Deviation 27.37	-7.1 Scores on a scale Standard Deviation 23.61
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Cognitive functioning	-7.4 Scores on a scale Standard Deviation 21.41	-10.4 Scores on a scale Standard Deviation 21.98
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Social functioning	-4.9 Scores on a scale Standard Deviation 32.54	-0.5 Scores on a scale Standard Deviation 26.52
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Fatigue	5.5 Scores on a scale Standard Deviation 26.42	5.6 Scores on a scale Standard Deviation 25.30
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Nausea and vomiting	3.3 Scores on a scale Standard Deviation 27.69	4.4 Scores on a scale Standard Deviation 20.62
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Pain	4.9 Scores on a scale Standard Deviation 30.48	7.7 Scores on a scale Standard Deviation 30.06
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Dyspnoea	6.7 Scores on a scale Standard Deviation 26.61	7.8 Scores on a scale Standard Deviation 27.70
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Insomnia	0.0 Scores on a scale Standard Deviation 33.33	3.3 Scores on a scale Standard Deviation 35.09
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Appetite loss	-0.5 Scores on a scale Standard Deviation 39.20	5.5 Scores on a scale Standard Deviation 37.11
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Constipation	-0.6 Scores on a scale Standard Deviation 32.18	-3.8 Scores on a scale Standard Deviation 34.48
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Diarrhoea	4.4 Scores on a scale Standard Deviation 29.49	1.1 Scores on a scale Standard Deviation 23.95
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores Financial difficulties	0.0 Scores on a scale Standard Deviation 29.81	0.6 Scores on a scale Standard Deviation 24.16