Trial Outcomes & Findings for A Study of Herceptin (Trastuzumab) in Combination With Cisplatin/Capecitabine Chemotherapy in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Gastric or Gastro-Esophageal Junction Cancer (NCT NCT01450696)

Last Updated: 2016-11-28

Results Overview

The percentage of participants who died as of the analysis data cutoff date of 13 February 2015 was reported among participants from the FAS with available data.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

296 participants

Primary outcome timeframe

From date of randomization until death or premature withdrawal (up to approximately 31 months or data cutoff date of 13 February 2015)

Results posted on

2016-11-28

Participant Flow

A total of 248 participants (124 participants per arm) were randomized in the study up to data cutoff date of 13 February 2015, and 48 additional participants (24 participants per arm) were randomized between data cutoff date of 13 February 2015 and end of study (25 August 2015) for additional safety data.

Participant milestones

Participant milestones
Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) Participants received Herceptin at a loading dose of 8 milligrams per kilogram (mg/kg) on Day 1 of Cycle 1 followed by 6 mg/kg every three weeks (q3w) as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 milligrams per meter-squared (mg/m\^2) intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
Overall Study STARTED	148	148
Overall Study Treated (Safety Population)	147	147
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	148	148

Reasons for withdrawal

Reasons for withdrawal
Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) Participants received Herceptin at a loading dose of 8 milligrams per kilogram (mg/kg) on Day 1 of Cycle 1 followed by 6 mg/kg every three weeks (q3w) as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 milligrams per meter-squared (mg/m\^2) intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
Overall Study Never Treated	1	1
Overall Study Death	77	84
Overall Study Lost to Follow-up	3	3
Overall Study Non-Compliance	1	0
Overall Study Withdrawal by Subject	13	2
Overall Study Study Terminated by Sponsor	53	58

Baseline Characteristics

A Study of Herceptin (Trastuzumab) in Combination With Cisplatin/Capecitabine Chemotherapy in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Gastric or Gastro-Esophageal Junction Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) n=148 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg q3w as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) n=148 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Total n=296 Participants Total of all reporting groups
Age, Continuous	59.5 years STANDARD_DEVIATION 10.6 • n=5 Participants	62.4 years STANDARD_DEVIATION 10.7 • n=7 Participants	60.0 years STANDARD_DEVIATION 10.7 • n=5 Participants
Sex: Female, Male Female	32 Participants n=5 Participants	37 Participants n=7 Participants	69 Participants n=5 Participants
Sex: Female, Male Male	116 Participants n=5 Participants	111 Participants n=7 Participants	227 Participants n=5 Participants

PRIMARY outcome

Timeframe: From date of randomization until death or premature withdrawal (up to approximately 31 months or data cutoff date of 13 February 2015)

Population: FAS population. Here, number of participants analyzed reflects the number of participants who were evaluable for this outcome measure.

The percentage of participants who died as of the analysis data cutoff date of 13 February 2015 was reported among participants from the FAS with available data.

Outcome measures

Outcome measures
Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) n=124 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg q3w as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) n=124 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
Percentage of Participants Who Died - FAS	46.8 percentage of participants	54.0 percentage of participants

PRIMARY outcome

Timeframe: From date of randomization until death or premature withdrawal (up to approximately 31 months or data cutoff date of 13 February 2015)

Population: FAS population. Here, number of participants analyzed reflects the number of participants who were evaluable for this outcome measure.

Overall survival was defined as the time from the date of randomization to the date of death from any cause. Overall survival was estimated among participants from the FAS using the Kaplan-Meier approach. The 95 percent (%) confidence interval (CI) for median was computed using the method of Brookmeyer and Crowley.

Outcome measures

Outcome measures
Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) n=124 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg q3w as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) n=124 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
Overall Survival - FAS	12.485 months Interval 10.086 to 13.864	10.612 months Interval 9.363 to 12.419

SECONDARY outcome

Timeframe: From date of randomization until death or premature withdrawal (up to approximately 31 months or data cutoff date of 13 February 2015)

Population: The PPS included all participants who were found to have a trastuzumab minimum plasma concentration (Cmin) less than (\<) 12 micrograms per milliliter (μg/mL) on treatment Day 21 of Cycle 1 following the initial loading dose of 8 mg/kg.

The percentage of participants who died as of the analysis data cutoff date of 13 February 2015 was reported among participants from the PPS.

Outcome measures

Outcome measures
Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) n=33 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg q3w as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) n=32 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
Percentage of Participants Who Died - Per Protocol Set (PPS)	51.5 percentage of participants	59.4 percentage of participants

SECONDARY outcome

Timeframe: From date of randomization until death or premature withdrawal (up to approximately 31 months or data cutoff date of 13 February 2015)

Population: PPS population.

Overall survival was defined as the time from the date of randomization to the date of death from any cause. Overall survival was estimated among participants from the PPS using the Kaplan-Meier approach. The 95% CI for median was computed using the method of Brookmeyer and Crowley.

Outcome measures

Outcome measures
Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) n=33 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg q3w as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) n=32 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
Overall Survival - PPS	10.809 months Interval 8.082 to 14.752	9.363 months Interval 5.552 to 14.357

SECONDARY outcome

Timeframe: From date of randomization until first occurrence of disease progression or death; assessed every 6 weeks (up to approximately 31 months or data cutoff date of 13 February 2015)

Population: PPS population.

Disease progression was defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as a ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including Baseline (nadir). In addition to the relative increase of 20%, the sum was also required to demonstrate an absolute increase of ≥5 millimeters (mm). The percentage of participants who died or experienced disease progression as of the analysis data cutoff date of 13 February 2015 was reported among participants from the PPS.

Outcome measures

Outcome measures
Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) n=33 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg q3w as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) n=32 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
Percentage of Participants With Disease Progression or Death - PPS	75.8 percentage of participants	81.3 percentage of participants

SECONDARY outcome

Timeframe: From date of randomization until first occurrence of disease progression or death; assessed every 6 weeks (up to approximately 31 months or data cutoff date of 13 February 2015)

Population: PPS population.

Progression-free survival was defined as the time between the day of randomization and the date of first documentation of disease progression or date of death, whichever occurred first, measured following RECIST Version 1.1 criteria. Disease progression was defined as a ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including Baseline (nadir). In addition to the relative increase of 20%, the sum was also required to demonstrate an absolute increase of ≥5 mm. The 95% CI for median was computed using the method of Brookmeyer and Crowley.

Outcome measures

Outcome measures
Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) n=33 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg q3w as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) n=32 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
Progression-Free Survival - PPS	5.388 months Interval 2.793 to 7.721	4.370 months Interval 2.727 to 6.834

SECONDARY outcome

Timeframe: From date of randomization until first occurrence of disease progression or death; assessed every 6 weeks (up to approximately 31 months or data cutoff date of 13 February 2015)

Population: PPS population.

Objective response was defined as the occurrence of either a complete response (CR) or partial response (PR) as determined by RECIST Version 1.1 based on investigator assessment. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) were required to have reduction in short axis to \<10 mm. PR was defined as a ≥30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters. The 95% CI was constructed using Blyth-Still-Casella method.

Outcome measures

Outcome measures
Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) n=33 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg q3w as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) n=32 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
Percentage of Participants With Objective Response - PPS	57.6 percentage of participants Interval 40.12 to 73.16	50.0 percentage of participants Interval 31.89 to 68.11

SECONDARY outcome

Timeframe: Day 21 of Cycle 1, 2, 3, 4, 5, 7, 9, 11 (cycle length = 21 days)

Population: FAS population. Here, number of participants analyzed reflects the number of participants who were evaluable for this outcome measure. Here also, "n" reflects the number of participants who were evaluable for each category in the respective arms.

Cmin samples were obtained in all participants randomized to receive Herceptin (FAS). The observed Cmin was recorded, averaged among all participants, and expressed in μg/mL.

Outcome measures

Outcome measures
Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) n=100 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg q3w as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) n=99 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
Trastuzumab Cmin on Day 21 of Cycles 1 to 11 - FAS Cycle 3 (n=77,71)	23.2 μg/mL Standard Deviation 11.8	40.7 μg/mL Standard Deviation 20.6
Trastuzumab Cmin on Day 21 of Cycles 1 to 11 - FAS Cycle 4 (n=73,61)	25.9 μg/mL Standard Deviation 12.1	47.6 μg/mL Standard Deviation 20.2
Trastuzumab Cmin on Day 21 of Cycles 1 to 11 - FAS Cycle 7 (n=51,44)	31.4 μg/mL Standard Deviation 14.2	58.1 μg/mL Standard Deviation 27.6
Trastuzumab Cmin on Day 21 of Cycles 1 to 11 - FAS Cycle 9 (n=31,24)	33.7 μg/mL Standard Deviation 17.6	61.0 μg/mL Standard Deviation 23.9
Trastuzumab Cmin on Day 21 of Cycles 1 to 11 - FAS Cycle 11 (n=24,16)	32.5 μg/mL Standard Deviation 14.7	68.4 μg/mL Standard Deviation 35.9
Trastuzumab Cmin on Day 21 of Cycles 1 to 11 - FAS Cycle 1 (n=100,99)	17.1 μg/mL Standard Deviation 14.3	18.1 μg/mL Standard Deviation 18.1
Trastuzumab Cmin on Day 21 of Cycles 1 to 11 - FAS Cycle 2 (n=93,76)	19.2 μg/mL Standard Deviation 8.8	35.3 μg/mL Standard Deviation 19.4
Trastuzumab Cmin on Day 21 of Cycles 1 to 11 - FAS Cycle 5 (n=70,60)	26.7 μg/mL Standard Deviation 10.6	49.3 μg/mL Standard Deviation 23.2

SECONDARY outcome

Timeframe: Pre-dose (0 minutes) and within 15 minutes after end of 2-hour Herceptin infusion on Day 1 of Cycle 1 (cycle length = 21 days)

Trastuzumab serum concentration samples were obtained in all participants randomized to receive Herceptin (FAS). The observed concentration values were recorded, averaged among all participants, and expressed in μg/mL.

Outcome measures

Outcome measures
Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) n=110 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg q3w as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) n=111 Participants Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
Trastuzumab Serum Concentration on Day 1 of Cycle 1 - FAS End of infusion (n=110,111)	126 μg/mL Standard Deviation 59.6	137 μg/mL Standard Deviation 55.7
Trastuzumab Serum Concentration on Day 1 of Cycle 1 - FAS Pre-dose (n=109,110)	0.168 μg/mL Standard Deviation 1.69	0.0204 μg/mL Standard Deviation 0.123

Adverse Events

Capecitabine + Cisplatin + Herceptin (6 mg/kg)

Serious events: 35 serious events

Other events: 123 other events

Deaths: 0 deaths

Capecitabine + Cisplatin + Herceptin (10 mg/kg)

Serious events: 38 serious events

Other events: 122 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Capecitabine + Cisplatin + Herceptin (6 mg/kg) n=147 participants at risk Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg q3w as standard of care from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).	Capecitabine + Cisplatin + Herceptin (10 mg/kg) n=147 participants at risk Participants received Herceptin at a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 10 mg/kg q3w from Day 1 of Cycle 2 until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason (cycle length = 21 days). Participants also received cisplatin 80 mg/m\^2 intravenously q3w plus capecitabine 800 mg/m\^2 orally twice daily for 14 days q3w for up to 6 treatment cycles (Cycles 1 to 6).
Blood and lymphatic system disorders Anaemia	32.0% 47/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	27.2% 40/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Blood and lymphatic system disorders Leukopenia	17.7% 26/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	16.3% 24/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Blood and lymphatic system disorders Neutropenia	41.5% 61/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	46.9% 69/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Blood and lymphatic system disorders Thrombocytopenia	9.5% 14/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	9.5% 14/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Gastrointestinal disorders Abdominal pain	5.4% 8/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	4.8% 7/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Gastrointestinal disorders Abdominal pain upper	8.2% 12/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	7.5% 11/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Gastrointestinal disorders Constipation	12.9% 19/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	17.0% 25/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Gastrointestinal disorders Diarrhoea	16.3% 24/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	20.4% 30/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Gastrointestinal disorders Nausea	37.4% 55/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	37.4% 55/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Gastrointestinal disorders Vomiting	24.5% 36/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	28.6% 42/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
General disorders Asthenia	10.9% 16/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	7.5% 11/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
General disorders Fatigue	17.0% 25/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	15.6% 23/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
General disorders Oedema peripheral	6.1% 9/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	4.1% 6/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
General disorders Pyrexia	10.2% 15/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	9.5% 14/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Investigations Weight decreased	6.8% 10/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	11.6% 17/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Metabolism and nutrition disorders Decreased appetite	21.8% 32/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	18.4% 27/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Metabolism and nutrition disorders Hypoalbuminaemia	3.4% 5/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	6.8% 10/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Metabolism and nutrition disorders Hypocalcaemia	6.1% 9/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	6.1% 9/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Metabolism and nutrition disorders Hypokalaemia	4.1% 6/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	10.2% 15/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Metabolism and nutrition disorders Hyponatraemia	2.0% 3/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	5.4% 8/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Nervous system disorders Dizziness	5.4% 8/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	1.4% 2/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Renal and urinary disorders Chronic kidney disease	4.8% 7/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	8.8% 13/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Renal and urinary disorders Renal failure	3.4% 5/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	5.4% 8/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Respiratory, thoracic and mediastinal disorders Cough	6.1% 9/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	2.0% 3/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	9.5% 14/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.	13.6% 20/147 • From date of randomization until 6 months after last dose of study drug or end of study (up to approximately 32 months or final data collection date of 25 August 2015) Safety evaluable population included all participants who were randomized and received at least one dose of any component of study treatment.