Trial Outcomes & Findings for A Study of T-DXd in Participants With or Without Brain Metastasis Who Have Previously Treated Advanced or Metastatic HER2 Positive Breast Cancer (NCT NCT04739761)

Last Updated: 2026-02-11

Results Overview

The ORR is defined as the percentage (%) of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

506 participants

Primary outcome timeframe

From first dose (Day 1) to progression of disease (up to 2 years 7 months)

Results posted on

2026-02-11

Participant Flow

Participants were enrolled in this study from 22 June 2021 (First participant in) and the analyses presented in this results form are based on a final data cut-off of 08 February 2024 and final database lock of 22 April 2024.

Participants meeting eligibility criteria predefined in protocol were enrolled in the study. Assessments were to be performed as per the schedule of the assessments. However, 2 participants were in early withdrawal status since they completed enrollment but never received any treatment.

Participant milestones

Participant milestones
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Overall Study STARTED	241	263
Overall Study COMPLETED	30	34
Overall Study NOT COMPLETED	211	229

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Overall Study Participant ongoing study at data cutoff date of 08Feb24	167	189
Overall Study By complete response from the participant	1	0
Overall Study Lost to Follow-up	3	3
Overall Study Death	13	13
Overall Study Participant reports worsening of the general critical condition and will not continue	0	1
Overall Study Participant is in poor health and will not come to the study site	0	1
Overall Study Progression confirmed in magnetic resonance imaging	0	1
Overall Study Adverse Event	0	3
Overall Study Participant decision	1	0
Overall Study Sub investigator decision approved by medical monitor	1	0
Overall Study Participant immediately started next line of treatment	1	0
Overall Study Participant's decision because the treatment makes them anxious	1	0
Overall Study Lack of clinical benefit	1	0
Overall Study Disease progression	5	5
Overall Study Withdrawal by Subject	14	13
Overall Study Protocol Violation	1	0
Overall Study Physician Decision	2	0

Baseline Characteristics

A Study of T-DXd in Participants With or Without Brain Metastasis Who Have Previously Treated Advanced or Metastatic HER2 Positive Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=241 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=263 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.	Total n=504 Participants Total of all reporting groups
Age, Continuous	54.8 Years STANDARD_DEVIATION 11.9 • n=4 Participants	52.8 Years STANDARD_DEVIATION 11.2 • n=4 Participants	53.8 Years STANDARD_DEVIATION 11.6 • n=8 Participants
Sex: Female, Male Female	241 Participants n=4 Participants	263 Participants n=4 Participants	504 Participants n=8 Participants
Sex: Female, Male Male	0 Participants n=4 Participants	0 Participants n=4 Participants	0 Participants n=8 Participants
Race/Ethnicity, Customized Asian	15 Participants n=4 Participants	19 Participants n=4 Participants	34 Participants n=8 Participants
Race/Ethnicity, Customized Black or African American	2 Participants n=4 Participants	4 Participants n=4 Participants	6 Participants n=8 Participants
Race/Ethnicity, Customized White	209 Participants n=4 Participants	231 Participants n=4 Participants	440 Participants n=8 Participants
Race/Ethnicity, Customized Other	13 Participants n=4 Participants	6 Participants n=4 Participants	19 Participants n=8 Participants
Race/Ethnicity, Customized Not reported	1 Participants n=4 Participants	1 Participants n=4 Participants	2 Participants n=8 Participants
Race/Ethnicity, Customized Missing	2 Participants n=4 Participants	3 Participants n=4 Participants	5 Participants n=8 Participants
Race/Ethnicity, Customized Hispanic or Latino	20 Participants n=4 Participants	15 Participants n=4 Participants	35 Participants n=8 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	219 Participants n=4 Participants	245 Participants n=4 Participants	464 Participants n=8 Participants

PRIMARY outcome

Timeframe: From first dose (Day 1) to progression of disease (up to 2 years 7 months)

Population: The full analysis set (FAS) included all participants who were enrolled in the study and received at least 1 dose of treatment.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=241 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Objective Response Rate (ORR) in Cohort 1 (Participants Without Brain Metastasis at Baseline)	62.7 Percentage of participants Interval 56.5 to 68.8	—

PRIMARY outcome

Timeframe: At 12 months

Population: The FAS set included all the participants who were enrolled in the study and received at least 1 dose of treatment.

The PFS rate is the percentage of participants alive and free of disease progression at 12 months, estimated by the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=263 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Progression-free Survival (PFS) Rate at 12 Months in Cohort 2 (Participants With Brain Metastasis at Baseline)	61.6 Percentage of participants Interval 54.92 to 67.61	—

SECONDARY outcome

Timeframe: At 12 Months

Population: The FAS included all participants who were enrolled in the study and received at least 1 dose of treatment.

Survival rate is the percentage of participants alive at 12 months, estimated by the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=241 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=263 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Survival Rate at 12 Months	90.6 Percentage of Participants Interval 85.97 to 93.8	90.3 Percentage of Participants Interval 85.89 to 93.41

SECONDARY outcome

Timeframe: From first dose (Day 1) to progression of disease (up to 2 years 7 months)

Population: The FAS included all the participants who were enrolled in the study and received at least 1 dose of treatment.

The ORR is defined as the percentage of participants who have a confirmed CR or confirmed PR, as determined by ICR per RECIST 1.1.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=263 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Objective Response Rate in Cohort 2 (Participants With Brain Metastasis at Baseline)	51.7 Percentage of participants Interval 45.7 to 57.8	—

SECONDARY outcome

Timeframe: From the date of first documented confirmed response until date of documented progression (up to 2 years 7 months)

Population: The FAS included all participants who were enrolled in the study and received at least 1 dose of treatment.

Duration of response is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1 as assessed by ICR or death due to any cause.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=241 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=263 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Duration of Response (DoR)	NA Months Interval 9.5 to In line with methods prespecified in the SAP, the median and 75th percentile were not calculable because \<50% of participants had an event.	NA Months Interval 8.1 to In line with methods prespecified in the SAP, the median and 75th percentile were not calculable because \<50% of participants had an event.

SECONDARY outcome

Timeframe: From first dose (Day 1) to progression of disease (up to 2 years 7 months)

Population: The FAS included all the participants who were enrolled in the study and received at least 1 dose of treatment.

Time to progression by RECIST 1.1 per ICR is defined as the time from the date of the first dose of study intervention to the date of documented disease progression.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=241 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=263 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Time to Progression	NA Months As pre-specified in SAP, median and 95% confidence interval (CI) were not calculable where less than 50% of participants had events.	NA Months As pre-specified in SAP, median and 95% CI were not calculable where less than 50% of participants had events.

SECONDARY outcome

Timeframe: From the date of first dose of a subsequent therapy until date of last dose of therapy (up to 2 years 7 months)

Population: The Full analysis set-subsequent therapy included all participants in FAS had RECIST progression, as assessed by investigator, during the study and received subsequent anti-cancer therapy. The "number analyzed" refers to the number of participants included in analysis in specific time points in each row.

Duration of treatment on subsequent therapy is defined as the time from the date of first dose of a subsequent therapy until date of the last dose of that therapy.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=68 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=66 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Duration of Treatment on Subsequent Lines of Therapy First subsequent line of therapy	4.4 Months Interval 3.3 to 6.3	6.5 Months Interval 3.9 to 8.8
Duration of Treatment on Subsequent Lines of Therapy First completed subsequent line of therapy	3.0 Months Interval 2.1 to 3.5	3.0 Months Interval 2.1 to 3.5

SECONDARY outcome

Timeframe: At 12 Months

Population: The FAS included all the participants who were enrolled in the study and received at least 1 dose of treatment.

Second progression-free survival rate is the percentage of participants alive and free from a second progression on next-line treatment at 12 months, estimated by the Kaplan-Meier method. The second progression is defined as the earliest progression event subsequent to the first anti-cancer therapy after the initial progression.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=241 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=263 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Second Progression-Free Survival Rate at 12 Months	81.1 Percentage of Participants Interval 74.85 to 85.92	83.1 Percentage of Participants Interval 77.46 to 87.44

SECONDARY outcome

Timeframe: From first dose (Day 1) to end of treatment (up to 2 years 7 months)

Population: The FAS included all the participants who were involved in the study and received at least 1 dose of treatment.

The incidence rate is defined as proportion of participants with new symptomatic CNS metastases during treatment period in participants without symptomatic CNS metastasis at baseline.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=241 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Incidence of New Symptomatic Central Nervous System (CNS) Metastasis During Treatment Without CNS Metastasis at Baseline (Cohort 1)	0.017 Proportion of participants Interval 0.00452 to 0.0425	—

SECONDARY outcome

Timeframe: From date of first documented isolated CNS progression to the date of the next documented disease progression (up to 2 years 7 months)

Population: The FAS for isolated CNS progression analyses included participants that received at least 1 dose of treatment who developed isolated CNS progression, per investigator assessment, received local therapy, and continued on protocol therapy.

The time to next progression is defined as the time from the date of the first documented isolated CNS progression to the date of the next documented disease progression (CNS or extracranial) per RECIST 1.1 or death and has been summarized descriptively in participants who have developed isolated CNS progression, receive local therapy, and continue on protocol therapy.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=2 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=18 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Time to Next Progression (CNS or Extracranial) or Death	3.7 Months Interval 3.7 to As pre-specified in SAP, upper limit of 95% CI was not calculable where less than 50% of participants had events.	0.2 Months Interval 0.1 to 0.3

SECONDARY outcome

Timeframe: From the date of the first documented isolated CNS progression to the date of the next documented CNS disease progression (up to 2 years 7 months)

Site of next progression (CNS \[CNS RECIST 1.1\] or extracranial \[systemic RECIST 1.1\] in participants who developed isolated CNS progression, received local therapy, and continued on protocol therapy.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=2 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=18 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Site (CNS vs Extracranial vs Both) of Next Progression CNS	0 Participants	6 Participants
Site (CNS vs Extracranial vs Both) of Next Progression Extracranial	0 Participants	2 Participants
Site (CNS vs Extracranial vs Both) of Next Progression Both	0 Participants	4 Participants

SECONDARY outcome

Timeframe: At 12 Months

Population: The FAS included all the participants who were enrolled in the study and received at least 1 dose of treatment.

Central nervous system progression free survival rate is the percentage of participants free from central nervous system progression at 12 months, estimated by the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=263 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Central Nervous System Progression-free Survival Rate at 12 Months in Participants With Brain Metastasis at Baseline (Cohort 2)	58.9 Percentage of Participants Interval 51.93 to 65.3	—

SECONDARY outcome

Timeframe: From first dose (Day 1) to the date of documented new CNS lesions (up to 2 years 7 months)

Population: The FAS included all participants who were enrolled in the study and received at least 1 dose of treatment.

The time to new CNS lesions is defined as the time from the date of the first dose of study intervention to the date of documented new CNS lesions by RECIST 1.1 per ICR.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=263 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Time to New CNS Lesions in Participants With Brain Metastasis at Baseline (Cohort 2)	NA Months As pre-specified in SAP, median and 95% CI were not calculable where less than 50% of participants had events.	—

SECONDARY outcome

Timeframe: From first dose (Day 1) until CNS progression of disease (up to 2 years 7 months)

Population: The FAS included all participants who were enrolled in the study and received at least 1 dose of treatment. Here, number of participants analyzed represents participants who had measurable CNS disease at baseline.

The CNS ORR is defined as the percentage of participants with measurable brain metastasis at baseline who have a confirmed CR or confirmed PR of brain lesions, as determined by ICR per CNS RECIST 1.1.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=138 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Central Nervous System Objective Response Rate in Participants With Brain Metastasis at Baseline by ICR (Cohort 2)	71.7 Percentage of participants Interval 64.2 to 79.3	—

SECONDARY outcome

Timeframe: From date of first documented confirmed CNS response until CNS progression of disease (up to 2 years 7 months)

Population: The FAS included all participants who were enrolled in the study and received at least 1 dose of treatment.

The CNS DoR is defined as the time from the date of first documented confirmed CNS response until date of documented CNS progression per CNS RECIST 1.1 as assessed by ICR or death due to any cause.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=263 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Central Nervous System Duration of Response in Participants With Brain Metastasis at Baseline (Cohort 2)	NA Months Interval 6.9 to In line with methods prespecified in the SAP, the median and 75th percentile were not calculable because \<50% of participants had an event.	—

SECONDARY outcome

Timeframe: Time from first dose up to 47 days after last dose, or prior to starting any subsequent therapy, or for up to 2 years 7 months, whichever occurred first

Population: The safety analysis set included all the participants who have received at least 1 dose of treatment. The "overall number of participants analyzed" represents only participants who were not missing baseline data. The "number analyzed" refers to the number of participants included in each row for each response category.

The EORTC QLQ-C30 is a 30-item questionnaire for cancer assessment. Increased scores indicate improvement; decreased scores indicate deterioration. Physical function: ≥+9= improvement, ≤-10=deterioration, otherwise=no change; Role functioning: ≤-6=deterioration, otherwise=no change; Social functioning: ≥+8=improvement, ≤-7=deterioration, otherwise=no change; Cognitive functioning: ≥+ 5=improvement, ≤- 4=deterioration, otherwise=no change; Global Health Status: ≥+2=improvement, ≤-8=deterioration, otherwise=no change; Fatigue: ≥+8=improvement, ≤-8=deterioration, otherwise=no change; Nausea and vomiting: ≤-11=deterioration, otherwise=no change; Appetite loss: ≤-14=deterioration, otherwise=no change; rest of scales: ≥+10=improvement, ≤-10=deterioration, otherwise=no change. Best on treatment response is best response category (improvement, no change, and deterioration) achieved by participants between first dose and 47 days after last dose, and prior to starting any anticancer therapy.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=207 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=224 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Fatigue: Best on-treatment response: Improvement	97 Participants	119 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Fatigue: Best on-treatment response: No change	65 Participants	68 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Fatigue: Best on-treatment response: No follow-up	17 Participants	14 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Fatigue: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Financial difficulties: Best on-treatment response: Deterioration	7 Participants	9 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Financial difficulties: Best on-treatment response: Improvement	46 Participants	58 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Financial difficulties: Best on-treatment response: No change	135 Participants	140 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Financial difficulties: Best on-treatment response: No follow-up	18 Participants	16 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Financial difficulties: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Global health status / QoL: Best on-treatment response: Deterioration	28 Participants	34 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Global health status / QoL: Best on-treatment response: Improvement	86 Participants	111 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Global health status / QoL: Best on-treatment response: No change	75 Participants	65 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Global health status / QoL: Best on-treatment response: No follow-up	18 Participants	13 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Global health status / QoL: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Insomnia: Best on-treatment response: Deterioration	8 Participants	7 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Insomnia: Best on-treatment response: Improvement	87 Participants	103 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Insomnia: Best on-treatment response: No change	92 Participants	98 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Insomnia: Best on-treatment response: No follow-up	20 Participants	16 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Insomnia: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Nausea and vomiting: Best on-treatment response: Deterioration	17 Participants	9 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Nausea and vomiting: Best on-treatment response: No change	167 Participants	201 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Nausea and vomiting: Best on-treatment response: No follow-up	23 Participants	14 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Nausea and vomiting: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Pain: Best on-treatment response: Deterioration	4 Participants	8 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Pain: Best on-treatment response: Improvement	91 Participants	115 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Pain: Best on-treatment response: No change	94 Participants	89 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Pain: Best on-treatment response: No follow-up	18 Participants	12 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Pain: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Physical Functioning: Best on-treatment response: Deterioration	10 Participants	13 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Physical Functioning: Best on-treatment response: Improvement	54 Participants	71 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Physical Functioning: Best on-treatment response: No change	122 Participants	124 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Physical Functioning: Best on-treatment response: No follow-up	21 Participants	16 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Physical Functioning: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Role Functioning: Best on-treatment response: Deterioration	20 Participants	15 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Role Functioning: Best on-treatment response: No change	167 Participants	197 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Appetite loss: Best on-treatment response: Deterioration	15 Participants	9 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Appetite loss: Best on-treatment response: No change	171 Participants	200 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Appetite loss: Best on-treatment response: No follow-up	21 Participants	15 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Appetite loss: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Cognitive Functioning: Best on-treatment response: Deterioration	16 Participants	12 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Cognitive Functioning: Best on-treatment response: Improvement	57 Participants	87 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Cognitive Functioning: Best on-treatment response: No change	116 Participants	107 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Cognitive Functioning: Best on-treatment response: No follow-up	18 Participants	17 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Cognitive Functioning: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Constipation: Best on-treatment response: Deterioration	18 Participants	13 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Constipation: Best on-treatment response: Improvement	36 Participants	59 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Constipation: Best on-treatment response: No change	134 Participants	139 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Constipation: Best on-treatment response: No follow-up	19 Participants	13 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Constipation: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Diarrhoea: Best on-treatment response: Deterioration	2 Participants	4 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Role Functioning: Best on-treatment response: No follow-up	20 Participants	12 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Role Functioning: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Social Functioning: Best on-treatment response: Deterioration	19 Participants	16 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Social Functioning: Best on-treatment response: Improvement	81 Participants	109 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Social Functioning: Best on-treatment response: No change	87 Participants	83 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Social Functioning: Best on-treatment response: No follow-up	20 Participants	15 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Social Functioning: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Diarrhoea: Best on-treatment response: Improvement	32 Participants	28 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Diarrhoea: Best on-treatment response: No change	153 Participants	174 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Diarrhoea: Best on-treatment response: No follow-up	20 Participants	17 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Diarrhoea: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Dyspnea: Best on-treatment response: Deterioration	6 Participants	5 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Dyspnea: Best on-treatment response: Improvement	48 Participants	49 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Dyspnea: Best on-treatment response: No change	131 Participants	154 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Dyspnea: Cycle Best on-treatment response: No follow-up	22 Participants	16 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Dyspnea: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Emotional Functioning: Best on-treatment response: Deterioration	4 Participants	7 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Emotional Functioning: Best on-treatment response: Improvement	109 Participants	98 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Emotional Functioning: Best on-treatment response: No change	77 Participants	103 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Emotional Functioning: Best on-treatment response: No follow-up	17 Participants	15 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Emotional Functioning: Best on-treatment response: Missing	0 Participants	0 Participants
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Fatigue: Best on-treatment response: Deterioration	28 Participants	23 Participants

SECONDARY outcome

Timeframe: Time from first dose up to 47 days after last dose, or prior to starting any subsequent therapy, or for up to 2 years 7 months, whichever occurred first

Population: The FAS included all the participants who were enrolled in the study and received at least 1 dose of treatment.

The NANO scale is a clinician-reported assessment of neurologic functioning in neuro-oncology participants. The instrument captures 9 domains (gait, strength, ataxia, sensation, visual fields, facial strength, language, level of consciousness, and behavior) and was developed to provide a simple, objective assessment of neurologic function that would be combined with radiographic assessment to provide an overall outcome assessment for neuro-oncology participants in clinical trials and in daily practice. The soring scale for Gait consists of score range 0-3, Strength consists of score range 0-2, ataxia (upper extremity) consists of scale range 0-2 and sensation as 0. Higher scores indicate worse neurologic function. The response categories reported are changes from first post-baseline score to worst on-treatment score at any point of treatment.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=236 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=254 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Number of Participants With Neurologic Assessment in Neuro-Oncology Scale (NANO Scale) Neurologic stability	217 Participants	220 Participants
Number of Participants With Neurologic Assessment in Neuro-Oncology Scale (NANO Scale) Neurologic progression	16 Participants	25 Participants
Number of Participants With Neurologic Assessment in Neuro-Oncology Scale (NANO Scale) Not assessed	0 Participants	5 Participants
Number of Participants With Neurologic Assessment in Neuro-Oncology Scale (NANO Scale) Non-evaluable	0 Participants	0 Participants
Number of Participants With Neurologic Assessment in Neuro-Oncology Scale (NANO Scale) Neurologic response	3 Participants	4 Participants

SECONDARY outcome

Timeframe: Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)

Population: The FAS included all the participants who were enrolled in the study and received at least 1 dose of treatment. The "number analyzed" refers to the number of participants included in the analysis at specific time points in each row.

The PAL is a computerized, self-completed cognitive test used to capture cognitive function, including attention, memory, and executive function. This gamified test included PAL and was a low-burden, highly sensitive, precise measure of cognitive function. The PALFAMS is the number of times a participant chose the correct box on their first attempt when recalling the pattern locations, calculated across all assessed trials. A higher number of events of selecting correct boxes indicates better cognitive function. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=206 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=238 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Cognitive Functions Tests: Paired Associates Learning (PAL) First Attempt Memory Score (PALFAMS) PAL first attempt Memory score: Cycle 17 Day 1	13.2 Number of Events Standard Deviation 4.61	12.2 Number of Events Standard Deviation 5.07
Cognitive Functions Tests: Paired Associates Learning (PAL) First Attempt Memory Score (PALFAMS) Paired Assistance Learning (PAL) first attempt Memory score: Baseline	10.9 Number of Events Standard Deviation 4.63	10.4 Number of Events Standard Deviation 4.71
Cognitive Functions Tests: Paired Associates Learning (PAL) First Attempt Memory Score (PALFAMS) PAL first attempt Memory score: Cycle 5 Day 1	11.7 Number of Events Standard Deviation 4.81	10.8 Number of Events Standard Deviation 4.48
Cognitive Functions Tests: Paired Associates Learning (PAL) First Attempt Memory Score (PALFAMS) PAL first attempt Memory score: Cycle 9 Day 1	12.5 Number of Events Standard Deviation 4.36	11.4 Number of Events Standard Deviation 4.59
Cognitive Functions Tests: Paired Associates Learning (PAL) First Attempt Memory Score (PALFAMS) PAL first attempt Memory score: Cycle 13 Day 1	12.4 Number of Events Standard Deviation 4.86	11.8 Number of Events Standard Deviation 4.56

SECONDARY outcome

Timeframe: Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)

The PAL is a computerized, self-completed cognitive test used to capture cognitive function, including attention, memory, and executive function. This gamified test included PALTEA and was a low-burden, highly sensitive, precise measure of cognitive function. PALTEA is the number of times a participant chose the incorrect box for a stimulus on assessment problems, plus an adjustment for the estimated number of errors they would have made on any problems, attempts, and recalls they did not reach. A higher number of events of selecting incorrect boxes indicates worse cognitive function. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=206 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=238 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Cognitive Functions Tests: Paired Associates Learning Total Errors Adjusted (PALTEA) PAL Total Errors (Adjusted): Baseline	21.8 Number of Events Standard Deviation 17.18	24.8 Number of Events Standard Deviation 17.59
Cognitive Functions Tests: Paired Associates Learning Total Errors Adjusted (PALTEA) PAL Total Errors (Adjusted): Cycle 5 Day 1	19.2 Number of Events Standard Deviation 16.47	23.1 Number of Events Standard Deviation 17.53
Cognitive Functions Tests: Paired Associates Learning Total Errors Adjusted (PALTEA) PAL Total Errors (Adjusted): Cycle 9 Day 1	17.2 Number of Events Standard Deviation 15.17	21.5 Number of Events Standard Deviation 17.32
Cognitive Functions Tests: Paired Associates Learning Total Errors Adjusted (PALTEA) PAL Total Errors (Adjusted): Cycle 13 Day 1	17.5 Number of Events Standard Deviation 16.33	19.2 Number of Events Standard Deviation 16.31
Cognitive Functions Tests: Paired Associates Learning Total Errors Adjusted (PALTEA) PAL Total Errors (Adjusted): Cycle 17 Day 1	15.0 Number of Events Standard Deviation 14.92	19.2 Number of Events Standard Deviation 17.66

SECONDARY outcome

Timeframe: Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)

This is a computerized, self-completed cognitive test used to capture cognitive function, including attention, memory, and executive function. This gamified test included Reaction Time Task (RTI) and was low-burden, highly sensitive, precise measures of cognitive function. RTI Median Five-Choice Movement Time: median time taken for a participant to release response button and select target stimulus after it flashed yellow on screen. Calculated across correct, assessed trials in which stimulus could appear in any one of five locations. RTI Median Five-Choice Reaction Time: median duration it took for a participant to release response button after presentation of target stimulus. Calculated across correct, assessed trials in which stimulus could appear in any one of five locations. Measured in milliseconds. Higher reaction times indicate worse cognitive function. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=206 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=239 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Cognitive Functions Tests: Reaction Time (RTI) Reaction time (RTI) Median Five-Choice Movement Time: Baseline	314.7 Millisecond (msec) Standard Deviation 117.03	329.4 Millisecond (msec) Standard Deviation 141.24
Cognitive Functions Tests: Reaction Time (RTI) RTI Median Five-Choice Movement Time: Cycle 5 Day 1	309.1 Millisecond (msec) Standard Deviation 94.85	310.5 Millisecond (msec) Standard Deviation 110.94
Cognitive Functions Tests: Reaction Time (RTI) RTI Median Five-Choice Movement Time: Cycle 9 Day 1	305.3 Millisecond (msec) Standard Deviation 93.47	326.7 Millisecond (msec) Standard Deviation 106.02
Cognitive Functions Tests: Reaction Time (RTI) RTI Median Five-Choice Movement Time: Cycle 13 Day 1	308.4 Millisecond (msec) Standard Deviation 89.55	324.1 Millisecond (msec) Standard Deviation 115.24
Cognitive Functions Tests: Reaction Time (RTI) RTI Median Five-Choice Movement Time: Cycle 17 Day 1	319.6 Millisecond (msec) Standard Deviation 151.42	316.4 Millisecond (msec) Standard Deviation 96.69
Cognitive Functions Tests: Reaction Time (RTI) RTI Median Five-Choice Reaction Time: Baseline	401.3 Millisecond (msec) Standard Deviation 70.63	423.6 Millisecond (msec) Standard Deviation 115.56
Cognitive Functions Tests: Reaction Time (RTI) RTI Median Five-Choice Reaction Time: Cycle 5 Day 1	408.7 Millisecond (msec) Standard Deviation 119.26	413.0 Millisecond (msec) Standard Deviation 84.25
Cognitive Functions Tests: Reaction Time (RTI) RTI Median Five-Choice Reaction Time: Cycle 9 Day 1	401.5 Millisecond (msec) Standard Deviation 73.18	414.5 Millisecond (msec) Standard Deviation 67.68
Cognitive Functions Tests: Reaction Time (RTI) RTI Median Five-Choice Reaction Time: Cycle 13 Day 1	401.0 Millisecond (msec) Standard Deviation 63.56	412.3 Millisecond (msec) Standard Deviation 77.07
Cognitive Functions Tests: Reaction Time (RTI) RTI Median Five-Choice Reaction Time: Cycle 17 Day 1	396.8 Millisecond (msec) Standard Deviation 81.63	402.8 Millisecond (msec) Standard Deviation 51.93

SECONDARY outcome

Timeframe: Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)

The SWM is a computerized cognitive test. The SWM Between Errors (SWMBE) is number of times a participant incorrectly revisits a box in which a token has previously been found, calculated across all 4, 6, and 8 token trials. SWM Between Errors 4 Boxes (SWMBE4), SWM Between Errors 6 Boxes (SWMBE6), and SWM Between Errors 8 Boxes (SWMBE8) are number of times a participant revisits a box in which a token has previously been found. These are calculated across all trials with 4 tokens only for SWMBE4, 6 tokens only for SWMBE6, and 8 tokens only for SWMBE8. SWM Total Errors is number of times a box is selected that is certain not to contain a token and therefore should not have been visited by participant. A higher number of incorrect revisit events to previously found token boxes indicates worse cognitive function, and a lower number of revisit events indicates better cognitive function. Here, baseline was last non-missing value prior to administration of first dose of study intervention.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=206 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=237 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Cognitive Functions Tests: Spatial Working Memory (SWM) Spatial working memory (SWM) Between Errors: Baseline	17.2 Number of Events Standard Deviation 8.89	18.6 Number of Events Standard Deviation 8.69
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors: Cycle 5 Day 1	15.5 Number of Events Standard Deviation 10.11	16.8 Number of Events Standard Deviation 8.39
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors: Cycle 9 Day 1	15.1 Number of Events Standard Deviation 9.78	16.3 Number of Events Standard Deviation 9.22
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors: Cycle 13 Day 1	13.4 Number of Events Standard Deviation 9.56	15.0 Number of Events Standard Deviation 8.85
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors: Cycle 17 Day 1	13.5 Number of Events Standard Deviation 9.48	13.7 Number of Events Standard Deviation 9.50
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 4 Boxes: Baseline	1.4 Number of Events Standard Deviation 1.39	1.4 Number of Events Standard Deviation 1.46
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 4 Boxes: Cycle 5 Day 1	1.0 Number of Events Standard Deviation 1.39	1.1 Number of Events Standard Deviation 1.42
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 4 Boxes: Cycle 9 Day 1	0.9 Number of Events Standard Deviation 1.33	1.1 Number of Events Standard Deviation 1.42
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 4 Boxes: Cycle 13 Day 1	0.8 Number of Events Standard Deviation 1.23	0.9 Number of Events Standard Deviation 1.37
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 4 Boxes: Cycle 17 Day 1	0.9 Number of Events Standard Deviation 1.32	0.7 Number of Events Standard Deviation 1.17
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 6 Boxes: Baseline	5.0 Number of Events Standard Deviation 3.44	5.2 Number of Events Standard Deviation 3.53
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 6 Boxes: Cycle 5 Day 1	4.3 Number of Events Standard Deviation 3.41	4.6 Number of Events Standard Deviation 3.42
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 6 Boxes: Cycle 9 Day 1	4.2 Number of Events Standard Deviation 3.64	4.7 Number of Events Standard Deviation 3.84
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 6 Boxes: Cycle 13 Day 1	3.2 Number of Events Standard Deviation 3.38	4.1 Number of Events Standard Deviation 3.34
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 6 Boxes: Cycle 17 Day 1	3.7 Number of Events Standard Deviation 3.25	4.0 Number of Events Standard Deviation 3.51
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 8 Boxes: Baseline	10.9 Number of Events Standard Deviation 5.66	12.1 Number of Events Standard Deviation 5.45
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 8 Boxes: Cycle 5 Day 1	10.2 Number of Events Standard Deviation 6.61	11.2 Number of Events Standard Deviation 5.31
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 8 Boxes: Cycle 9 Day 1	10.0 Number of Events Standard Deviation 6.31	10.5 Number of Events Standard Deviation 5.52
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 8 Boxes: Cycle 13 Day 1	9.3 Number of Events Standard Deviation 6.27	9.9 Number of Events Standard Deviation 5.91
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Between Errors 8 Boxes: Cycle 17 Day 1	8.9 Number of Events Standard Deviation 6.42	9.0 Number of Events Standard Deviation 6.33
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Total Errors: Baseline	17.5 Number of Events Standard Deviation 8.96	19.0 Number of Events Standard Deviation 8.75
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Total Errors: Cycle 5 Day 1	15.9 Number of Events Standard Deviation 10.24	17.3 Number of Events Standard Deviation 8.59
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Total Errors: Cycle 9 Day 1	15.5 Number of Events Standard Deviation 9.89	16.7 Number of Events Standard Deviation 9.42
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Total Errors: Cycle 13 Day 1	13.7 Number of Events Standard Deviation 9.71	15.3 Number of Events Standard Deviation 8.91
Cognitive Functions Tests: Spatial Working Memory (SWM) SWM Total Errors: Cycle 17 Day 1	13.8 Number of Events Standard Deviation 9.63	13.9 Number of Events Standard Deviation 9.63

SECONDARY outcome

Timeframe: Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)

The SWM is a computerized cognitive test. The SWMS, the number of times a participant restarted search patterns from the same initial box, indicating their use of a planned strategy to find tokens. An increased number of events where search patterns started from the same initial box suggested participants were using a planned strategy to find tokens, which indicated better cognitive function. Here, a low score indicated high strategy use (1 = they always began the search from the same box). Conversely, high scores represented a decrease in events of beginning searches from the same box. Instead, starting from many different boxes suggested the participant was not using a consistent strategy, which indicated worse cognitive function. This was calculated across assessed trials with 6 tokens or more. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=206 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=237 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Cognitive Functions Tests: Spatial Working Memory Strategy (SWMS) SWM Strategy (6-8 Boxes): Baseline	8.8 Number of Events Standard Deviation 2.30	9.1 Number of Events Standard Deviation 2.32
Cognitive Functions Tests: Spatial Working Memory Strategy (SWMS) SWM Strategy (6-8 Boxes): Cycle 5 Day 1	8.4 Number of Events Standard Deviation 2.80	8.8 Number of Events Standard Deviation 2.42
Cognitive Functions Tests: Spatial Working Memory Strategy (SWMS) SWM Strategy (6-8 Boxes): Cycle 9 Day 1	8.2 Number of Events Standard Deviation 2.70	8.5 Number of Events Standard Deviation 2.44
Cognitive Functions Tests: Spatial Working Memory Strategy (SWMS) SWM Strategy (6-8 Boxes): Cycle 13 Day 1	7.9 Number of Events Standard Deviation 3.18	8.6 Number of Events Standard Deviation 2.79
Cognitive Functions Tests: Spatial Working Memory Strategy (SWMS) SWM Strategy (6-8 Boxes): Cycle 17 Day 1	7.9 Number of Events Standard Deviation 3.13	8.0 Number of Events Standard Deviation 3.08

SECONDARY outcome

Timeframe: From time of ILD/pneumonitis diagnosis (every week) until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)

Population: The safety analysis set- ILD consisted of participants who developed ILD/Pneumonitis. The "number analyzed" refers to the number of participants included in the analysis at specific time points in each row.

The effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline brain metastasis was evaluated. The SGRQ-I is an idiopathic pulmonary fibrosis-specific version of the instrument developed and validated for use among participants with idiopathic pulmonary fibrosis, a type of ILD. The SGRQ-I was used to assess the HRQoL among participants who have been diagnosed with ILD/pneumonitis. It includes 34 of the original SGRQ items determined to be most reliable for assessing the HRQoL of participants with idiopathic pulmonary fibrosis. The instrument yields 3 domain scores (symptoms, activity, and impact) as well as a total score, with scores ranging from 0 to 100. Higher scores indicate greater impairment in HRQoL.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=14 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=27 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 9	8.0 Score on scale Standard Deviation 4.29	23.3 Score on scale Standard Deviation 17.20
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Baseline	32.1 Score on scale Standard Deviation 19.31	27.6 Score on scale Standard Deviation 20.97
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 1	28.2 Score on scale Standard Deviation 17.10	33.1 Score on scale Standard Deviation 30.33
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 2	23.3 Score on scale Standard Deviation 22.91	21.5 Score on scale Standard Deviation 14.48
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 3	19.5 Score on scale Standard Deviation 20.10	15.3 Score on scale Standard Deviation 15.23
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 4	4.2 Score on scale Standard Deviation 1.09	17.8 Score on scale Standard Deviation 15.49
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 5	8.0 Score on scale Standard Deviation 6.40	15.9 Score on scale Standard Deviation 15.43
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 6	6.7 Score on scale Standard Deviation 2.39	16.4 Score on scale Standard Deviation 11.95
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 7	5.4 Score on scale Standard Deviation 3.49	14.8 Score on scale Standard Deviation 15.73
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 8	3.3 Score on scale Standard Deviation 1.75	16.9 Score on scale Standard Deviation 17.04
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 10	6.6 Score on scale Standard Deviation 2.36	18.6 Score on scale Standard Deviation 14.54
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 11	8.9 Score on scale Standard Deviation 1.79	20.3 Score on scale Standard Deviation 14.92
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 12	8.4 Score on scale Standard Deviation 2.73	21.8 Score on scale Standard Deviation 14.40
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 13	6.2 Score on scale Standard Deviation 0.27	20.4 Score on scale Standard Deviation 17.95
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 14	5.5 Score on scale Standard Deviation 2.97	8.6 Score on scale Standard Deviation 7.19
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 15	4.2 Score on scale Standard Deviation 1.09	12.9 Score on scale Standard Deviation 10.49
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 16	4.2 Score on scale Standard Deviation 1.09	12.3 Score on scale Standard Deviation 10.10
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 17	4.2 Score on scale Standard Deviation 1.09	12.1 Score on scale Standard Deviation 15.07
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 18	4.2 Score on scale Standard Deviation 1.09	13.3 Score on scale Standard Deviation 16.29
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 19	9.1 Score on scale Standard Deviation 7.02	8.7 Score on scale Standard Deviation 9.07
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 20	7.9 Score on scale Standard Deviation 6.41	6.2 Score on scale Standard Deviation 3.86
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 21	7.5 Score on scale Standard Deviation 5.78	5.2 Score on scale Standard Deviation 2.58
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 22	6.7 Score on scale Standard Deviation 2.44	15.4 Score on scale Standard Deviation 13.24
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 25	5.6 Score on scale Standard Deviation 2.56	11.0 Score on scale Standard Deviation 10.90
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 23	6.7 Score on scale Standard Deviation 2.44	9.8 Score on scale Standard Deviation 9.74
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 24	6.7 Score on scale Standard Deviation 2.44	17.3 Score on scale Standard Deviation 15.09
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 26	5.6 Score on scale Standard Deviation 2.56	10.5 Score on scale Standard Deviation 10.81
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 27	5.6 Score on scale Standard Deviation 2.56	13.5 Score on scale Standard Deviation 11.53
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 28	5.6 Score on scale Standard Deviation 2.56	10.7 Score on scale Standard Deviation 11.13
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 29	6.7 Score on scale Standard Deviation 2.44	16.5 Score on scale Standard Deviation 16.52
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 30	4.7 Score on scale Standard Deviation 1.19	19.6 Score on scale Standard Deviation 18.60
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 31	5.6 Score on scale Standard Deviation 2.56	15.9 Score on scale Standard Deviation 13.98
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 32	5.6 Score on scale Standard Deviation 2.56	11.4 Score on scale Standard Deviation 10.89
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 33	6.7 Score on scale Standard Deviation 2.44	5.2 Score on scale Standard Deviation 3.15
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 34	5.5 Score on scale Standard Deviation 2.62	11.9 Score on scale Standard Deviation 10.36
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 35	6.6 Score on scale Standard Deviation 2.76	11.9 Score on scale Standard Deviation 10.32
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 36	6.7 Score on scale Standard Deviation 2.44	15.9 Score on scale Standard Deviation 17.62
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 37	5.4 Score on scale Standard Deviation 2.45	11.5 Score on scale Standard Deviation 9.72
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 38	6.7 Score on scale Standard Deviation 2.44	11.8 Score on scale Standard Deviation 10.13
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 39	5.0 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.	6.2 Score on scale Standard Deviation 3.86
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 40	5.6 Score on scale Standard Deviation 2.56	6.2 Score on scale Standard Deviation 3.86
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 41	5.6 Score on scale Standard Deviation 2.56	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 42	6.7 Score on scale Standard Deviation 2.44	6.2 Score on scale Standard Deviation 3.86
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 43	5.6 Score on scale Standard Deviation 2.56	6.2 Score on scale Standard Deviation 3.86
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 44	7.4 Score on scale Standard Deviation 5.54	6.2 Score on scale Standard Deviation 3.86
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 45	9.5 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.	6.2 Score on scale Standard Deviation 3.86
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 46	6.7 Score on scale Standard Deviation 2.44	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 47	6.7 Score on scale Standard Deviation 2.44	6.2 Score on scale Standard Deviation 3.86
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 48	6.7 Score on scale Standard Deviation 2.44	6.2 Score on scale Standard Deviation 3.86
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 49	6.7 Score on scale Standard Deviation 2.44	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 50	9.1 Score on scale Standard Deviation 0.99	6.2 Score on scale Standard Deviation 3.86
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 51	8.2 Score on scale Standard Deviation 0.32	10.4 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 52	6.7 Score on scale Standard Deviation 2.44	—
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 53	6.7 Score on scale Standard Deviation 2.44	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 54	6.7 Score on scale Standard Deviation 2.44	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 55	6.7 Score on scale Standard Deviation 2.44	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 56	7.5 Score on scale Standard Deviation 3.53	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 57	8.4 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 58	8.4 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 59	10.0 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 60	8.4 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 61	8.4 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 62	8.4 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 63	10.0 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 64	8.4 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 65	—	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 66	—	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 67	—	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 68	—	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 69	—	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 70	—	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 71	—	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Total: Week 72	—	8.9 Score on scale Standard Deviation NA Since the number of participants is 1, SD was not calculable.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis End of treatment	31.1 Score on scale Standard Deviation 18.65	18.0 Score on scale Standard Deviation 19.16
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis Safety Follow-up	23.4 Score on scale Standard Deviation 6.38	21.4 Score on scale Standard Deviation 25.36

SECONDARY outcome

Timeframe: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 39 Day 1 (21 days cycle)

The T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline brain metastasis was evaluated. The MDASI brain tumor module includes 9 symptoms specific to brain tumors (weakness on one side of the body, difficulty understanding, difficulty speaking, seizures, difficulty concentrating, problems with vision, change in appearance, change in bowel pattern (diarrhea or constipation), and irritability). These 9 items will be used to capture symptoms associated with brain metastasis for those diagnosed with brain metastasis. Each item is rated on an 11-point numeric rating scale on a scale of 0-10, with higher scores indicating greater symptom severity. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=213 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Change in Appearance at Its Worst: Baseline	1.8 Score on scale Standard Deviation 2.44	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Change in Appearance at Its Worst: Cycle 2 Day 1	1.9 Score on scale Standard Deviation 2.44	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Change in Appearance at Its Worst: Cycle 3 Day 1	2.1 Score on scale Standard Deviation 2.51	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Change in Appearance at Its Worst: Cycle 4 Day 1	1.9 Score on scale Standard Deviation 2.20	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Change in Appearance at Its Worst: Cycle 5 Day 1	2.1 Score on scale Standard Deviation 2.45	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Change in Appearance at Its Worst: Cycle 39 Day 1	3.0 Score on scale Standard Deviation NA Since there is only 1 participant, SD was not calculable.	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Change in Bowel Pattern at Its Worst: Baseline	1.7 Score on scale Standard Deviation 2.46	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Change in Bowel Pattern at Its Worst: Cycle 2 Day 1	2.5 Score on scale Standard Deviation 2.55	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Change in Bowel Pattern at Its Worst: Cycle 3 Day 1	2.7 Score on scale Standard Deviation 2.67	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Change in Bowel Pattern at Its Worst: Cycle 4 Day 1	3.0 Score on scale Standard Deviation 2.74	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Change in Bowel Pattern at Its Worst: Cycle 5 Day 1	2.8 Score on scale Standard Deviation 2.69	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Change in Bowel Pattern at Its Worst: Cycle 39 Day 1	0 Score on scale Standard Deviation NA Since there is only 1 participant, SD was not calculable.	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Concentrating at Its Worst: Baseline	1.8 Score on scale Standard Deviation 2.23	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Concentrating at Its Worst: Cycle 2 Day 1	1.7 Score on scale Standard Deviation 2.03	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Concentrating at Its Worst: Cycle 3 Day 1	1.9 Score on scale Standard Deviation 2.27	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Concentrating at Its Worst: Cycle 4 Day 1	1.6 Score on scale Standard Deviation 2.03	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Concentrating at Its Worst: Cycle 5 Day 1	1.5 Score on scale Standard Deviation 1.95	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Concentrating at Its Worst: Cycle 39 Day 1	1.0 Score on scale Standard Deviation NA Since there is only 1 participant, SD was not calculable.	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Speaking at Its Worst: Baseline	1.4 Score on scale Standard Deviation 2.18	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Speaking at Its Worst: Cycle 2 Day 1	1.3 Score on scale Standard Deviation 1.96	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Speaking at Its Worst: Cycle 3 Day 1	1.4 Score on scale Standard Deviation 1.97	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Speaking at Its Worst: Cycle 4 Day 1	1.1 Score on scale Standard Deviation 1.80	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Speaking at Its Worst: Cycle 5 Day 1	1.3 Score on scale Standard Deviation 1.98	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Speaking at Its Worst: Cycle 39 Day 1	1.0 Score on scale Standard Deviation NA Since there is only 1 participant, SD was not calculable.	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Understanding at Its Worst: Baseline	1.5 Score on scale Standard Deviation 2.29	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Understanding at Its Worst: Cycle 2 Day 1	0.9 Score on scale Standard Deviation 1.67	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Understanding at Its Worst: Cycle 3 Day 1	1.2 Score on scale Standard Deviation 1.87	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Understanding at Its Worst: Cycle 4 Day 1	1.0 Score on scale Standard Deviation 1.83	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Understanding at Its Worst: Cycle 5 Day 1	0.9 Score on scale Standard Deviation 1.68	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Difficulty Understanding at Its Worst: Cycle 39 Day 1	0 Score on scale Standard Deviation NA Since there is only 1 participant, SD was not calculable.	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Irritability at its Worst: Baseline	1.8 Score on scale Standard Deviation 2.27	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Irritability at its Worst: Cycle 2 Day 1	1.9 Score on scale Standard Deviation 2.23	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Irritability at its Worst: Cycle 3 Day 1	1.8 Score on scale Standard Deviation 2.04	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Irritability at its Worst: Cycle 4 Day 1	1.9 Score on scale Standard Deviation 2.06	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Irritability at its Worst: Cycle 5 Day 1	1.9 Score on scale Standard Deviation 2.12	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Irritability at its Worst: Cycle 39 Day 1	4.0 Score on scale Standard Deviation NA Since there is only 1 participant, SD was not calculable.	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Seizures at Its Worst: Baseline	0.5 Score on scale Standard Deviation 1.58	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Seizures at Its Worst: Cycle 2 Day 1	0.5 Score on scale Standard Deviation 1.38	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Seizures at Its Worst: Cycle 3 Day 1	0.5 Score on scale Standard Deviation 1.52	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Seizures at Its Worst: Cycle 4 Day 1	0.5 Score on scale Standard Deviation 1.47	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Seizures at Its Worst: Cycle 5 Day 1	0.5 Score on scale Standard Deviation 1.40	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Seizures at Its Worst: Cycle 39 Day 1	0 Score on scale Standard Deviation NA Since there is only 1 participant, SD was not calculable.	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Vision at Its Worst: Baseline	1.6 Score on scale Standard Deviation 2.28	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Vision at Its Worst: Cycle 2 Day 1	1.6 Score on scale Standard Deviation 2.24	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Vision at Its Worst: Cycle 3 Day 1	1.5 Score on scale Standard Deviation 2.10	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Vision at Its Worst: Cycle 4 Day 1	1.4 Score on scale Standard Deviation 1.94	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Vision at Its Worst: Cycle 5 Day 1	1.5 Score on scale Standard Deviation 2.01	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Vision at Its Worst: Cycle 39 Day 1	1.0 Score on scale Standard Deviation NA Since there is only 1 participant, SD was not calculable.	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Weakness on One Body Side at Its Worst: Baseline	2.1 Score on scale Standard Deviation 2.54	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Weakness on One Body Side at Its Worst: Cycle 2 Day 1	1.7 Score on scale Standard Deviation 2.35	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Weakness on One Body Side at Its Worst: Cycle 3 Day 1	1.8 Score on scale Standard Deviation 2.28	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Weakness on One Body Side at Its Worst: Cycle 4 Day 1	1.8 Score on scale Standard Deviation 2.48	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Weakness on One Body Side at Its Worst: Cycle 5 Day 1	1.6 Score on scale Standard Deviation 2.18	—
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Weakness on One Body Side at Its Worst: Cycle 39 Day 1	0 Score on scale Standard Deviation NA Since there is only 1 participant, SD was not calculable.	—

SECONDARY outcome

Timeframe: From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)

Population: The Safety analysis set included all participants who had received at least 1 dose of treatment.

The safety and tolerability of the participants who received T-DXd was evaluated. SAE=Serious adverse events; CTCAE=Common Terminology for Adverse Events

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=241 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=263 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Number of Participants With Adverse Events (AEs) Any AE leading to dose interruption, possibly related to treatment	82 Participants	83 Participants
Number of Participants With Adverse Events (AEs) Any AE leading to discontinuation of treatment	23 Participants	40 Participants
Number of Participants With Adverse Events (AEs) Any AE leading to discontinuation of treatment, excluding AEs associated with COVID-19	23 Participants	39 Participants
Number of Participants With Adverse Events (AEs) Any AE leading to discontinuation of treatment, associated with COVID-19	0 Participants	1 Participants
Number of Participants With Adverse Events (AEs) Any AE leading to discontinuation of treatment, possibly related to treatment	20 Participants	34 Participants
Number of Participants With Adverse Events (AEs) Any SAE leading to discontinuation of treatment	8 Participants	18 Participants
Number of Participants With Adverse Events (AEs) Any SAE leading to discontinuation of treatment, possibly related to treatment	6 Participants	13 Participants
Number of Participants With Adverse Events (AEs) Any Other Adverse events (OAE)	0 Participants	5 Participants
Number of Participants With Adverse Events (AEs) Any Adverse event of special event	54 Participants	71 Participants
Number of Participants With Adverse Events (AEs) Any AE with outcome = death	6 Participants	8 Participants
Number of Participants With Adverse Events (AEs) Any AE with outcome = death, excluding AEs associated with COVID-19	6 Participants	8 Participants
Number of Participants With Adverse Events (AEs) Any AE with outcome = death, associated with COVID-19	0 Participants	0 Participants
Number of Participants With Adverse Events (AEs) Any AE with outcome = death, possibly related to treatment	5 Participants	6 Participants
Number of Participants With Adverse Events (AEs) Any SAE (events with outcome = death)	46 Participants	62 Participants
Number of Participants With Adverse Events (AEs) Any SAE (events with outcome = death), possibly related to treatment	25 Participants	25 Participants
Number of Participants With Adverse Events (AEs) Any AE leading to dose reduction	65 Participants	60 Participants
Number of Participants With Adverse Events (AEs) Any AE leading to dose reduction, possibly related to treatment	63 Participants	53 Participants
Number of Participants With Adverse Events (AEs) Any AE leading to dose interruption	124 Participants	146 Participants
Number of Participants With Adverse Events (AEs) Any AE	237 Participants	259 Participants
Number of Participants With Adverse Events (AEs) Any AE, excluding AEs associated with COVID-19	237 Participants	259 Participants
Number of Participants With Adverse Events (AEs) Any AE associated with COVID-19	45 Participants	54 Participants
Number of Participants With Adverse Events (AEs) Any AE possibly related to treatment	230 Participants	242 Participants
Number of Participants With Adverse Events (AEs) Any AE of CTCAE grade 3 or higher	118 Participants	134 Participants
Number of Participants With Adverse Events (AEs) Any AE of CTCAE grade 3 or higher, possibly related to treatment	98 Participants	100 Participants

SECONDARY outcome

Timeframe: From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)

Population: The Safety analysis set consisted of all participants who had received at least 1 dose of treatment.

The number of participants with ILD/Pneumonitis were by grouped term based on Investigator-reported preferred terms. No adjudication was performed.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=241 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=263 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Number of Participants With Investigator-assessed ILD/Pneumonitis Pneumonitis	10 Participants	24 Participants
Number of Participants With Investigator-assessed ILD/Pneumonitis Interstitial lung disease	19 Participants	17 Participants
Number of Participants With Investigator-assessed ILD/Pneumonitis Lung opacity	2 Participants	0 Participants
Number of Participants With Investigator-assessed ILD/Pneumonitis Pulmonary fibrosis	1 Participants	1 Participants
Number of Participants With Investigator-assessed ILD/Pneumonitis Radiation pneumonitis	1 Participants	0 Participants
Number of Participants With Investigator-assessed ILD/Pneumonitis Lung infiltration	0 Participants	1 Participants

SECONDARY outcome

Timeframe: From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)

Population: The Safety analysis set-ILD consisted of all participants who had developed ILD/Pneumonitis. Here, the "overall number of participants analyzed" represents those who were treated with a high dose of steroids. Participants could have multiple ILD events with different statuses.

The number of participants with ILD clinical symptoms resolution in ILD/Pneumonitis participants who have been treated with high dose steroid (\>2 mg dexamethasone) were evaluated.

Outcome measures

Outcome measures
Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=26 Participants Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=39 Participants Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Number of Participants With ILD Clinical Symptoms Resolution Among ILD/Pneumonitis Participants Who Have Been Treated With High Dose Steroid Resolved: Recovered/resolved	18 Participants	24 Participants
Number of Participants With ILD Clinical Symptoms Resolution Among ILD/Pneumonitis Participants Who Have Been Treated With High Dose Steroid Resolved: Recovering/resolving	1 Participants	2 Participants
Number of Participants With ILD Clinical Symptoms Resolution Among ILD/Pneumonitis Participants Who Have Been Treated With High Dose Steroid Resolved: Recovered/resolved with sequelae	1 Participants	1 Participants
Number of Participants With ILD Clinical Symptoms Resolution Among ILD/Pneumonitis Participants Who Have Been Treated With High Dose Steroid Unresolved: Not recovered/resolved	6 Participants	6 Participants
Number of Participants With ILD Clinical Symptoms Resolution Among ILD/Pneumonitis Participants Who Have Been Treated With High Dose Steroid Unresolved: Fatal	3 Participants	6 Participants

Adverse Events

Cohort 1: Trastuzumab Deruxtecan (T-DXd)

Serious events: 46 serious events

Other events: 235 other events

Deaths: 41 deaths

Cohort 2: Trastuzumab Deruxtecan (T-DXd)

Serious events: 62 serious events

Other events: 253 other events

Deaths: 43 deaths

Serious adverse events

Other adverse events

Additional Information

Global Clinical Lead

AstraZeneca

Phone: 1-877-240-9479

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee No unpublished information contained herein may be disclosed without prior written approval from AstraZeneca AB.
Publication restrictions are in place

Restriction type: OTHER

Measure	Cohort 1: Trastuzumab Deruxtecan (T-DXd) n=241 participants at risk Participants without brain metastasis at baseline received T-DXd in Cohort 1 of the study.	Cohort 2: Trastuzumab Deruxtecan (T-DXd) n=263 participants at risk Participants with brain metastasis at baseline received T-DXd in Cohort 2 of the study.
Gastrointestinal disorders Dyspepsia	13.7% 33/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	8.4% 22/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Gastrointestinal disorders Nausea	71.0% 171/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	63.9% 168/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Gastrointestinal disorders Stomatitis	13.3% 32/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	9.1% 24/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Gastrointestinal disorders Vomiting	33.2% 80/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	27.8% 73/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Skin and subcutaneous tissue disorders Alopecia	34.4% 83/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	28.5% 75/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Musculoskeletal and connective tissue disorders Arthralgia	12.4% 30/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	14.1% 37/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Musculoskeletal and connective tissue disorders Back pain	6.2% 15/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	9.9% 26/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Musculoskeletal and connective tissue disorders Muscle spasms	5.4% 13/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	0.00% 0/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Musculoskeletal and connective tissue disorders Pain in extremity	8.7% 21/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	0.00% 0/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
General disorders Asthenia	42.7% 103/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	27.0% 71/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
General disorders Fatigue	32.0% 77/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	36.1% 95/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
General disorders Oedema peripheral	7.9% 19/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	5.3% 14/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
General disorders Pyrexia	14.5% 35/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	11.4% 30/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Investigations Alanine aminotransferase increased	10.8% 26/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	13.7% 36/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Investigations Aspartate aminotransferase increased	15.8% 38/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	11.8% 31/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Investigations Blood bilirubin increased	6.6% 16/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	0.00% 0/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Investigations Ejection fraction decreased	9.5% 23/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	11.0% 29/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Investigations Gamma-glutamyl transferase increased	7.5% 18/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	6.1% 16/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Investigations Neutrophil count decreased	11.2% 27/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	9.1% 24/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Investigations Platelet count decreased	6.6% 16/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	6.1% 16/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Investigations Weight decreased	0.00% 0/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	7.2% 19/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Investigations White blood cell count decreased	0.00% 0/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	6.8% 18/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Eye disorders Dry eye	0.00% 0/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	7.2% 19/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	6.5% 17/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	6.8% 18/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Infections and infestations COVID-19	16.6% 40/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	19.0% 50/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Infections and infestations Nasopharyngitis	7.1% 17/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	9.9% 26/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Infections and infestations Upper respiratory tract infection	6.2% 15/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	7.2% 19/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Infections and infestations Urinary tract infection	8.7% 21/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	11.0% 29/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Blood and lymphatic system disorders Anaemia	25.7% 62/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	25.5% 67/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Blood and lymphatic system disorders Leukopenia	6.2% 15/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	5.7% 15/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Blood and lymphatic system disorders Neutropenia	26.1% 63/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	22.1% 58/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Blood and lymphatic system disorders Thrombocytopenia	6.6% 16/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	8.7% 23/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Metabolism and nutrition disorders Decreased appetite	18.3% 44/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	20.5% 54/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Metabolism and nutrition disorders Hypokalaemia	6.2% 15/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	6.1% 16/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Psychiatric disorders Insomnia	8.7% 21/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	10.6% 28/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Nervous system disorders Dizziness	7.1% 17/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	8.7% 23/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Nervous system disorders Dysgeusia	9.1% 22/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	0.00% 0/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Nervous system disorders Headache	19.9% 48/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	20.9% 55/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Nervous system disorders Paraesthesia	6.6% 16/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	0.00% 0/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Respiratory, thoracic and mediastinal disorders Cough	17.4% 42/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	15.6% 41/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Respiratory, thoracic and mediastinal disorders Dyspnoea	8.7% 21/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	5.3% 14/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Respiratory, thoracic and mediastinal disorders Epistaxis	5.4% 13/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	8.4% 22/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	7.1% 17/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	5.3% 14/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	6.2% 15/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	0.00% 0/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Gastrointestinal disorders Abdominal pain	7.5% 18/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	6.5% 17/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Gastrointestinal disorders Abdominal pain upper	13.3% 32/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	9.9% 26/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Gastrointestinal disorders Constipation	40.7% 98/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	39.9% 105/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Gastrointestinal disorders Diarrhoea	35.3% 85/241 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)	28.1% 74/263 • From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)