Trastuzumab Deruxtecan (DS-8201a) Versus Investigator's Choice for HER2-low Breast Cancer That Has Spread or Cannot be Surgically Removed [DESTINY-Breast04]

• ClinicalTrials.gov Identifier: NCT03734029
• Recruitment Status: Active, not recruiting
• First Posted: November 7, 2018
• Results First Posted: June 15, 2023
• Last Update Posted: April 11, 2024
• Sponsor: Daiichi Sankyo
• Collaborators: Daiichi Sankyo Co., Ltd.; AstraZeneca
• Information provided by (Responsible Party): Daiichi Sankyo

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Drug: Trastuzumab deruxtecan (DS-8201a); Drug: Capecitabine; Drug: Eribulin; Drug: Gemcitabine; Drug: Paclitaxel; Drug: Nab-paclitaxel
• Enrollment: 557

Participant Flow

Recruitment Details

A total of 557 participants were enrolled and randomized to treatment at 161 study sites in the United States (27 study sites), Japan (18 sites), France (16 sites), China (15 sites), Italy (13 sites), Spain (12 sites), Greece (8 sites), Portugal (8 sites), Republic of Korea (8 sites), Israel (6 sites), Switzerland (6 sites), Austria (4 sites), Belgium (4 sites), Russia (3 sites), Sweden (3 sites), Taiwan (3 sites), Unted Kingdom (3 sites), Canada (2 sites), and Hungary (2 sites).

Pre-assignment Details

All participants had been previously treated with at least 1 and no more than 2 prior lines of chemotherapy in the recurrent or metastatic setting. The treatment chosen for the Physician's Choice arm was based on the label approved in the country of drug administration. The Physician's Choice group was combined to ensure an appropriate sample size for the comparator group.

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Period Title: Overall Study
Started	373	184
Full Analysis Set (All Randomized Patients)	373	184
Safety Analysis Set (All Randomized Patients Who Received at Least 1 Dose of Study Treatment)	371	172
Completed [1]	58	3
Not Completed	315	181
Reason Not Completed
Progressive disease as per RECIST v1.1	220	130
Adverse Event	60	14
Withdrawal by Subject	12	11
Clinical progression by investigator	10	8
Death	5	2
Physician Decision	4	3
Other	2	0
Lost to Follow-up	0	1
Randomized, but not treated	2	12
[1] Ongoing as of 11 Jan 2022

Baseline Characteristics

Arm/Group Title		Trastuzumab Deruxtecan (T-DXd)	Physician's Choice	Total
Arm/Group Description		Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.	Total of all reporting groups
Overall Number of Baseline Participants		373	184	557
Baseline Analysis Population Description		Baseline characteristics were assessed in the Full Analysis Set. The Full Analysis Set included all participants randomized into the study, including those who did not receive a dose of study treatment. Participants were analyzed according to the treatments and strata assigned at randomization.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	373 participants	184 participants	557 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	290 77.7%	136 73.9%	426 76.5%
	>=65 years	83 22.3%	48 26.1%	131 23.5%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	373 participants	184 participants	557 participants
		56.5 (10.6)	56.5 (11.5)	56.5 (10.9)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	373 participants	184 participants	557 participants
	Female	371 99.5%	184 100.0%	555 99.6%
	Male	2 0.5%	0 0.0%	2 0.4%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	373 participants	184 participants	557 participants
White		176 47.2%	91 49.5%	267 47.9%
Black or African American		7 1.9%	3 1.6%	10 1.8%
Asian		151 40.5%	72 39.1%	223 40.0%
Native Hawaiian or other Pacific Islander		1 0.3%	0 0.0%	1 0.2%
Other		38 10.2%	17 9.2%	55 9.9%
Missing		0 0.0%	1 0.5%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) Based on Blinded Independent Central Review (BICR) in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer
Description	Progression-free survival (PFS), defined as at least a 20% increase in the sum of diameters of target lesions, was assessed from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever came first. PFS was based on blinded independent central review (BICR) in the hormone receptor-positive cohort according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. Median PFS was from Kaplan-Meier analysis. Confidence interval for median was computed using the Brookmeyer-Crowley method.
Time Frame	From the date of randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Progression-free survival (PFS) was assessed in the Hormone Receptor-Positive cohort of Full Analysis Set.

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description:	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Overall Number of Participants Analyzed	331	163
Median (95% Confidence Interval); Unit of Measure: months
	10.1; (9.5 to 11.5)	5.4; (4.4 to 7.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab Deruxtecan (T-DXd), Physician's Choice
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Two-sided p-value from stratified log-rank test, Hazard ratio and 95% CI from stratified Cox proportional hazards model using stratification factors: HER2 status, number of prior lines of chemotherapy, hormone Receptor/CDK status, as defined by IXRS.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.5085
	Confidence Interval	(2-Sided) 95%; 0.4012 to 0.6444
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Progression-free Survival (PFS) Based on Blinded Independent Central Review (BICR) in Participants With HER2-low Breast Cancer (All Patients) Regardless of Hormone Receptor Status
Description	Progression-free survival (PFS), defined as at least a 20% increase in the sum of diameters of target lesions, was assessed from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever came first. PFS was based on blinded independent central review (BICR) according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. Median PFS was from Kaplan-Meier analysis. Confidence interval for median was computed using the Brookmeyer-Crowley method.
Time Frame	From the date of randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Progression-free survival (PFS) was assessed in the Full Analysis Set.

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description:	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Overall Number of Participants Analyzed	373	184
Median (95% Confidence Interval); Unit of Measure: months
	9.9; (9.0 to 11.3)	5.1; (4.2 to 6.8)

3. Secondary Outcome

Title	Progression-free Survival Based on Investigator Assessment in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer
Description	Progression-free survival (PFS), defined as at least a 20% increase in the sum of diameters of target lesions, was assessed from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever came first. PFS was based on investigator assessment in the hormone receptor-positive cohort according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. Median PFS was from Kaplan-Meier analysis. Confidence interval for median was computed using the Brookmeyer-Crowley method.
Time Frame	From the date of randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Progression-free survival (PFS) was assessed in the Hormone Receptor-Positive cohort of Full Analysis Set.

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description:	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Overall Number of Participants Analyzed	331	163
Median (95% Confidence Interval); Unit of Measure: months
	9.6; (8.4 to 10.0)	4.2; (3.4 to 4.9)

4. Secondary Outcome

Title	Progression-free Survival Based on Investigator Assessment in Participants With HER2-low Breast Cancer (All Patients)
Description	Progression-free survival (PFS), defined as at least a 20% increase in the sum of diameters of target lesions, was assessed from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever came first. PFS was based on investigator assessment according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. Median PFS was from Kaplan-Meier analysis. Confidence interval for median was computed using the Brookmeyer-Crowley method.
Time Frame	From the date of randomization to the earliest date of the first objective documentation of radiographic disease progression or death due to any cause, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Progression-free survival (PFS) was assessed in the Full Analysis Set.

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description:	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Overall Number of Participants Analyzed	373	184
Median (95% Confidence Interval); Unit of Measure: months
	8.8; (8.3 to 9.8)	4.2; (3.0 to 4.5)

5. Secondary Outcome

Title	Overall Survival (OS) in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer
Description	Overall survival (OS) was defined as the time from the date of randomization to the date of death due to any cause. If there was no death reported for a participant before the data cutoff for OS analysis, OS was censored at the last contact date at which the participant was known to be alive.
Time Frame	From the date of randomization up to the date of death due to any cause, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Overall survival (OS) was assessed in the Hormone Receptor-Positive cohort of Full Analysis Set.

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description:	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Overall Number of Participants Analyzed	331	163
Median (95% Confidence Interval); Unit of Measure: months
	23.9; (20.8 to 24.8)	17.5; (15.2 to 22.4)

6. Secondary Outcome

Title	Number of Overall Survival Events (Deaths)
Description	[Not Specified]
Time Frame	From the date of randomization up to the date of death due to any cause, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Overall survival events (deaths) were analyzed in the Full Analysis Set (defined as all randomized participants).

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description:	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Overall Number of Participants Analyzed	373	184
Measure Type: Number; Unit of Measure: events (deaths)
	149	90

7. Secondary Outcome

Title	Overall Survival (OS) in All Patients
Description	Overall survival (OS) was defined as the time from the date of randomization to the date of death due to any cause. If there was no death reported for a participant before the data cutoff for OS analysis, OS was censored at the last contact date at which the participant was known to be alive.
Time Frame	From the date of randomization up to the date of death due to any cause, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Overall survival (OS) was assessed in the Full Analysis Set (defined as all randomized participants).

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description:	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Overall Number of Participants Analyzed	373	184
Median (95% Confidence Interval); Unit of Measure: months
	23.4; (20.0 to 24.8)	16.8; (14.5 to 20.0)

8. Secondary Outcome

Title	Best Overall Response and Confirmed Objective Response Rate (ORR) in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer
Description	Best overall response rate and confirmed objective response rate (ORR) were assessed by blinded independent central review (BICR) and investigator assessment. Complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Confirmed ORR was defined as the number of participants with complete and partial responses and confirmed by a second assessment.
Time Frame	From screening and every 6 weeks up to withdrawal of subject consent, progressive disease (PD), or unacceptable toxicity, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Best overall response and confirmed objective response rate were assessed in the Hormone Receptor-Positive cohort of Full Analysis Set.

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description:	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Overall Number of Participants Analyzed	331	163
Measure Type: Count of Participants; Unit of Measure: Participants
BICR: Complete response	12 3.6%	1 0.6%
BICR: Partial response	164 49.5%	26 16.0%
BICR: Stable disease	115 34.7%	81 49.7%
BICR: Progressive disease	26 7.9%	34 20.9%
BICR: Not evaluable	14 4.2%	21 12.9%
Investigator: Complete response	5 1.5%	0 0.0%
Investigator: Partial response	163 49.2%	30 18.4%
Investigator: Stable disease	124 37.5%	80 49.1%
Investigator: Progressive disease	28 8.5%	34 20.9%
Investigator: Not evaluable	11 3.3%	19 11.7%
BICR: Confirmed Objective response rate	175 52.9%	27 16.6%
Investigator: Confirmed Objective response rate	168 50.8%	30 18.4%

9. Secondary Outcome

Title	Best Overall Response and Confirmed Objective Response Rate (ORR) in Participants With HER2-low Breast Cancer (All Patients)
Description	Best overall response rate and confirmed objective response rate (ORR) were assessed by blinded independent central review (BICR) and investigator assessment. Complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Confirmed ORR was defined as the number of participants with complete and partial responses and confirmed by a second assessment.
Time Frame	From screening and every 6 weeks up to withdrawal of subject consent, progressive disease (PD), or unacceptable toxicity, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Best overall response and confirmed objective response rate were assessed in the Full Analysis Set.

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description:	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Overall Number of Participants Analyzed	373	184
Measure Type: Count of Participants; Unit of Measure: Participants
BICR: Complete response	13 3.5%	2 1.1%
BICR: Partial response	183 49.1%	28 15.2%
BICR: Stable disease	129 34.6%	91 49.5%
BICR: Progressive disease	31 8.3%	41 22.3%
BICR: Not evaluable	17 4.6%	22 12.0%
Investigator: Complete response	6 1.6%	0 0.0%
Investigator: Partial response	187 50.1%	31 16.8%
Investigator: Stable disease	135 36.2%	93 50.5%
Investigator: Progressive disease	32 8.6%	40 21.7%
Investigator: Not evaluable	13 3.5%	20 10.9%
BICR: Confirmed Objective response rate	195 52.3%	30 16.3%
Investigator: Confirmed Objective response rate	193 51.7%	31 16.8%

10. Secondary Outcome

Title	Duration of Response in the Hormone Receptor-Positive Cohort in Participants With HER2-low Breast Cancer
Description	Duration of Response (DoR) is defined as the date of the first documented objective response (complete response [CR] or partial response [PR]) to the first documented disease progression or death, whichever occurs first. DoR was based on blinded independent central review (BICR) and investigator assessment. Median was from Kaplan-Meier estimate. Confidence interval for median was computed using the Brookmeyer-Crowley method.
Time Frame	From the date of the first documented objective response (CR or PR) to the first documented disease progression or death, whichever occurs first, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Duration of response was assessed in the Hormone Receptor-Positive cohort of Full Analysis Set.

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description:	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Overall Number of Participants Analyzed	331	163
Median (95% Confidence Interval); Unit of Measure: months
BICR: DoR	10.7; (8.5 to 13.7)	6.8; (6.5 to 9.9)
Investigator: DoR	8.3; (7.1 to 11.1)	5.6; (3.6 to 6.8)

11. Secondary Outcome

Title	Duration of Response in Participants With HER2-low Breast Cancer (All Patients)
Description	Duration of Response (DoR) is defined as the date of the first documented objective response (complete response [CR] or partial response [PR]) to the first documented disease progression or death, whichever occurs first. DoR was based on blinded independent central review (BICR) and investigator assessment. Median was from Kaplan-Meier estimate. Confidence interval for median was computed using the Brookmeyer-Crowley method.
Time Frame	From the date of the first documented objective response (CR or PR) to the first documented disease progression or death, whichever occurs first, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Duration of response was assessed in the Full Analysis Set.

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description:	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Overall Number of Participants Analyzed	373	184
Median (95% Confidence Interval); Unit of Measure: months
BICR: DoR	10.7; (8.5 to 13.2)	6.8; (6.0 to 9.9)
Investigator: DoR	8.3; (7.0 to 9.9)	5.6; (3.7 to 6.6)

12. Other Pre-specified Outcome

Title	All-Cause Mortality
Description	All-cause mortality is defined as all anticipated and unanticipated deaths due to any cause, with the number and frequency of such events by arm or comparison group of the clinical study.
Time Frame	From the date of randomization up to the date of death due to any cause, up to approximately 3 years

Outcome Measure Data

Analysis Population Description

All-cause mortality was assessed in the Safety Analysis Set.

Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description:	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
Overall Number of Participants Analyzed	371	172
Measure Type: Count of Participants; Unit of Measure: Participants
	148 39.9%	88 51.2%

Adverse Events

Time Frame	Adverse events (AEs) were collected from the time of signing the main informed consent form up to 40 days (+7 days) after the last treatment, whether observed by the investigator or reported by the participant, up to approximately 3 years in the Safety Analysis Set.
Adverse Event Reporting Description	All-cause mortality was assessed in all participants who were randomized (Full Analysis Set). Please refer to the other prespecified outcome measure that also reports all-cause mortality from the Safety Analysis Set. Other AEs and SAEs were assessed in the Safety Analysis Set. The Physician's Choice (PC) treatment was based on the label approved in each country. As prespecified in the protocol for safety analysis, the PC group was combined for an appropriate sample size for the comparator group.
Arm/Group Title	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
Arm/Group Description	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy were randomized to receive an intravenous infusion of DS8201a (initial dose of 5.4 mg/kg) over approximately 90 minutes. If there was no infusion-related reaction (IRR), T-DXd doses after the initial dose of 5.4 mg/kg were infused over a minimum of 30 minutes.	Participants with HER2-low, unresectable, and/or metastatic breast cancer who were previously treated with chemotherapy and randomized to a physician's choice (capecitabine, eribulin, gemcitabine, paclitaxel, and nab-paclitaxel) in which the dose, regimen, administration, and dose modification followed the label approved in the country of drug administration or the National Comprehensive Cancer Network guidelines.
All-Cause Mortality
	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
	Affected / at Risk (%)	Affected / at Risk (%)
Total	149/373 (39.95%)	90/184 (48.91%)
Serious Adverse Events
	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
	Affected / at Risk (%)	Affected / at Risk (%)
Total	103/371 (27.76%)	43/172 (25.00%)
Blood and lymphatic system disorders
Febrile neutropenia † 1	4/371 (1.08%)	4/172 (2.33%)
Anaemia † 1	4/371 (1.08%)	1/172 (0.58%)
Disseminated intravascular coagulation † 1	1/371 (0.27%)	0/172 (0.00%)
Thrombocytopenia † 1	1/371 (0.27%)	0/172 (0.00%)
Neutropenia † 1	0/371 (0.00%)	2/172 (1.16%)
Cardiac disorders
Cardiac failure † 1	1/371 (0.27%)	0/172 (0.00%)
Stress cardiomyopathy † 1	1/371 (0.27%)	0/172 (0.00%)
Pericardial effusion † 1	0/371 (0.00%)	1/172 (0.58%)
Ear and labyrinth disorders
Meniere's disease † 1	0/371 (0.00%)	1/172 (0.58%)
Endocrine disorders
Adrenal insufficiency † 1	1/371 (0.27%)	0/172 (0.00%)
Eye disorders
Cataract † 1	1/371 (0.27%)	1/172 (0.58%)
Gastrointestinal disorders
Nausea † 1	4/371 (1.08%)	0/172 (0.00%)
Vomiting † 1	4/371 (1.08%)	0/172 (0.00%)
Constipation † 1	3/371 (0.81%)	0/172 (0.00%)
Ascites † 1	1/371 (0.27%)	0/172 (0.00%)
Colitis ischaemic † 1	1/371 (0.27%)	0/172 (0.00%)
Gastrointestinal obstruction † 1	1/371 (0.27%)	0/172 (0.00%)
Oesophageal varices haemorrhage † 1	1/371 (0.27%)	0/172 (0.00%)
Pancreatitis † 1	1/371 (0.27%)	0/172 (0.00%)
Small intestinal obstruction † 1	1/371 (0.27%)	0/172 (0.00%)
Subileus † 1	1/371 (0.27%)	0/172 (0.00%)
Upper gastrointestinal haemorrhage † 1	1/371 (0.27%)	0/172 (0.00%)
Colitis † 1	0/371 (0.00%)	2/172 (1.16%)
Ileus † 1	0/371 (0.00%)	1/172 (0.58%)
General disorders
Pyrexia † 1	4/371 (1.08%)	0/172 (0.00%)
Disease progression † 1	2/371 (0.54%)	2/172 (1.16%)
Asthenia † 1	2/371 (0.54%)	0/172 (0.00%)
General physical health deterioration † 1	2/371 (0.54%)	0/172 (0.00%)
Fatigue † 1	1/371 (0.27%)	1/172 (0.58%)
Death † 1	1/371 (0.27%)	0/172 (0.00%)
Discomfort † 1	1/371 (0.27%)	0/172 (0.00%)
Mucosal inflammation † 1	1/371 (0.27%)	0/172 (0.00%)
Non-cardiac chest pain † 1	1/371 (0.27%)	0/172 (0.00%)
Oedema peripheral † 1	1/371 (0.27%)	0/172 (0.00%)
Pain † 1	1/371 (0.27%)	0/172 (0.00%)
Malaise † 1	0/371 (0.00%)	1/172 (0.58%)
Hepatobiliary disorders
Cholecystitis † 1	2/371 (0.54%)	0/172 (0.00%)
Hepatic failure † 1	1/371 (0.27%)	2/172 (1.16%)
Hepatic function abnormal † 1	1/371 (0.27%)	1/172 (0.58%)
Hyperbilirubinaemia † 1	1/371 (0.27%)	0/172 (0.00%)
Jaundice † 1	1/371 (0.27%)	0/172 (0.00%)
Liver injury † 1	1/371 (0.27%)	0/172 (0.00%)
Immune system disorders
Contrast media allergy † 1	1/371 (0.27%)	0/172 (0.00%)
Sarcoidosis † 1	0/371 (0.00%)	1/172 (0.58%)
Infections and infestations
Pneumonia † 1	7/371 (1.89%)	1/172 (0.58%)
Sepsis † 1	5/371 (1.35%)	0/172 (0.00%)
COVID-19 † 1	3/371 (0.81%)	1/172 (0.58%)
Urinary tract infection † 1	3/371 (0.81%)	0/172 (0.00%)
Urosepsis † 1	2/371 (0.54%)	0/172 (0.00%)
Appendicitis † 1	1/371 (0.27%)	0/172 (0.00%)
Cellulitis † 1	1/371 (0.27%)	0/172 (0.00%)
Cytomegalovirus infection reactivation † 1	1/371 (0.27%)	0/172 (0.00%)
Device related infection † 1	1/371 (0.27%)	0/172 (0.00%)
Empyema † 1	1/371 (0.27%)	0/172 (0.00%)
Escherichia bacteraemia † 1	1/371 (0.27%)	0/172 (0.00%)
Herpes zoster † 1	1/371 (0.27%)	0/172 (0.00%)
Osteomyelitis † 1	1/371 (0.27%)	0/172 (0.00%)
Peritonitis † 1	1/371 (0.27%)	0/172 (0.00%)
Peritonitis bacterial † 1	1/371 (0.27%)	0/172 (0.00%)
Pneumocystis jirovecii pneumonia † 1	1/371 (0.27%)	0/172 (0.00%)
Pyelonephritis † 1	1/371 (0.27%)	0/172 (0.00%)
Staphylococcal bacteraemia † 1	1/371 (0.27%)	0/172 (0.00%)
Streptococcal bacteraemia † 1	1/371 (0.27%)	0/172 (0.00%)
Upper respiratory tract infection † 1	1/371 (0.27%)	0/172 (0.00%)
Injury, poisoning and procedural complications
Thoracic vertebral fracture † 1	1/371 (0.27%)	1/172 (0.58%)
Ankle fracture † 1	1/371 (0.27%)	0/172 (0.00%)
Chemical peritonitis † 1	1/371 (0.27%)	0/172 (0.00%)
Fall † 1	1/371 (0.27%)	0/172 (0.00%)
Femoral neck fracture † 1	1/371 (0.27%)	0/172 (0.00%)
Radius fracture † 1	1/371 (0.27%)	0/172 (0.00%)
Tracheal obstruction † 1	1/371 (0.27%)	0/172 (0.00%)
Overdose † 1	0/371 (0.00%)	5/172 (2.91%)
Medication error † 1	0/371 (0.00%)	3/172 (1.74%)
Femur fracture † 1	0/371 (0.00%)	2/172 (1.16%)
Accidental overdose † 1	0/371 (0.00%)	1/172 (0.58%)
Lumbar vertebral fracture † 1	0/371 (0.00%)	1/172 (0.58%)
Investigations
Neutrophil count decreased † 1	2/371 (0.54%)	2/172 (1.16%)
Platelet count decreased † 1	2/371 (0.54%)	0/172 (0.00%)
Blood bilirubin increased † 1	1/371 (0.27%)	0/172 (0.00%)
Blood creatinine increased † 1	1/371 (0.27%)	0/172 (0.00%)
Weight decreased † 1	1/371 (0.27%)	0/172 (0.00%)
Metabolism and nutrition disorders
Hypercalcaemia † 1	4/371 (1.08%)	0/172 (0.00%)
Hyponatraemia † 1	1/371 (0.27%)	2/172 (1.16%)
Cachexia † 1	1/371 (0.27%)	0/172 (0.00%)
Hypokalaemia † 1	1/371 (0.27%)	0/172 (0.00%)
Hypomagnesaemia † 1	1/371 (0.27%)	0/172 (0.00%)
Musculoskeletal and connective tissue disorders
Bone pain † 1	2/371 (0.54%)	0/172 (0.00%)
Osteonecrosis of jaw † 1	1/371 (0.27%)	1/172 (0.58%)
Back pain † 1	1/371 (0.27%)	0/172 (0.00%)
Intervertebral disc protrusion † 1	1/371 (0.27%)	0/172 (0.00%)
Musculoskeletal chest pain † 1	1/371 (0.27%)	0/172 (0.00%)
Pain in extremity † 1	1/371 (0.27%)	0/172 (0.00%)
Pathological fracture † 1	1/371 (0.27%)	0/172 (0.00%)
Muscular weakness † 1	0/371 (0.00%)	1/172 (0.58%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Meningioma † 1	1/371 (0.27%)	0/172 (0.00%)
Adenocarcinoma gastric † 1	0/371 (0.00%)	1/172 (0.58%)
Metastases to meninges † 1	0/371 (0.00%)	1/172 (0.58%)
Nervous system disorders
Epilepsy † 1	1/371 (0.27%)	0/172 (0.00%)
Headache † 1	1/371 (0.27%)	0/172 (0.00%)
Movement disorder † 1	1/371 (0.27%)	0/172 (0.00%)
Hypoglycaemic coma † 1	0/371 (0.00%)	1/172 (0.58%)
Psychiatric disorders
Confusional state † 1	0/371 (0.00%)	1/172 (0.58%)
Renal and urinary disorders
Hydronephrosis † 1	2/371 (0.54%)	0/172 (0.00%)
Renal colic † 1	1/371 (0.27%)	0/172 (0.00%)
Renal failure † 1	1/371 (0.27%)	0/172 (0.00%)
Ureteric obstruction † 1	0/371 (0.00%)	1/172 (0.58%)
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease † 1	7/371 (1.89%)	0/172 (0.00%)
Pneumonitis † 1	7/371 (1.89%)	0/172 (0.00%)
Dyspnoea † 1	5/371 (1.35%)	2/172 (1.16%)
Pleural effusion † 1	3/371 (0.81%)	2/172 (1.16%)
Cough † 1	1/371 (0.27%)	0/172 (0.00%)
Haemoptysis † 1	1/371 (0.27%)	0/172 (0.00%)
Hydrothorax † 1	1/371 (0.27%)	0/172 (0.00%)
Pulmonary embolism † 1	1/371 (0.27%)	0/172 (0.00%)
Pulmonary toxicity † 1	1/371 (0.27%)	0/172 (0.00%)
Respiratory failure † 1	1/371 (0.27%)	0/172 (0.00%)
Hypoxia † 1	0/371 (0.00%)	1/172 (0.58%)
Social circumstances
Social problem † 1	1/371 (0.27%)	0/172 (0.00%)
Vascular disorders
Embolism † 1	1/371 (0.27%)	1/172 (0.58%)
Hypotension † 1	1/371 (0.27%)	0/172 (0.00%)
Superior vena cava occlusion † 1	0/371 (0.00%)	1/172 (0.58%)
1 Term from vocabulary, MedDRA 24.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Trastuzumab Deruxtecan (T-DXd)	Physician's Choice
	Affected / at Risk (%)	Affected / at Risk (%)
Total	366/371 (98.65%)	167/172 (97.09%)
Blood and lymphatic system disorders
Anaemia † 1	137/371 (36.93%)	44/172 (25.58%)
Neutropenia † 1	49/371 (13.21%)	29/172 (16.86%)
Thrombocytopenia † 1	23/371 (6.20%)	4/172 (2.33%)
Gastrointestinal disorders
Nausea † 1	281/371 (75.74%)	52/172 (30.23%)
Vomiting † 1	148/371 (39.89%)	23/172 (13.37%)
Constipation † 1	124/371 (33.42%)	38/172 (22.09%)
Diarrhoea † 1	100/371 (26.95%)	38/172 (22.09%)
Stomatitis † 1	41/371 (11.05%)	17/172 (9.88%)
Abdominal pain † 1	35/371 (9.43%)	8/172 (4.65%)
Dyspepsia † 1	34/371 (9.16%)	11/172 (6.40%)
Abdominal pain upper † 1	31/371 (8.36%)	13/172 (7.56%)
Dry mouth † 1	26/371 (7.01%)	9/172 (5.23%)
Gastrooesophageal reflux disease † 1	23/371 (6.20%)	3/172 (1.74%)
Abdominal distension † 1	20/371 (5.39%)	5/172 (2.91%)
General disorders
Fatigue † 1	110/371 (29.65%)	49/172 (28.49%)
Asthenia † 1	69/371 (18.60%)	25/172 (14.53%)
Pyrexia † 1	42/371 (11.32%)	22/172 (12.79%)
Malaise † 1	33/371 (8.89%)	10/172 (5.81%)
Oedema peripheral † 1	24/371 (6.47%)	10/172 (5.81%)
Infections and infestations
Urinary tract infection † 1	27/371 (7.28%)	6/172 (3.49%)
Investigations
Aspartate aminotransferase increased † 1	92/371 (24.80%)	42/172 (24.42%)
Neutrophil count decreased † 1	81/371 (21.83%)	61/172 (35.47%)
White blood cell count decreased † 1	78/371 (21.02%)	49/172 (28.49%)
Alanine aminotransferase increased † 1	75/371 (20.22%)	43/172 (25.00%)
Platelet count decreased † 1	72/371 (19.41%)	12/172 (6.98%)
Weight decreased † 1	59/371 (15.90%)	14/172 (8.14%)
Blood alkaline phosphatase increased † 1	36/371 (9.70%)	5/172 (2.91%)
Lymphocyte count decreased † 1	29/371 (7.82%)	12/172 (6.98%)
Blood bilirubin increased † 1	25/371 (6.74%)	7/172 (4.07%)
Gamma-glutamyltransferase increased † 1	20/371 (5.39%)	8/172 (4.65%)
Blood lactate dehydrogenase increased † 1	19/371 (5.12%)	9/172 (5.23%)
Metabolism and nutrition disorders
Decreased appetite † 1	118/371 (31.81%)	33/172 (19.19%)
Hypokalaemia † 1	38/371 (10.24%)	12/172 (6.98%)
Hypoalbuminaemia † 1	32/371 (8.63%)	8/172 (4.65%)
Hypocalcaemia † 1	19/371 (5.12%)	5/172 (2.91%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	43/371 (11.59%)	20/172 (11.63%)
Back pain † 1	33/371 (8.89%)	10/172 (5.81%)
Pain in extremity † 1	29/371 (7.82%)	5/172 (2.91%)
Myalgia † 1	22/371 (5.93%)	16/172 (9.30%)
Nervous system disorders
Headache † 1	53/371 (14.29%)	11/172 (6.40%)
Dysgeusia † 1	37/371 (9.97%)	16/172 (9.30%)
Dizziness † 1	32/371 (8.63%)	9/172 (5.23%)
Peripheral sensory neuropathy † 1	18/371 (4.85%)	19/172 (11.05%)
Neuropathy peripheral † 1	13/371 (3.50%)	16/172 (9.30%)
Paraesthesia † 1	8/371 (2.16%)	9/172 (5.23%)
Psychiatric disorders
Insomnia † 1	24/371 (6.47%)	9/172 (5.23%)
Respiratory, thoracic and mediastinal disorders
Epistaxis † 1	39/371 (10.51%)	2/172 (1.16%)
Dyspnoea † 1	34/371 (9.16%)	14/172 (8.14%)
Cough † 1	35/371 (9.43%)	14/172 (8.14%)
Pneumonitis † 1	21/371 (5.66%)	0/172 (0.00%)
Skin and subcutaneous tissue disorders
Alopecia † 1	147/371 (39.62%)	57/172 (33.14%)
Rash † 1	24/371 (6.47%)	9/172 (5.23%)
Palmar-plantar erythrodysaesthesia syndrome † 1	5/371 (1.35%)	24/172 (13.95%)
1 Term from vocabulary, MedDRA 24.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Contact for Clinical Trial Information
• Organization: Daiichi Sankyo
• Phone: 908-992-6400
• EMail: CTRinfo@dsi.com

Publications of Results:

Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5.

• Responsible Party: Daiichi Sankyo
• ClinicalTrials.gov Identifier: NCT03734029
• Other Study ID Numbers: DS8201-A-U303; 2018-003069-33 ( EudraCT Number ); 184223 ( Registry Identifier: JAPIC CTI ); DESTINY-B04 ( Other Identifier: Daiichi Sankyo and AstraZeneca )
• First Submitted: November 6, 2018
• First Posted: November 7, 2018
• Results First Submitted: January 11, 2023
• Results First Posted: June 15, 2023
• Last Update Posted: April 11, 2024