Safety Update: September 7, 2021 Data Cut-off

DESTINY-Breast03 Safety Update: Results (September 7, 2021 DCO Date)

Safety Update Overview
TEAEs Associated With Drug Discontinuation
Exposure-Adjusted Incidence Rates
Drug-Related TEAEs Reported in ≥20% of Patients
Time to First Onset of Selected TEAEs
Proportion of Patients With Hematologic TEAEs
Time to First Occurrence of Nausea, Vomiting, Fatigue, and Alopecia
Prevalence of Nausea, Vomiting, Fatigue, and Alopecia
Adjudicated Drug-Related ILD

Safety Update Overview

Safety Update Overview¹

Rates of TEAEs (any grade and grade ≥3) and serious TEAEs were similar between T-DXd and T-DM1 arms¹
TEAEs associated with drug discontinuation occurred in 38 patients (14.8%) in the T-DXd arm and 19 patients (7.3%) in the T-DM1 arm¹

Safety Update Overview.

n (%)	T-DXd (n=257)	T-DM1 (n=261)
Patients discontinued from study treatment	141 (54.9)	222 (85.1)
Any-grade TEAE	256 (99.6)	249 (95.4)
Grade ≥3 TEAE	137 (53.3)	130 (49.8)
Any-grade serious TEAE	54 (21.0)	50 (19.2)
Grade ≥3 serious TEAE	39 (15.2)	38 (14.6)
TEAE associated with drug discontinuation	38 (14.8)	19 (7.3)
TEAE associated with dose reduction	59 (23.0)	36 (13.8)

TEAEs Associated With Drug Discontinuation

TEAEs Associated With Drug Discontinuation¹

TEAEs that were associated with drug discontinuation were¹:
- Adjudicated drug-related ILD in the T-DXd group (per defined protocol criteria)
- Thrombocytopenia in the T-DM1 group

Selected TEAEs Associated With Drug Discontinuation.

n (%)	T-DXd (n=257)	T-DM1 (n=261)
TEAEs associated with drug discontinuation	38 (14.8)	19 (7.3)
Most common TEAEs associated with drug discontinuation^a
Adjudicated drug-related ILD^b	21 (8.2)	3 (1.1)
Thrombocytopenia	3 (1.2)	7 (2.7)
Fatigue	1 (0.4)	0
Neutropenia	1 (0.4)	0
Vomiting	1 (0.4)	0

^aSelected TEAEs (and preferred terms included): neutropenia (neutrophil count decreased, neutropenia); thrombocytopenia (platelet count decreased, thrombocytopenia); fatigue (fatigue, asthenia, malaise); ^bAdjudicated drug-related ILD included the preferred terms: pneumonitis, ILD, organizing pneumonia, pneumonia, pulmonary mass, alveolitis, radiation pneumonitis, and respiratory failure.

Exposure-Adjusted Incidence Rates

Exposure-Adjusted Incidence Rates¹

EAIRs were measured to account for differences in treatment duration exposure between T-DXd and T-DM1 and provide a more meaningful comparison¹
EAIRs per patient-year were lower in the T-DXd arm than the T-DM1 arm except for TEAEs associated with drug discontinuation, which were primarily associated with ILD/pneumonitis in the T-DXd arm¹
- EAIR for grade ≥3 TEAEs was 0.42 for T-DXd and 0.70 for T-DM1
- EAIR for any-grade serious TEAEs was 0.17 for T-DXd and 0.27 for T-DM1

EAIRs.

	T-DXd (n=257)	T-DM1 (n=261)
Patients remaining on treatment, n (%)	116 (45.1)	39 (14.9)
Median treatment duration, months (range)	16.1 (0.7-33.0)	6.9 (0.7-28.5)
Exposure, patient years^a	327.2	186.3
EAIR, grade ≥3 TEAE	0.42	0.70
EAIR, any-grade serious TEAE	0.17	0.27
EAIR, grade ≥3 serious TEAE	0.12	0.20
EAIR, TEAE associated with drug discontinuation	0.12	0.10
EAIR, TEAE associated with dose reduction	0.18	0.19

Note: EAIR was the number of patients with at least 1 event incidence divided by the sum of patient-years of exposure over patients in the safety analysis set (total patient-years of exposure)

^aPatient years of exposure were the treatment duration with year as unit.

EAIRs for selected grade ≥3 TEAEs were generally similar between both arms¹

EAIRs for Selected Grade ≥3 TEAEs.

	T-DXd (n=257)	T-DM1 (n=261)
Anemia	0.06	0.08
Lymphopenia	0.03	0.02
Thrombocytopenia	0.06	0.36
Fatigue	0.06	0.01
Leukopenia	0.05	0.01
Neutropenia	0.16	0.04
Nausea	0.05	0.01
Vomiting	0.01	0.01

Note: EAIR was the number of patients with at least one event incidence divided by the sum of patient-years of exposure over patients in the safety analysis set (total patient-years of exposure; 327.2 patient-years in the T-DXd arm and 186.3 patient-years in the T-DM1 arm). Patient years of exposure were the treatment duration with year as unit

Drug-Related TEAEs Reported in ≥20% of Patients

Drug-Related TEAEs Reported in ≥20% of Patients¹

Most of the selected drug-related TEAEs in either treatment arm were hematologic or gastrointestinal¹

Drug-Related TEAEs Reported in ≥20% of Patients in Either Treatment Arm.

n (%)	T-DXd (n=257)		T-DM1 (n=261)
n (%)	Any Grade	Grade ≥3	Any Grade	Grade ≥3
Nausea	189 (73.5)	17 (6.6)	72 (27.6)	1 (0.4)
Fatigue	118 (45.9)	16 (6.2)	76 (29.1)	2 (0.8)
Vomiting	114 (44.4)	4 (1.6)	15 (5.7)	1 (0.4)
Neutropenia	111 (43.2)	51 (19.8)	30 (11.5)	8 (3.1)
Alopecia	97 (37.7)	1 (0.4)	7 (2.7)	0
Anemia	82 (31.9)	16 (6.2)	37 (14.2)	11 (4.2)
Leukopenia	79 (30.7)	17 (6.6)	21 (8.0)	2 (0.8)
Decreased appetite	68 (26.5)	3 (1.2)	34 (13.0)	0
Thrombocytopenia	65 (25.3)	19 (7.4)	137 (52.5)	65 (24.9)
Diarrhea	61 (23.7)	1 (0.4)	11 (4.2)	2 (0.8)
Constipation	60 (23.3)	0	25 (9.6)	0

Note: Selected TEAEs (and preferred terms included): anemia (hemoglobin decreased, red blood cell count decreased, anemia, hematocrit decreased); neutropenia (neutrophil count decreased, neutropenia); thrombocytopenia (platelet count decreased, thrombocytopenia); fatigue (fatigue, asthenia, malaise).

Note: Based on nonclinical data, clinical data, epidemiology data, and reported data from drugs in a similar class (anti-HER2 therapies), selected TEAEs for T-DXd were reviewed for additional characterization.

Time to First Onset of Selected TEAEs

Time to First Onset of Selected TEAEs¹

TEAEs associated with first drug discontinuation or first dose reduction occurred later with T-DXd treatment than with T-DM1 treatment¹
Median time to any TEAE associated with first dose reduction was longer in the T-DXd arm at 96 days compared with the T-DM1 arm at 19 days¹

Time to First Onset of Selected TEAEs.

Median time to event, days	T-DXd (n=257)	T-DM1 (n=261)
TEAE associated with treatment discontinuation	224	147
TEAE associated with first dose reduction	96	19
Selected TEAEs
Anemia	70.0	42.0
Lymphopenia	196.0	168.0
Thrombocytopenia	132.0	8.0
Fatigue	22.0	24.0
Leukopenia	74.5	92.0
Neutropenia^a	64.0	105.0
Nausea	2.0	3.0
Vomiting	10.0	6.0
Alopecia	27.0	43.0

Note: Selected TEAEs (and preferred terms included): anemia (hemoglobin decreased, red blood cell count decreased, anemia, hematocrit decreased); lymphopenia (lymphocyte count decreased, lymphopenia); neutropenia (neutrophil count decreased, neutropenia); thrombocytopenia (platelet count decreased, thrombocytopenia); leukopenia (white blood cell count decreased, leukopenia); fatigue (fatigue, asthenia, malaise).

^a11.7% of patients in the T-DXd group and 2.3% of patients in the T-DM1 group were treated with G-CSF within 28 days after onset of neutropenia, including febrile neutropenia.

Proportion of Patients With Hematologic TEAEs

Proportion of Patients With Hematologic TEAEs¹

The overall rates of TEAEs decreased over time and were highest in the first few cycles¹

Proportion of Patients With Hematologic TEAEs.

n/N (%)

T-DXd

(n=257)

T-DM1

(n=261)

Neutropenia

Cycle 1

Cycle 2

Cycle 3

37/257 (14.4)

21/256 (8.2)

22/254 (8.7)

7/261 (2.7)

6/252 (2.4)

5/221 (2.3)

Febrile neutropenia

Cycle 1

Cycle 2

Cycle 3

1/257 (0.4)

Anemia

Cycle 1

Cycle 2

Cycle 3

30/257 (11.7)

5/256 (2.0)

6/254 (2.4)

17/261 (6.5)

11/252 (4.4)

6/221 (2.7)

Lymphopenia

Cycle 1

Cycle 2

Cycle 3

3/257 (1.2)

3/256 (1.2)

3/254 (1.2)

3/261 (1.1)

1/252 (0.4)

1/221 (0.5)

Thrombocytopenia

Cycle 1

Cycle 2

Cycle 3

28/257 (10.9)

7/256 (2.7)

4/254 (1.6)

122/261 (46.7)

16/252 (6.3)

5/221 (2.3)

Leukopenia

Cycle 1

Cycle 2

Cycle 3

27/257 (10.5)

12/256 (4.7)

6/254 (2.4)

6/261 (2.3)

5/252 (2.0)

2/221 (0.9)

Note: For rates per treatment cycle, percentages were calculated using the number of patients with the selected TEAE as the numerator and the number of patients at risk at any point in the cycle window as the denominator. One complete cycle consists of 21 days of follow-up after study drug administration on day 1 of the cycle. Selected hematologic TEAEs (and preferred terms included) are anemia (hemoglobin decreased, red blood cell count decreased, anemia, hematocrit decreased); lymphopenia (lymphocyte count decreased, lymphopenia); neutropenia (neutrophil count decreased, neutropenia); thrombocytopenia (platelet count decreased, thrombocytopenia); leukopenia (white blood cell count decreased, leukopenia).

Time to First Occurrence of Nausea, Vomiting, Fatigue, and Alopecia

Time to First Occurrence of Nausea, Vomiting, Fatigue, and Alopecia¹

Risk of first event of nausea and vomiting was higher with T-DXd in earlier cycles¹
The cumulative incidence and trend of fatigue over time was similar between T-DXd and T-DM1¹
Risk of first event of alopecia was higher with T-DXd in earlier cycles¹

Prevalence of Nausea, Vomiting, Fatigue, and Alopecia

Prevalence of Nausea, Vomiting, Fatigue, and Alopecia¹

The prevalence of nausea and vomiting was higher with T-DXd than with T-DM1 and was relatively consistent over time¹
Majority of events with T-DXd were grade 1 and 2 and resolved, and one patient discontinued study drug due to vomiting¹
- Antiemetic prophylaxis recommendations were updated during the study based on emerging data supporting the moderately emetogenic potential of T-DXd
The prevalence of fatigue and alopecia was relatively consistent over time¹

Adjudicated Drug-Related ILD

Adjudicated Drug-Related ILD¹

For this safety update:¹

Majority of adjudicated ILD cases were low grade and no new grade 4 or 5 events occurred in either treatment arm
One additional grade 2 adjudicated drug-related ILD occurred
The majority of events resolved with ongoing follow-up

Adjudicated Drug-Related ILD.

T-DXd

(n=257)

T-DM1

(n=261)

Any grade, n (%)

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

28 (10.9)

7 (2.7)

19 (7.4)

2 (0.8)

5 (1.9)

4 (1.5)

1 (0.4)

Median time to first onset,^a days (range)

181 (33-507)

289 (80-499)

Outcome of worst event, n (%)

Fatal

Not recovered/not resolved^b

Recovering/resolving^c

Recovered/resolved with sequelae^d

Recovered/resolved^e

8 (28.6)

2 (7.1)

16 (57.1)

1 (20.0)^f

4 (80.0)

^aAs adjudicated by the ILD adjudication committee; ^bThe event itself was still present and observable; ^cThe event had improved but not fully resolved; ^dResidual effects of the event were still present and observable including sequelae/residual effects; ^eFully recovered with no residual effect observed; ^fPatient had an event of pulmonary embolism that the investigator considered to be grade 5. This event was initially reported as respiratory failure but subsequently updated to pulmonary embolism. The ILD adjudication committee adjudicated this event as drug-related grade 1 ILD/pneumonitis. The death was not evaluable for adjudication. The investigator recorded disease progression as the primary cause of death..

Abbreviations

DCO = data cut-off

;

EAIR = exposure-adjusted incidence rate

;

ILD = interstitial lung disease

;

T-DM1 = trastuzumab emtansine

;

T-DXd = trastuzumab deruxtecan

;

TEAE = treatment-emergent adverse event

References

1. Hamilton E, Petry V, Yeo W, et al. Trastuzumab deruxtecan vs trastuzumab emtansine in patients with HER2-positive unresectable and/or metastatic breast cancer: safety follow-up of the randomized, phase 3 study DESTINY-Breast03 [presentation and supplement]. Presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022. J Clin Oncol. 2022;40(suppl 16). Abs 1000.

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Document ID: 8db67364-6c52-4ea0-b987-9d4900884ec2
Last updated: 27-June-2024

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