Safety

DESTINY-Breast03: Safety Results (November 20, 2023 DCO Date)

Overall Safety Summary
Drug-Related TEAEs Associated With Study Drug Discontinuation by Preferred Term
TEAEs Reported in ≥20% of Patients
Exposure-Adjusted Incidence Rates
Adjudicated Drug-Related ILD/Pneumonitis

Overall Safety Summary

Overall Safety Summary^1,2

Median treatment duration:

T-DXd: 18.2 months (range, 0.7-56.6 months)
T-DM1: 6.9 months (range, 0.7-55.2 months)

Overall Safety Summary.

n (%)

T-DXd

n = 257^a

T-DM1

n = 261^a

Any-grade TEAEs

Drug-related

256 (99.6)

252 (98.1)

249 (95.4)

228 (87.4)

Grade ≥3 TEAEs

Drug-related

149 (58.0)

125 (48.6)

136 (52.1)

111 (42.5)

Serious TEAEs

Drug-related

71 (27.6)

35 (13.6)

59 (22.6)

20 (7.7)

TEAEs leading to drug discontinuation

Drug-related

63 (24.5)

58 (22.6)

27 (10.3)

19 (7.3)

TEAEs leading to dose reduction

Drug-related

73 (28.4)

72 (28.0)

40 (15.3)

TEAEs leading to drug interruption

Drug-related

146 (56.8)

113 (44.0)

78 (29.9)

48 (18.4)

TEAEs associated with death

Drug-related

9 (3.5)

7 (2.7)

^aIncludes all randomized patients who received at least 1 dose of study treatment.

Drug-Related TEAEs Associated With Study Drug Discontinuation by Preferred Term

Drug-Related TEAEs Associated With Study Drug Discontinuation by Preferred Term²

Drug-Related TEAEs Associated With Study Drug Discontinuation by Preferred Term

n (%)	T-DXd n = 257	T-DM1 n = 261
Drug-related TEAEs associated with discontinuation	58 (22.6)	19 (7.3)
Pneumonitis	17 (6.6)	4 (1.5)
Interstitial lung disease	14 (5.4)	2 (0.8)
Pneumonia	5 (1.9)	0
Platelet count decreased	4 (1.6)	4 (1.5)
Organizing pneumonia	3 (1.2)	0
Fatigue	3 (1.2)	0
Anemia	2 (0.8)	0
Blood bilirubin increased	1 (0.4)	2 (0.8)
Dyspnea	1 (0.4)	2 (0.8)
Epilepsy	1 (0.4)	0
Gamma-glutamyl transferase increased	1 (0.4)	0
Hypokalemia	1 (0.4)	0
Pancreatic carcinoma	1 (0.4)	0
Pneumatosis intestinalis	1 (0.4)	0
Pyrexia	1 (0.4)	0
Vomiting	1 (0.4)	0
Thrombocytopenia	0	3 (1.1)
Epistaxis	0	1 (0.4)
Hepatic atrophy	0	1 (0.4)

TEAEs Reported in ≥20% of Patients

TEAEs Reported in ≥20% of Patients²

TEAEs Reported in ≥20% of Patients

Systemic Organ Class Preferred Term, n (%)	T-DXd n = 257	T-DM1 n = 261
Any TEAEs	256 (99.6)	249 (95.4)
Blood and lymphatic system disorders
Neutropenia^a	117 (45.5)	38 (14.6)
Anemia^b	98 (38.1)	53 (20.3)
Leukopenia^c	88 (34.2)	25 (9.6)
Thrombocytopenia^d	81 (31.5)	146 (55.9)
Gastrointestinal disorders
Nausea	198 (77.0)	79 (30.3)
Vomiting	136 (52.9)	28 (10.7)
Constipation	97 (37.7)	51 (19.5)
Diarrhea	86 (33.5)	21 (8.0)
Abdominal pain^e	64 (24.9)	25 (9.6)
Stomatitis^f	60 (23.3)	14 (5.4)
General disorders
Fatigue^g	137 (53.3)	92 (35.2)
Infections and infestations
Upper respiratory tract infection^h	76 (29.6)	41 (15.7)
Investigations
Transminases increasedⁱ	89 (34.6)	124 (47.5)
Metabolism and nutrition disorders
Decreased appetite	80 (31.1)	46 (17.6)
Weight decreased	61 (23.7)	24 (9.2)
Muscoloskeletal and connective tissue disorders
Musculoskeletal pain^j	88 (34.2)	65 (24.9)
Nervous system disorders
Headache^k	69 (26.8)	47 (18.0)
Skin and subcutaneous disorders
Alopecia	103 (40.1)	10 (3.8)

¹¹Includes the preferred terms migraine, headache, and sinus headache; ^aIncludes the preferred terms neutrophil count decreased and neutropenia; ^bIncludes the preferred terms hemoglobin decreased, red blood cell count decreased, anemia, and hematocrit decreased; ^c Includes the preferred terms white blood cell count decreased and leukopenia; ^dIncludes the preferred terms platelet count decreased and thrombocytopenia; ^eIncludes the preferred terms abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain; ^fIncludes the preferred terms stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, and oral mucosal eruption; ^gIncludes the preferred terms fatigue, asthenia, malaise, and lethargy; ^h Includes the preferred terms influenza, influenza like illness, and upper respiratory tract infection; ⁱIncludes the preferred terms transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, hepatic function abnormal, and liver function test increased; ^jIncludes the preferred terms back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort; ^k Includes the preferred terms migraine, headache, and sinus headache.

Exposure-Adjusted Incidence Rates

Exposure-Adjusted Incidence Rates^1,2

Exposure-Adjusted Incidence Rates^,^a

T-DXd

n = 257

T-DM1

n = 261

Total patient-years of exposure^a

484.20

226.23

Any TEAEs, n (%)

EAIR per patient-year

256 (99.6)

0.53

249 (95.4)

1.10

Grade >3 TEAEs, n (%)

EAIR per patient-year

149 (58.0)

0.31

136 (52.1)

0.60

Any serious TEAEs, n (%)

EAIR per patient-year

71 (27.6)

0.15

59 (22.6)

0.26

Any AESI, n (%)

EAIR per patient-year

ILD/pneumonitis, n (%)

EAIR per patient-year

LVEF decreased, n (%)

EAIR per patient-year

53 (20.6)

0.11

43 (16.7)

0.09

11 (4.3)

0.02

12 (4.6)

0.05

9 (3.4)

0.04

4 (1.5)

0.02

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

Adjudicated Drug-Related ILD/Pneumonitis

Adjudicated Drug-Related ILD/Pneumonitis^1,2

Adjudicated Drug-Related ILD/Pneumonitis^,^a

n (%)^b

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Any Grade

T‑DXd (n = 257)^c

T-DM1 (n = 261)^c

11 (4.3)

5 (1.9)

30 (11.7)

3 (1.1)

2 (0.8)

1 (0.4)

43 (16.7)

9 (3.4)

Time to first adjudicated drug-related ILD/pneumonitis^d in the T-DXd group by CTCAE grade at the time of diagnosis

<6 months

>6 to <12 months

>12 to <24 months

>24 months

3 (1.1)

5 (1.9)

1 (0.4)

10 (3.8)

7 (2.7)

5 (1.9)

1 (0.4)

14 (5.4)

12 (4.6)

11 (4.2)

6 (2.3)

^aThere were 4 new events (all grade 2) reported since the previous data cutoff (July 25, 2022) with a time to onset of 832 days (not recovered/resolved), 851 days (recovered/resolved with sequelae), 910 days (recovered/resolved with sequelae), and 961 days (recovered/resolved); ^b Grade is based on the worst CTCAE grade within the same AE/ILD event.; ^cIncludes all randomized patients who received at least 1 dose of study treatment; ^dTime to first adjudicated ILD onset (months) = (onset date of first ILD adjudicated as drug-related − first dose date + 1)/365.25*12.

Adjudicated drug-related ILD/pneumonitis occurred in 43 patients (16.7%) in the T-DXd group and 9 patients (3.4%) in the T-DM1 group
Since the previous analyses, 4 new events (all grade 2) occurred in the T-DXd group
- Outcomes of those 4 patients: not recovered/not resolved (n = 1), recovered/resolved with sequelae (n = 2), recovered/resolved (n = 1)
In the T-DM1 group, there was 1 additional grade 1 event since the previous data cutoff
As previously reported, only 2 patients had grade 3 events in the T-DXd group (both events resolved)
No grade 4 or 5 events were observed
Most ILD/pneumonitis events occurred within the first year of T-DXd treatment

Outcomes of ILD/Pneumonitis Events^,^a

Outcome of the worst ILD/pneumonitis event, n (%)	T-DXd n = 257	T-DM1 n = 261
Fatal	0	1 (12.5)^b
Not Recovered/Not Resolved	6 (15.4)	1 (12.5)
Recovering/Resolving	2 (5.1)	1 (12.5)
Recovered/Resolved with Sequelae	2 (5.1)	0
Recovered/Resolved	29 (74.4)	5 (62.5)
Missing/Unknown	0	0

Note: The outcome of the worst ILD event denominator was based on the number of events adjudicated as drug-related ILD

^aDCO July 25, 2022; ^bThe majority of ILD/pneumonitis events in both treatment arms resolved, with 1 fatal case reported in the T-DM1 arm. The patient had an event of pulmonary embolism adjudicated as drug-related grade 1 ILD.

LVEF decrease

n (%)^a	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5	Any Grade
T-DXd (n = 257)	0	8 (3.1)	1 (0.4)	0	0	9 (3.5)
T-DM1 (n = 261)	0	1 (0.4)	1 (0.4)	0	0	2 (0.8)

^aThere was 1 event (0.4%) of left ventricular dysfunction in the T-DXd arm and none in the T-DM1 arm.

Abbreviations

AE = adverse event

;

AESI = adverse event of special interest

;

CTCAE = Common Terminology Criteria for Adverse Events

;

DCO = data cut-off

;

EAIR = exposure-adjusted incidence rate

;

ILD = interstitial lung disease

;

LVEF = left ventricular ejection fraction

;

T-DM1 = trastuzumab emtansine

;

T-DXd = trastuzumab deruxtecan

;

TEAE = treatment-emergent adverse event

References

1. Hamilton E, Hurvitz SA, Im S-A, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated survival results from the randomized, phase 3, DESTINY-Breast03 trial. Presented at: American Society for Clinical Oncology; May 31-June 4, 2024. Poster 1025

2. Cortés J, Hurvitz SA, Im S-A, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from the randomized, phase 3 DESTINY-Breast03 trial. Nat Med. 2024.

3. Cortés J, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386:1143-1154.

4. Data on file. Daiichi Sankyo, Inc., Basking Ridge, NJ.

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

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