DESTINY-Breast03: trial | Bending the Curve: Trial by Trial

DESTINY-Breast03

A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study of DS-8201a (Trastuzumab Deruxtecan), an Anti-HER2 Antibody Drug Conjugate (ADC), Versus Ado Trastuzumab Emtansine (T-DM1) for HER2-Positive, Unresectable and/or Metastatic Breast Cancer Subjects Previously Treated With Trastuzumab and Taxane

Phase 3N = 524NCT03529110

Population

HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane

Design

Multicentre open-label randomised phase 3 trial, 1:1 allocation to trastuzumab deruxtecan 5.4 mg/kg or trastuzumab emtansine 3.6 mg/kg every 3 weeks; stratified by hormone receptor status, prior pertuzumab and visceral disease. Primary endpoint: PFS by blinded independent central review.

Primary endpoint

PFS

Arms

Trastuzumab emtansine (T-DM1) (control, n = 263): Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks
Trastuzumab deruxtecan (experimental, n = 261): Trastuzumab deruxtecan 5.4 mg/kg intravenously every 3 weeks

People

Cortés J

PFSHR 0.28 (95% CI 0.22–0.37)Δ 12-month PFS+41.7 pointsOSHR 0.55 (95% CI 0.36–0.86)Δ 12-month OS+8.2 pointsΔ ORR+45.5 pointsPFSHR 0.33 (95% CI 0.26–0.43)

Show the numbers

Results reported for DESTINY-Breast03
Endpoint	Analysis	Trastuzumab deruxtecan	Trastuzumab emtansine (T-DM1)	Effect
PFSAll randomised patients (524)PFS by blinded independent central review; the abstract gives 12-month landmark rates rather than medians	primaryCortés 2022	75.8% at 12 mo (69.8–80.7%)	34.1% at 12 mo (27.7–40.5%)	HR 0.28 (95% CI 0.22–0.37)P<0.001
OSAll randomised patients (524)	interimCortés 2022	94.1% at 12 mo (90.3–96.4%)	85.9% at 12 mo (80.9–89.7%)	HR 0.55 (95% CI 0.36–0.86)The abstract states the prespecified significance boundary was not reached at this analysis.
ORRAll randomised patients (524)	primaryCortés 2022	79.7% (74.3–84.4%)	34.2% (28.5–40.3%)	Overall response (complete or partial).
PFSFull analysis set (524 randomised)PFS by blinded independent central review	long term-updateHurvitz 2023	median 28.8 months (22.4–37.9)	median 6.8 months (5.6–8.2)	HR 0.33 (95% CI 0.26–0.43)P<0.0001Updated analysis alongside the second interim overall survival analysis; nominal p value. Median follow-up 28.4 months with trastuzumab deruxtecan and 26.5 months with trastuzumab emtansine.
OSFull analysis set (524 randomised)	interimHurvitz 2023	—	—	HR 0.64 (95% CI 0.47–0.87)P=0.0037Second interim overall survival analysis. Median OS not reached in either group (95% CI 40.5 months to not estimable with trastuzumab deruxtecan; 34.0 months to not estimable with trastuzumab emtansine); 72 (28%) vs 97 (37%) overall survival events.

Results reported for DESTINY-Breast03
Endpoint	Analysis	Trastuzumab deruxtecan	Trastuzumab emtansine (T-DM1)	Effect
PFSAll randomised patients (524)PFS by blinded independent central review; the abstract gives 12-month landmark rates rather than medians	primaryCortés 2022	75.8% at 12 mo (69.8–80.7%)	34.1% at 12 mo (27.7–40.5%)	HR 0.28 (95% CI 0.22–0.37)P<0.001
OSAll randomised patients (524)	interimCortés 2022	94.1% at 12 mo (90.3–96.4%)	85.9% at 12 mo (80.9–89.7%)	HR 0.55 (95% CI 0.36–0.86)The abstract states the prespecified significance boundary was not reached at this analysis.
ORRAll randomised patients (524)	primaryCortés 2022	79.7% (74.3–84.4%)	34.2% (28.5–40.3%)	Overall response (complete or partial).
PFSFull analysis set (524 randomised)PFS by blinded independent central review	long term-updateHurvitz 2023	median 28.8 months (22.4–37.9)	median 6.8 months (5.6–8.2)	HR 0.33 (95% CI 0.26–0.43)P<0.0001Updated analysis alongside the second interim overall survival analysis; nominal p value. Median follow-up 28.4 months with trastuzumab deruxtecan and 26.5 months with trastuzumab emtansine.
OSFull analysis set (524 randomised)	interimHurvitz 2023	—	—	HR 0.64 (95% CI 0.47–0.87)P=0.0037Second interim overall survival analysis. Median OS not reached in either group (95% CI 40.5 months to not estimable with trastuzumab deruxtecan; 34.0 months to not estimable with trastuzumab emtansine); 72 (28%) vs 97 (37%) overall survival events.

Hazard ratio (95% CI) by endpoint. Values below 1 favour the experimental arm.

Data table

Endpoint	HR	95% CI
PFS	0.28	0.22–0.37
OS	0.55	0.36–0.86
PFS	0.33	0.26–0.43
OS	0.64	0.47–0.87

Illustrative — modelled from reported values, not trial data. PFS, long term-update.

Show curves

Trastuzumab emtansine (T-DM1) (control)
Trastuzumab deruxtecan (experimental)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)

Months	Trastuzumab emtansine (T-DM1)	Trastuzumab deruxtecan
0	100.0%	100.0%
18	16.0%	64.8%
36	2.5%	42.0%
54	0.4%	27.3%
72	0.1%	17.7%

Appears in

2022 DESTINY-Breast03: T-DXd versus T-DM1 in HER2-positive disease

Sources

Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022;386(12):1143-1154.
PubMed DOI
Hurvitz SA, Hegg R, Chung WP, Im SA, Jacot W, Ganju V, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023;401(10371):105-117.
PubMed DOI