EVIDENCE CARD · NCT05950945 · Breast cancer landscape

Trastuzumab Deruxtecan (Enhertu, T-DXd) in HER2-Low Metastatic Breast Cancer

A multicenter global Phase 3b rollover trial (Daiichi Sankyo / AstraZeneca) providing access to T-DXd for patients with HR-negative and HR-positive HER2-low metastatic breast cancer who have exhausted approved options and require continued treatment while awaiting reimbursement or local approval.

Evidence: High

Phase 3b, N = 250, open-label rollover, recruiting since July 2023, 88 sites in 15+ countries (US 5 sites). The core evidence supporting T-DXd in HER2-low breast is Level I randomized: DESTINY-Breast04 (Modi NEJM 2022, N=557, mPFS 10.1 vs 5.4 mo HR 0.51, mOS 23.9 vs 17.5 mo HR 0.64) and DESTINY-Breast06 (Bardia NEJM 2024, N=866 HR+ HER2-low/ultralow post-endocrine, mPFS 12.9-14 vs 6.5-8.2 mo). FDA-approved for HER2-low mBC since Aug 2022; label expanded Jan 2025 to include HER2-ultralow (IHC 0 with faint staining). Primary completion for this rollover: Oct 2027.

⚠ Critical safety signal — interstitial lung disease (ILD) / pneumonitis. Adjudicated drug-related ILD occurred in 12.1% of DESTINY-Breast04 patients (0.8% grade 5, i.e. fatal) and 13.6% (2.2% grade 5) in the earlier HER2-positive DESTINY-Breast01 population. Consider T-DXd only with pulmonary monitoring and immediate steroid protocols on suspected ILD. This is not a reason to avoid T-DXd — it is a reason to demand active surveillance.

Phase

3b (rollover)

Enrollment

250 (target)

Design

Non-randomized, open-label, global

Status

Recruiting

First posted

2023-07-18

Primary completion

Oct 2027

Primary endpoint

TTNT (time to next therapy)

Sponsor

Daiichi Sankyo / AstraZeneca

Evidence supporting T-DXd in HER2-low breast cancer

Pivotal (Level I, randomized vs standard chemotherapy)

Pivotal Ph3 HR-neg + HR-pos HER2-low DESTINY-Breast04 — T-DXd vs Physician's Choice Chemo in HER2-Low mBC

Modi S et al. N Engl J Med 2022 Jul · NCT03734029 · PMID 35665782

Randomized (2:1)
557 (494 HR+ / 63 HR-)

HR+ mPFS
10.1 vs 5.4 mo (HR 0.51, p<0.001)

HR+ mOS
23.9 vs 17.5 mo (HR 0.64, p=0.003)

All-patient mPFS
9.9 vs 5.1 mo (HR 0.50)

All-patient mOS
23.4 vs 16.8 mo (HR 0.64, p=0.001)

Grade ≥3 TRAE
52.6% vs 67.4%

ILD / pneumonitis
12.1% (0.8% grade 5)

Population
1-2 prior chemo lines
Pivotal Ph3 Extended to ultralow, first-line-post-endocrine DESTINY-Breast06 — T-DXd vs TPC in HR+ HER2-Low or HER2-Ultralow mBC After Endocrine

Bardia A et al. N Engl J Med 2024 Sep · NCT04494425 · PMID 39282896 (primary); Curigliano G et al. Ann Oncol 2026 Jun (subgroup analyses) · PMID 41780642

Randomized (1:1)
866 HR+ HER2-low/ultralow

mPFS
12.9-14.0 vs 6.5-8.2 mo (across subgroups)

Confirmed ORR
36.7-67.7% vs 16.7-37.5%

Population
Post-ET+CDK4/6i, chemo-naive in mBC setting

Ultralow subgroup
PFS benefit consistent with HER2-low

Safety
No new signals vs DB04 (ILD comparable)

Foundational (single-arm HER2-positive proof-of-concept)

Foundational Ph2 DESTINY-Breast01 — T-DXd in Heavily Pretreated HER2-Positive mBC

Modi S et al. N Engl J Med 2020 Feb · NCT03248492 · PMID 31825192 · Established T-DXd as a durable ADC in HER2+; safety benchmark for the ILD watch.

Patients
184 (median 6 prior therapies)

Confirmed ORR
60.9% (95% CI 53.4-68.0)

Median DoR
14.8 mo

Median PFS
16.4 mo

Grade ≥3 neutropenia
20.7%

ILD / pneumonitis
13.6% (2.2% grade 5)

Regulatory

Approved · FDA T-DXd (Enhertu) — HER2-low mBC approval, August 2022

Based on DESTINY-Breast04 · First-ever "HER2-low" indication in oncology · Companion diagnostic: Ventana 4B5 IHC assay

Approved for unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer in adults who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.
Label expanded · FDA HER2-ultralow T-DXd label extended to HER2-Ultralow HR+ mBC, January 2025

Based on DESTINY-Breast06 · First "HER2-ultralow" (IHC 0 with faint membrane staining, ≤10% of cells) recognized as an actionable expression tier

Approved for unresectable or metastatic HR+ HER2-low or HER2-ultralow breast cancer whose disease has progressed on one or more endocrine therapies in the metastatic setting.

Timeline — T-DXd in breast cancer

2019 Dec

First pivotal readout — DESTINY-Breast01, HER2+ pretreated, ORR 60.9% (NEJM 2020, PMID 31825192)

2019 Dec

FDA accelerated approval — HER2+ mBC, ≥2 prior anti-HER2 lines

2022 Jun

DESTINY-Breast04 readout — the HER2-low landmark, mPFS HR 0.51, mOS HR 0.64 vs chemo (NEJM 2022, PMID 35665782)

2022 Aug

FDA HER2-low approval — first-ever HER2-low label in oncology; creates the diagnostic tier and the market

2023 Jul

NCT05950945 registered — global Phase 3b rollover for HR-neg + HR-pos HER2-low, N=250

2024 Sep

DESTINY-Breast06 readout — extends to HR+ HER2-low/ultralow post-endocrine, N=866 (NEJM 2024, PMID 39282896)

2025 Jan

FDA label expansion — HER2-ultralow HR+ mBC after endocrine therapy; new diagnostic tier

2026 Jun

DESTINY-Breast06 subgroup analyses — PFS benefit consistent across TTP-on-CDK4/6i, disease burden, endocrine resistance (Ann Oncol 2026, PMID 41780642)

2027 Oct

NCT05950945 expected primary completion

How this strength score was computed

Dimension	Score	Basis
Study design	High	Two independent Level I randomized Phase 3 RCTs (DB04, DB06) vs standard chemotherapy, both positive on both PFS and OS/interim OS. Foundational Ph2 single-arm (DB01) for HER2+ safety anchor.
Sample size	High	Randomized N = 557 (DB04) + 866 (DB06) = 1,423 patients across the two pivotal trials. Comfortably powered for the HR+ HER2-low subgroup.
Follow-up maturity	High	Both pivotals have mature OS readouts, not interim-only. HR is stable across follow-up updates.
Source quality	High	Two NEJM primary papers + Ann Oncol subgroup + Daiichi/AZ sponsor + FDA approvals in two label-expansion rounds.
Endpoint quality	High	Blinded independent central review PFS + OS in both pivotals (gold-standard endpoints). This rollover uses TTNT (time-to-next-therapy) as its own primary — a real-world-usage endpoint, not a substitute for the pivotals.
Consistency	High	PFS/OS benefit consistent across HR+/HR-, HER2-low/ultralow, prior-therapy subgroups. Only outlier is HER2-null (IHC 0 without faint staining) — efficacy uncertain, deliberately excluded from the label.

Limitations of this evidence base:

NCT05950945 itself is a rollover / expanded-access Phase 3b, not a randomized comparison. Its N=250 is small vs the pivotals it draws on; its role is continued access, not new evidence.
Efficacy in HER2-null (IHC 0, no faint membrane staining) tumors remains uncertain. The DAISY trial suggested some activity even at very low HER2 expression, but regulatory eligibility currently requires detectable staining. Diagnostic-assay variability at the HER2-low/ultralow/null boundary is a real clinical problem (see Torlakovic Curr Oncol 2026, PMID 42041700).
ILD/pneumonitis remains the dose-limiting toxicity: 12.1% in DB04 (0.8% grade 5), 13.6% in DB01 (2.2% grade 5). Any new cough, dyspnea, or fever needs immediate imaging + steroid protocol. Do NOT delay evaluation.
All pivotals used the Ventana 4B5 IHC assay as companion diagnostic. Patients tested with the legacy Dako HercepTest may need reassessment before eligibility — ~60% discordance rate documented in one MD Anderson series (Yamaguchi Breast Cancer Res Treat 2026, PMID 42329461); ~1/4 of discordant cases lose HER2-low status.
The Phase 3b rollover has 88 sites but only 5 in the US; patient discoverability in the US is best via the pivotal trials' registered sites or standard commercial-supply T-DXd (which is FDA-approved and reimbursable).

Are you or a loved one considering T-DXd for HER2-low breast cancer? Get a personalized ranked list of breast-cancer trials you may qualify for — free, no login.

Find Matching Breast Cancer Trials

Evidence current through September 2026. This card is compiled from ClinicalTrials.gov v2 + PubMed abstracts; hand-check against the linked primary sources for clinical decision-making. Not medical advice.

Sources on this card: PMID 35665782 (DB04) · 39282896 (DB06 primary) · 41780642 (DB06 subgroup) · 31825192 (DB01) · CT.gov NCT05950945

Related recruiting T-DXd breast-cancer trials in the ClinTrialFinder corpus: /drugs/trastuzumab-deruxtecan (147 recruiting trials, all cancer types) · other Cards: MRG003+Pucotenlimab NPC (NCT06976190)