Table 1:

List of completed and ongoing clinical trials that includes HER2-low breast cancer

Trial Name/ Identifier	Class of Drug and Anti-HER2-agent	Phase, Estimated Enrollment	Study Design	Population	Intervention	10 Outcome Measures	Key 20 Outcome Measures	Estimated 10 completion date	Results
Completed Trials
NCT01275677	ADC, Transtuzumab	Phase III, N = 3270	Randomized, Open label, two arm	Pre-treated node-positive or high-Risk node-negative HER2-low early-stage invasive BC	Chemotherapy alone (TC or ACT) vs Chemotherapy (TC or ACT) + Trastuzumab	IDFS	BCFS, RFI, DRFI, OS, AE	Completed 31-Jul-2017	Addition of trastuzumab to chemotherapy failed to show clinical benefit: 5-year IDFS= 89.8% vs 89.2%, HR= 0.98, p= 0.85; 5-year DRFI= 92.7% vs 93.6%, HR= 1.1, p= 0.55; OS= 94.8% vs 96.3%, HR= 1.33, p= 0.15
NCT02491892	ADC, Pertuzumab	Phase II, N = 78	Randomized, Open label	Pre-treated metastatic HER2-low BC	Two different doses of pertuzumab (1050 mg vs loading dose of 840 mg followed by maintenance dose of 420 mg)	ORR	Time to response, OS	Completed 01-April-2005	ORR 2.5%
NCT01828021	ADC, Margetuximab	Phase II, N = 25	Single arm, open label	Relapse refractory or advanced HER2-low BC	Margetuximab monotherapy	ORR	Response rate	Completed 14-April-2017	Results pending
NCT04420598/ DEBBRAH	ADC, T-DXd	Phase II, N = 41	Single arm, multi-cohort, open label	HER2-positive and HER2-low advanced BC with brain metastasis and LMC	Single agent T-DXd	PFS, ORR-IC, OS	ORR, TTR, clinical best response, DoR, best percentage of change, safety and tolerability of T-DXd	Completed 07-April-2022	Results pending
Ongoing Clinical Trials
NCT03734029/DESTINY-Breast 04	ADC, T-DXd	Phase III, N = 557	Randomized, open label, 2 arm	Pre-treated metastatic HER2-low BC	T-DXd vs treatment of physician's choice of chemotherapy (capecitabine or eribulin or gemcitabine or paclitaxel or nab-paclitaxel)	PFS	OS, ORR, DoR	1-Mar-23	Active, not recruiting. Results: T-DXd arm had improved PFS, and OS compared to physician's choice of chemotherapy (mPFS= 9.9 vs 5.1, HR= 0.5, p<0.0001; OS= 23.4 vs 16.8, HR= 0.64, p= 0.001)
NCT04556773/DESTINY-Breast 08	ADC, T-DXd	Phase 1b, N = 182	Non-randomized, open label, 5 study arms	HER2-low advanced/metastatic BC	T-DXd + capecitabine or T-DXd + durvalumab + paclitaxel or T-DXd + capivasertib or T-DXd + anastrozole or T-DXd + fulvestrant	AE, SAE	ORR, PFS, DoR, OS	26-Jan-24	Active, Recruiting
NCT04494425/DESTINY-Breast 06	ADC, T-DXd	Phase III, N = 850	Randomized, open label (sponsor-blind), dual arm CT	HER2-low HR+ metastatic BC with progression on ET, includes HER2-ultra-low BC patients	T-DXd vs standard of care (capecitabine or paclitaxel or nab-paclitaxel)	PFS	OS, ORR, DoR, AEs, serum concentration/ immunogenicity of T-DXd, health-related quality of life	19-Jun-26	Active, Recruiting
NCT04132960/DAISY	ADC, T-DXd	Phase II, N= 186	Single group assignment, Open-label, 3 cohorts	Advanced HER2+, HER2-low, HER2-zero BC	Single agent T-DXd	BOR	PFS, DoR	30-Mar-25	Active, Not recruiting
NCT04553770 (TRIO-US B-12 TALENT)	ADC, T-DXd	Phase II, N = 88	Randomized, open-label, dual arm CT	Early stage HER2-low HR+ BC	T-DXd alone vs T-DXd + Anastrozole	pCR	AEs, clinical objective response, Biomarker analyses, Molecular changes in tumour biomarkers (Ki67 expresion)	30-Sep-25	Active, Recruiting
NCT03052634	ADC, RC48	Phase Ib, N = 112	Non-randomized, open-label, single arm CT	Advanced HER2+/HER2-low BC	3 treatment arms with RC48 at doses of 1.5/2/2.5 mg/kg in HER2-positive, and 1 arm at dose of 2 mg/kg in HER2-low	RP2D	AUC, Cmax, Tmax, ORR, CBR, PFS	1-Dec-22	Active, Not recruiting
NCT03742102/ BEGONIA	ADC, T-DXd, Dato-DXd	Phase Ib/II, N = 210	Randomized, Open-label, 5 arm CT	Advanced/ unresectable/ metastatic TNBC (with HER2-low expression for Durvalumab/T-DXd arm)	5 treatment arms - (durvalumab + paclitaxel) vs (durvalumab + paclitaxel + capivasertib) vs (durvalumab + paclitaxel + oleclumab) vs (durvalumab + T-Dxd) vs (durvalumab + Dato-Dxd)	AE, Safety/ tolerability	ORR, PFS, DoR, OS	13-Feb-23	Active, Not recruiting
NCT05104866/ TROPION-Breast01	ADC, Dato-DXd	Phase III, N = 700	Randomized, Open-label, dual arm CT	Inoperable or metastatic HR+ HER2− BC with prior 1/2 lines of systemic chemotherapy	Dato-DXd vs investigators choice of chemotherapy (capecitabine or gemcitabine or eribulin or vinorelbine)	PFS, OS	ORR, DoR, DCR	18-Jul-25	Active, Recruiting
NCT04742153	ADC, MRG002	Phase II, N = 66	Non-randomized, open-label, single arm	Locally advanced or metastatic HER2-low BC	Single agent MRG002 IV infusion	ORR	PFS, 6-month/12-month PFSR, TTR, DoR, DCR, OS, Aes	1-Feb-23	Active, Recruiting
NCT05165225/ PILHLE-001	Pan-ERB TKI, Pyrotinib	Phase II, N = 46	Open label, single arm CT	Early/locally advanced HER2-low/HR+ BC	Pyrotinib + epirubicin and cyclophosphamide followed by docetaxel (neoadjuvant)	pCR	Miller-Payne grade PR, ORR, BCR, DFS, OS	19-May-28	Active, Recruiting

ADC = Antibody drug conjugate; HER2= human epidermal growth factor receptor 2; CT= Clinical trial; BC= Breast cancer; TC= Docetaxel and Cyclophosphamide; ACT= Doxorubicin, Cyclophosphamide and Paclitaxel; IDFS: Invasive disease-free survival; BCFS= Breast cancer free survival; RFI= Relapse free interval; DRFI= Distant relapse free interval; OS= Overall survival; AE= Adverse events; HR= Hormone receptor; Dato-DXd= Datopotamab deruxtecan, LMC= Leptomeningeal Carcinomatosis; Pan-ERB TKI = pan-Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor; ICPI = Immune Checkpoint Inhibitors; TNBC = Triple negative Breast Cancer; T-DXd = trastuzumab Deruxtecan; RP2D = Recommended Phase II dose; pCR = pathologic Complete Response rate; SAEs = Serious Adverse Events; Cmax = Maximum Observed Plasma Concentration; AUC = Area Under Curve; Tmax = Time for Cmax, ORR = Overall Response Rate; CBR = Clinical Benefit Rate; PFS = Progression Free Survival; DoR = Duration of Response; PFSR= Progression free survival rate; ITT = Intention To Treat; DCR = Disease Control Rate; TTD = Time to Deterioration; TTR= Time to response; BOR= Best Objective Response rate