Investigational antibody-drug conjugates in clinical trials for the treatment of breast cancer

Figures & data

Figure 1. The mechanism of action of antibody-drug conjugates

Abbreviations: ADC = antibody-drug conjugate, Ag = antigen.

Table 1. ADCs in clinical practice and in late stages of development in breast cancer

ADC	Ab target	Linker	Payload and ADR	Status	Clinical trial in MBC (N)	RR p-value	Median PFS/months (HR, p-value)	Median OS/months (HR, p-value)
Approved ADCs
Trastuzumab emtansine (T-DM1)	HER2	Stable thioether linker	DM1 (microtubule inhibitor) ADR 3–4	Approved in HER2+ MBC after trastuzumab plus taxane	EMILIA [2] (N = 991) T-DM1 vs lapatinib/ Capecitabine	43.6% vs 30.8% P < 0.001	9.6 vs 6.4 months (HR 0.65; 95% CI, 0.55–0.77) P < 0.001)	30.9 vs 25.1 months (HR 0.68, 95% CI, 0.55–0.85) P < 0.001
Trastuzumab emtansine (T-DM1)	HER2	Stable thioether linker	DM1 (microtubule inhibitor) ADR 3–4	Approved in HER2+ MBC after trastuzumab plus taxane	TH3RESA [3] (n = 602) T-DM1 Vs TPC	31% Vs 9% p < 0 · 0001	6 · 2 vs 3 · 3 months (HR 0 · 52,895% CI 0 · 422–0 · 661) p < 0 · 0001	22 · 7 vs 15 · 8 months (HR 0 · 68 (95% CI 0 · 54–0 · 8)) p = 0 · 0007
Trastuzumab emtansine (T-DM1)	HER2	Stable thioether linker	DM1 (microtubule inhibitor) ADR 3–4	Approved in HER2+ EBC with residual disease after NAC	KATHERINE [8] (n = 1486) T-DM1 Vs trastuzumab	N/A	3-year iDFS: 88.3% Vs 77.0% (HR 0.50; 95%CI, 0.39–0.64) P < 0.001	NR
Trastuzumab deruxtecan (DS8201a, T-DXd)	HER2	cleavable tetrapeptide-based linker	Deruxtecan, an exatecan derivative (Topoisomerase I inhibitor) ADR 8	Approved in HER2+ MBC In development in HER2 low MBC and HER2+ EBC	DESTINY-Breast01 [9] (n = 184) Trastuzumab deruxtecan, phase 2) – updated results SABCS 2020*	61.4%	19.4 months (95% CI, 14.1 – NE)	24.6 months (95% CI, 23.1- NE)
Sacituzumab Govitecan (IMMU-132, SG)	Trop-2	Hydrolysable linker	SN-38 (Topoisomerase inhibitor) ADR up to 8	Approved in metastatic TNBC In development in ER+/HER2 negative MBC and HER2 negative EBC	ASCENT [20] (n = 529) Sacituzumab govitecan vs TPC Phase 3)*	35% vs 5%	5.6 vs 1.7 months, (HR: 0.41, 95%CI, 0.32–0.52) P < 0 .0001	12.1 vs 6.7 months, (HR: 0.48, 95% CI, 0.38–0.59) P < 0.0001
ADCs in phase 2/3 development
Trastuzumab duocarmazine (SYD-985)	HER2	Cleavable linker vc-seco-DUBA	Duocarmycin (alkylating agent) ADR 2.8	In development in HER2+ (TULIP phase 3 trial NCT03262935 completed accrual) and HER2 low MBC	Saura et al. [13] (n = 99) HER2+ (n = 50) HER2 Low (N = 49)	33% (20 · 4–48 · 4) ER+: 27% (13 · 8–46 · 8), ER-: 40% (16 · 3–67 · 6)	7.6 months (95% CI, 4.2–10.9) ER+: 4.1 months (95% CI, 2.4–5.4), ER-: 4.9 months (95% CI, 4.1-NE)	NR
RC48-ADC	HER2	Protease cleavable linker	Monomethyl auristatin E (microtubule disrupting agent) ADR 4	In development in HER2+ and HER2 low MBC	Xu B et al. [14] (n = 70) RC48-ADC, phase 1*	31.4%	5.8 months	NR
Patritumab deruxtecan (U3-1402, HER3-DXd)	HER3	Cleavable tetrapeptide based linker	Deruxtecan (Topoisomerase I inhibitor) ADR 7.8	In development in HER3+ MBC	Yonemori et al. [16] (n = 42) U3-1402, phase 1/2	43%	8 months	NR
SGN-LIV1A (ladiratuzumab vedotin)	LIV-1	Protease cleavable dipeptide linker	Monomethyl auristatin E (microtubule disrupting agent) ADR 4	In development in TNBC	Modi et al. [23] (n = 44) SGN-LIVA, phase 1, TNBC cohort	34.6%	11.3 weeks (95% CI, 6.1–17.1)	NR
Enfortumab vedotin (EV)	Nectin-4	Protease cleavable linker	Monomethyl auristatin E (microtubule disrupting agent) ADR 3.8	In development in ER+/HER2 negative MBC and TNBC	Rosenberg et al. [25] (n = 125) EV, phase 2, metastatic urothelial cancer)	44% (35.1%-53.2%)	5.8 months (95% CI, 4.9–7.5 months)	11.7 months (95% CI, 9.1 – NR)

Key: ADR = antibody drug ratio, EBC = early breast cancer, ER = estrogen receptor, iDFS = invasive disease-free survival, MBC = metastatic breast cancer, NAC = neo-adjuvant chemotherapy, N = number of patients, N/A = not applicable, NR = not reported, TN = triple negative, TNBC = triple negative breast cancer,

* = presented not published.

Table 2. Currently recruiting and planned studies with approved ADCs alone and in novel combinations, plus novel ADCs in development in breast cancer

Trial name Clinical trials.gov identifier	Patient population	ADC	Target	Combination	Phase	Planned n
Approved ADC Novel Combination Studies:
NCT04457596 (CompassHER2 RD)	HER2+ EBC with residual disease after NAC	T-DM1	HER2	Tucatinib	3	1031
NCT03975647 (HER2CLIMB-02)	HER2+ MBC or unresectable locally advanced disease	T-DM1	HER2	Tucatinib	3	460
NCT04158947 (HER2BAT)	HER2+ MBC with active refractory brain metastases	T-DM1	HER2	Afatinib	2	130
NCT01494662	HER2+ MBC with brain metastases	T-DM1	HER2	Neratinib	2	168
NCT03190967	HER2+ MBC with brain metastases after SRS	T-DM1	HER2	Metronomic temozolomide	1/2	125
NCT03530696	HER2+ MBC	T-DM1	HER2	Palbociclib	2	132
NCT04351230	HER2+ MBC	T-DM1	HER2	Abemaciclib	2	126
NCT04509596	HER2+ MBC	T-DM1	HER2	DZD 1516	1	94
NCT04740918 (KATE3)	HER2+ and PD-L1 positive MBC	T-DM1	HER2	Atezolizumab	3	350
NCT04538742 (DESTINY-Breast07)	HER2+ MBC (including those with active brain metastases)	T-DXd	HER2	Combination with durvalumab, pertuzumab, paclitaxel, tucatinib	1b/2	350
NCT04556773 (DESTINY-Breast08)	HER2-low MBC	T-DXd	HER2	Combination with durvalumab, paclitaxel, capivasertib, anastrozole, fulvestrant or capecitabine	1b	185
NCT04784715 (DESTINY-Breast09)	HER2+ MBC (first line)	T-DXd	HER2	Combination with or without pertuzumab vs taxane, trastuzumab and pertuzumab	Randomised phase 3	1134
NCT04539938 (HER2CLIMB-04)	HER2+ MBC	T-DXd	HER2	Tucatinib	2	70
NCT03523572	HER2 expressing MBC (or urothelial) cancer	T-DXd	HER2	Nivolumab	1	99
NCT04042701	HER2+ or HER2 low MBC (or NSCLC)	T-DXd	HER2	Pembrolizumab	1b	115
NCT04553770	HER2-low, HR+ EBC	T-Dxd	HER2	Anastrozole	2	88
NCT04704661	Advanced solid tumours with HER2 expression	T-DXd	HER2	AZD6738	1	15
NCT04039230	Metastatic TNBC	Sacituzumab govitecan	TROP-2	Talozaparib	1/2	75
NCT04468061	Metastatic TNBC	Sacituzumab govitecan	TROP-2	Pembrolizumab	Randomised phase 2	110
NCT04448886	ER+ Her2 negative MBC	Sacituzumab govitecan	TROP-2	Pembrolizumab	Randomised phase 2	110
NCT04230109 (NeoSTAR)	Early TNBC	Sacituzumab govitecan	TROP-2	Pembrolizumab	Randomised phase 2	100
NCT03992131 (SEASTAR)	Metastatic TNBC (and other selected solid tumours)	Sacituzumab govitecan	TROP-2	Rucaparib	1/2	329
NCT03424005 (Morpheus-TNBC)	Metastatic TNBC	Sacituzumab govitecan	TROP-2	Atezolizumab	1/2	280
Approved ADC single agent studies
NCT03523585 (DESTINY-Breast02)	HER2+ MBC (3^rd line after T-DM1)	T-DXd vs TPC	HER2	N/A	Randomised phase 3	600
NCT03529110 (DESTINY-Breast03)	HER2+ MBC (2^nd line after trastuzumab + taxane)	T-DXd vs T-DM1	HER2	N/A	Randomised phase 3	500
NCT03734029 (DESTINY-Breast04)	HER2 low MBC	T-DXd vs TPC	HER2	N/A	Randomised phase 3	557
NCT04622319 (DESTINY-Breast05)	High risk HER2+ve primary cancer + residual invasive disease following neoadjuvant chemotherapy	T-DXd vs T-DM1	HER2	N/A	Randomised phase 3	1600
NCT04739761 (DESTINY-Breast12)	HER2+ MBC with or without brain metastases	T-DXd	HER2	N/A	Phase 3b/4	500
NCT04752059 (TUXEDO-1)	HER2+ MBC with newly diagnosed or progressing brain metastases	T-DXd	HER2	N/A	2	15
NCT04420598 (DEBBRAH)	HER2+ or HER2 low MBC with brain metastases of leptomeningeal disease	T-DXd	HER2	N/A	2	39
NCT03901339 TROPICS-02	ER+ HER2- MBC (3^rd line)	Sacituzumab govitecan	TROP-2	N/A	Randomised phase 3	543
NCT04647916	HER2- MBC with brain metastases	Sacituzumab govitecan	TROP-2	N/A	2	44
Novel ADCs in phase 1 development in breast cancer
NCT03255070	HER2 expressing cancers	ARX788	HER2	Monotherapy	1	60
NCT03944499	HER2+ MBC	FS-1502	HER2	Monotherapy	1	92
NCT04492488	HER2+ solid tumours	MRG002	HER2	Monotherapy	1/2	152
NCT04742153	HER2-low MBC	MRG002	HER2	Monotherapy	2	66
NCT03284723	HER2+ MBC (and other solid tumours)	PF- 06804103	HER2	Monotherapy and with palbociclib and letrozole	1	148
NCT03602079	HER2+ solid tumours	A166	HER2	Monotherapy	1/2	82
NCT04152499	TNBC (and other solid tumours)	SKB264	TROP2	Monotherapy	1/2	78
NCT03243331	TNBC	PF-00647020 (PF7020, PTK7-ADC)	Protein kinase 7	Combination with Gedatolisib	1	18
NCT04064359	CD205+ HER2-negative MBC (plus other solid tumours)	OBT076	CD205	Monotherapy	1	70
NCT03504488	TNBC (or NSCLC, or STS)	CAB-ROR2-ADC	ROR2	Monotherapy	1/2	120
NCT04504916	ER+, HER2+ or TNBC (and other solid tumours)	VLS-101	ROR1	Monotherapy	2	90
NCT03729596	TNBC (and other solid tumours)	MGC018	B7-H3	Monotherapy and combination with MGA012 (anti-PD1)	1/2	150
NCT03621982	TNBC (and other solid tumours)	ADCT-301	CD25	Monotherapy and combination with pembrolizumab	1	95
NCT04300556	TNBC and other selected solid tumours	MORAb-202	Folate receptor alpha	Monotherapy	1/2	196
NCT03401385	TNBC and ER+ breast cancer (and NSCLC)	DS-1062 (Datopotamab Detuxtecan, Dato-Dxd)	TROP2	Monotherapy	1	770
NCT03742102	TNBC	DS-1062 (Datopotamab Detuxtecan, Dato-Dxd)	TROP2	Combination with durvalumab	1/2	57

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