Antibody-Drug Conjugates in Breast Cancer: A Comprehensive Review of How to Selectively Deliver Payloads

Figures & data

Figure 1 Structure and Mechanism of Action of Antibody-Drug Conjugates in the Treatment of Breast Cancer.

Note: (A) The figure displays the components of Antibody-Drug Conjugates (ADCs), comprising the antibody, linker, and payload. (B). Sacituzumab Govitecan targets TROP-2-expressing cancer cells using the humanized antibody RS7. Following cellular internalization, the topoisomerase I inhibitor SN-38 is released, leading to DNA damage-mediated apoptosis. (C) Trastuzumab-Deruxitecan (T-DXd), another ADC, binds to HER2 on tumor cells and undergoes internalization. Intracellular linker cleavage by lysosomal enzymes ensues, liberating the membrane-permeable DXd. Once released, DXd enters the nucleus, causing DNA damage and inducing apoptotic cell death. Notably, the high membrane permeability of the payload enables a cytotoxic bystander effect on neighboring tumor cells, regardless of their HER2 expression levels. (D) Trastuzumab emtansine (T-DM1), a representative ADC, binds to HER2 via the Fc receptor. Upon internalization of the TDM-1/HER2 complex by endosomes, subsequent degradation occurs within lysosomes, leading to the release of emtansine. Emtansine then binds to microtubules, impeding their polymerization. Additionally, TDM-1 inhibits downstream HER2 signaling, resulting in the prevention of cell proliferation and the induction of apoptosis. Moreover, TDM-1 binds to natural killer (NK) cells through Fc gamma receptors (FcƴR), eliciting cell death via immune system activation.

Table 1 Pivotal Trials with ADCs for Breast Cancer Treatment

HER2 Positive
ADC	Trial	Setting	N	ORR	PFS / DFS	OS
TDM1	EMILIA^Citation21	2nd line MBC	991	43.6 vs 31%	9.6 vs 6.4 mo (HR 0.65, p<0.001)	30.9 vs 25.1 mo^§ (HR 0.68, p<0.001)
	TH3RESA^Citation22	≥3rd line MBC	602	31 vs 9%	6.2 vs 3.3 mo (HR 0.52, p<0.0001)	22.7 vs 15.8 mo (HR 0.68, p=0.0007)
	KATHERINE^Citation26	EBC with residual disease	1486	NA	3y DFS 88.3 vs 77% (HR 0.5, p<0.001)	HR 0.7 (0.47–1.05, p=0.08) ^ß
T-Dxd	DESTINY BREAST 01^Citation30	≥3rd line MBC	184	60.9% ^¶	16 mo ^¶	93.9% 6 mo 58% 24 mo
	DESTINY BREAST 02^Citation31	≥3rd line MBC	608	69.7 vs 29.2%	17.8 vs 6.9 mo (HR 0.36, p<0.0001)	39.2 vs 26.5 mo (HR 0.66, p=0.0021)
	DESTINY BREAST 03^Citation32	2nd line MBC	524	79.7 vs 34.2%	25.1 vs 7.2 mo (HR 0.26, p<0.001)	HR 0.64 (0.47–0.87, p=0.0037)
SYD985	TULIP^Citation34	≥3rd line MBC	437	27.8 vs 29.5%	7.0 vs 4.9 mo (HR 0.64, p = 0.002)	HR 0.83 (0.62–1.09, p=0.153)
Triple Negative
SG	ASCENT^Citation35	≥3rd line MBC	468	35 vs 5%	5.6 vs 1.7 mo (HR 0.41, p<0.001)	12.1 vs 6.7 mo (HR 0.48, p<0.001)
T-Dxd	DESTINY BREAST 04^Citation36	2nd line HER-low MBC	63	50 vs 16.7%	8.5 vs 2.9 mo (HR 0.46–0.24-0.89)*	18.2 vs 8.3 mo (HR 0.48–0.24 - 0.95)*
Hormone Receptor Positive
T-Dxd	DESTINY BREAST 04^Citation36	≥2nd line MBC	494	52.6 vs 16.3%	10.1 vs 5.4 mo (HR 0.51, p<0.001)	23.9 vs 17.5 mo (HR 0.64, p=0.003)
SG	TROPICS-02^Citation37	≥3rd line MBC	543	21 vs 14%	5.5 vs 4 mo (HR 0.66, p=0.0003)	13.9 vs 12.3 mo (HR 0.84, p=0.143)

Notes: *Subgroup analysis; ^§Second interim analysis, ^¶Phase 2 single group, ^ßData immature.

Abbreviations: DFS, disease free survival; EBC, early breast cancer; HR, hazard ratio; MBC, metastatic breast cancer; ORR, overall response rate; OS, overall survival; PFS, progression free survival; SG, Sacituzumab Govitecan; SYD985, trastuzumab duocarmazine; TDM1, Ado-trastuzumab Emtansine; T-Dxd, Fam-trastuzumab Deruxtecan.

Table 2 Ongoing Trials: HER2-Positive Breast Cancer

Early Breast Cancer
Ph	NCT identifier	Trial Name	Target	Payload	Experimental Arm	Control Arm	Setting	Population	Primary endpoint
III	NCT04622319	Destiny Breast 05	HER2	Deruxtecan (Top1)	T-DXd	T-DM1	Post-neoadjuvant	HER2 positive EBC with residual disease	IDFS
	NCT05113251	Destiny Breast 11	HER2	Deruxtecan (Top1)	T-DXd or T-DXd + THP	AC-THP	Neoadjuvant	HER2 positive high risk EBC	pCR
	NCT04873362	Astefania	HER2	DM1 (MI)	TDM-1 + Atezolizumab	TDM-1	Post-neoadjuvant	HER2 positive high-risk EBC	IDFS
	NCT04457596	CompassHER2 RD	HER2	DM1 (MI)	TDM-1 + Tucatinib	TDM-1	Post-neoadjuvant	HER2 positive EBC with residual disease	IDFS
Metastatic Breast Cancer
Ph	NCT identifier	Trial Name	Target	Payload	Experimental Arm	Control Arm	Setting	Population	Primary endpoint
III	NCT04784715	Destiny Breast 09	HER2	Deruxtecan (Top1)	T-DXd ± Pertuzumab	Taxane + TP	1st line - No prior chemo for MBC	HER2 positive MBC	PFS
	NCT03262935	TULIP	HER2	DUBA (AA)	SYD985 (trastuzumab duocarmazine)	Investigator choice	≥2 HER2 lines or POD on TDM-1	HER2 positive MBC	PFS
	NCT03500380	NA	HER2	MMAE (MI)	RC48-ADC - Disitamab vedotin	Lapatinib + capecitabine	Up to 2 lines, previous taxane	HER2 positive MBC	PFS
I/II	NCT04539938	HER2CLIMB--04	HER2	Deruxtecan (Top1)	T-DXd + Tucatinib	NA	POD on taxane + trastuzumab	HER2 positive MBC	ORR
	NCT04042701	NA	HER2	Deruxtecan (Top1)	T-DXd + Pembrolizumab	NA	1: POD on TDM1 2: POD after SOC therapies	1: HER2 positive MBC 2: HER2 low MBC	Safety, ORR
	NCT02952729	NA	HER2	Auristatin (MI)	XMT-1522 / TAK-522	NA	POD after all SOC therapies	1: HER2 low MBC 2: HER2 positive MBC	Safety
	NCT04829604	ACE-Breast 03	HER2	MMAF (MI)	ARX788	NA	POD on TDXd	HER2 positive MBC	ORR
	NCT03284723	NA	HER2	Aur0101 (MI)	PF-06804103 + Palbociclib + Letrozole	NA	POD after all SOC therapies	HER2 positive or low MBC	Safety, ORR, PFS
	NCT04492488	NA	HER2	MMAE (MI)	MRG002	NA	POD after all SOC therapies	HER2 positive MBC	Safety, RP2D, ORR
	NCT04280341	NA	HER2	MMAE (MI)	RC48-ADC + JS001 (anti PD1)	NA	POD after all SOC therapies	HER2 positive or low MBC	Safety, ORR, DOR
	NCT04278144	NA	HER2	TLR 7/8 agonist	BDC-1001 ± Nivolumab	NA	POD after all SOC therapies	HER2 positive or low MBC	Safety, ORR
	NCT03602079	NA	HER2	Auristatin (MI)	A166	NA	POD after all SOC therapies	1: HER2 positive MBC 3: HER2 low MBC	Safety
	NCT03821233	ZWI ZW49-101	HER2	Auristatin (MI)	ZW49 - Zanidatamab Zovodotin	NA	POD after all SOC therapies	HER2 positive MBC	Safety

Abbreviations: AA, DNA alkylating agent; DOR, duration of response; EBC, early breast cancer; IDFS, invasive disease free survival; MBC, metastatic breast cancer; MI, Microtubule inhibitor; MMAE, Monomethyl Auristatin E; MMAF, Monomethyl Auristatin F; pCR, pathologic complete response;; PFS, progression free survival; Ph, Phase; POD, progression of disease; SOC, standard of care; ORR, overall response rate; RP2D, Recommended phase 2 dose.

Table 3 Ongoing Trials: Triple Negative Breast Cancer

Early Breast Cancer
Ph	NCT identifier	Trial Name	Target	Payload	Experimental Arm	Control Arm	Setting	Population	Primary endpoint
III	NCT04595565	SASCIA	TROP-2	SN-38 (Top 1)	Sacituzumab govitecan	TPC	Post neoadjuvant	EBC with residual disease	IDFS
III	NCT05629585	TROPION-Breast-03	TROP2	Deruxtecan (Top1)	Dato-DXd ± durvalumab	TPC	Post neoadjuvant	EBC with residual disease	IDFS
Metastatic Breast Cancer
Ph	NCT identifier	Trial Name	Target	Payload	Experimental Arm	Control Arm	Setting	Population	Primary endpoint
III	NCT05382299	ASCENT-03	TROP2	SN-38 (Top1)	Sacituzumab govitecan	TPC	1st line, no prior ICI on MBC setting	TN MBC	PFS
	NCT05382286	ASCENT-04	TROP2	SN-38 (Top1)	Sacituzumab govitecan + Pembro	Pembro + ChT	1st line, PDL1 positive	TN MBC	PFS
	NCT05374512	TROPION-Breast-02	TROP2	Deruxtecan (Top1)	Dato-DXd	TPC	1st line, not suitable for PD1/PDL1 inhibitor	TN MBC	PFS, OS
	NCT05347134	KL264-01	TROP2	Belotecan (Top1)	SKB-264	TPC	≥2 lines, including taxanes	TN MBC	PFS
I/II	NCT04494425	BEGONIA	HER2 TROP2	Deruxtecan (Top1)	T-DXd (arm 6) ou Dato-DXd (arm 7) + Durvalumab	NA	1st line amr 7: no prior ICI	TN MBC arm 6: HER2 low	Safety, ORR
	NCT03310957	KEYNOTE 721	LIV1	MMAE (MI)	Ladiratuzumab vedotin (SGN-LIV1A) + Pembrolizumab	NA	1st line	TN MBC	Safety, ORR
	NCT04300556	MORAb202-G000-201	FRα	Eribulin (MI)	Farletuzumab Ecteribulin (MORAb-202)	NA	≥1 prior chemo	TN MBC	Safety, ORR
	NCT04699630	BRE-354	HER3	Deruxtecan (Top1)	Patritumab deruxtecan	NA	1–3 prior lines chemo	TN MBC	ORR, PFS-6m
	NCT03729596	CP-MCG018-01	B7H3	DUBA (AA)	Vobramitamab duocarmazine ± retifanlimab (anti-PD1)	NA	≥1 prior chemo	TN MBC	Safety
	NCT04504916	MK-2104-002	ROR2	MMAE (MI)	Zilovertamab Vedotin	NA	POD after all SOC therapies	HER2 negative MBC	ORR
	NCT04659603	CARMEN-BT01	CEACAM5	DM4	Tusamitamab ravtansine	NA	≥1 prior chemo, CEACAM5 IHC expression	TN MBC	ORR, Safety
	NCT03424005	Morpheus-TNBC	TROP2 LIV1	SN38 MMAE	Atezo + SG and atezo + SGN-LIV1A	NA	1^st or 2^nd line, no prior ICI	TN MBC	ORR, Safety
	NCT05143229	ASSET	TROP2	SN38	SG + Alpelisib	NA	≥1 prior chemo	HER2 negative MBC	RP2D
	NCT04602117	ISPY-P1-01	HER2	DUBA (AA)	SYD985 (trastuzumab duocarmazine) + Paclitaxel	NA	≥1 prior chemo	TN MBC HER2low	ORR, Safety
	NCT04556773	Destiny-Breast 08	HER2	Deruxtecan (Top1)	T-Dxd	NA	Part 1: ≥1 prior chemo. Part 2: 1^st line	TN MBC HER2low	Safety
	NCT04039230	NA	TROP2	SN38	SG + Talazoparib	NA	NA	TN MBC	Safety
	NCT03504488	NA	ROR2	MMAE (MI)	CAB-ROR2-ADC (BA3021) ± anti-PD1	NA	POD after all SOC therapies	TN MBC	ORR, Safety

Abbreviations: Ph, Phase; POD, progression of disease; SOC, standard of care; ICI, immune checkpoint inhibitor; MBC, metastatic breast cancer; EBC, early breast cancer; TN, triple negative; ChT, chemotherapy; TPC, treatment of physician’s choice; PFS, progression free survival; ORR, overall response rate; RP2D, Recommended phase 2 dose; Top1, DNA topoisomerase 1 inhibitor; MMAE, Monomethyl Auristatin E; MI, Microtubule inhibitor; AA, DNA alkylating agent; SG, sacituzumab govitecan.

Table 4 Ongoing Trials: Hormone Receptor Positive Breast Cancer

Early Breast Cancer
Ph	NCT identifier	Trial Name	Target	Payload	Experimental Arm	Control Arm	Setting	Population	Primary Endpoint
III	NCT04595565	SASCIA	TROP-2	SN-38 (Top1)	SG	TPC	Post neoadjuvant	HER2 negative EBC with residual disease	IDFS
I/II	NCT04553770	TRIO-US B12 TALENT	HER2	Deruxtecan (Top1)	T-DXd ± anastrozole	NA	Neoadjuvant	HER2 low EBC	pCR
Metastatic Breast Cancer
Ph	NCT identifier	Trial Name	Target	Payload	Experimental Arm	Control Arm	Setting	Population	Primary endpoint
III	NCT04494425	Destiny Breast 06	HER2	Deruxtecan (Top1)	T-DXd	TPC	≥2 lines ET or POD on 1st line CDK4/6i	HER2 low or ultra-low MBC	PFS
	NCT05104866	TROPION-Breast-01	TROP2	Deruxtecan (Top1)	Dato-DXd	TPC	1–2 lines prior chemo	MBC, resistance to endocrine therapy	PFS
I/II	NCT04965766	ICARUS-BREAST	HER3	Deruxtecan (Top1)	Patritumab deruxtecan	NA	>75% HER 3 expression	MBC, resistance to endocrine therapy	ORR
	NCT04504916	MK-2104-002	ROR2	MMAE (MI)	Zilovertamab Vedotin	NA	POD after all SOC therapies	HER2 negative MBC	ORR
	NCT04659603	CARMEN-BT01	CEACAM5	DM4 (MI)	Tusamitamab ravtansine	NA	≥2 prior chemo, CEACAM5 IHC expression	HER2 negative MBC	ORR, Safety

Abbreviations: Ph, Phase; POD, progression of disease; SOC, standard of care; MBC, metastatic breast cancer; EBC, early breast cancer; TPC, treatment of physician’s choice; PFS, progression free survival; ORR, overall response rate; Top1, DNA topoisomerase 1 inhibitor; MMAE, Monomethyl Auristatin E; MI, Microtubule inhibitor; SG, sacituzumab govitecan.

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