Advances of antibody-drug conjugates in the treatment of metastatic triple-negative breast cancer

doi:10.16139/j.1007-9610.2024.06.13

Abstract

Abstract:

Triple-negative breast cancer (TNBC) is insensitive to endocrine therapy or anti-human epidermal growth factor receptor(HER)-2 targeted therapy due to its lack of expression of hormone receptors and HER-2. Antibody-drug conjugates(ADCs) recognize specific antigens on the surface of cancer cells through specific antibodies, form antigen-antibody complexes that are then internalized, and subsequently release their payloads to kill cancer cells, which offering a novel therapeutic option for metastatic TNBC. Currently, ADCs undergoing research and clinical application in metastatic TNBC include sacituzumab govitecan, datopotamab deruxtecan (Dato-DXd), SKB264, and trastuzumab deruxtecan (T-DXd). This article summarized the targets and structural characteristics of ADCs in metastatic TNBC, systematically reviewed the efficacy and safety of ADCs from relevant clinical studies, and discussed the issues of the clinical application of ADCs.

Key words: Breast cancer, Triple-negative, Antibody-drug conjugate(ADC)

CLC Number:

R737.9

TONG Yiwei, CHEN Xiaosong. Advances of antibody-drug conjugates in the treatment of metastatic triple-negative breast cancer[J]. Journal of Surgery Concepts & Practice, 2024, 29(06): 533-536.

Figures/Tables 3

Tab 1

Tab 2

Tab 3

References 16

[1]	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249.
[2]	国家肿瘤质控中心乳腺癌专家委员会, 中国抗癌协会乳腺癌专业委员会, 中国抗癌协会肿瘤药物临床研究专业委员会. 中国晚期乳腺癌规范诊疗指南(2022版)[J]. 中华肿瘤杂志, 2022, 44(12):1262-1287.
	National Cancer Quality Control Center Breast Cancer Expert Committee, China Anti-Cancer Association Breast Cancer Professional Committee, China Anti-Cancer Association Oncology Drug Clinical Research Professional Committee. Guidelines for standardized diagnosis and treatment of advanced breast cancer in China (2022 edition)[J]. Chin J Oncol, 2022, 44(12):1262-1287.
[3]	王杰强. Trop2基因与三阴性乳腺癌的研究进展[J]. 外科理论与实践, 2022, 27(5):473-477.
	WANG J Q. Research progress on Trop2 gene and triple-negative breast cancer[J]. J Surg Concepts Pract, 2022, 27(5):473-477.
[4]	QIU S, ZHANG J, WANG Z, et al. Targeting Trop-2 in cancer: recent research progress and clinical application[J]. Biochim Biophys Acta Rev Cancer, 2023, 1878(4):188902.
[5]	BARDIA A, MAYER I A, DIAMOND J R, et al. Efficacy and safety of anti-Trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer[J]. J Clin Oncol, 2017, 35(19):2141-2148. doi: 10.1200/JCO.2016.70.8297 pmid: 28291390
[6]	JEON Y, JO U, HONG J, et al. Trophoblast cell-surface antigen 2 (TROP2) expression in triple-negative breast cancer[J]. BMC Cancer, 2022, 22(1):1014. doi: 10.1186/s12885-022-10076-7 pmid: 36153494
[7]	MIGLIETTA F, GRIGUOLO G, BOTTOSSO M, et al. Evolution of HER2-low expression from primary to recurrent breast cancer[J]. NPJ Breast Cancer, 2021, 7(1):137. doi: 10.1038/s41523-021-00343-4 pmid: 34642348
[8]	LINDSTRÖM L S, KARLSSON E, WILKING U M, et al. Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression[J]. J Clin Oncol, 2012, 30(21):2601-2608. doi: 10.1200/JCO.2011.37.2482 pmid: 22711854
[9]	BARDIA A, HURVITZ S A, TOLANEY S M, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer[J]. N Engl J Med, 2021, 384(16):1529-1541.
[10]	XU B, MA F, WANG T, et al. A Phase Ⅱb, single arm, multicenter trial of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer who received at least two prior treatments[J]. Int J Cancer, 2023, 152(10):2134-2144.
[11]	YIN Y M, WU X H, OUYANG Q C, et al. Abstract OT1-03-02: efficacy and safety of SKB264 for previously treated metastatic triple negative breast cancer in phase 2 study[J]. Cancer Research, 2023, 83(5_Supplement):OT1-03-02.
[12]	XU B H, YIN Y M, FAN Y, et al. Abstract 104: sacituzumab tirumotecan (SKB264/MK-2870) in patients (pts) with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC): results from the phase Ⅲ OptiTROP-Breast01 study[J]. J Clin Oncol, 2024, 42(16_Supplement):104.
[13]	BARDIA A, KROP I, MERIC-BERNSTAM F, et al. Abstract P6-10-03: datopotamab deruxtecan (Dato-DXd) in advanced triple-negative breast cancer (TNBC): updated results from the phase 1 TROPION-PanTumor01 study[J]. Cancer Research, 2023, 83(5_Supplement):P6-10-03.
[14]	MODI S, JACOT W, YAMASHITA T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer[J]. N Engl J Med, 2022, 387(1):9-20.
[15]	中国医师协会肿瘤医师分会乳腺癌学组, 中国抗癌协会国际医疗交流分会. 中国乳腺癌抗体药物偶联物安全性管理专家共识[J]. 中华肿瘤杂志, 2022, 44(9):913-927.
	Chinese Society Of Oncology, Breast Cancer Working Group, China Anti-Cancer Association, International Medical Exchange Branch. Chinese expert consensus on safety management of antibody-drug conjugates for breast cancer treatment[J]. Chin J Oncol, 2022, 44(9):913-927.
[16]	SCHMID P, WYSOCKI P J, MA C X, et al. 379MO Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): Updated results from BEGONIA, a phase Ib/II study[J]. Ann Oncol, 2023,34,S337.

Drug	SG	Dato-DXd	SKB264	T-DXd
Target	Trop-2	Trop-2	Trop-2	HER-2
Antibody	hRS7	MAAP-9001a	hRS7	hIgG1 trastuzumab
Linker	pH-sensitive cleavable	Enzyme cleavable	Kthiol-conjugated, pH-sensitive cleavable	Enzyme cleavable
DAR	7.6	4	7.4	8
Payload classification	Topoisomerase Ⅰ Inhibitor	Topoisomerase Ⅰ Inhibitor	Topoisomerase Ⅰ Inhibitor	Topoisomerase Ⅰ Inhibitor
Payload	Irinotecan metabolite SN-38	Irinotecan derivative Dxd	Belotecan metabolite KL610023	Irinotecan derivative Dxd
Bystander effect	Yes	Yes	Yes	Yes

Trial	ASCENT^[9]	EVER-132-01^[10]	NCT04152499^[11]	OptiTROP- Breast01^[12]	TROPION- PanTumor01^[13]	DESTINY- Breast04^[14]
Drug	SG vs. TPC	SG	SKB264	SKB264 vs. TPC	Dato-DXd	T-DXd vs. TPC
Phase	Ⅲ	Ⅱb	Ⅱ	Ⅲ	Ⅰ	Ⅲ
Design	RCT	Single-arm	Single-arm	RCT	Single-arm	RCT
Number of participants	468	80	59	263	44	58^d)
Median lines of previous treatment	3	4	3^a）	3	3	3^d)
Median PFS (month)	5.6 vs. 1.7	5.6	5.7	6.7 vs. 2.5	4.3	8.5 vs. 2.9^d)
Median OS (month)	12.1 vs. 7.7	-	-	NR vs. 9.4	12.9	18.2 vs. 8.3^d)
ORR (%)	35 vs. 5	38.8	40^b)	45.4 vs. 12.0	32	50.0 vs. 16.7^d)
CBR (%)	45 vs. 9	43.8	-^c)	-	34	62.5 vs. 27.8^d)
Median duration of response (month)	6.3 vs. 3.6	5.6	-	7.1 vs. 3.0	-	8.6 vs. 4.9^d)

Trial	ASCENT^[9]	EVER-132-01^[10]	NCT04152499^[11]	OptiTROP-Breast01^[12]	TROPION-PanTumor01^[13]	DESTINY-Breast04^[14]
Drug	SG	SG	SKB264	SKB264	Dato-DXd	T-DXd
Any TRAE	97.7%	98.8%	-	100%	100%^a)	99.5%^{a,) b)}
≥Grade 3 TRAE	64.3%	71.3%	55.9%	57.7%	50%^a)	54.4%^{a), b)}
Hematology toxicity
Neutropenia	51%	62.5%	23.7%	32.3%	2%	13.7%^b)
Anemia	8%	21.3%	20.3%	27.7%	-	8.1%^b)
Leucopenia	11%	10%	-	25.4%	-	6.5%^b)
Febrile neutropenia	6%	-	-	-	-	-
Decreased platelet count	-	3.8%	16.9%	12%	-	5.1%^b)
Gastrointestinal toxicity
Diarrhea	10%	2.5%	-	-	0	1.1%^b)
Vomiting	<3%	0	-	-	5%	1.3%^b)
Others
Stomatitis	-	-	-	9%	11%	-
Fatigue	3%	3.8%	-	-	7%	7.5%^b)
Discontinuation rate	5%	6.3%	6.8%	1.5%	2%	16.2%^b)