Table Info

Table 1.

Results of the completed phase 3 studies for T-DXd [16], trastuzumab duocarmazine [28] and SG [9]

Study		Comparators	Study population	Primary outcome	Important results
T-DXd	DESTINY-Breast03 (n = 524)	T-DXd versus T-DM1	HER2-positive, unresectable and/or MBC, previously treated with trastuzumab and taxane	PFS (BICR)	HR 0.2840 (PFS not reached and 6.8 months, P = 7.8 × 10⁻²²)
Trastuzumab duocarmazine	TULIP (n = 437)	Trastuzumab duocarmazine versus treatment of physician’s choice	HER2-positive, locally advanced or MBC, ≥ 2 previous MBC regimens or previous treatment with T-DM1	PFS (BICR)	HR 0.64 (PFS 7.0 and 4.9 months, P = 0.002)
SG	ASCENT (n = 468)	SG versus single-agent chemotherapy of physician’s choice	TNBC relapsed or refractory to ≥ 2 previous standard chemotherapy for advanced or MBC, taxane must be included in the previous therapies	PFS (BICR)	HR 0.41 (5.6 and 1.7 months, P < 0.001)

MBC: metastatic breast cancer; PFS: progression-free survival ; BICR: blinded independent central review; HR: hazard ratio

Declarations

Author contributions

KLK wrote the first draft of the manuscript; all authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

KLK declares that she has no conflicts of interest. MJ is the investigator in Daiichi-Sankyo trials. JH receives research funding (top institution) from Celgene, Novartis, Hexal, Lilly; receives honoraria from Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene, Eisai, Abbvie, Seagen, Gilead; has consulting advisory relationship with Lilly, Novartis, Roche, Pfizer, Hexal, AstraZeneca, MSD, Celgene, Abbvie, Seagen, Gilead; receives travel expenses from Roche, Pfizer, Novartis, Celgene, Daiichi.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Barroso-Sousa R, Tolaney SM. Clinical development of new antibody-drug conjugates in breast cancer: to infinity and beyond. BioDrugs. 2021;35:159–74. [DOI] [PubMed] [PMC]

Joubert N, Beck A, Dumontet C, Denevault-Sabourin C. Antibody-drug conjugates: the last decade. Pharmaceuticals (Basel). 2020;13:245. [DOI] [PubMed] [PMC]

Birrer MJ, Moore KN, Betella I, Bates RC. Antibody-drug conjugate-based therapeutics: state of the science. J Natl Cancer Inst. 2019;111:538–49. [DOI] [PubMed]

Lambert JM, Berkenblit A. Antibody-drug conjugates for cancer treatment. Annu Rev Med. 2018;69:191–207. [DOI] [PubMed]

Staudacher AH, Brown MP. Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required? Br J Cancer. 2017;117:1736–42. [DOI] [PubMed] [PMC]

Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783–91. [DOI] [PubMed] [PMC]

von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380:617–28. [DOI] [PubMed]

Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610–21. [DOI] [PubMed] [PMC]

Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384:1529–41. [DOI] [PubMed]

10.

Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res. 2016;22:5097–108. [DOI] [PubMed]

11.

Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T. Bystander killing effect of DS-8201a, a novel anti- human epidermal growth factor receptor 2 antibody–drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016;107:1039–46. [DOI] [PubMed] [PMC]

12.

Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol. 2017;18:1512–22. [DOI] [PubMed]

13.

Tamura K, Tsurutani J, Takahashi S, Iwata H, Krop IE, Redfern C, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol. 2019;20:816–26. [DOI] [PubMed]

14.

Modi S, Park H, Murthy RK, Iwata H, Tamura K, Tsurutani J, et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. J Clin Oncol. 2020;38:1887–96. [DOI] [PubMed] [PMC]

15.

Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, et al. Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer [abstract]. Cancer Res. 2021;81:PD3–06. [DOI]

16.

Cortes J, Kim S, Chung W, Im S, Park YH, Hegg R, et al. LBA1 trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2⁺ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study. Ann Oncol. 2021;32:S1283–346. [DOI]

17.

Goldenberg DM, Cardillo TM, Govindan SV, Rossi EA, Sharkey RM. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). Oncotarget. 2015;6:22496–512. [DOI] [PubMed] [PMC]

18.

Stepan LP, Trueblood ES, Hale K, Babcook J, Borges L, Sutherland CL. Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. J Histochem Cytochem. 2011;59:701–10. [DOI] [PubMed] [PMC]

19.

Liu LF, Desai SD, Li TK, Mao Y, Sun M, Sim SP. Mechanism of action of camptothecin. Ann N Y Acad Sci. 2000;922:1–10. [DOI] [PubMed]

20.

Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res. 2001;7:2182–94. [PubMed]

21.

Sharkey RM, McBride WJ, Cardillo TM, Govindan SV, Wang Y, Rossi EA, et al. Enhanced delivery of SN-38 to human tumor xenografts with an anti-trop-2-SN-38 antibody conjugate (sacituzumab govitecan). Clin Cancer Res. 2015;21:5131–8. [DOI] [PubMed]

22.

Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380:741–51. [DOI] [PubMed]

23.

Kalinsky K, Diamond JR, Vahdat LT, Tolaney SM, Juric D, O’Shaughnessy J, et al. Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: final results from a phase I/II, single-arm, basket trial. Ann Oncol. 2020;31:1709–18. [DOI] [PubMed]

24.

Bardia A, Tolaney SM, Punie K, Loirat D, Oliveira M, Kalinsky K, et al. Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Ann Oncol. 2021;32:1148–56. [DOI] [PubMed]

25.

Diéras V, Weaver R, Tolaney SM, Bardia A, Punie K, Brufsky A, et al. Subgroup analysis of patients with brain metastases from the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in metastatic triple-negative breast cancer [abstract]. Cancer Res. 2021;81:PD13–07. [DOI]

26.

Dokter W, Ubink R, van der Lee M, van der Vleuten M, van Achterberg T, Jacobs D, et al. Preclinical profile of the HER2-targeting ADC SYD983/SYD985: introduction of a new duocarmycin-based linker-drug platform. Mol Cancer Ther. 2014;13:2618–29. [DOI] [PubMed]

27.

Banerji U, van Herpen CML, Saura C, Thistlethwaite F, Lord S, Moreno V, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019;20:1124–35. [DOI] [PubMed]

28.

Saura Manich C, O’Shaughnessy J, Aftimos PG, van den Tweel E, Oesterholt M, Escrivá-de-Romaní SI, et al. LBA15—Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. Ann Oncol. 2021;32:S1283–346. [DOI]

29.

Yao X, Jiang J, Wang X, Huang C, Li D, Xie K, et al. A novel humanized anti-HER2 antibody conjugated with MMAE exerts potent anti-tumor activity. Breast Cancer Res Treat. 2015;153:123–33. [DOI] [PubMed]

30.

Xu B, Wang J, Fang J, Chen X, Han Y, Li Q, et al. Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer [abstract]. Cancer Res. 2020;80:PD4–06. [DOI]

31.

Sussman D, Smith LM, Anderson ME, Duniho S, Hunter JH, Kostner H, et al. SGN–LIV1A: a novel antibody–drug conjugate targeting LIV-1 for the treatment of metastatic breast cancer. Mol Cancer Ther. 2014;13:2991–3000. [DOI] [PubMed]

32.

Modi S, Pusztai L, Forero A, Mita M, Miller K, Weise A, et al. Phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer [abstract]. Cancer Res. 2018;78:PD3–14. [DOI]

33.

Tsai M, Han HS, Montero AJ, Tkaczuk K, Assad H, Pusztai L, et al. 259P weekly ladiratuzumab vedotin monotherapy for metastatic triple-negative breast cancer. Ann Oncol. 2021;32:S474–5. [DOI]

34.

Beckwith H, Schwab R, Yau C, Stringer-Reasor E, Wei S, Chien AJ, et al. Evaluation of SGN-LIV1a followed by AC in high-risk HER2 negative stage II/III breast cancer: results from the I-SPY 2 TRIAL [abstract]. Cancer Res. 2021;81:PD1–10. [DOI]

35.

Han H, Diab S, Alemany C, Basho R, Brown-Glaberman U, Meisel J, et al. Open label phase 1b/2 study of ladiratuzumab vedotin in combination with pembrolizumab for first-line treatment of patients with unresectable locally-advanced or metastatic triple-negative breast cancer [abstract]. Cancer Res. 2020;80:PD1–06. [DOI]