Disitamab vedotin, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpression and HER2-low advanced breast cancer: a phase I/Ib study

Abstract

Background: Disitamab vedotin (DV; RC48-ADC) is an antibody-drug conjugate comprising a human epidermal growth factor receptor 2 (HER2)-directed antibody, linker and monomethyl auristatin E. Preclinical studies have shown that DV demonstrated potent antitumor activity in preclinical models of breast, gastric, and ovarian cancers with different levels of HER2 expression. In this pooled analysis, we report the safety and efficacy of DV in patients with HER2-overexpression and HER2-low advanced breast cancer (ABC).

Methods: In the phase I dose-escalation study (C001 CANCER), HER2-overexpression ABC patients received DV at doses of 0.5-2.5 mg/kg once every two weeks (Q2W) until unacceptable toxicity or progressive disease. The dose range, safety, and pharmacokinetics (PK) were determined. The phase Ib dose-range and expansion study (C003 CANCER) enrolled two cohorts: HER2-overexpression ABC patients receiving DV at doses of 1.5-2.5 mg/kg Q2W, with the recommended phase 2 dose (RP2D) determined, and HER2-low ABC patients receiving DV at doses of 2.0 mg/kg Q2W to explore the efficacy and safety of DV in HER2-low ABC.

Results: Twenty-four patients with HER2-overexpression ABC in C001 CANCER, 46 patients with HER2-overexpression ABC and 66 patients with HER2-low ABC in C003 CANCER were enrolled. At 2.0 mg/kg RP2D Q2W, the confirmed objective response rates were 42.9% (9/21; 95% confidence interval [CI]: 21.8%-66.0%) and 33.3% (22/66; 95% CI: 22.2%-46.0%), with median progression-free survival (PFS) of 5.7 months (95% CI: 5.3-8.4 months) and 5.1 months (95% CI: 4.1-6.6 months) for HER2-overexpression and HER2-low ABC, respectively. Common (≥5%) grade 3 or higher treatment-emergent adverse events included neutrophil count decreased (17.6%), gamma-glutamyl transferase increased (13.2%), asthenia (11.0%), white blood cell count decreased (9.6%), peripheral neuropathy such as hypoesthesia (5.9%) and neurotoxicity (0.7%), and pain (5.9%).

Conclusion: DV demonstrated promising efficacy in HER2-overexpression and HER2-low ABC, with a favorable safety profile at 2.0 mg/kg Q2W.

Keywords

antibody-drug conjugate / breast cancer / clinical trials / disitamab vedotin / HER2-low / HER2-overexpression

References

[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3): 209–249.

[2] Dieci MV, Miglietta F, Griguolo G, Guarneri V. Biomarkers for HER2-positive metastatic breast cancer: Beyond hormone receptors. Cancer Treat Rev. 2020; 88: 102064.

[3] Tarantino P, Hamilton E, Tolaney SM, Cortes J, Morganti S, Ferraro E, et al. HER2-Low Breast Cancer: Pathological and Clinical Landscape. J Clin Oncol. 2020; 38(17): 1951–1962.

[4] Xu B, Ma F, Wang T, Wang S, Tong Z, Li W, 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. Int J Cancer. 2023; 152(10): 2134–2144.

[5] National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology-Breast cancer. 2023 version 4. National Comprehensive Cancer Network, Inc. Accessed 06 Apr 2023 https://www.nccn.org

[6] Li J, Jiang Z. Chinese Society of Clinical Oncology (CSCO) Breast Cancer Guidelines 2022: stratification and classification. Cancer Biol Med. 2022; 19(6): 769–773.

[7] Tong JTW, Harris PWR, Brimble MA, Kavianinia I. An Insight into FDA Approved Antibody–Drug Conjugates for Cancer Therapy. Molecules. 2021; 26(19): 5847.

[8] Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022; 387(1): 9–20.

[9] Rugo HS, Bardia A, Tolaney SM, Arteaga C, Cortes J, Sohn J, et al. TROPiCS-02: A Phase III study investigating sacituzumab govitecan in the treatment of HR+/HER2-metastatic breast cancer. Future Oncol. 2020; 16(12): 705–715.

[10] 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: 741–751.

[11] 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 antitumor activity. Breast Cancer Res Treat. 2015; 153(1): 123–133.

[12] Peng Z, Liu T, Wei J, Wang A, He Y, Yang L, et al. Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase II study. Cancer Commun (Lond). 2021; 41(11): 1173–1182.

[13] Li F, Emmerton KK, Jonas M, Zhang X, Miyamoto JB, Setter JR, et al. Intracellular Released Payload Influences Potency and Bystander-Killing Effects of Antibody–Drug Conjugates in Preclinical Models. Cancer Res. 2016; 76(9): 2710–2719.

[14] Li H, Yu C, Jiang J, Huang C, Yao X, Xu Q, et al. An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer. Cancer Biol Ther. 2016; 17(4): 346–354.

[15] Jiang J, Dong L, Wang L, Wang L, Zhang J, Chen F, et al. HER2-targeted antibody drug conjugates for ovarian cancer therapy. Eur J Pharm Sci. 2016; 93: 274–286.

[16] Wang J, Xu B, Wang W, Fang J, et al. An open-label, dose-escalation phas. I study to evaluate RC48-ADC, a novel antibody–drug conjugate, in patients with HER2-positive metastatic breast cancer. J Clin Oncol. 2018; 36(15_suppl): 1030.

[17] Wang J, Liu Y, Zhang Q, Fang J, Chen X, Han Y, et al. RC48-ADC, a HER2-targeting antibody–drug conjugate, in patients with HER2-positive and HER2-low expressing advanced or metastatic breast cancer: a pooled analysis of two studies. J Clin Oncol. 2021; 39(15_suppl): 1022.

[18] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2): 228–247.

[19] Guideline Recommendations for HER2 Detection in Breast Cancer Group. [Guidelines for HER2 detection in breast cancer, the 2014 version]. Zhonghua Bing Li Xue Za Zhi. 2014; 43(4): 262–267.

[20] Medical Dictionary for Regulatory Activities (MedDRA). Accessed Mar 1, 2020. https://www.meddra.Org

[21] National Cancer Institute. Common terminology criteria for adverse events, version 4.0. 2010. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc

[22] Corti C, Giugliano F, Nicolò E, Ascione L, Curigliano G. Antibody–drug conjugates for the treatment of breast cancer. Cancers (Basel). 2021; 13(12): 2898.

[23] Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017; 18(6): 732–742.

[24] Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022; 386(12): 1143–1154.

[25] 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(7): 610–621

[26] 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(8): 741–751.

[27] Xu Y, Wang Y, Gong J, Zhang X, Peng Z, Sheng X, et al. Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors. Gastric Cancer. 2021; 24(4): 913–925.

[28] Sheng X, Yan X, Wang L, Shi Y, Yao X, Luo H, et al. Open-label, Multicenter, Phase II Study of RC48-ADC, a HER2-targeting antibody–drug conjugate, in patients with locally advanced or metastatic urothelial carcinoma a phase II study of RC48-ADC in advanced urothelial carcinoma. Clin Cancer Res. 2021; 27(1): 43–51.

[29] KADCYLA® (ado-trastuzumab emtansine) for injection. Prescribing information. Genetech, Inc; Initial U.S. Approval: 2013. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125427s105lbl.pdf

[30] Herceptin® (trastuzumab): EPAR -Product Information. Roche Pharma AG; First published in EMA: 2010. http://www.ema.europa.eu

[31] HERCEPTIN® (trastuzumab) for injection. Prescribing information. Genentech, Inc; Initial U.S. Approval: 1998. http://www.gene.com/download/pdf/herceptin_prescribing.pdf

[32] Perjeta® (pertuzumab): EPAR -Product Information. Roche Pharma AG; First published in EMA: 2013. http://www.ema.europa.eu

[33] PERJETA® (pertuzumab) injection. Prescribing information. Genetech, Inc; Initial U.S. Approval: 2012. http://www.fda.gov/

[34] Best RL, LaPointe NE, Azarenko O, Miller H, Genualdi C, Chih S, et al. Microtubule and tubulin binding and regulation of microtubule dynamics by the antibody drug conjugate (ADC) payload, monomethyl auristatin E (MMAE): Mechanistic insights into MMAE ADC peripheral neuropathy. Toxicol Appl Pharmacol. 2021; 421: 115534.

[35] Meyer L, Taleb O, Patte-Mensah C. Mensah-Nyagan AG. Neurosteroids and neuropathic pain management: Basic evidence and therapeutic perspectives. Front Neuroendocrinol. 2019; 55: 100795.

[36] Hayashi R, Xiao W, Kawamoto M, Yuge O, Bennett GJ. Systemic glucocorticoid therapy reduces pain and the number of endoneurial tumor necrosis factor-alpha (TNFalpha)-positive mast cells in rats with a painful peripheral neuropathy. J Pharmacol Sci. 2008; 106(4): 559–565.

[37] Rugo HS, Im SA, Cardoso F, Cortés J, Curigliano G, Musolino A, et al. Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol. 2021; 7(4): 573–584.

[38] Krop IE, Kim SB, González-Martín A, LoRusso PM, Ferrero JM, Smitt M, et al. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014; 15(7): 689–699.

[39] Saura C, Oliveira M, Feng YH, Dai MS, Chen SW, Hurvitz SA, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020; 38(27): 3138–3149.

[40] Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020; 382(7): 597–609.

[41] Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008; 112(3): 533–543.

[42] Zhang J, Ji D, Shen W, Xiao Q, Gu Y, O’Shaughnessy J, et al. Phase I trial of a novel anti-HER2 antibody–drug conjugate, ARX788, for the treatment of HER2-positive metastatic breast cancer. Clin Cancer Res. 2022; 28(19): 4212–4221.

[43] Banerji U, van Herpen CM, 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(8): 1124–1135.

[44] Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, et al. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019; 112: 57–65.

[45] Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015; 33(6): 594–601.

[46] Chinese Anticancer Association, Committee of Breast Cancer Society. Chinese Anticancer Association Guidelines and Norms on the Diagnosis and Treatment of Breast Cancer 2021[J]. Chinese J Cancer. 2021, 31(10): 954–1040.

RIGHTS & PERMISSIONS

2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat-sen University Cancer Center.