Antibody-Drug Conjugates in Breast Cancer: New Era in Cancer Treatment

Crimson Publishers Mini Review Wings to the Research

Jin Sun Lee, Susan E Yost and Yuan Yuan* Department of Medical Oncology & Molecular Therapeutics, USA

ISSN: 2637-773X Mini Review Antibody-drug conjugates (ADCs) have been recently spotlighted as a new type of targeted

potential drugs and their clinical trials. New ADCs have been approved in breast cancer with therapy in solid tumor. The rapid progression of the field has promoted a large number of new

significantAntibody-drug clinical benefits. conjugates (ADCs) are a novel class of “designer drugs” in cancer therapy

by combining the specificity of monoclonal antibodies and cytotoxic chemotherapy with the goal of enhanced target-specific drug delivery and reduced toxicity [1]. ADCs are composed of three elements: monoclonal antibodies, cytotoxic agents (“payloads”) and linkers. The antibody recognizes tumor specific molecular target which is differentially expressed on *Corresponding author: Yuan Yuan, the surface of tumor cells. The payload is usually potent cytotoxic agent and resistant to Department of Medical Oncology & multi-drug resistance (MDR) based efflux. Currently there are three FDA approved ADCs in (Enhertu®) and sacituzumabgovitecan (Trodelvy®). Molecular Therapeutics, 1500 E. Duarte breast cancer: Trastuzumab emtansine (T-DM1, Kadcyla®), fam-trastuzumab deruxtecan Road, Duarte, CA 91010, USA

The KATHERINE trial published in 2019 demonstrated the efficacy of T-DM1,the first ADC Submission: May 19, 2020 of HER2 positive breast cancer that has residual cancer after neoadjuvant chemotherapy. used for breast cancer in the adjuvant setting [2]. This result has changed the standard practice Published: June 16, 2020 T-DM1is composed of the monoclonal antibody, trastuzumab, attached to derivative of the

Volume 4 - Issue 5 cytotoxic drug, maytansine (DM1)[3]. Trastuzumab targets HER2 over expressed cells and : Jin Sun Lee, How to cite this article DM1 results in cell death after being released in the cells. Its survival benefits in advanced Susan E Yost, Yuan Yuan. Antibody- various ADCs have been introduced for breast cancer. A few of the agents have been adopted Drug Conjugates in Breast Cancer: New breast cancer were proven previously in the EMILIA trial [4]. After the success of T-DM1 trials, Era in Cancer Treatment. Nov Appro in cancer, and other agents are being evaluated in early phase trials. Can Study. 4(5). NACS.000600. 2020. in clinical practice after the clinical trials showing survival benefits mainly in advanced breast DOI: 10.31031/NACS.2020.04.000600

Copyright@ Yuan Yuan, This article is For HER2 positive or HER2 expressed breast cancer, ADCs have been developed linked distributed under the terms of the Creative Commons Attribution 4.0 International with HER2 monoclonal antibodies such as trastuzumab. Trastuzumab deruxtecan is designed with a novel cytotoxic topoisomerase I inhibitor (exatecan mesylate derivative) at a payload License, which permits unrestricted use (RR) of 60.9% in patients who had received T-DM1 and other HER2 targeted treatment. The and redistribution provided that the of 8 molecules per antibody [5]. In a phase 2 study, it showed an astonishing response rate original author and source are credited. median response duration was 14.8 months [6]. Trastuzumab duocarmazineis another HER2 targeting ADC comprised of trastuzumab bound to a linker drug containing cytotoxic agent, duocarmycin, isolated from streptomyces streptomyces [7]. The phase 1 dose-escalation and dose-expansion study demonstrated antitumor activity (33% of RR) with manageable toxicity in heavily pretreated patients with HER2expressed metastatic breast cancer [8]. The response was observed in HER2low-expressedbreast cancer (IHC 2+ or 1+ and ISH-negative).

While HER2 monoclonal antibodies are utilized only in HER2 over expressed breast cancer, defined by IHC 3+ or FISH amplification, ADCs formed with HER2 monoclonal antibody have been demonstrating antitumor activity in HER2-low expressed tumor. Most of the ongoing trials of ADCs targeted HER2 receptor (Table 1). clinical trials enroll patients with HER2 low expressed tumors. There are multiple ongoing

Novel Approaches in Cancer Study 423 NACS.000600. 4(5).2020 424

Table 1: HER2-targeting ADCs trials.

NCT Identifier Studied Drug Phase Main Eligibility Criteria Target Accrual NCT03281824 1 HER2-positive metastatic breast cancer 30

XMT-1522ALT-P7 1b 120 Advanced breast cancer and either a HER2 IHC score of at least 1+ using a validated IHC NCT02952729 NCT03052634 RC48-ADC 1b/2 HER2-positive,assay or locallywith evidence advanced of orHER2 metastatic amplification. breast cancer 165 NCT03944499 1 92 Phase 1a: HER2 expressed advanced malignant solid tumor had failed to standard FS-1502 therapy; Phase 1b: HER2 positive (defined as IHC3+ or IHC2+/FISH+) breast cancer 1 80 Phase 1a: ISH positive or IHC 2+ or 3+; Phase 1b cohort 1: advanced breast cancer, ISH NCT02512237 ARX788 positive or IHC 3+; Phase 1b cohort 2: advanced breast cancer, ISH negative with IHC 2+; Phase 1b cohort 3: advanced gastric cancer, ISH positive or IHC 3+. 1 esophageal or other solid tumors); Phase 1b cohort 1: advanced breast cancer, ISH 60 Phase 1a: ISH positive or IHC 3+ advanced cancer (including breast or gastric/ NCT03255070 ARX788 positive or IHC 3+; Phase 1b cohort 2: advanced breast cancer, ISH negative with IHC 2+. ADCs have been developed for HER2 negative breast cancer. in aphase 2 trial by MD Anderson group, and the result has not been Triple negative breast cancer (TNBC) was considered non-targetable cancer, but the recent evolution of molecular characterization has published (NCT03106077). Cristae et al. [13] at City of Hope is currently conducting a phase 1 study of mirvetuximab soravtansine Sacituzumab govitecan, an ADC targeting Trop-2, a surface epithelial ovarian, endometrial cancer, or TNBC (NCT02996825) identified multiple targets that can be targeted for the treatment. and gemcitabinein patients with FOLR1-positive recurrent can deliver SN-38, the active metabolite of irinotecan. In the phase glycoprotein expressed on many epithelial tumors including TNBC, [13]. In addition, the first ADC targeting CD205conjugated to DM4 1/2 single-arm open-label study, the response rate (3 complete and breast cancer and other solid tumors (NCT04064359). (OBT076) is being evaluated in a clinical trial for HER2 negative The development of ADCs is rapidly evolving under the 24.6 to 43.1) in patients with TNBC who had received a median of 3 33 partial responses) was 33.3% (95% confidence interval [CI], discovery of potential targets. The advance of ADCs may provide a previous treatments [9]. The median duration of response was 7.7 of targets such as TNBC. stunning clinical benefit, particularly for the tumors with a paucity months. The phase 3 confirmatory ASCENT study was halted due govitecan for patients with metastatic TNBC who have received at References to compelling evidence of efficacy, and FDA approved sacituzumab 1. Pondé N, Aftimos P, Piccart M (2019) Antibody-drug conjugates in govitecan breast cancer: A comprehensive review. Current Treatment Options in least two prior treatments. The final result is expected. Sacituzumab Ladiratuzumab vedotin is a LIV1-targeted monoclonal antibody 2. Oncology 20(5): 37. (2019) Trastuzumab emtansine for residual invasive HER2-positive von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, et al. linked to a potent microtubule-disrupting agent, monomethyl 3. auristatin E (MMAE) by a protease-cleavable linker [10]. LIV1 is breast cancer. N Engl J Med 380(7): 617-628. response rates of 25% (15 of 60 patients) and median progression Targeting HER2-positive breast cancer with trastuzumab-DM1, an expressed in the most advanced breast cancer. It demonstrated Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, et al. (2008)

4. antibody-cytotoxic drug conjugate. Cancer Research 68(22):9280-9290. free survival (PFS) of 11.6 weeks for patients with heavily pretreated ladiratuzumab vedotin combination with pembrolizumab as the emtansine for HER2-positive advanced breast cancer. N Engl J Med metastatic TNBC in the phase 1 trial [11]. The phase 1b/2 trial of Verma S, Miles D, Gianni L, Krop IE, Welslau M, et al. (2012) Trastuzumab

5. 367(19):1783-1791.Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, et al. (2016) DS-8201a, first line treatment in advanced TNBC is ongoing and recruiting A novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, patients (NCT03310957). The other ADC formed with MMAE endpoint in a randomized study: METRIC trial was a randomized showed clinical activity, but did not meet the primary efficacy demonstrates a promising antitumor efficacy with differentiation from 6. T-DM1. Clin Cancer Res 22(20): 5097-5108. phase 2b study to evaluate the efficacy of glembatumumab vedotin, Modi S, Saura C, Yamashita T, Park YH, Kim SB, et al. (2020) Trastuzumab designed to target the glycoprotein NMB (gpNMB) linked to a potent deruxtecan in previously treated HER2-positive breast cancer. N Engl J The result was reported that there was no therapeutic advantage in cytotoxic MMAE, in gpNMB over expressed metastatic TNBC [12]. Med 382(7): 610-621. 7. Dokter W, Ubink R, van der Lee M, van der Vleuten M, van Achterberg RR, PFS,ADCs or with overall other survival novel (OS)targets when have compared been emerged. with capecitabine. The folate MolT, et Canceral. (2618) Ther Preclinical 13(11): 2618-2629. profile of the HER2-targeting ADC SYD983/ SYD985: Introduction of a new duocarmycin-based linker-drug platform. 8. Trastuzumab duocarmazine in locally advanced and metastatic solid receptor alpha (FOLR1) is related with tumor growth and its over Banerji U, van Herpen CML, Saura C, Thistlethwaite F, Lord S, et al. (2019) expression is observed in solid tumor. Mirvetuximab soravtansine tumours and HER2-expressing breast cancer: A phase 1 dose-escalation is an ADC targeting the FOLR1 linked to maytan sinoid derivate, and dose-expansion study. The Lancet Oncology 20(8):1124-1135. DM4. The efficacy of this agent as the first line in TNBC was studied

9. 12. Sacituzumab govitecan-hziy in refractory metastatic triple-negative Abstract P6-20-01: METRIC: A randomized international phase 2b study Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, et al. (2019) Vahdat L, Forero-Torres A, Schmid P, Blackwell K, Telli M, et al. (2019)

10. breastSussman cancer. D, Smith N Engl LM, J MedAnderson 380(8): ME, 741-751. Duniho S, Hunter JH, et al. (2014) of the antibody-drug conjugate (ADC) glembatumumab vedotin (GV) in gpNMB-overexpressing, metastatic, triple-negative breast cancer treatment of metastatic breast cancer. Mol Cancer Ther 13(12): 2991- 13. (mTNBC). Cancer Res 79(4 Suppl): P6-20-01. 3000.SGN–LIV1A: A novel antibody-drug conjugate targeting LIV-1 for the Cristea MC, Frankel PH, Synold TW, Mortimer JE, Stewart DB, et al. 11. ovarian(2019) A(EOC), phase endometrial I study of mirvetuximab cancer (EC), or soravtansine triple-negative (IMGN853) breast cancer and gemcitabine (G) in patients with FOLR1-positive recurrent epithelial pretreatedModi S, Pusztai triple-negative L, Forero Ametastatic (2017) Phase breast 1 cancer.study of the antibody-drug conjugate ladiratuzumab vedotin (SGN-LIV1A) in patients with heavily (TNBC). JCO 37(15 Suppl): 3009-3009.

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