Biomedical Research

Abstract

Following advances in molecular biology and better understanding of the mechanisms of carcinogenesis, new therapies have been developed with new agents that target tumor cells with minimal effects on normal cells. Monoclonal antibodies represent the model of success of this approach; they are directed against antigens selectively expressed by tumor cells. The conjugation of these monoclonal antibodies with potent cytotoxic drugs makes it possible to improve their efficacy while maintaining a favorable tolerance profile. T-DM1 (Trastuzumab Emtansine) is the first example of advanced development of a conjugated antibody. It works by associating an antitumor activity specific to trastuzumab with the efficient delivery of a potent cytotoxic, delivered selectively and targeted to cancer cells overexpressing HER2. Unlike trastuzumab emtansine, trastuzumab deruxtecan has a released payload that easily crosses the cell membrane, which potentially allows for a potent cytotoxic effect on neighboring tumor cells regardless of target expression. In addition, the released payload has a short half-life, which is designed to minimize systemic exposure. DESTINY breast-01 study has demonstrated the efficacy of trastuzumab deruxtecan in patients with HER2- positive metastatic breast cancer previously treated with trastuzumab emtansine. Trastuzumab deruxtecan is FDA-approved. Sacituzumab govitecan (sacituzumab govitecan-hziy) is a conjugated monoclonal antibody developed by site-specific conjugation of the active metabolite of irinotecan, SN-38 (govitecan). It has demonstrated promising activity in advanced lines for triple-negative breast cancer in a phase I/II study and recently in ASCENT trial phase III. Conjugated monoclonal antibodies have been shown to be effective in different subtypes of metastatic breast cancer.

Keywords

Conjugated Antibody, Breast Cancer, Molecular Biology.

Introduction

Advanced and metastatic breast cancer remains a virtually incurable disease, with a median Overall Survival (OS) of about 3 years and a 5-year survival rate of around 25%, even in countries without major accessibility problems [1]. Survival is strongly related to breast cancer subtype, [2] with more favourable outcomes for patients with HR or HER2 positive tumors than for patients with triple negative breast cancer [3].

The development of monoclonal antibodies in combination with chemotherapy agents has changed the prognosis of some cancers, notably HER2 positive breast cancer, the prognosis of which has been completely altered by the arrival of trastuzumab [4]. Monoclonal antibodies can be used in addition to their specific action as vectors for selectively delivering cytotoxic to tumors: this is the principle of conjugated antibodies [5,6]. In solid tumors, trastuzumab, a monoclonal antibody to epidermal growth factor receptor 2 (HER2), was the basis for the development of T-DM1, a conjugated antibody in HER2- positive breast cancers [7]. T-DM1 is the first example of advanced development of a conjugated antibody. It works by associating an antitumor activity specific to trastuzumab with the efficient delivery of a potent cytotoxic, delivered selectively and targeted to cancer cells overexpressing HER2 [7]. The aim of this review is to focus on the benefit provided by the new monoclonal conjugated antibodies used in breast cancer, namely trastuzumab deruxtecan and Sacituzumab Govitecan.

Trastuzumab-Emtansine (TDM1): The first monoclonal antibody conjugates in solid tumors

Following advances in molecular biology and better understanding of the mechanisms of carcinogenesis, new therapies have been developed with new agents that target tumor cells with minimal effects on normal cells [8]. Monoclonal antibodies represent the model of success of this approach, they are directed against antigens selectively expressed by tumor cells. The conjugation of these monoclonal antibodies with potent cytotoxic drugs makes it possible to improve their efficacy while maintaining a favourable tolerance profile [8,9]. Trastuzumab emtansine (TDM1) is a conjugated monoclonal antibody. It combines the humanized antibody Trastuzumab, which targets Human Epidermal growth factor Receptor 2 (HER2) on cancer cells, and the potent antimicrotubular agent DM1 using a single, highly stable linker. When T-DM1 binds to HER2, it is believed that part of the receptors is internalized by the process of receptor endocytosis, followed by the intracellular release of an active form of DM1, which in turn kills the tumor cell [8]. This approach not only maximizes the potential for antitumor efficacy of the cytotoxic agent but also minimizes the exposure of normal tissues, thus improving the therapeutic index [10,11]. The clinical benefit of T-DM1 was confirmed in a randomized, multicenter, open-label phase III clinical study (EMILIA), evaluating the efficacy and safety of T-DM1 vs. lapatinib plus capecitabine, in patients with locally advanced or metastatic HER2-positive breast cancer, pretreated with trastuzumab and taxane. The median follow-up was 19.1 months for the T-DM1 group and 18.6 months for the lapatinib plus capecitabine group. The main objective of the study, the median PFS, evaluated by an independent review committee, was in favor of T-DM1 (9.6 vs. 6.4 months; HR=0.650 [95% CI: 0.549-0.771]; P<0.0001). The median overall survival was 30.9 months in the T-DM1 group, while it was 25.1 months in the lapatinib plus capecitabine group (HR=0.682 [95% CI: 0.55-0.85]; P=0.0006). The objective response rate was higher in the T-DM1 group (43.6% vs. 30.8%, P=0.0002). T-DM1 was well tolerated with a favorable toxicity profile [12]. FDA granted T-DM1 regulatory approval on 22 February 2013 for HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane [13]. The benefit of TDM1 does not stop there, two other phase III studies evaluating TDM1 have also been carried out: MARIANNE carried out in patients with locally advanced or metastatic HER2-positive breast cancer and not previously treated [13], and THERESA trial, which compared trastuzumab emtansine with a treatment of the physician’s choice after two previous anti-HER2 regimens, the investigators found a response rate of 31% in the trastuzumab emtansine group and 9% in the comparator group (median progression-free survival, 6.2 months vs. 3.3 months) [14].

Trastuzumab Deruxtecan: Conjugated monoclonal antibody in Previously Treated HER2-Positive Breast Cancer

Overexpression and amplification of human epidermal growth factor receptor 2 (HER2) accounts for approximately 15-20% of metastatic breast cancers [15,16]. The recommended first-line treatment for HER2- positive metastatic breast cancer is trastuzumab and pertuzumab given with a taxane according to the results of the CLEOPATRA trial (the combination of trastuzumab, pertuzumab and docetaxel resulted in a median duration of progression-free survival and overall survival of 18.7 months and 56.5 months, respectively) [17]. The standard second-line treatment is trastuzumab emtansine, based on data from the EMILIA study as described above. After progression with trastuzumab emtansine, the currently available treatment options offer limited benefit, with response rates of around 9 to 31% and a progression-free survival time of around 3 to 6 months for third-line therapy [18]. The Antibody–Drug Conjugate (ADC) trastuzumab deruxtecan (also known as DS-8201), engineered using novel linker-payload technology, addresses limitations of compounds from the previous generation through conjugation of a humanised anti-HER2 antibody with a topoisomerase I inhibitor payload (an exatecan derivative), using a self-immolative, enzymatically cleavable peptide linker [19]. Unlike trastuzumab emtansine, trastuzumab deruxtecan has a released payload that easily crosses the cell membrane, which potentially allows for a potent cytotoxic effect on neighboring tumor cells regardless of target expression. In addition, the released payload has a short half-life, which is designed to minimize systemic exposure [18,20]. Modi et al. (DESTINY breast01) have demonstrated the efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine [18]. In this two-part, open-label, multicenter, phase II study Trastuzumab deruxtecan, demonstrated a response rate of 60.6% and an unprecedented median PFS of 16.4 months (median six lines, range 2-27 lines, including trastuzumab and T-DM1). Trastuzumab deruxtecan was associated with a 13.6% risk of interstitial lung disease/pneumonitis, fatal in 2.2% of cases, which needed appropriate and rapid diagnosis and treatment [1,18].

Following these encouraging data, two phase III studies are being evaluated of Trastuzumab Deruxtecan in other situations.

DESTINY breast03 is designed to compare the anti-tumor activity as well as the safety and efficacy of DS-8201a versus T-DM1 in HER2-positive, unresectable and/or metastatic breast cancer subjects previously treated with trastuzumab and taxane [21].

DESTINY breast02 is designed to compare DS 8201a versus standard of care (investigator's choice) in subjects with unresectable and/or metastatic breast cancer previously treated with T-DM1 [22].

Trastuzumab deruxtecan is FDA-approved and await evaluation by the EMA (European Medicines Agency) [1].

Sacituzumab Govitecan: Conjugated monoclonal antibody with promising activity in advanced lines for triple-negative breast cancer

In Triple Negative Metastatic Breast Cancer (mTNBC): the situation is more complicated since it is a disease that is associated with an aggressive clinical course and a poor prognosis compared to other breast cancer subtypes [23]. Recently the IMpassion130 trial provided evidence to support the use of a combination of immunotherapy and taxane in the first-line setting of PD-L1 positive mTNBC [24]. However, patients eventually have disease progression after first-line treatment and will require cytotoxic chemotherapy which remains the standard of care in patients with relapsing or refractory disease. Chemotherapy in these situations has limited response rates which are only about 10-15% in pretreated patients and the mean progression-free survival is short [25]. To better improve the prognosis of these patients, many therapeutic advances have been made such as the development of sacitizumab Govitecan, a conjugated monoclonal antibody.

Sacituzumab govitecan (sacituzumab govitecan-hziy) is a conjugated monoclonal antibody developed by site- specific conjugation of the active metabolite of irinotecan, SN-38 (govitecan), to a humanized monoclonal antibody (hRS7) against cell surface antigen trophoblastic-2 (Trop- 2) [26,27]. Trop-2 has limited expression in normal tissue and plays a role in oncogenesis [28]. Sacituzumab govitecan has demonstrated promising activity in advanced lines for triple-negative breast cancer in a phase I/II study of 108 patients who had received a range of 2-10 prior treatments for metastatic disease. The overall response rate was 33.3% (95% CI 24.6-43.1), with a median duration of response of 7.7 months (95% CI 4.9-10.8). Of the patients with a response to sacituzumab govitecan-hziy, 55.6% maintained their response for ≥ 6 months and 16.7% maintained their response for ≥ 12 months [29]. Based on these preliminary results, the FDA has granted accelerated approval in the USA on 22 April 2020 [1,30].

A confirmatory multicenter, randomized, phase 3 trial was developed

(ASCENT; ClinicalTrials.gov number, NCT02574455). This is an international, multi-center, open-label, randomized, Phase III study in patients with metastatic TNBC refractory or relapsing after at least 2 prior chemotherapies (including a taxane) for their metastatic disease. Patients meeting eligibility is randomized 1:1 to receive either sacituzumab govitecan or treatment of physician choice (TPC) [29]. A few weeks ago, the first data from this trial were presented at the ESMO 2020 (European Society for Medical Oncology) conference. The benefit on progression-free survival (5.6 vs. 1.7 months) in patients without and with brain metastases (PFS) is significant in favor of Sacituzumab Govitecan and the median OS (secondary objective) was 12.1 vs. 6,7 months (IC 95%). Sacituzumab govitecan was then included in other trials with several combinations and combinations. In Hormone receptor-positive/ HER negative breast cancer, TROPICS-02 is an open-label, randomized, multicenter Phase 3 study to compare the efficacy and safety of Sacituzumab Govitecan versus TPC in subjects with metastatic or locally recurrent inoperable HR+/ HER2-MBC, after failure of at least 2, and no more than 4, prior chemotherapy regimens for metastatic disease [31].

Other studies with other combinations: A phase I/II trial is evaluating sacituzumab govitecan in combination with a PARP inhibitor (talazoparib) in patients with metastatic breast cancer. In addition, a phase I/II, open-label, multicentre, randomized umbrella study is evaluating the efficacy and safety of multiple immunotherapy-based treatment combinations, including sacituzumab govitecan, in patients with mTNBC [25].

Conclusion

Conjugated monoclonal antibodies have been shown to be effective in different subtypes of metastatic breast cancer. In metastatic breast cancer with HER2 overexpression, the prognosis was markedly improved with trastuzumab emtansine and trastuzumab deruxtecan, especially in the advanced therapeutic lines. In triple-negative metastatic breast cancers where treatment options are limited, Sacituzumab Govitecan improved the prognosis of this population of patients in whom cytotoxic chemotherapy does not provide a satisfactory response rate. Based on these relevant clinical data, it has become important and urgent to carry out large-scale clinical trials to approve the value of the use of conjugated monoclonal antibodies in patients with metastatic breast cancer.

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