Ladiratuzumab vedotin for metastatic triple negative cancer: preliminary results, key challenges, and clinical potential

KEYWORDS:

• Breast cancer
• triple negative breast cancer
• combinations
• antibody drug conjugate
• sacituzumab govitecan
• ladiratuzumab vedotin

1. Introduction

Several potential therapeutic targets for antibody drug conjugates (ADCs) have been highlighted in breast cancer, including, among the others, HER2, TROP-2, PTK7, and LIV-1 (Figure 1) (Table 1) [1]. As regards the latter, LIV-1 is a transmembrane protein with zinc transporter and metalloproteinase activity [2]; interestingly, LIV-1 was firstly described as an estrogen-induced gene in breast cancer cell lines and was later associated with epidermal-to-mesenchymal transition (EMT) [3]. Despite LIV-1 expression has been suggested to differ according to cancer subtype, this potential therapeutic target is expressed in a moderate/high level in the majority of breast cancers [4]. Following the results of recently presented and published clinical trials, a number of ADCs have been approved in breast cancer and several other agents are in development, including the LIV-1 directed ADC ladiratuzumab vedotin (SGN-LIV1A) [5]. This ADC presents three distinct parts: 1) a monoclonal antibody able to target LIV-1; 2) a protease-cleavable linker; 3) a microtubule-disrupting agent, the monomethyl auristatin E (MMAE) payload (Figure 2) [6]. Ladiratuzumab vedotin is currently studied in early-phase clinical trials on breast cancer patients, as monotherapy or in combination with other anticancer agents, including immune checkpoint inhibitors (ICIs), and some of these studies have already reported encouraging signs of activity [7,8].

Figure 1. Schematic figure reporting the mechanism of action of antibody–drug conjugates (ADCs).

Figure 2. Schematic representation of the antibody–drug conjugate (ADC) ladiratuzumab vedotin. This ADC consists of a monoclonal antibody targeting LIV-1, a protease-cleavable linker and a microtubule-disrupting agent, the monomethyl auristatin E (MMAE).

Table 1. Summary of three main antibody–drug conjugates under assessment in breast cancer clinical trials

ADC	Target	Linker	Payload	Payload Mechanism of action
Sacituzumab Govitecan	TROP-2	Hydrolysable link, with short polyethylene glycol moiety (CL2A)	SN-38	Topoisomerase inhibitor
Ladiratuzumab Vedotin	LIV-1	Protease-cleavable dipeptide linker	MMAE	Microtubule polymerization inhibitor
Trastuzumab Deruxtecan	HER2	Protease-cleavable tetrapeptide linker	DXd	Topoisomerase inhibitor

Abbreviations: DXd: exatecan derivative; MMAE: monomethyl auristatin E.

In the current Editorial, we provide a critical overview of available evidence of ladiratuzumab vedotin for metastatic triple-negative breast cancer, discussing present and future challenges regarding this investigational agent.

2. Preliminary results and ongoing trials

Following preclinical evidence supporting the activity of this ADC, ladiratuzumab vedotin has been assessed in the phase I, multi-part, dose-escalation SGNLVA-001 trial [9]. Eligible subjects included two patient populations: 1) patients with first- or second-line endocrine therapy refractory hormone receptor-positive/HER2-negative metastatic breast cancer; 2) patients with second-line refractory metastatic triple-negative breast cancer [9]. No LIV-1 expression requirement was necessary for the study. According to the preliminary results of this study, overall response rate (ORR) and disease control rate (DCR) were 32% and 64%, respectively, among patients with metastatic triple-negative breast cancer, with a median progression-free survival (PFS) of 11.3 weeks. The majority of treatment-related adverse events were grade 1 or 2, the most commonly of which included fatigue (59%), nausea (51%), peripheral neuropathy (44%), and alopecia (36%). Two patients experienced febrile neutropenia, and one treatment-related death was reported; treatment discontinuation due to adverse events was observed in seven subjects. The updated results of this trial have been recently presented by Tsai and colleagues [10]. In second-line refractory triple negative breast cancer patients, ladiratuzumab vedotin at a dose of 1.25 mg/kg showed an ORR of 28%, confirming the promising activity of this agent.

The advent of ICIs has recently made a breakthrough in several hematological and solid tumors including, among the others, non-small cell lung cancer (NSCLC), renal cell carcinoma, melanoma, urothelial carcinoma, hepatocellular carcinoma (HCC), and PD-L1 positive triple negative breast cancer [^11–13]. These agents are able to enhance antitumor activity, leading to an increase in the cytotoxicity of T cells and blocking down-regulators of immunity, such as programmed cell death protein 1 (PD-1), its ligand PD-L1, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and lymphocyte activating-3 (LAG-3) [14]. However, the identification of reliable predictive biomarkers of response to immunotherapy remains a priority in this setting, and the breast cancer medical community is called to focus its efforts toward this direction since only a proportion of patients benefit from ICIs. In order to boost the antitumor activity of ADCs, the combination of ICIs plus ladiratuzumab vedotin is under evaluation in an ongoing open-label phase Ib/II trial (SGNLVA-002/KEYNOTE 721) assessing the PD-1 inhibitor pembrolizumab plus ladiratuzumab vedotin in treatment-naïve triple-negative breast cancer with unresectable locally advanced or metastatic disease [15]. Enrolled patients are not selected according to LIV-1 expression or PD-L1 status. The primary endpoints of this trial are safety, ORR, and the recommended phase II dose and schedule of ladiratuzumab vedotin plus pembrolizumab; secondary outcome measures included duration of response, DCR, PFS, and OS. According to the preliminary results of SGNLVA-002, the combination achieved an ORR of 35% among 66 patients, including 2 cases of complete response and 21 partial responses. Stable disease was achieved in 32 subjects; diarrhea, nausea, fatigue, peripheral neuropathy, and neutropenia were the most commonly observed treatment-related toxicities.

Another ongoing trial, the phase Ib/II Morpheus-TNBC (NCT03424005), is evaluating the role of ADCs plus ICIs; in particular, this umbrella trial presents six different treatment arms, including the combination of ladiratuzumab vedotin plus the PD-L1 inhibitor atezolizumab and sacituzumab govitecan plus atezolizumab.

3. Expert opinion

Treatment options remain limited for patients with pretreated advanced breast cancer, and several ADCs are under clinical investigation [16,17]. In addition, ADCs that are currently approved for a subset of patients with breast cancer are being studied in other patient populations, and future treatment options may include combination therapies based on approved ADCs plus those in development. Among these, ladiratuzumab vedotin has reported encouraging safety and efficacy data, and results of ongoing trials with more mature follow-up data are highly awaited.

In our view, some points regarding recently presented studies on ladiratuzumab vedotin would deserve specific discussion. As regards the combination of the ADC plus the PD-1 inhibitor pembrolizumab, a biological rationale strongly supports this strategy; in fact, preclinical studies have highlighted that ladiratuzumab vedotin may induce immunogenic cell death, modifying tumor microenvironment and boosting the efficacy of immunotherapy [18]. Interestingly, looking at the patient population of SGNLVA-002, some comments come to mind. In particular, ORR was significantly higher in patients with de novo stage IV disease compared with patients with initial early-stage disease (69% versus 26%, respectively), something that suggests some differential responses according to stage at diagnosis. Further investigation is needed to better understand the impact of this parameter.

Treatment paradigms for metastatic triple negative breast cancer have completely changed within few years. In this setting, several compelling challenges remain to be addressed, including the identification of biomarkers of response to ADCs and ADC-containing combinations, as in the case of LIV-1 expression. Another interesting point will be to understand how patients’ individual co-medications could alter response to ladiratuzumab vedotin, as monotherapy or in combination with immunotherapy. For example, a plethora of clinical trials have investigated the impact of concomitant drugs (e.g. statins, proton pump inhibitors, angiotensin-converting enzyme inhibitors, insulin, etc.), with some of these co-medications suggested to decrease or increase immune response in patients receiving ICIs [19,20]. Similarly, it would be interesting also to investigate how commonly prescribed co-medications could modify response to ADCs such as ladiratuzumab vedotin, since these interactions need to be frequently assessed in clinical practice, but little attention is paid to their putative effect in clinical trials.

Finally, ADCs have been shown to differ not only with respect to therapeutic targets but also in terms of their immunomodulatory properties, something that should be kept in mind when interpreting the results of investigational combinations including ICIs [21]. This point is particularly important in triple negative breast cancer, since this specific subtype is known to present higher levels of several immune-related signatures, higher proportion of tumor infiltrating lymphocytes (TILs), PD-1, and other inhibitory checkpoint molecules [22]. Moreover, several reports have highlighted that triple negative breast cancer has a higher rate of genomic complexity, resulting in the formation of tumor-specific neoantigens.

Certainly, recent years have witnessed the emergence of novel treatment options in triple negative breast cancer, with ongoing studies having the potential to further modify the first- and second-line scenario; at the same time, there is a strong need to answer multiple questions and issues, in order to maximize clinical efficacy while balancing safety in this patient population. Metastatic triple negative breast cancer is an area of high clinical need, and the disease remains a difficult-to-treat malignancy with aggressive clinical course and poor response to traditional chemotherapies.

Bringing the right treatment to the individual patient: the long road toward finding more effective treatment options in triple negative breast cancer will probably have to go through this basic point.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Disclosure statement

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This research received no financial support.