TROP-2 directed antibody-drug conjugates (ADCs): The revolution of smart drug delivery in advanced non-small cell lung cancer (NSCLC) (2023)

Introduction

Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer death in both male and female worldwide, accounting for nearly 20% of all cancer deaths in Europe [1], [2].

NSCLC is diagnosed at an advanced stage in nearly 56% of patients. The introduction of anti-PD-(L)1 monoclonal antibodies in the first line treatment has improved the 5-year survival rate in advanced NSCLC without oncogenic drivers [3], [4], [5], [6]. Programmed cell death ligand-1 (PD-L1) and molecular testing are essential for the therapeutic decision strategies at the time of lung cancer diagnosis. Both the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) guidelines recommend performing a comprehensive molecular analysis using multiplex platforms (Next-Generation Sequencing, NGS), considering its advantages in terms of coverage, time, and favorable economic profile [7], [8], [9], [10]. Overall, approximately 60% of lung adenocarcinomas (LUADs) harbor oncogenic drivers [11]. Personalized lung cancer treatment paradigm is now established and the body of data in this field is rapidly expanding, with novel therapeutic targets demonstrating promising clinical significance [12].

At the present time, the targetable biomarkers in NSCLC are gene mutations or fusions/rearrangements in EGFR, ALK, ROS1, BRAF V600E, NTRK, RET, MET exon 14 skipping, KRAS G12C and HER2. Currently, molecular biomarkers recommended by the ESMO and the National Comprehensive Cancer Network (NCCN) guidelines in advanced LUAD include EGFR, BRAF V600E, KRAS G12C, HER2 mutations, MET amplifications or exon 14 skipping mutations and rearrangements of ALK, ROS1, NTRK, RET [13], [14]. Next generation molecular biomarkers (e.g, nectin-4, TROP-2, CEACAM5, HER3, c-MET mutations/amplification) in advanced/ metastatic non-oncogene-addicted diseases are emerging as promising therapeutic targets and are being explored with novel therapeutics, such as the Antibody Drug Conjugates (ADCs).

Antibody drug conjugates (ADCs) are a new generation of bio-pharmaceutical compounds that combine the precision of targeted therapy with the cytotoxic effect of chemotherapy [15]. The core structure of ADCs consists of three main elements: a monoclonal antibody (mAb), a chemical linker and a cytotoxic payload. mAbs are used to deliver the effector (payload) directly to the target cancer cells [16]. ADCs function is related to antigen’s expression at the tumor’s cell surface [17]. High affinity and avidity for antibody recognition are also essential prerequisites for achieving good clinical activity. In addition, a long half-life is required to ensure that the ADCs remain effective until the target tissue is reached [17]. Cytotoxic payloads for ADCs are generally highly potent derivatives from natural sources and belong to two main classes: tubulin inhibitors (e.g., derivatives of maytansine 1, DM1, and monomethyl auristatin E, MMAE) and DNA-damaging agents, including calicheamicins and camptothecins such as topoisomerase I inhibitors (e.g., SN-38, Deruxtecan) [18]. Linkers are classified as cleavable and non-cleavable [17]. Non-cleavable linkers depend on lysosomal degradation, resulting in cleavage into tumor cells. Non-cleavable ADCs are primarily suited for treating cancers with high and homogenous expression of the target antigen. Non-cleavable linkers result in limited off-target adverse events (AEs), due to the avoidance effect on normal tissue [19]. Since the approval of the first-in-class ADC, Trastuzumab Emtansine (T-DM1), for advanced HER-2 positive breast cancer [20], novel ADCs with improved biochemical properties have been developed by pharmaceutical companies. Novel generation ADCs incorporate cleavable linkers (e.g., cleaved by low pH or proteases), which have greater impact on the intracellular stability of the payload. They also exert efficient payload release at the target site [17]. Once the ADC-antigen complex is internalized or hydrolysis of the linker occurs, the payload is released, causing death of the target cells. In addition, payload transmembrane diffusion may influence surrounding antigen negative cells, in a “bystander effect.” [21]. Some ADCs may display antibody (Ab) mediated-immune effector functions, including complement-dependent cytotoxicity (CDC), Ab dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP) [17], [18]. With a unique mechanism of action, ADCs represent a new and promising therapeutic strategy in lung cancer treatment [15].

Trophoblastic Cell Surface Antigen 2 (TROP-2) is a surface glycoprotein member of the epithelial cell adhesion molecule (EpCAM) family, that is expressed in normal tissues and in many epithelial tumors, including breast, cervix, colorectal, esophagus, gastric and lung cancer [22], [23]. Next to its function in regulating normal fetal development, TROP-2 is an intracellular calcium signal transducer and a key component of cell adhesion in human tissues, playing an important role in stabilizing epithelial tight junctions [22], [24]. TROP-2 has a regulating function of cell growth, transformation, and proliferation, which explains why its overexpression can lead to the emergence and progression of cancer [16], [25]. TROP-2 mediates several intracellular signaling pathways including PTEN/PIK3CA/Akt, MAPK/ERK, JAK/STAT, ErbB, TGFβ and WNT/βcatenin (Fig. 1) [26]. In NSCLC, high TROP-2 expression has been observed in 64% of adenocarcinomas and 75% of squamous cell carcinomas (SqCCs) [27]. TROP-2 overexpression has been reported to be associated with poor prognosis in a number of epithelial tumors, including NSCLC [28], [29], although some discrepancies exists in the literature [30]. The prognostic association of high TROP-2 expression was studied in a series of 586 lung cancer patients and significant difference emerged according to histological subtypes. High TROP-2 expression was associated with higher lung cancer-specific mortality in adenocarcinomas [univariable hazard ratio (HR)=1.60, 95% CI=1.07–2.44, P=0.022)], but not in SqCCs [univariable HR=0.79, 95% CI=0.35–1.94, P=0.79] [27]. Worse recurrence-free survival due to tyrosine kinase inhibitors (TKIs)-induced cell apoptosis rescued by TROP-2 overexpression has been described in HER2-positive breast cancer [31]. TROP-2 may also function as a key player in resistance mechanisms to anti-EGFR treatment in NSCLC. In a study of 164 NSCLC, TROP-2 was aberrantly expressed in EGFR-mutant NSCLC, and by interacting with the insulin growth factor axis (IGF2-IGF1R-Akt), TROP-2 mediated high cytokine production and remodeling of the tumor microenvironment (TME), leading to in vitro and in vivo gefitinib resistance [32].

According to the Cochrane Handbook for Systematic Reviews of Interventions [33], a systematic literature search was conducted using PubMed [keyword (Title/abstracts: “lung carcinoma” or “lung cancer” or “NSCLC” and “TROP-2” or “Trop-2” or “Tropohoblast cell-surface antigen), filter ‘clinical trial’], Cochrane Library [keyword (Title/abstracts: “TROP-2” or “Trop-2” and “lung” or “NSCLC”), filter ‘trials’] and ClinicalTrials.gov [keyword “NSCLC” “TROP-2”, filter ‘completed’] to identify relevant studies published up to November 30, 2022, with no language restrictions. Two reviewers (CP and LM) independently screened the titles and abstracts of all citations identified using the search strategies. After eliminating duplicates and updated results from previous studies, 3/41 results (7.3%) fulfilled the criteria of publications on clinical trials of TROP-2 in NSCLC. Search for recent ASCO conferences (meeting.asco.org, keyword “TROP-2”, filter ‘abstracts and presentations’), ESMO and AACR conferences (keyword “TROP-2”, filter ‘NSCLC’ ‘webcast’, ‘e-poster’) and research articles on aacrjournals.org (keyword “TROP-2” “NSCLC”, filter “research articles”), with no language restrictions was also conducted. Overall, 85 results were obtained. After eliminating duplicates and updated results from previous studies, 1 result (1.2%) was finally suitable to be included in our systematic review.

Sacituzumab govitecan (IMMU-132) is a first-in-class TROP-2-directed ADC. Sacituzumab govitecan (SG) is linked to the cytotoxic payload SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of topoisomerase I inhibitor irinotecan, via a hydrolysable linker [34]. SN-38 is nearly 1000 times more active than irinotecan; its toxicity and poor solubility makes it unmanageable as an unbound drug [35]. SG is characterized by a high drug-to-antibody ratio (DAR), owing to the presence of seven to eight cytotoxic molecules per antibody molecule. A high DAR increases antitumoral efficacy despite the low antigen density on tumor cells. Internalization and enzymatic cleavage by tumor cells is not required for the release of SN-38 from the antibody. As a result of linker’s hydrolysis, SN-38 is released into the tumor microenvironment, via a bystander effect.

In 2015, a first-in-human phase I trial of SG showed good antitumor activity in heavily pretreated patients with diverse metastatic solid tumors not pre-selected for Trop-2 expression. Patients with refractory metastatic epithelial cancers received intravenous SG (at the dose of 8, 10, 12, or 18mg/kg) on days 1 and 8 of the 21-day cycles until disease progression or unacceptable toxicity. The trial also included patients with NSCLC (n=1/25) [36], [37]. Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Discontinuation due to AEs occurred in 8.3% of patients. The dose used for future development was 10mg/kg [38].

SG proved to be clinically beneficial in a single-arm multicenter trial that enrolled pretreated NSCLC patients (n=54). Objective response rate (ORR) evaluable in the study population and intention-to-treat (ITT) population was 19% and 17%, respectively. The ITT mPFS and mOS were 5.2months (95%CI: 2.6–7.1) and 9.5months (95%CI: 5.9–16.7), respectively. Of note, more than 90% (24/26) of samples showed moderate to strong TROP-2 expression, suggesting that TROP-2 expression testing may not be required prior to treatment. Since the sample size is small, the predictive value of TROP-2 expression requires further investigation. In this study, SG demonstrated a manageable safety profile, with the most common all grades’ AEs being nausea (80%), diarrhea (61%), fatigue (46%), alopecia (39%) and neutropenia (37%). Neutropenia was the most common among grade 3–4 AEs (28%), but rate of febrile neutropenia was low (4%). 49% of patients in the study required a 25% dose reduction, mainly due to neutropenia. Discontinuation due to TRAEs occurred in two patients (4%) [39]. Proactive toxicity monitoring and management to optimize SG use in older patients may be required in clinical practice, based on the results of the ASCENT study in TNBC patients [37].

The phase II open-label TROPICS-03 trial (NCT03964727) is currently enrolling participants with solid tumors, selected based on elevated TROP-2 expression by IHC assay, including NSCLC [40]. To date, SG has been approved by the FDA for metastatic TNBC based on the results of the ASCENT study [41]. Aside from TNBC, SG is also now FDA approved for hormone receptor positive, HER2-ve metastatic breast cancer based on tropics-02 study and it was granted accelerated approval for metastatic urothelial cancer based on the results of the TROPHY-U-01 study [42], [43], [44].

Datopotamab Deruxtecan (Dato-DXd, DS-1062), is a humanized TROP-2-directed antibody linked to a topoisomerase 1 inhibitor payload (exatacan derivative) via a tetrapeptide-based cleavable linker [45]. The linker releases DXd after proteolytic processing by lysosomal proteases such as cathepsins. Dato-DXd has an optimized DAR of four, which is expected to maximize the therapeutic window. In preclinical studies, Dato-DXd remarkably reduced the growth of TROP-2-high cell lines but was not effective in inhibiting cell growth with low TROP-2 levels. In addition, Dato-Dxd induced tumor inhibition in TROP-2-high NSCLC PDX models [45].

In the phase 1 TROPION-PanTumor01 study, Dato-DXd was administered across different doses (4.0mg/kg n=50, 6.0mg/kg n=50, 8.0mg/kg n=80) every 3weeks (Q3W) in pretreated NSCLC patients (n=34). Most patients had previously been treated with at least three lines of therapy, including platinum-based chemotherapy (94%), immunotherapy (84%) and TKIs (17%). Notably, the study enrolled NSCLC patients with oncogenic drivers such as EGFR mutations, as well as patients with central nervous system (CNS) involvement, equally represented across the three doses cohorts. The ADC yielded an encouraging antitumor activity (ORR 24% at 4.0mg/kg, 26% at 6.0mg/kg, 24% at 8mg/kg) and responses were generally durable. Of note, median duration of response (mDOR) was 10.5months in the 6mg/Kg cohort. Drug-related interstitial lung disease (ILD) occurred in 11% of patients, with 3 grade 5 at a dose of 8mg/kg [46]. The dose of 6mg/kg was chosen for future clinical development. Drug-related grade≥3 AEs occurred in 14%, 26% and 35% respectively at the dose of 4, 6 and 8mg/Kg. Discontinuation due treatment-emergent adverse events (TEAEs) was reported in 16%, 14% and 24%, respectively. Dose reduction increased with dose and was required in 2%, 10% and 29% of patients according to the different doses. In pharmacometric analyses, the incidence of dose reduction and grade≥2 stomatitis/mucositis positively correlated with exposure [47]. Of note, antitumor activity in NSCLC patients with actionable genomic alterations was also encouraging, with a confirmed ORR across doses of 35% (95% CI, 19.7–53.5), as preliminary reported by Garon et al [48].

At World Conference on Lung Cancer (WCLC, August 2022) Levy B. et al. presented initial results of TROPION-Lung02 trial; ORR was 62% with Dato-DXd and Pembrolizumab arm (n=13) and 50% in the Dato-DXd, Pembrolizumab and platinum-chemotherapy arm (n=20). The safety profile was characterized by drug-related ILD emerging as a grade 3 adverse event in 3% of patients (n=1/40) in doublet arm and 2% (n=1/48) in triplet arm [49] (Fig. 2).

The NCT02122146 trial was a phase 1 dose-finding study evaluating the ADC PF-06664178, which targets TROP-2 for the selective delivery of the cytotoxic payload Aur010. The results showed toxicity at high dose levels with modest antitumor activity; the trial was prematurely discontinued owing to a pharmaceutical-related decision [50].

ADCs represent a smart-drug delivery technology that encompasses the process of drug evolution from classic monoclonal antibodies to highly precise and potentially immunogenic conjugates. ADCs are intended to exploit the presence of a target antigen to introduce potent cytotoxic drugs into tumor cells, with subsequent effects on surrounding cells and minimal toxicity to normal tissues. Most AEs induced by ADCs administration are on-target/off-cancer effects related to the expression of TROP-2 in normal tissues. Membrane-permeable ADCs are commonly associated with off-target toxicities owing to drug uptake by antigen-negative cells. The biochemical properties of linkers are the main cause of toxicity, as they affect the concentration of circulating free drug versus its release in cells. As mentioned above, the main AEs associated with SG are likely to be observed with irinotecan, including gastrointestinal effects (e.g., diarrhea) and hematotoxicity (e.g., neutropenia), related to SN-38. In a recently conducted meta-analysis of ADCs related AEs, the authors, based on indirect comparisons of different drugs, payload types, and target drugs from the available RCTs, reported a higher mean incidence of all grade AEs for SG (OR, 10.94; 95% CI, 4.59–26.04; P<0.0001). SN-38–targeted ADCs resulted in a higher mean incidence of grade≥3 AEs s (OR, 2.05; 95% CI, 1.42–2.95; P=0.0001) compared with other payload categories. Glucuronidation of SN-38 by uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) is a key step in the payload’s metabolism [51]. Patients with UGT1A1 polymorphisms may have a higher incidence of certain toxicities due to differences in SN-38 metabolism [52]. In the ASCENT study, patients who were homozygous for the UGT1A1 *28 allele displayed a higher rate of>grade 3 neutropenia, neutropenic fever, anemia, and diarrhea than patients with wild-type or heterozygous UGT1A1 [53]. Routine testing for UGT1A1 polymorphisms is not currently recommended. However, patients with UGT1A1 *28 homozygous should be closely monitored for side effects, as there is known increased risk of toxicities. In cases of severe AEs, including neutropenia, the SG dose can be reduced or discontinued (Table 1).

Cytotoxic payload may be responsible for specific on-target off-tumor toxicities, including ILD which occur in 5–16% of patients treated with novel ADCs. Several factors have been likely considered predictors of ILD in patients receiving Trastuzumab Deruxtecan. They include age younger than 65years, lung comorbidities, a moderate/severe decrease in baseline renal function and drug’s dose greater than 6.4mg/kg [54]. Novel evidence shows that ILD caused by ADCs such as Trastuzumab Deruxtecan, may be explained by the uptake of conjugate by intra-alveolar macrophages rather than by circulation of unconjugated payload [55]. This biological mechanism has not been proven for ADCs targeting TROP-2. In addition, ILD is likely related to the exatecan rather than govitecan payload, since it has been consistently described in 7–15% of patients receiving HER2-DXD, HER3-DXD, or TROP2-DXD, but not in patients receiving SG[54]. In this regard, the presence of dyspnea at rest due to complications of advanced malignancy, comorbidities, and/or concurrent pulmonary radiation therapy may represent predisposing factors for the emergence of AE. Temporary discontinuation of the ADC and steroids for≥grade 2 ILD is the backbone of treatment [56].

The mechanisms of resistance are unique and complex compared to traditional targeted therapies. They may involve all the different steps in the activation cascade of ADC delivery, such as downregulation/loss of the targeted surface antigen, elimination/mutation of the binding site by alternative splicing, and impaired release of the toxic payload (e.g., by overexpression of drug efflux transporters or by reduced lysosomal proteolytic activity) [57]. Increased production of ligands and activation of alternative receptor tyrosine kinases (RTKs) are responsible for the refractoriness to TDM-1 in breast cancer [58]. Parallel RNA and whole-exome sequencing allowed to identify one possible mechanism to acquired resistance to anti-TROP-2 ADCs; mutually exclusive somatic mutations in genes encoding both TROP-2 (target of antibody) and TOP1 (target of payload) emerged as a putative cause of acquired resistance to SG [59].

© 2023 Elsevier Ltd. All rights reserved.

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