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A comprehensive review on antibody-drug conjugates (ADCs) in the treatment landscape of non-small cell lung cancer (NSCLC)

  • Ziad Abuhelwa
    Affiliations
    Department of Internal Medicine, University of Toledo, Toledo, OH, USA
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  • Abdurahman Alloghbi
    Affiliations
    Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Cancer Research Unit, King Khalid University, Abha, Saudi Arabia

    Department of Oncology, King Khalid University, Abha, Saudi Arabia
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  • Misako Nagasaka
    Correspondence
    Corresponding author at: Division of Hematology/Oncology, Department of Medicine, UCI Health, 101 The City Drive South, Building 200, Room 410, ZOT 4061, Orange, CA 92868, Tel.: 714-456-5153; fax: 714-456-2242.
    Affiliations
    Department of Oncology, University of California Irvine, Orange, CA, USA

    Department of Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
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Open AccessPublished:April 13, 2022DOI:https://doi.org/10.1016/j.ctrv.2022.102393

      Highlights

      • ADCs deliver highly potent cytotoxic drugs in a “targeted” fashion.
      • ADCs are made of an antibody and a cytotoxic drug connected via a linker.
      • Targets for ADCs include HER2, Trop2, HER3, MET and others.
      • ADCs have an unique mechanism of action.
      • Clinicians should be aware of efficacy and safety data on emerging ADCs.

      Abstract

      Even though both targeted and immunotherapy-based therapies have been established as frontline standard-of-care for patients with advanced lung cancer, adverse events, resistance, and disease progression remain unavoidable in most instances. In this scenario, chemotherapy is a popular salvage option, but it has restricted therapeutic index. Antibody-drug conjugates (ADCs) have emerged as a viable option. ADCs combine the specificity of monoclonal antibodies with the cytotoxic effects of chemotherapy to deliver cytotoxic payloads to cancer cells in a direct fashion. Among the promising ADCs used in advanced solid tumors, HER2 targeted ADCs of trastuzumab ematansine and trastuzumab deruxtecan are key drugs in this field.

      Keywords

      Introduction

      Chemotherapy, the most commonly used anticancer treatment, has proven benefits over many decades. However, benefits are limited by a relatively narrow therapeutic index and non-selective mechanism of action leading to systemic toxicity. The evolution of targeted therapy in cancer treatment has resulted in a significant survival improvement. Immunotherapy-based strategies including monoclonal antibodies have significantly improved the mortality in patients with non-small cell lung cancer (NSCLC) [
      • Howlader N.
      • et al.
      The effect of advances in lung-cancer treatment on population mortality.
      ]. However, the majority of patients will develop acquired resistance to front line chemotherapy, immmunotherapy or targeted therapy, necessitating alternate treatment.
      Recently, the development of antibody-drug conjugates (ADCs) that combine monoclonal antibodies with the cytotoxic effects of chemotherapy, has shown promising efficacy with limited toxicities compared to conventional treatment. At the time of manuscript preparation, eleven different ADCs had been granted U.S. Food and Drug Administration (FDA) approval. Five of them; trastuzumab emtansine, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan and tisotumab vedotin, were approved for the use in solid malignancies including breast, urothelial, gastric, and cervical cancers. Many ADCs are undergoing clinical development in lung cancer patients. However, none has been granted FDA approval at this time. In this review, we will focus on the use of ADCs in advanced or metastatic NSCLC. We will first discuss the structure and mechanism of action of ADCs in general. Then, we will review the promising antigenic targets and ADC pharmacologic agents in NSCLC and provide an overview of clinical trials of ADCs in NSCLC.

      Structure and mechanism of action of ADCs

      In this section, we briefly review the key aspects of ADC design and how they affect drug efficacy and toxicity and the mechanism of action.

      Structure of ADCs

      As the name implies, the basic components of an ADC are an antigen-specific monoclonal antibody and a potent cytotoxic drug connected with each other via a chemical linker (Fig. 1).
      • 1.
        Monoclonal antibody: The monoclonal antibody is the main component of the ADC structure. It should be targeted against a specific unique antigen with minimal cross reactivity and immunogenicity with normal tissue [
        • Wang W.
        • Wang E.Q.
        • Balthasar J.P.
        Monoclonal antibody pharmacokinetics and pharmacodynamics.
        ]. The IgG type of immunoglobulin, specifically IgG1, is the most frequently used antibody format in antibody mediated therapeutics due to the ease of manufacturing, low clearance from circulation and as it can offer strong antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) [
        • Beck A.
        • et al.
        Strategies and challenges for the next generation of antibody-drug conjugates.
        ].
      • 2.
        Cytotoxic drug: It is commonly referred to as the “payload” or “warhead”. An ideal cytotoxic drug should have high stability in the systemic circulation and lysosomes, low immunogenicity, small molecular weight and long half-life [
        • Li F.
        • et al.
        Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models.
        ].There are different types of cytotoxic drugs commonly used in ADCs, and they are mainly microtubule disturbing agents or DNA damaging agents [
        • Hafeez U.
        • et al.
        Antibody-drug conjugates for cancer therapy.
        ]. An important consideration in the design of ADCs is the drug to antibody ratio (DAR) as ADCs with low DAR may not offer the desired clinical effect while ADCs with high DAR can result in increased plasma concentration and off-target toxicity [
        • Hamblett K.J.
        • et al.
        Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate.
        ].
      • 3.
        Linker: As the name states, its function is to link the monoclonal antibody with the cytotoxic drug. Ideally, the linker must be stable in the systemic circulation and efficiently cleaved inside the tumor cell to release the cytotoxic drug as premature release of cytotoxic drugs in the systemic circulation can result in toxicity [
        • Perez H.L.
        • et al.
        Antibody–drug conjugates: current status and future directions.
        ]. Linkers can be divided into two main subtypes based on the cytotoxic drug release mechanism: non-cleavable and cleavable linkers [
        • Chau C.H.
        • Steeg P.S.
        • Figg W.D.
        Antibody-drug conjugates for cancer.
        ]. The non-cleavable linkers such as thioethers are more stable in the systemic circulation and they depend on lysosomal degradation for cytotoxic drug release [
        • Frigerio M.
        • Kyle A.F.
        The chemical design and synthesis of linkers used in antibody drug conjugates.
        ]. On the other hand, the cleavable linkers are less stable in the systemic circulation, and they depend on physiological conditions of the endosomes for the cytotoxic drug release [
        • Lu J.
        • et al.
        Linkers having a crucial role in antibody-drug conjugates.
        ]. They can be acid-labile linkers cleaved by a low pH, peptide linkers cleaved via protease activity or disulfide linkers cleaved through reduction via increased glutathione concentrate [
        • Jaracz S.
        • et al.
        Recent advances in tumor-targeting anticancer drug conjugates.
        ].
      Figure thumbnail gr1
      Fig. 1It demonstrates the three components of ADCs; the monocolonal antibody, cytotoxic drug (payload) and the linker.

      ADCs mechanism of action

      The basic idea behind the creation of ADCs is to deliver a highly potent cytotoxic drug to effectively kill tumor cells in a “targeted” fashion. ADCs are administered intravenously due to poor bioavailability and in order to avoid gastric acidity and proteolytic enzymes from destroying the monoclonal antibodies [
      • Peters C.
      • Brown S.
      Antibody-drug conjugates as novel anti-cancer chemotherapeutics.
      ]. The action of ADCs with cleavable linkers starts with circulating ADCs binding to the target antigen, internalization of ADC-antigen complex, then lysosomal fusion with the endosome resulting in the cytotoxic drug release (Fig. 2). In addition to the anti-tumor activity of the cytotoxic drugs, monoclonal antibodies can possess direct and indirect anti-tumor activity [
      • Green M.C.
      • Murray J.L.
      • Hortobagyi G.N.
      Monoclonal antibody therapy for solid tumors.
      ]. Certain monoclonal antibodies can exert anti-tumor activity from direct modulation of the biological activity of the target antigen such as trastuzumab, anti-HER-2 monoclonal antibody [
      • Baselga J.
      • et al.
      Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.
      ]. Other monoclonal antibodies have indirect immune mediated cytotoxicity including ADCC, or CDC [
      • Natsume A.
      • Niwa R.
      • Satoh M.
      Improving effector functions of antibodies for cancer treatment: Enhancing ADCC and CDC.
      ].
      Figure thumbnail gr2
      Fig. 2It shows the step by step mechanisom of action of ADCs. Circulating ADCs bind to the target antigen forming an ADC-antigen complex (1). Then, the complex is internalized via endocytosis (2). Linker cleavage leads to cytotoxic drug release (3) and elicit anti-tumor effects (4).

      Bystander effect or killing

      In addition to ADCs direct anti-tumor effects on antigen-positive tumor cells, they also have the capacity to kill adjacent antigen-negative tumor cells, and this is called “bystander effect” or “bystander killing” [
      • Singh A.P.
      • Shah D.K.
      A “dual” cell-level systems PK-PD model to characterize the bystander effect of ADC.
      ]. This occurs when the cytotoxic drug of an ADC is released from the antigen-positive tumor cell after internalization and degradation [
      • Staudacher A.H.
      • Brown M.P.
      Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required?.
      ]. Bystander effect depends on different factors including physiochemical characteristics of the cytotoxic drug; for example, the positive charge of the cytotoxic drug “emtansine” in ado-trastuzumab emtansine prohibit it from penetrating the cell membrane thus limiting its bystander effect [
      • Erickson H.K.
      • et al.
      Tumor delivery and in vivo processing of disulfide-linked and thioether-linked antibody-maytansinoid conjugates.
      ]. Another important factor that can affect bystander killing is ADC internalization after binding to target antigen as well as the type of linker; cleavable vs non-cleavable [
      • Staudacher A.H.
      • Brown M.P.
      Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required?.
      ]. In ADCs with non-cleavable linkers, after lysosomal degradation the linker will remain attached to the monoclonal antibody and thus enhance cytotoxic drug retention into the tumor cells; therefore, they do not cause bystander effect [
      • Kovtun Y.V.
      • et al.
      Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen.
      ]. On the other hand, ADCs with cleavable linkers tend to be less stable and cleaved after internalization releasing the free cytotoxic drug that can kill both antigen positive tumor cells and surrounding antigen negative tumor cells [
      • Staudacher A.H.
      • Brown M.P.
      Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required?.
      ].

      Antigenic targets and ADC pharmacologic agents in NSCLC

      There are various antigenic targets used in ADCs development. In this section, we briefly review these antigenic targets and their ADCs that are being studied in NSCLC.

      Human epidermal growth factor receptor 2 (HER2)

      HER2 is a receptor tyrosine kinase encoded by erb-b2 receptor tyrosine kinase 2 (ERBB2) gene [
      • Hynes N.E.
      • Stern D.F.
      The biology of erbB-2/neu/HER-2 and its role in cancer.
      ]. ERBB2 alterations have been identified as oncogenic drivers and potential therapeutic targets in lung cancer [

      Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511(7511): 543–50.

      ]. These alterations are diverse and can include HER2 gene mutation, HER2 gene amplification, and HER2 protein overexpression [
      • Yoshizawa A.
      • et al.
      HER2 status in lung adenocarcinoma: A comparison of immunohistochemistry, fluorescence in situ hybridization (FISH), dual-ISH, and gene mutations.
      ]. HER2 gene mutations has been identified in about 2–4% of patients with NSCLC [
      • Ninomiya K.
      • et al.
      A prospective cohort study to define the clinical features and outcome of lung cancers harboring HER2 aberration in Japan (HER2-CS STUDY).
      ]. HER2 gene amplification, defined as HER2/CEP17 ratio ≥ 2.0 via fluorescence in situ hybridization, has been reported in approximately 2–5% of lung adenocarcinomas [
      • Yoshizawa A.
      • et al.
      HER2 status in lung adenocarcinoma: A comparison of immunohistochemistry, fluorescence in situ hybridization (FISH), dual-ISH, and gene mutations.
      ]. HER2 is an attractive target for ADCs (Table 1).
      Table 1Common antigenic targets for antibody-drug conjugates used in non-small cell lung cancer.
      TargetADCmAbLinkerPayloadDAR
      HER2Ado-trastuzumab Emtansine (T-DM1)TrastuzumabNon-cleavableEmtansine3.5
      Trastuzumab Deruxtecan (T-DXd)TrastuzumabCleavableDeruxtecan8
      A166TrastuzumabCleavableDuostatin-5
      XMT-1522HT-19CleavableAuristatin F-hydroxypropylamide12
      HER3Patritumab Deruxtecan (HER3-DXd)PatritumabCleavableDeruxtecan8
      Trop-2Sacituzumab Govitecan (SG)SacituzumabCleavableSN-387.6
      Datopotamab Deruxtecan (Dato-DXd)DatopotamabCleavableDeruxtecan4
      METTelisotuzumab Vedotin (Teliso-V)ABT-700CleavableMonomethyl auristatin E3.1
      GPNMBGlembatumumab VedotinGlembatumumabCleavableMonomethyl auristatin E
      PTK7Cofetuzumab PelidotinCofetuzumabCleavableAur01014
      MSLNAnetumab RavtansineMF-TCleavableMaytansinoid DM43.2
      B7-H3MGC018Anti-B7-H3 mAbCleavableDuocarmycin2.7
      DS-7300aAnti-B7-H3 mAbCleavableExatecan derivative4
      TFTisotumab VedotinTF-011CleavableMonomethyl auristatin E4.1
      AXLEnapotamab Vedotin (EnaV)AXL-107CleavableMonomethyl auristatin E4
      BA3011Anti-AXL mAbCleavableMonomethyl auristatin E
      EGFRMRG003Anti-EGFR mAbCleavableMonomethyl auristatin E
      NaPi2bXMT-1536Anti-NaPi2b mAbCleavableAuristatin F- hydroxypropylamide10–15
      XMT-1592Anti-NaPi2b mAbDolasynthenMonomethyl auristatin-F6
      CEACAM5SAR408701 (tusamitamab ravtansine)Anti-CEACAM5 mAbMaytansinoid DM4
      ROR2BA3021Anti-ROR2 mAbMonomethyl auristatin E
      Abbreviations: ADC, Antibody-Drug Conjugate; mAb, monoclonal antibody; DAR, Drug-Antibody Ratio.

      Ado-trastuzumab ematansine (T-DM1)

      T-DM1 is a novel ADC that consists of anti-HER2 monoclonal antibody trastuzumab linked to the microtubule inhibitor ematansine (DM1) via non-cleavable linker with DAR of 3.5 [
      • He J.
      • et al.
      Characterization of in vivo biotransformations for trastuzumab emtansine by high-resolution accurate-mass mass spectrometry.
      ]. T-DM1 was approved by the FDA in February 2013 for the treatment of advanced HER2-positive breast cancer in patients who previously received trastuzumab and a taxane therapy separately or in combination [
      • Amiri-Kordestani L.
      • et al.
      FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer.
      ].
      Li et al. conducted a phase II basket trial on 18 patients with HER2-mutant metastatic lung adenocarcinoma that showed promising efficacy. T-DM1 was delivered for a median of six cycles (range 2–19). Eight patients experienced partial response (PR) with an objective response rate (ORR) of 44%. The median progression free survival (PFS) was 5 months [
      • Li B.T.
      • et al.
      Ado-Trastuzumab Emtansine for Patients With HER2-Mutant Lung Cancers: Results From a Phase II Basket Trial.
      ]. Later, Li et al. included more patients with HER2-amplified or mutant metastatic NSCLC to reach a total of 49. In this study, T-DM1 showed an ORR of 51% with a median PFS of 5 months. Interestingly, consistent responses were observed across HER2 status, with ORR of 55% (6/11), 50% (14/28), and 50% (5/10) observed in HER2-amplifed, mutant, and co-mutant/amplified patients respectively. Treatment was tolerated with no reported grade 4 or 5 AEs and only one (2%) patient with grade 3 febrile neutropenia [
      • Li B.T.
      • et al.
      HER2-mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers.
      ].

      Trastuzumab Deruxtecan (T-DXd or DS-8201a)

      T-DXd is a novel ADC that consists of anti-HER2 monoclonal antibody trastuzumab conjugated to topoisomerase I inhibitor deruxtecan via a protease cleavable peptide linker with DAR of 8 [
      • Ogitani Y.
      • et al.
      DS-8201a, A novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1.
      ]. T-DXd is characterized by high membrane permeability and high DAR along with the cleavable linker which allow for greater bystander effect thus more anti-tumor activity despite low HER2 antigen density on tumor cells [
      • Ogitani Y.
      • et al.
      Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody–drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity.
      ]. In December 2019, T-DXd was approved by the FDA for treatment of unresectable or metastatic HER2-positive breast cancer in patients who received two or more prior anti-HER2 based regimens in the metastatic settings [
      • Keam S.J.
      Trastuzumab deruxtecan: first approval.
      ]. Additionally, in January 2021 the FDA approved the use of T-DXd for treatment of HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen [

      Food and Drug Administration. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. 2021 [cited 2021 December 29, 2021]; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-positive-gastric-adenocarcinomas.

      ]. In NSCLC, first-in-human phase I trial of T-DXd in advanced solid tumor included 11 patients with HER2-mutant NSCLC. T-DXd demonstrated a promising anti-tumor activity with an ORR of 72.7%. The median duration of response (DOR), PFS and overall survival (OS) were 9.9, 11.3 and 17.3 months respectively [
      • Tsurutani J.
      • et al.
      Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors.
      ].
      Recently, phase II clinical trial, DESTINY-Lung01, evaluated the efficacy of T-DXd in relapsed or refractory NSCLC in two separate cohorts: HER2 mutated and overexpressed. The HER2 mutated cohort of the DESTINY-Lung01 study evaluated 91 patients with HER2-mutant NSCLC for a median follow up of 13.1 (range: 0.7–29.1) months. One patient (1.1%) had complete response (CR) and 49 (53.8%) had PRs with OR of 54.9%. The median DOR, PFS and OS were 9.3, 8.2 and 17.8 months respectively. Any grade AEs were reported in 88 (96.7%) including 42 (46%) patients with grade ≥ 3. Any grade interstitial lung disease (ILD) was reported in 24 (26.4%) patients and resulted in 2 grade 5 events [
      • Li B.T.
      • et al.
      Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer.
      ]. In HER2-overexpressed cohort, out of 49 patients one patient had CR and 11 had PRs with a reported ORR of 24.5%. The ORR did not differ in terms HER2 IHC expression status (ORR 20.0% versus 25.6% in IHC3 + and IHC2 + patients, respectively). The median DOR and PFS were 6 and 5.4 months respectively. Grade ≥ 3 AEs were reported in 73.5% with neutropenia and fatigue being the most common; 20.4% and 10.2% respectively. Eight patients (16.3%) developed drug related ILD, of them, 3 had a grade 5 event. AEs leading to treatment discontinuation occurred in 11 (22.4%) patients [
      • Nakagawa K.
      • et al.
      OA04.05 trastuzumab deruxtecan in HER2-overexpressing metastatic non-small cell lung cancer: interim results of DESTINY-Lung01.
      ].
      Current data regarding T-DXd in advanced NSCLC is showing a very promising therapeutic benefit. There are multiple ongoing clinical trials on T-DXd in advanced NSCLC (Table 2).
      Table 2Current recruiting, active or ongoing clinical trials on different ADCs involved in NSCLC treatment.
      ADCAntigenPhase (ID); NameStudy SubjectsInterventionLocationPrimary outcome
      T-DM1HER2II (NCT02675829)Cohort 1: HER2-mutant lung cancers, Cohort 2: HER2-amplified lung cancersT-DM1 3.6 mg/kg q3wUSAORR
      II (NCT03784599); TRAEMOSEGFR-mutant, advanced NSCLC with HER2 bypass track resistanceT-DM1 3.6 mg/kg q3w + Osimertinib 80 mg qdNetherlandsSafety, ORR
      II (NCT2465060); MATCHHER2-amplified, treatment refractory tumors (sub-protocol Q of NCI-MATCH)T-DM1USAORR
      II (NCT04591431); ROMEHER2-amplified or mutated solid tumors (includes NSCLC)T-DM1ItalyORR
      T-DXdHER2II (NCT03505710); DESTINY-Lung01HER2-overexpressing or mutant, advanced or metastatic NSCLCT-DXd 6.4 or 5.4 mg/kg q3wInternationalORR
      II (NCT04644237); DESTINY-LUNG02HER2-mutant, metastatic NSCLCT-DXd 6.4 or 5.4 mg/kg q3wInternationalORR
      Ib (NCT04686305); DESTINY-Lung03HER2-positive, advanced, or metastatic NSQ-NSCLCT-DXd + chemotherapyInternationalSafety
      III (NCT05048797); DESTINY-Lung04HER2-mutant, advanced or metastatic NSQ-NSCLCT-DXd vs. standard of care (cisplatin, carboplatin, pembrolizumab, pemetrexed)InternationalPFS
      I (NCT04042701)HER2-expressing or mutant NSCLCT-DXd 3.2 or 5.4 mg/kg q3w + pembrolizumab 200 mg q3wInternationalDLTs, MTD, ORR
      II (NCT03334617); HUDSONUmbrella-study of NSCLC patients progressed on anti-PD-1/PD-L1 therapyT-DXd 5.4 mg/kg q3w + durvalumab 1120 mg q3wInternationalORR
      A166HER2I/II (NCT03602079)HER2-expressing or amplified, relapsed or refractory cancers (includes lung cancers)Dose-escalation A166 q3wUSAORR, safety
      HER3-DXdHER3II (NCT04619004); HERTHENA-Lung01EGFR-mutant, previously treated, advanced, or metastatic NSCLCHER3-DXd 5.6 mg/kg q3w or dose-escalation to 6.4 mg/kg q3wInternationalORR
      I (NCT04676477)EGFR-mutant, treatment refractory and naïve, advanced, or metastatic NSCLCCofetuzumab pelidotin 2.8 mg/kg q3wInternationalORR, safety
      I (NCT03260491)Treatment-refractory EGFR-mutant and EGFR-wild type NSCLCDose-escalation and expansion HER3-DXdInternationalORR, safety
      SGTrop-2II (NCT03964727); TROPICS-03Metastatic solid tumors including NSCLCSG 10 mg/kg on day 1 and 8 of 21-day cycleUSAORR
      I/II (NCT03337698); Morpheus LungUmbrella study of immunotherapy-based combinations in treatment-naïve and -refractory metastatic NSCLCSG + multiple immunotherapeutic agentsInternationalORR
      III (NCT05089734)Treatment refractory, advanced or metastatic NSCLCSG 10 mg/kg on day 1 and 8 of 21-day cycle vs docetaxel 75 mg/m2 q3w*OS
      Dato-DXdTrop-2III (NCT04656652); TROPION-LUNG01Previously treated, advanced or metastatic NSCLCDato-DXd 6 mg/kg q3w vs docetaxel 75 mg/m2 q3wInternationalPFS, OS
      I (NCT04526691); TROPION-LUNG02Previously treated or treatment naïve, advanced or metastatic NSCLCDose-escalation Dato-DXd q3w + pembrolizumab 200 mg q3w + carboplatin/cisplatin q3wInternationalSafety
      I (NCT04612751); TROPION-LUNG04Previously treated or treatment naïve, advanced or metastatic NSCLCDose-escalation Dato-DXd q3w + duralumab 1120 mg q3w + carboplatin/cisplatin q3wInternationalSafety
      I (NCT03401385); TROPION-PanTumor01Advanced solid tumors (includes NSCLC)Dose-escalation and expansion Dato-DXdInternationalSafety
      Teliso-VMETII (NCT03539536)MET-positive, previously treated, advanced or metastatic non-squamous NSCLCDose-escalation teliso-VInternationalORR
      III (NCT04928846)MET-positive, previously treated, advanced or metastatic non-squamous NSCLCTeliso-V every 2 weeks vs docetaxel q3wInternationalPFS, OS
      Cofetuzumab PelidotinPTK7I (NCT04189614)PTK7-expressing, recurrent NSCLCCofetuzumab pelidotin 2.8 mg/kg qw3InternationalORR
      Anetumab RavtansineMSLNI (NCT03102320)MSLN-expressing advanced solid tumors (includes NSCLC)Anetumab ravtansine 6.5 mg/kg q3wInternationalORR
      MGC018B7-H3I/II (NCT03729596)Advanced or metastatic solid tumors (includes NSCLC)MGC018 monotherapy, MCG018 + MGA012 (Anti-PD-1 antibody)InternationalAEs, MTD
      DS-7300aB7-H3I/II (NCT04145622)Advanced Solid Malignant Tumors (includes NSCLC)Dose-escalation and expansion DS-7300aInternationalDLTs, AEs, anti-tumor activity
      Tisotumab VedotinTFII (NCT03485209); innovaTV 207Relapsed, advanced or metastatic solid tumors (includes NSCLC)Dose-escalation tisotumab vedotinInternationalORR
      Enapotamab VedotinAXLI/II (NCT02988817)Relapsed, advanced or metastatic solid tumors (includes NSCLC)Dose-escalation and expansion enapotamab vedotinInternationalDLTs, AEs
      BA3011AXLI/II (NCT03425279)Advanced solid tumors (includes NSCLC)Dose-escalation and expansion BA3011 alone and in combination with a PD-1 InhibitorUSAORR, safety
      II (NCT04681131)Metastatic NSCLC progressed on a PD-1/L-1 InhibitorBA3011 alone and in combination with a PD-1 inhibitorUSAORR, safety
      MRG003EGFRII (NCT04838548)EGFR-positive advanced NSCLCMRG003 2 mg/kg q3wChinaORR
      XMT-1536NaPi2bI/II (NCT03319628)Platinum-resistant ovarian cancer and lung adenocarcinomaDose-escalation and expansion XMT-1536InternationalMTD, safety, ORR
      XMT-1592NaPi2bI (NCT04396340)Ovarian cancer and NSCLCDose-escalation and expansion XMT-1536USAMTD
      Tusamitamab RavtansineCEACAM5III (NCT04154956); CARMEN-LC03CEACAM5-positive, previously treated, metastatic NSQ NSCLCtusamitamab ravtansine q2w vs. docetaxel q3wInternationalPFS, OS
      II (NCT04394624); CARMEN-LC04CEACAM5-positive, previously treated, metastatic NSQ NSCLCtusamitamab ravtansine + ramucirumabInternationalDLTs, ORR
      II (NCT04524689); CARMEN-LC05CEACAM5-positive, previously treated, metastatic NSQ NSCLCCombination of tusamitamab ravtansine + pembrolizumab with pembrolizumab, platinum chemo, pemetrexedInternationalDLTS
      BA3021ROR2I/II (NCT03504488)Advanced or metastatic solid tumors (includes NSCLC)Dose-escalation and expansion BA3021 alone and in combination with a PD-1 inhibitorUSAORR, safety
      II (NCT04681131)Metastatic NSCLCBA3021 alone and in combination with a PD-1 inhibitorUSAORR, AEs
      Abbreviations: ADC, Antibody-Drug Conjugate; q3w, every 3 weeks; qd, every day; ORR, Objective Response Rate; OS, Overall Survival; PFS, Progression Free Survival; DLTs, Drug Limiting Toxicities; MTD, Maximum Tolerated Dose; AEs, Adverse Events; NSQ-NSCLC, non-squamous non-small cell lung cancer.

      A166

      A166 is an ADC composed of anti-HER2 monoclonal antibody trastuzumab linked to monomethyl aurstatin F derivative duostatin-5 via protease cleavable linker [

      Liu Y, et al. A first in-human study of A166 in patients with locally advanced/metastatic solid tumors which are HER2-positive or HER2-amplified who did not respond or stopped responding to approved therapies. American Society of Clinical Oncology; 2020.

      ]. A first-in-human trial of A166 in solid tumor is currently ongoing. Thirty-five patients with HER2-positive or amplified metastatic solid tumors received A166. Interim results revealed an ORR of 26% (7 had PRs out of 27 evaluable patients) with responses seen only at doses 3.6 mg/kg and 4.8 mg/kg [

      Liu Y, et al. A first in-human study of A166 in patients with locally advanced/metastatic solid tumors which are HER2-positive or HER2-amplified who did not respond or stopped responding to approved therapies. American Society of Clinical Oncology; 2020.

      ]. Preliminary results of another phase I trial in 23 patients with HER2-expressing, mutated or amplified metastatic solid tumors showed ORR 50% (4 had PRs out of 8 evaluable patients) [
      • Lopez D.M.
      • et al.
      Abstract B005: A phase I study of A166, a novel anti-HER2 antibody-drug conjugate (ADC), in patients with locally advanced/metastatic solid tumors.
      ]. In terms of AEs, three patients had ophthalmic toxicity after 2 or more cycles that was treated with topical steroids and lubricants [
      • Sharma A.
      • et al.
      Reversible HER2 antibody-drug conjugate–induced ocular toxicity.
      ].

      XMT-1522

      XMT-1522 is a novel ADC that consists of anti-HER2 monoclonal antibody HT-19 conjugated to auristatin F-hydroxypropylamide cytotoxic drug via cleavable linker with DAR of 12 [
      • Le Joncour V.
      • et al.
      A novel anti-HER2 antibody-drug conjugate XMT-1522 for HER2-positive breast and gastric cancers resistant to trastuzumab emtansine.
      ]. In a phase I clinical trial, XMT-1522 was administered to 19 patients with advanced HER2-expressing breast, gastric and NSCLC. XMT-1522 demonstrated a tolerable toxicity up to the dose 21.3 mg/m2. Most treatment related AEs were grades 1 or 2 including hepatoxicity and fatigue. Interim results showed disease control rate (DCR) of 83% (5 out of 6 patients who received 16 and 21.3 mg/m2 dose levels) [
      • Hamilton E.P.
      • et al.
      Phase 1 dose escalation of XMT-1522, a novel HER2-targeting antibody-drug conjugate (ADC), in patients (pts) with HER2-expressing breast, lung and gastric tumors.
      ].

      Human epidermal growth factor receptor 3 (HER3)

      HER3, or ERBB3, is one of the four members of HER family. While it is not extensively studied as other HER family proteins, HER3 is expressed in several cancers including breast, gastric, colon, head and neck and lung cancers [
      • Ocana A.
      • et al.
      HER3 overexpression and survival in solid tumors: a meta-analysis.
      ]. Moreover, resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in lung cancer can be induced via MET amplification via HER3 activation of downstream signaling pathway [
      • Engelman J.A.
      • et al.
      MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.
      ]. Based on these, HER3 is becoming an attractive therapeutic target for ADCs (Table 1).

      Patritumab Deruxtecan (HER3-DXd)

      HER3-DXd is a novel ADC that consists of anti-HER3 monoclonal antibody patritumab linked to the topoisomerase I inhibitor DXd via a cleavable tetrapeptide linker with DAR of 8 [
      • Hashimoto Y.
      • et al.
      A novel HER3-targeting antibody-drug conjugate, U3–1402, exhibits potent therapeutic efficacy through the delivery of cytotoxic payload by efficient internalization.
      ]. Patients with EGFR-mutated NSCLC are associated with higher expression of HER3 compared with patients with EGFR wild-type NSCLC [
      • Kawano O.
      • et al.
      ErbB3 mRNA expression correlated with specific clinicopathologic features of Japanese lung cancers.
      ]. In a phase I trial, HER3-DXd was evaluated in patients with EGFR-mutant NSCLC with prior EGFR TKI therapy. Fifty-seven patients received intravenous HER3-DXd. After a median follow up of 10.2 (range: 5.2–19.9) months, the ORR was 39% and DCR was 72% with a median DOR and PFS of 6.9 and 8.2 months respectively. The study demonstrated that HER3-DXd has antitumor activity across the spectrum of known and unknown EGFR TKI resistance mechanisms including EGFR C797S, MET or HER2 amplification, and BRAF fusion [
      • Jänne P.A.
      • et al.
      Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer.
      ]. Grade ≥ 3 treatment related AEs occurred in 64% of patients with the most common being thrombocytopenia (26%; 21/81), neutropenia (15%; 12/81), and fatigue (10%; 8/81). Treatment related ILDs occurred in 4 patients, and all resolved after drug discontinuation. There were no treatment related AEs associated with death [
      • Jänne P.A.
      • et al.
      Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer.
      ]. Based on these promising results of HER-DXd use in NSCLC, FDA has given its breakthrough therapy designation and there are multiple ongoing clinical trials on HER3-DXd use especially in EGFR-mutant NSCLC (Table2).

      Trophoblast cell-surface antigen (Trop-2)

      Trop-2 is a cell surface glycoprotein that is also known as tumor-associated calcium signal transducer (TACSTD2), epithelial glycoprotein-1 (EGP-1), and gastric antigen (GA733-1) [
      • Cardillo T.M.
      • et al.
      Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys.
      ]. Trop-2 was first discovered on the human trophoblast cells but later it was found to be expressed in many epithelial cancer cells including lung cancer [
      • Goldenberg D.M.
      • et al.
      Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC)*.
      ]. Trop-2 is an attractive target for ADCs (Table1).

      Sacituzumab govitecan (SG)

      SG is a novel ADC that consists of anti-Trop-2 monoclonal antibody sacituzumab linked to the topoisomerase I inhibitor SN-38 via a hydrolysable cleavable linker with DAR of 7.6 [
      • Bardia A.
      • et al.
      Sacituzumab govitecan in metastatic triple-negative breast cancer.
      ]. In April 2020, SG was approved by the FDA for treatment of metastatic triple-negative breast cancer in patients who received at least two prior therapies for metastatic disease [

      Food and Drug Administration. FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. 2020 [cited 2021 Decemebr 29]; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-hziy-metastatic-triple-negative-breast-cancer.

      ]. Then, one year later, SG was approved by the FDA for patients with locally advanced or metastatic urothelial cancer who previously received chemotherapy and immunotherapy [

      Food and Drug Administration. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. 2021 [cited 2021 December 29, 2021]; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-advanced-urothelial-cancer.

      ]. The first-in-human SG trial demonstrated promising anti-tumor efficacy with acceptable tolerability in Trop-2-positive, refractory, metastatic epithelial cancers including NSCLC and SCLC. Fifty-four patients with metastatic NSCLC received intravenous SG at either 8, 10 or 12 mg/kg doses on days 1 and 8 of a 21-day cycle. In the NSCLC subgroup, PRs were seen in 9 patients with an ORR of 16.7%. The median DOR, PFS and OS were 6, 4.4 and 7.3 months respectively [
      • Heist R.S.
      • et al.
      Therapy of advanced non–small-cell lung cancer with an SN-38-anti-trop-2 drug conjugate, sacituzumab govitecan.
      ]. The most common reported grade ≥ 3 AEs were neutropenia (42.4%), anemia (10.3%), diarrhea (7.9%), fatigue (6.3%), and febrile neutropenia (5.2%). The dose limiting toxicity was neutropenia and the maximum tolerated dose was 12 mg/kg. The 10 mg/kg dose was selected for further development in dose-expansion studies (Table 2) [
      • Bardia A.
      • et al.
      Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial.
      ].

      Datopotamab Deruxtecan (Dato-DXd, DS-1062a)

      Dato-DXd is a novel ADC composed of anti-Trop-2 monoclonal antibody datopotamab linked to topoisomerase I inhibitor deruxtecan via peptide cleavable linker with DAR of 4 [
      • Okajima D.
      • et al.
      Datopotamab deruxtecan, a novel TROP2-directed antibody–drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells.
      ]. TROPION-PanTumor01 is an ongoing first-in-human clinical trial that is enrolling patients with Trop-2-expressing, advanced, or refractory solid tumors. Updated data of 175 patients with Trop-2-expressing advanced NSCLC who received intravenous Dato-DXd showed that ORRs were similar among the 4, 6 and 8 mg/kg groups: 23% (9/40), 21% (8/39) and 25% (20/80) respectively. Preliminary median PFS in 4, 6 and 8 mg/kg groups were 4.3, 8.2 and 5.4 months respectively. Grade ≥ 3 treatment related AEs and serious treatment related AEs were ≥ 2-fold higher with the 8 mg/kg dose group relative to the 4 and 6 mg/kg groups. Additionally, treatment related ILD were higher in the 8 mg/kg group than 4 and 6 mg/kg groups (15% vs 2% and 2%) respectively. Three patients in the 8 mg/kg group had grade 5 drug related ILD [
      • Meric-Bernstam F.
      • et al.
      TROPION-PanTumor01: Dose analysis of the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd, DS-1062) for the treatment (Tx) of advanced or metastatic non-small cell lung cancer (NSCLC).
      ]. Based on this data, Dato-DXd at a dose of 6 mg/kg was selected in ongoing clinical trials (Table 2).

      Mesenchymal-to-epithelial transition (MET)

      MET receptor, or hepatocyte growth factor (HGF) receptor, is a transmembrane tyrosine kinase receptor encoded by MET proto-oncogene [
      • Ma P.C.
      • et al.
      Expression and mutational analysis of MET in human solid cancers.
      ]. In NSCLC, activating mutations in MET, including MET exon-14 skipping mutations, occur in about 3% [
      • Awad M.M.
      • et al.
      MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-met overexpression.
      ]. MET amplification occurs in about 3% to 4% of NSCLC patients who has not received any previous systemic therapy [
      • Schildhaus H.-U.
      • et al.
      MET amplification status in therapy-naive adeno-and squamous cell carcinomas of the lung.
      ] and in up to 20% in patients with acquired resistance to EGFR TKI [
      • Sequist L.V.
      • et al.
      Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.
      ]. Due to increased prevalence of MET alterations and being involved in treatment resistance in NSCLC, MET represent a promising target for ADCs in NSCLC (Table1).

      Telisotuzumab vedotin (Teliso-V)

      Teliso-V is a novel ADC that consists of anti-MET monoclonal antibody ABT-700 linked to the microtubule inhibitor monomethyl auristatin E cytotoxic drug via a cleavable linker with DAR of 3.1 [
      • Wang J.
      • et al.
      ABBV-399, a c-met antibody-drug conjugate that targets both MET-amplified and c-met-overexpressing tumors, irrespective of MET pathway dependence.
      ]. In the first-in-human trial of teliso-V, 16 patients with MET-overexpressing NSCLC were treated at 2.4 to 3 mg/kg every 3 weeks dose. The reported ORR for this group was 19% (3 PRs out of 16). The median PFS was 5.7 months. Grade ≥ 3 treatment related AEs were reported in 17% with fatigue, hypoalbuminemia, anemia, and neutropenia being the most common (2 patients, 4% in each). No treatment related deaths were reported. The recommended phase II dose was 2.7 mg/kg every 3 weeks [
      • Strickler J.H.
      • et al.
      First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody-drug conjugate targeting c-met, in patients with advanced solid tumors.
      ]. Based on these results, teliso-V was studied in phase II Lung-MAP S1400K trial. Twenty-three previously treated MET-positive (IHC H-score ≥ 150) advanced squamous NSCLC received intravenous teliso-V 2.7 mg/kg every 3 weeks. Unfortunately, this trial was discontinued owing to lack of efficacy with an ORR of 9%. Additionally, there were 3 grade 5 AEs including 2 patients with pneumonitis and 1 patient with bronchopulmonary hemorrhage [
      • Waqar S.N.
      • et al.
      A phase II study of telisotuzumab vedotin in patients with c–MET-positive stage IV or recurrent squamous cell lung cancer (LUNG-MAP Sub-study S1400K, NCT03574753).
      ].
      Moreover, teliso-V has been studied in patients with EGFR-mutant TKI-refractory NSCLC. In a phase Ib trial, 29 patients with MET-positive EGFR-mutant advanced NSCLC with prior EGFR TKI therapy were enrolled. Patients received a combination of oral erlotinib 150 mg daily (or prior tolerated dose) plus intravenous teliso-V 2.4 or 2.7 mg/kg every 3 weeks. After 4 months of a median follow up, results were promising with an ORR was 34.5%. Treatment was well tolerated and most treatment related AEs were low grade [
      • Camidge D.R.
      • et al.
      Results of the phase 1b study of ABBV-399 (telisotuzumab vedotin; teliso-v) in combination with erlotinib in patients with c-Met+ non-small cell lung cancer by EGFR mutation status.
      ]. Currently, there are 2 active clinical trials on teliso-V use in MET-positive refractory NSCLC (Table2).

      Glycoprotein non-metastatic melanoma protein B (GPNMB)

      GPNMB is a transmembrane protein that is overexpressed in multiple cancers including melanoma, glioblastoma, breast cancer and lung cancer [
      • Kuan C.-T.
      • et al.
      Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme.
      ,
      • Rose A.A.
      • et al.
      Glycoprotein nonmetastatic B is an independent prognostic indicator of recurrence and a novel therapeutic target in breast cancer.
      ]. The ADC glembatumumab vedotin utilizes GPNMB and it has been studied in NSCLC (Table 1).

      Glembatumumab vedotin

      Glembatumumab vedotin is a novel ADC composed from anti-GPNMB monoclonal antibody conjugated to monomethyl auristatin E via cleavable linker [
      • Naumovski L.
      • Junutula J.R.
      Glembatumumab vedotin, a conjugate of an anti-glycoprotein non-metastatic melanoma protein B mAb and monomethyl auristatin E for the treatment of melanoma and breast cancer.
      ]. Glembatumumab vedotin was studied in phase I dose escalation trial in 13 patients with advanced squamous NSCLC. The reported ORR was 7.7% (one patient with PR). The median PFS and OS were 2.5 and 5.7 months respectively. For AEs, a total of 3 patients had grade 5 AEs that were attributed either partially or wholly to disease progression [
      • Khan S.A.
      • et al.
      Efficacy and safety of glembatumumab vedotin in patients with advanced or metastatic squamous cell carcinoma of the lung (PrECOG 0504).
      ]. Further development of glembatumumab vedotin was discontinued.

      Protein tyrosine kinase 7 (PTK7)

      PTK7 is a member of the pseudokinase family of receptor tyrosine kinases. PTK7 plays an essential role in canonical and noncanonical Wnt as well as vascular endothelial growth factor (VEGF) signaling [
      • Damelin M.
      • et al.
      A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions.
      ]. PTK7 can present on multiple tumor types including breast, colon, esophageal, and lung cancers [
      • Gärtner S.
      • et al.
      PTK 7 is a transforming gene and prognostic marker for breast cancer and nodal metastasis involvement.
      ,
      • Meng L.
      • et al.
      Silencing of PTK7 in colon cancer cells: caspase-10-dependent apoptosis via mitochondrial pathway.
      ,
      • Chen R.
      • et al.
      A meta-analysis of lung cancer gene expression identifies PTK7 as a survival gene in lung adenocarcinoma.
      ]. Cofetuzumab pelidotin is an ADC that uses PTK7 as an antigenic target (Table 1).

      Cofetuzumab pelidotin

      Cofetuzumab pelidotin is an ADC that consists of anti-PTK7 monoclonal antibody cofetuzumab conjugated to the microtubule inhibitor Aur0101 via cleavable linker with a DAR of 4 [
      • Damelin M.
      • et al.
      A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions.
      ]. Phase I trial of cofetuzumab pelidotin in patients with refractory, PTK7-expressing ovarian, triple-negative breast cancers and NSCLC revealed ORRs of 27% (17/63 patients), 21% (6/29 patients) and 19% (6/31 patients) respectively. The most commonly reported treatment related AEs were nausea, alopecia, fatigue, headache, and neutropenia; 25% of patients had grade ≥ 3 neutropenia. Dose-limiting toxicities were experienced in two patients: grade 3 headache and fatigue. The recommended phase II dose was 2.8 mg/kg every 3 weeks [
      • Maitland M.L.
      • et al.
      First-in-human study of PF-06647020 (Cofetuzumab Pelidotin), an antibody-drug conjugate targeting protein tyrosine kinase 7 (PTK7), in advanced solid tumors.
      ]. Currently, there is a phase I trial of cofetuzumab pelidotin in PTK7-expressing, refractory, and advanced NSCLC (Table 2).

      Mesothelin (MSLN)

      MSLN is a membrane-bound glycoprotein with a poorly understood function, but it appears to play a role in metastatic spread [
      • Hassan R.
      • Ho M.
      Mesothelin targeted cancer immunotherapy.
      ]. MSLN has limited expression in normal tissue, but it can be overexpressed in many malignancies including malignant mesothelioma and pancreatic, ovarian and lung adenocarcinomas [
      • Hassan R.
      • et al.
      Mesothelin immunotherapy for cancer: ready for prime time?.
      ]. The ADC anetumab ravtansine uses MSLN as an antigenic target (Table1).

      Anetumab ravtansine

      Anetumab ravtansine is an ADC that consists of anti-MSLN monoclonal antibody (MF-T) conjugated to the microtubule inhibitor maytansinoid DM4 via disulfide cleavable linker with DAR of 3.2 [
      • Golfier S.
      • et al.
      Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect.
      ]. First-in-human trial that involved 148 patients with advanced or metastatic solid tumors including mesothelioma, ovarian, pancreatic, NSCLC and breast cancers showed stable disease (SD) in 66 (1 patients with NSCLC), PR in 11 and CR in 1 patient. The highest ORR was 31% and occurred in mesothelioma subgroup treated with the dose 6.5 mg/kg every 3 weeks. The maximum tolerated and recommended dose for phase II trials was determined to be 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week [
      • Hassan R.
      • et al.
      First-in-human, multicenter, phase I dose-escalation and expansion study of anti-mesothelin antibody-drug conjugate anetumab ravtansine in advanced or metastatic solid tumors.
      ]. Based on the results of this study, subsequent phase II trial randomized 166 patients with advanced, refractory, MSLN-expressing, malignant pleural mesothelioma into anetumab ravtansine or vinorelbine treatment group. Unfortunately, this study failed to demonstrate superiority of anetumab ravtansine over vinorelbine [
      • Kindler H.L.
      • et al.
      OA 02.01 randomized phase II study of anetumab ravtansine or vinorelbine in patients with metastatic pleural mesothelioma.
      ]. Two separate studies of anetumab ravtansine in advanced mesothelin-expressing NSCLC (NCT03455556, NCT02839681) were terminated early due to slow, insufficient accrual.

      B7-H3 (or cD276)

      B7-H3 is a transmembrane glycoprotein with unclear exact function [
      • Nygren M.K.
      • et al.
      B7–H3 and its relevance in cancer; immunological and non-immunological perspectives.
      ]. B7-H3 can be overexpressed NSCLC cells with limited expression on normal tissues [
      • Jin Y.
      • et al.
      B7–H3 in combination with regulatory T cell is associated with tumor progression in primary human non-small cell lung cancer.
      ]. B7-H3 is an ideal target for ADCs (Table1).

      MGC018

      MGC018 is a novel ADC that consists of anti-B7-H3 monoclonal antibody conjugated to duocarmycin cytotoxic drug via protease cleavable linker with DAR of 2.7 [
      • Scribner J.A.
      • et al.
      Preclinical development of MGC018, a duocarmycin-based antibody-drug conjugate targeting B7–H3 for solid cancer.
      ]. Phase I trial on MGC018 in 29 patients with advanced solid tumors showed 2 dose-limiting toxicities: grade 4 neutropenia (2 mg/kg) and grade 3 fatigue (4 mg/kg). The recommended phase II dose was determined to be 3 mg/kg every 3 weeks and enrollment in multiple expansion groups including NSCLC is currently ongoing (Table 2) [
      • Jang S.
      • et al.
      Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors.
      ].

      DS-7300a

      DS-7300a is a ADC that consists of anti-B7-H3 monoclonal antibody conjugated to an exatecan derivative payload via cleavable linker with DAR of 4 [
      • Bendell J.C.
      • et al.
      A phase I/II, two-part, multicenter, first-in-human study of DS-7300a in patients with advanced solid malignant tumors.
      ]. First-in-human study of DS-7300a is currently recruiting (Table2).

      Tissue factor (TF)

      TF, also known as thromboplastin or factor III, is a transmembrane glycoprotein that initiates the coagulation cascade [
      • McVey J.H.
      The role of the tissue factor pathway in haemostasis and beyond.
      ]. TF is overexpressed in many types of cancers including prostate, colorectal, NSCLC and pancreatic cancer, and it is associated with poor prognosis [
      • Goldin-Lang P.
      • et al.
      Tissue factor expression pattern in human non-small cell lung cancer tissues indicate increased blood thrombogenicity and tumor metastasis.
      ]. The ADC tisotumab vedotin utilizes TF as an antigenic target (Table1).

      Tisotumab vedotin

      Tisotumab vedotin is an ADC that consists of anti-TF monoclonal antibody TF-011 conjugated to monomethyl auristatin E cytotoxic drug via protease cleavable linker with a DAR of 4.1 [
      • Markham A.
      Tisotumab vedotin: first approval.
      ]. Tisotumab vedotin was approved by FDA in United Stated in September 2021 for the treatment of recurrent or metastatic cervical cancer [
      • Markham A.
      Tisotumab vedotin: first approval.
      ]. First-in-human study of tisotumab vedotin enrolled 147 patients with advanced solid tumors including 15 patients with NSCLC. The reported ORR regardless of tumor types was 15.6% including 2 out 15 patients with NSCLC (ORR 13.3%). Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2.2 mg/kg dose; therefore, 2.0 mg/kg once every 3 weeks dose was recommended for phase II. There were 9 deaths across all study phases with only one case of pneumonia that was considered possibly related to study treatment [
      • de Bono J.S.
      • et al.
      Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1–2 trial.
      ]. Phase II trial in refractory solid tumors including NSCLC is currently ongoing (Table 2).

      AXL

      AXL is a transmembrane receptor tyrosine kinase and a member of TAM family [
      • Zhu C.
      • Wei Y.
      • Wei X.
      AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications.
      ]. AXL overexpression is associated with multiple malignancies including breast, NSCLC, and pancreatic cancers, and it appear to be associated with resistance to EGFR-targeted therapy [
      • Zhang Z.
      • et al.
      Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer.
      ]. AXL appears to be a promising target for ADC (Table 1).

      Enapotamab vedotin (EnaV)

      EnaV is a novel ADC that consists of anti-AXL monoclonal antibody AXL-107 conjugated to microtubule disrupting agent monomethyl auristatin E via a protease cleavable linker with a DAR of 4 [
      • Reuss J.E.
      • Gosa L.
      • Liu S.V.
      Antibody drug conjugates in lung cancer: state of the current therapeutic landscape and future developments.
      ]. First-in-human study of EnaV enrolled 47 patients with relapsed or refractory solid tumors including 8 patients with NSCLC. Three patients had PRs: one with NSCLC and tow with ovarian cancer. The recommended phase II dose was 2.2 mg/kg every 3 weeks [
      • Ameratunga M.
      • et al.
      First-in-human, dose-escalation, phase (ph) I trial to evaluate safety of anti-Axl antibody-drug conjugate (ADC) enapotamab vedotin (EnaV) in solid tumors.
      ]. Subsequent phase IIA expansion of this trial that included 26 patients with advanced treatment refractory NSCLC and showed an ORR of 19% with DCR of 50%. Grade ≥ 3 treatment related AEs occurred in 12 patients and most commonly were gastrointestinal symptoms [
      • Ramalingam S.
      • et al.
      OA02.05 first-in-human phase 1/2 trial of anti-AXL antibody-drug conjugate (ADC) Enapotamab Vedotin (EnaV) in advanced NSCLC.
      ].

      BA3011

      BA3011 is a novel ADC that consists of anti-AXL monoclonal antibody conjugated to monomethyl auristatin E cytotoxic agent via cleavable linker. BA3011 is a conditionally active biologic (CAB) that binds to its target antigen on the cancer cells, not normal tissue, under unique cancer microenvironment [
      • Ahnert J.R.
      • et al.
      A phase 1/2 dose-escalation and expansion study of a conditionally active anti-AXL humanized monoclonal antibody (BA3011) in patients with advanced solid tumors.
      ]. Two studies (NCT03425279, NCT04681131) evaluating BA3011 in NSCLC are ongoing (Table 2).

      Epidermal growth factor receptor (EGFR)

      EGFR, also known as HER1, is a tyrosine kinase receptor encoded by ERBB1 gene that is responsible for promoting cell proliferation via multiple downstream signaling pathways [
      • Sabbah D.A.
      • Hajjo R.
      • Sweidan K.
      Review on epidermal growth factor receptor (EGFR) structure, signaling pathways, interactions, and recent updates of EGFR inhibitors.
      ]. In EGFR-mutant NSCLC, EGFR-targeted therapies have become the frontline treatment [
      • Ramalingam S.S.
      • et al.
      Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.
      ]. All patients with metastatic solid tumors who initially benefited from EGFR targeted therapies eventually developed resistance [
      • Chong C.R.
      • Jänne P.A.
      The quest to overcome resistance to EGFR-targeted therapies in cancer.
      ]. Thus, there is always a need for further development in targeted therapies in the EGFR space. The ADC MRG003 utilizes EGFR as an antigenic target (Table 1).

      MRG003

      MRG003 is a novel ADC that consists of anti-EGFR monoclonal antibody conjugated to microtubule disrupting agent monomethyl auristatin E via a protease cleavable linker [
      • Xu R.-H.
      • et al.
      First-in-human dose-escalation study of anti-EGFR ADC MRG003 in patients with relapsed/refractory solid tumors.
      ]. Preliminary results of the phase I trial of MRG003 in 22 patients with refractory solid tumors showed a maximum tolerated dose of 2.5 mg/kg every 3 weeks. Regarding the EGFR status, 9 out of 22 patients tested positive for EFGR by IHC; among those who received MRG003 at doses ≥ 1.5 mg/kg; one had PR, four had SD with DCR of 100% [
      • Xu R.-H.
      • et al.
      First-in-human dose-escalation study of anti-EGFR ADC MRG003 in patients with relapsed/refractory solid tumors.
      ]. Phase II trial in patients with advanced EGFR-positive, and refractory NSCLC is ongoing (Table 2).

      Sodium dependent phosphate transporter type II (NaPi2b)

      Despite that NaPi2b, encoded by SLC34A2 gene, has unclear role in tumorigenesis, high expression was observed in two-thirds of patients with NSCLC [
      • Zhang Z.
      • et al.
      High expression of SLC34A2 is a favorable prognostic marker in lung adenocarcinoma patients.
      ]. NaPi2b appears to be an attractive target for ADC (Table1).

      XMT-1536 (or upifitamab rilsodotin)

      XMT-1536 is a novel ADC that consists of anti-NaPi2b monoclonal antibody linked to auristatin F- hydroxypropylamide cytotoxic drug via cleavable linker with a high DAR of 10 to 15 [
      • Bodyak N.D.
      • et al.
      The dolaflexin-based antibody-drug conjugate XMT-1536 targets the solid tumor lineage antigen SLC34A2/NaPi2b.
      ]. The cytotoxic drug auristatin F hydroxypropylamide was found to have bystander killing effect due to its high cellular permeability [
      • Bodyak N.D.
      • et al.
      The dolaflexin-based antibody-drug conjugate XMT-1536 targets the solid tumor lineage antigen SLC34A2/NaPi2b.
      ]. Preliminary results of phase I/II trial of XMT-1536 in previously treated ovarian cancer and NSCLC showed CR and PR in 2 and 5 patients among 20 evaluable patients with ovarian cancer, respectively (ORR 35%). In NSCLC, only 4 out of 7 patients were evaluable, limiting interpretation of efficacy in the group [
      • Richardson D.L.
      • et al.
      Phase I expansion study of XMT-1536, a novel NaPi2b-targeting antibody-drug conjugate (ADC): Preliminary efficacy, safety, and biomarker results in patients with previously treated metastatic ovarian cancer (OC) or non-small cell lung cancer (NSCLC).
      ]. Currently, this study is ongoing (Table 2).

      XMT-1592

      XMT-1592 is novel ADC that consists of anti-NaPi2b monoclonal antibody conjugated with anti-mitotic agent monomethyl auristatin-F via dolasynthen to yield a DAR of 6 [

      Fessler S, et al, XMT-1592, a site-specific Dolasynthen-based NaPi2b-targeted antibody-drug conjugate for the treatment of ovarian cancer and lung adenocarcinoma. AACR; 2020.

      ]. Currently, a first-in-human study of XMT-1592 in patients with NaPi2b-expressing ovarian cancer and NSCLC is ongoing (Table2).

      Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)

      CEACAM5 is a cell surface glycoprotein that is highly expressed in several types of epithelial tumors including carcinomas of gastrointestinal tract, genitourinary and respiratory systems [
      • Hammarström S.
      The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues.
      ]. CEACAM5 higher tumor expression relative to normal tissue makes it an attractive antigenic target for ADCs development (Table1).

      SAR408701 (tusamitamab ravtansine)

      SAR408701 is a novel ADC that couples anti-CEACAM5 monoclonal antibody to the microtubule destabilizing agent maytansinoid DM4 [
      • Decary S.
      • et al.
      Preclinical Activity of SAR408701: a novel anti-CEACAM5–maytansinoid antibody–drug conjugate for the treatment of CEACAM5-positive epithelial tumors.
      ]. First-in-human study of SAR408701 in CEACAM5-expression non-squamous NSCLC in 92 patients (28 moderate IHC expression and 64 high) showed ORR of 7.1% and 20.3% in moderate and high expressors respectively. Grade ≥ 3 treatment emergent AEs occurred in 47.8% of patients and were assessed as drug-related in 15.2% [
      • Gazzah A.
      • et al.
      Efficacy and safety of the antibody-drug conjugate (ADC) SAR408701 in patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5).
      ]. Phase III trial (NCT02187848) on SAR408701 in NSCLC is underway (Table 2).

      Receptor tyrosine kinase-like orphan receptor type 2 (ROR2)

      ROR2 is a transmembrane protein receptor that belongs to tyrosine kinase-like orphan receptor family that lacks kinase activity but interacts with the non-canonical Wnt pathway [
      • Debebe Z.
      • Rathmell W.K.
      Ror2 as a therapeutic target in cancer.
      ]. ROR2 is highly expressed in different types of malignancies including NSCLC. BA3021 is an ADC that utilizes ROR2 as a target antigen (Table 1).

      BA3021

      BA3021 is a novel CAB ADC that consists of anti-ROR2 monoclonal antibody conjugated to monomethyl auristatin E via linker. Two studies (NCT03504488, NCT04681131) evaluating BA3021 in NSCLC are currently recruiting (Table 2).

      Ongoing clinical trials on ADCs in NSCLC

      Major ongoing clinical trials on ADCs in advanced or metastatic NSCLC are summarized in Table 2.

      Conclusion

      ADCs are an innovative class of anticancer drugs that combine the strengths of targeted therapy to cytotoxic chemotherapy. Promising results have been demonstrated over the last few decades in both preclinical and clinical trials that have led to the FDA approval of eleven ADCs. Most of the currently approved ADCs are for the treatment of hematologic malignancies and breast cancer, and none has been approved for the treatment of NSCLC. The HER2 ADC trastuzumab deruxtecan is the furthest along but other ADCs targeting HER3 and MET will be more valuable as we start to encounter patients with NSCLC harboring EGFR mutations who have developed resistance to 3rd generation tyrosine kinase inhibitors. ADCs targeting TROP2 holds a particular advantage as TROP2 is known to be expressed in both squamous and nonsquamous NSCLC. With the rapid pace of drug development in NSCLC, we may soon encounter a time when ADCs become part of the standard of care for NSCLC. Thus, we must be prepared for the unique characteristics of this group of therapeutics.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgement

      Figures were created by BioRender.com

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