抽象 重试 错误原因 重试 错误原因
抗体-药物偶联物 （ADC） 是发展最快的肿瘤疗法之一，它结合了偶联有效载荷的细胞毒作用与靶向特定癌细胞膜抗原的单克隆抗体的高特异性和选择性。ADC 开发的主要靶点是肺癌细胞通常表达的抗原，但不在正常组织中表达。它们包括人表皮生长因子受体 2、人表皮生长因子受体 3、滋养层细胞表面抗原 2、c-MET、癌胚抗原相关细胞粘附分子 5 和 B7-H3，每个都有一个或多个特异性 ADC，在肺癌领域显示出令人鼓舞的结果，在非小细胞肺癌中比在小细胞肺癌组织学中更多。迄今为止，多种 ADC 正在单独或与不同分子（例如，化疗药物或免疫检查点抑制剂）联合评估中，选择可能从治疗中受益的患者的最佳策略正在不断发展，包括提高对生物标志物的理解，除了抗体靶点外，还涉及耐药或对有效载荷的反应标志物。在这篇综述中，我们讨论了 ADCs 治疗肺癌的现有证据和未来前景，包括对基于结构的药物设计、作用机制和耐药概念的全面讨论。数据按特异性靶抗原、生物学、疗效和安全性进行总结，根据 ADC 有效载荷及其药代动力学和药效学特性，ADC 不同。 重试 错误原因 重试 错误原因
介绍
抗体-药物偶联物 （ADC） 是由单克隆抗体 （mAb） 组成的新型治疗剂，单克隆抗体 （mAb） 通过接头携带细胞毒性药物 （有效载荷）。这类不断增长的抗癌药物已被开发出来，通过选择性递送到表达 mAb 靶抗原的肿瘤细胞来改善常规化疗的治疗窗口，从而限制潜在的脱靶全身毒性。1,2目前，评估的 ADC 携带高效的细胞毒性有效载荷，由于全身毒性高和治疗指数低，不适合全身使用。因此，有效载荷的短半衰期是理想的，以防止潜在的脱靶毒性。接头必须在血浆中高度稳定，以防止有效载荷在血液中循环时以非特异性方式释放，3,4 同时它们必须在肿瘤部位能够有效释放有效载荷。对于每种 ADC，药物抗体比 （DAR） 对应于与每种 mAb 相关的有效载荷部分的中位数（在当前批准的 ADC 中范围为 2 到 8），预计将反映药物效力和更高的细胞毒性5（表 1）。然而，尽管具有较高 DAR 的 ADC 具有更强的体外活性，但体内模型显示肝血浆清除速度更快，6,7 可能与化合物的整体大小使它们更容易被肝脏清除有关。7 因此，肝脏清除率增加可能导致肿瘤对药物的暴露量降低，并可能降低治疗指数。
Context
Key Objective
Antibody-drug conjugates (ADCs) represent a novel treatment strategy in clinical development in lung cancer. The purpose of this review is to provide the most updated evidence and scenarios of future perspectives on the use of ADCs in lung cancer treatment.
Knowledge Generated
ADCs targeting human epidermal growth factor receptor 2, human epidermal growth factor receptor 3, trophoblast cell surface antigen 2, c-MET, carcinoembryonic antigen–related cell adhesion molecule 5 (CEACAM5), and B7H3 are in late clinical development, and other targets are evaluated in early clinical trials. Biomarker selection, optimization of ADC structure, and combinatorial treatments represent key strategies to implement future development of this class drug in lung cancer.
Relevance (T.E. Stinchcombe)
Clinical trials of ADCs for non–small-cell lung cancer and small-cell lung cancer are ongoing, and many of these agents may become available in the near future.*
*Relevance section written by JCO Associate Editor Thomas E. Stinchcombe, MD.
Mechanism of Action of ADCs
The first requirement for ADC activity is adequate tumor penetration. Indeed, ADCs are able to reach target cancer cells via passive diffusion after extravasation, but mAbs are large molecules (approximately 150 kDa) and may have limited ability to passively diffuse across the tumor vasculature, particularly in tumors with high interstitial pressure.8,9 This mechanism implies that only a small fraction of the administered ADC dose actually binds tumor cells, usually with a pharmacologic peak in drug concentration at tumor sites 1-2 days after dosing in mouse models.10-12
The second crucial step consists of target engagement, namely the ADC binding to the target antigen on the cell surface through the specific mAb.13 This step might also result in a specific antibody-mediated immune activity, by blocking ligand binding, interfering with target protein dimerization, favoring target internalization and degradation, or through Fc-mediated antibody-dependent cellular cytotoxicity (ADCC).14-16 In addition, for some targets that are upstream of oncogenic signaling pathways (eg, human epidermal growth factor receptor 2 [HER2]), the antibody may exploit an intrinsic activity, notably via modulation of downstream signal transduction.17,18 The use of Ab targets that harbor an oncogenic function favors internalization and ubiquitination of target-ADC complex17-19 and results in a lower probability of downregulation of the target expression as a resistance mechanism.
After target engagement, the ADC-antigen complex is internalized via antigen-dependent endocytosis and trafficking along endosomes and/or lysosomes.20,21 The payload release occurs within early endosomes (those formed immediately after the invagination of the plasma membrane and characterized by low pH), for those with acid-cleavable linkers, and in late endosomes (formed from the maturation of early endosomes, characterized by a higher pH) or lysosomes for those with protease-cleavable linkers as well as for noncleavable linkers after proteolytic degradation.4,22 In addition, cleavable linkers can release their payloads extracellularly within the tumor tissue, because of the presence of a redox tumor microenvironment (TME), with low pH and high concentration of proteases.3,23 Together with the payload passive diffusion across the cell membrane after internalization and processing, payload release in the TME is responsible for the so-called bystander effect, a cytotoxic effect exerted on neighboring cells independent of the target antigen expression.24-26 However, not all ADCs exhibit the bystander effect. A higher bystander effect will be supported by a higher DAR and for ADCs with cleavable linkers, while the properties of the TME will regulate the cleavage of the linker and payload release.27 Finally, the tumor cell has to be sensitive to the cytotoxic payload within the ADC.
Leading Targets for ADCs in Lung Cancer
HER2
HER2 is a receptor tyrosine kinase (RTK), considered as a therapeutic target in non–small-cell lung cancer (NSCLC). Indeed, alterations of the corresponding oncogene ERBB2 may result in gene amplification (defined as HER2/CEP7 ratio ≥2, occurring in approximately 2%-5% of cases), gene mutations (2%-4%), or protein overexpression.28 HER2 mutations encompass heterogeneous alterations distributed in the extracellular, tyrosine kinase, or transmembrane domains. The dominant form of all mutations is an exon 20 insertion—and the most common variant is a 12-base-pair encoding YVMA in a frame within the kinase domain. As HER2 has no specific ligand, downstream signaling occurs through the formation of homodimers and heterodimers with HER1 and human epidermal growth factor receptor 3 (HER3).29,30 Since HER2 is less subject to internalization and degradation than other HER family members that demonstrate a higher receptor turnover, it can remain activated for a long time on the cell membrane and represents a theoretically ideal target for ADC development.29
Trastuzumab emtansine (T-DM1) is an ADC conjugating the anti-HER2 mAb trastuzumab with the microtubule inhibitor maytansine derivative emtansine (DM1) through a noncleavable thioether linker (Fig 1; DAR 3.1).31 In a phase II basket trial, 18 patients with HER2-mutant advanced NSCLC—either treatment-naïve or chemotherapy pretreated—received T-DM1 with an overall response rate (ORR) of 44% and median progression-free survival (mPFS) of 5 months. No predictive value of HER2 immunohistochemistry (IHC) expression was observed in this trial.32 Updated results, with additional 31 patients enrolled (HER2-mutant or -amplified), showed an ORR of 51%, with an mPFS of 5 months.19 Another phase II study evaluated T-DM1 specifically in pretreated HER2-overexpressing NSCLC, with limited responses (ORR 20%), confined to the IHC3+ cohort (n = 20).33 After the evidence of epidermal growth factor receptor (EGFR) upregulation in tumor cells upon T-DM1 treatment, a phase II trial (TRAEMOS) was conducted combining T-DM1 and osimertinib in EGFR-mutant patients with HER2 overexpression and/or amplification after progression on osimertinib (n = 27), but was stopped early because of very limited efficacy (ORR 13%, mPFS 2.8 months) demonstrated at the preplanned interim analysis.34
Trastuzumab deruxtecan is another HER2-directed ADC, where the mAb is conjugated through a cleavable linker—with a high DAR of 8—of the exatecan derivative topoisomerase I inhibitor deruxtecan (DXd; Fig 1).35 T-DXd received accelerated approval by the US Food and Drug Administration (FDA) for the treatment of HER2-mutant NSCLC who have received a prior systemic therapy.36,37 The approval was based on the results of the phase II DESTINY-Lung01 trial, which included two cohorts of patients: HER2-overexpressing and HER2-mutant advanced NSCLC. Ninety-one patients in the HER2-mutant cohort received T-DXd 6.4 mg/kg once every 3 weeks, with an ORR of 55%, a disease control rate (DCR) of 92%, an mPFS of 8.2 months (95% CI, 6.0 to 11.9), and a median overall survival (mOS) of 17.8 months.38,39 Responses were observed across different HER2 mutation subtypes, as well as across HER2 expression levels or regardless of the presence of HER2 amplification. One potential reason for efficacy in HER2-mutant NSCLC regardless of expression is the enhanced HER2 internalization in the presence of a mutation.19 Grade ≥3 drug-related adverse events occurred in 46% of patients, the most common being neutropenia and anemia. Of note, drug-related interstitial lung disease (ILD) occurred in 26% of patients.38 The phase II DESTINY-Lung02 trial randomly assigned patients with HER2-mutant NSCLC to receive T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. The results were consistent between the two cohorts, with a more favorable safety profile with 5.4 compared to 6.4 mg/kg (drug-related ILD in 5.9% and 14.0%, respectively).40 Clinical trials are ongoing to evaluate the use of 5.4 mg/kg of T-DXd in the frontline setting (DESTINY-Lung04), as well as in combination with PD-L1 inhibitors (Table 2).
HER3
HER3 is another member of the RTKs HER family, commonly expressed (in up to 83%) in NSCLC.29,41 The EGFR:HER3 heterodimerization has been reported as a mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) by potentiating ERBB3-dependent activation of oncogenic signaling.42
Patritumab deruxtecan is an HER3-targeted ADC, composed of a fully human anti-HER3 IgG1 mAb conjugated with the exatecan derivative DXd through a cleavable tetrapeptide-based linker (Fig 1; DAR 8).43 In the phase I dose expansion study HERTHENA-Lung01, 57 patients with EGFR-mutant adenocarcinoma progressing on previous EGFR TKIs and one or more prior platinum-based chemotherapy regimens in cohort 1 received patritumab deruxtecan 5.6 mg/kg once every 3 weeks.41 Confirmed ORR was 39%, and responses were observed across resistance mechanisms. HER3 membrane expression was observed in all patients, and ORR was observed across a wide range of baseline tumor HER3 membrane H-scores. DCR was 72% and mPFS was 8.2 months (95% CI, 4.4 to 8.3). Grade ≥3 treatment-related were observed in 54% of patients. Treatment-related ILDs occurred in 7% of patients treated at the recommended dose for expansion.41
In the dose expansion cohort 2, 47 patients with pretreated unselected NSCLC (without EGFR activating mutations) were included. ORR was 28% and mPFS was 5.4 months (95% CI, 3.9 to 12.7).44 Patritumab-DXd has received breakthrough designation from the FDA.
Trophoblast Cell Surface Antigen 2
Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein of the epithelial cell adhesion molecule (EpCAM) family, frequently expressed in many tumors but sporadically in normal tissue.45
Datopotamab deruxtecan (Dapo-DXd) is an ADC composed of an anti-TROP2 mAb and the DXd payload with a tetrapeptide-based cleavable linker (Fig 1; DAR 4).46 The first-in-human TROPION-PanTumor01 study included 175 patients with previously treated NSCLC, unselected for TROP2 expression, in the dose expansion cohort to receive Dato-DXd at the dose of 4, 6, or 8 mg/kg once every 3 weeks. ORR was 23%, 21%, and 25%, and mPFS was 4.3, 8.2, and 5.4 months, respectively.47-49 Of note, activity was observed in the subset analysis of patients with actionable genomic alterations (AGA, n = 34, 85% with EGFR mutations), showing an ORR of 35% and a medium duration of response (mDOR) 9.5 months.50 TEAEs in the overall study population were mainly dose-dependent, with ILD emerging in 15% of patients at 8 mg/kg dose compared with 2% at 4 mg/kg. In actionable genomic alteration population, drug-related grade ≥3 TEAEs were observed in 38% of patients, and only one case of adjudicated ILD (grade 5) occurred in a patient who received Dato-DXd 8 mg/kg.49
The 6 mg/kg dose was then selected for the ongoing registrational phase III randomized trial TROPION-Lung01, evaluating Dato-DXd versus docetaxel in previously treated NSCLC with or without genomic alterations.51 Combinatorial phase Ib studies are ongoing to evaluate safety and efficacy of Dato-DXd with PD-L1 inhibitors.52 Initial results from the TROPION-Lung02, evaluating the combination of Dato-DXd with pembrolizumab alone (doublet) or with platinum chemotherapy (triplet), have been presented.53 Notably, the combinatorial arm was designed with only carboplatin or cisplatin, assuming the ADC as replacement of the platinum-doublet compound. Overall, safety results were manageable, with stomatitis and nausea being the most frequent TEAEs, mostly grade 1-2. In the first-line setting, ORRs were 62% and 35% in the doublet and triplet cohort, respectively.53 Of note, patients in the trials with Dato-DXd are not selected by TROP2 expression on tumor tissue, although further retrospective evaluations are planned to evaluate whether expression correlates with clinical efficacy.
Sacituzumab govitecan is another TROP2 targeted ADC, composed of an anti-TROP2 mAb, the topoisomerase I inhibitor, irinotecan active metabolite camptothecin derivative, SN-38, and a cleavable linker (Fig 1; DAR 7.6).54
I/II 期 IMMU-132-01 试验共包括 495 名难治性转移性癌症患者，他们在第 1 天和第 8 天接受剂量为 8、10 或 12 mg/kg 的 sacituzumab govitecan，周期为 3 周。在 54 例 NSCLC 患者中，ORR 为 16.7%，mPFS 为 4.4 个月，mOS 为 7.3 个月。55,56 元值得注意的是，本研究中超过 90% 的可评估肿瘤标本具有高 TROP2 IHC 表达。Sacituzumab govitecan 目前正在评估与多西他赛的比较，用于预处理的 NSCLC 的 III 期试验，以及包括免疫检查点抑制剂和 PARP 抑制剂（ClinicalTrials.gov 标识符：NCT04826341）的组合方法。在同一项 IMMU-132-01 研究中，小细胞肺癌患者 （SCLC;n = 62） 的 ORR 为 17.7%，mPFS 为 3.7 个月，mOS 为 7.1 个月。56,57 元
遇到
在肝细胞生长因子结合时激活的跨膜 RTK c-MET 在几种癌症类型中失调。在 NSCLC 中，在 30%-50% 的病例中观察到 MET 过表达，而 MET 扩增 （1.5%） 或 MET 外显子 14 跳跃突变 （3%） 被确定为主要驱动改变——这些分子特征未被发现相关。58-60 元此外，MET 扩增可作为 EGFR 突变型 NSCLC 的耐药机制发生，对 EGFR TKI 耐药。在现有文献中，采用了 MET 扩增的可变分子定义，影响了试验之间的一致性和可比性。61 重试 错误原因 重试 错误原因
Telisotuzumab vedotin （Teliso-V） 是一种 ADC，由靶向 c-MET 的人源化 ABT-700 mAb 组成，通过可切割的缬氨酸-瓜氨酸接头与微管抑制剂单甲基澳瑞他汀 E （MMAE） 相连（图 1;DAR 3.1）。62 重试 错误原因 重试 错误原因
Teliso-V 以 2.4-3 mg/kg 每 3 周一次进行的首次人体试验包括 16 名 NSCLC 和 MET 过表达患者。ORR 为 19%，mPFS 为 5.7 个月，17% 的患者出现 ≥3 级 TEAE。63 在 II 期试验 Lung-MAP 子研究 S1400K 中，包括 23 名 MET 阳性鳞状 NSCLC 患者，以 2.7 mg/kg 的推荐剂量每 3 周一次接受治疗，ORR 为 9%。64 重试 错误原因 重试 错误原因
在一项 Ib 期研究中，Teliso-V 与厄洛替尼联合治疗 c-MET 阳性 NSCLC 患者进行了评估。65 在 EGFR 突变 （del19 或 L858R） 阳性且对 EGFR TKI 耐药的患者群体 （n = 28） 中，ORR 为 32.1%，DCR 为 85.7%，mPFS 为 5.9 个月。在那些 c-MET 表达高的 EGFR 突变阳性患者 （n = 15） 中，ORR 为 52.6%。与既往接受奥希替尼治疗的患者相比，既往未接受过第三代 EGFR TKI 治疗的患者的 ORR （39%） 和 DCR （100%） 更高 （ORR 27% 和 DCR 73.3%）。相反，EGFR WT 患者的 ORR 为 40%，DCR 为 80% （n = 5）。65 重试 错误原因 重试 错误原因
进行 Luminosity 试验以评估 Teliso-V 治疗的 c-MET 潜在预测生物标志物。在非鳞状 EGFR WT 亚组中，c-MET 高的 ORR 为 53.8%，c-MET 中间体的 ORR 为 25% （c-Met 过表达高：≥50% 的肿瘤细胞在 3+ 强度下;中间：25%-49%）。该队列目前正在扩展到第 2 阶段注册。66,67 元在非鳞状 EGFR 突变型 （ORR 13.3%） 和鳞状细胞型 （ORR 14.3%） 队列中，结果不太一致。 重试 错误原因 重试 错误原因
Teliso-V 和奥希替尼的组合已在 25 例对奥希替尼产生耐药且 c-Met 过表达高/中度的 EGFR 突变肿瘤 NSCLC 患者中进行了评估，ORR 为 58%，≥3 级 AE 为 20%。68
肺癌 ADC 开发的其他靶点
Focus on ADC Toxicities
The use of ADCs in the treatment of lung cancer has been challenged by their potential to cause toxicities. Although modern ADCs have improved safety profiles, they can still cause debilitating and potentially fatal adverse events, such as pulmonary, hepatic, neurologic, and ophthalmic events. These toxicities are mainly due to off-target effects resulting from the premature release of the ADC payload in circulation or TME (payload-related) or the binding of the ADC to noncancerous cells expressing the target antigen (target-related).69,70
Hence, the toxicity profile of ADCs can be influenced by the expression pattern of the target antigen, and toxicities can occur either on target or off target. Meta-analyses have shown that specific payloads, such as MMAE, are associated with anemia, neutropenia, and peripheral neuropathy, while others, such as DM1, are associated with thrombocytopenia and hepatotoxicity, regardless of the target antigen.70 In addition, T-Dxd has been related to high rate of ILD incidence across various types of tumors, while auristatin-based ADCs have been linked to high-grade neurologic and ocular toxicities (MMAF and also DM4).71
Toxicity profiles can also vary among different ADCs, even with similar payloads and linkers. For example, T-Dxd, patritumab-DXd, and Dato-DXd have different toxicity profiles despite having the same payload and linker. In particular, the incidence of ILD/pneumonitis in patients with lung cancer has been reported at variable rates across ADC clinical trials.72 The pathogenesis of ADC-related ILD and pneumonitis is not fully understood, but multiple and potentially overlapping mechanisms are proposed73,74: (1) bystander effect: a high affinity of the target antibody (HER2, TROP2, and HER3) for tumor cells might lead to increased exposure of normal lung tissue to the payload (through bystander effect), leading to a higher risk of dose-dependent and direct toxicity; (2) local inflammation: the antibody might bind to cancer cells and normal cells (expressing the target antigen) in the lung, leading to direct damage; (3) ADCC: through cell binding, the ADC can activate immune mediators leading to inflammatory processes and finally development of ILD.73
Since ILD can be a life-threatening adverse event, adequate patient selection, as well as early and accurate diagnosis and treatment, is crucial in the real-world setting. The discontinuation of the ADC may be necessary in symptomatic ILD, and reintroduction may be considered in asymptomatic cases at modulated doses after complete resolution of ILD. Corticosteroids remain the mainstay of ILD treatment, and the dose depends on the severity of the event.75
Strategies to Improve ADC Efficacy
Biomarker Selection
The activity of an ADC should theoretically depend on the effective presence of the target on tumor cell surface. However, treatment strategies using ADCs in lung cancer pursue either biomarker-driven or biomarker-agnostic approaches.
The ADC strategy in HER2- and MET-driven tumors requires the identification of enrichment in target expression on tumor tissue. However, accurate biomarker selection is still an open issue. Teliso-V is being evaluated in MET-overexpressing tumors, independently of MET amplification. However, different IHC levels and cutoffs might affect differential efficacy results across different trials, as well as the reproducibility in future clinical practice.61
Conversely, only the presence of HER2 mutations and not overexpression has been associated with response to anti-HER2 ADCs specifically in NSCLC. This is far different from the results observed in breast cancer, where HER2-low or -negative tumors showed responses to anti-HER2 ADCs currently in development.76 So far, such differential results remain unexplained, but are felt to be due to different tumor biology and notably cancer cell dependency on the specific oncogenic signaling—suggesting that stronger and established drivers might represent better targets.39
A biomarker-agnostic approach is instead applied today for other ADCs that bind to targets characterized by a high expression prevalence (ie, HER3, TROP2, B7H3, and nectin4) in lung cancer cells. To our knowledge, to date, no benefit for target enrichment has been shown for these compounds in exploratory analyses of early clinical trials. Although TROP2 enrichment was predictive of tumor inhibition with Dato-Dxd in in vitro models,46 no significant differences in survival were observed according to TROP2-high, -medium, and -low H-scores (evaluating intensity and percentage of cells staining positive) in clinical trials.77 These findings might suggest lack of selectivity of the TROP2 diagnostic antibodies used, and a refinement of TROP2 quantification could help to overcome this potential assessment bottleneck. Additional factors impairing the validity of current TROP2-related enrichment strategies include the expected dynamicity of receptor turnaround, and heterogeneity of target expression, which cannot be completely assessed with a small tumor biopsy specimen.
On the basis of these considerations, treatment optimization would benefit from extended assessment on tumor biopsies, immediately before treatment selection, which might encompass staining of multiple ADC targets—in a multiplex or sequential fashion—to guide ADC selection and potentially the most appropriate ADC-based strategy (eg, monotherapy, combinations, and sequencing) for each patient.
ADC Structure
There is no definitive hierarchy of key attributes that make a good ADC, as the design and selection of an ADC will depend on various factors, including the type of cancer, the target antigen, and the desired therapeutic effect.
As previously discussed, target selection is a key feature for a good ADC. Indeed, the identification of a well-established target is required to help ensuring that the ADC will effectively bind to and eliminate cancer cells.
Appropriate antibody selection is also a key attribute to consider, not only for the antibody immune-modulating properties of the antibody itself, but also for its pharmacochemical properties when linked to the payload. As the pharmacokinetic of the antibody-payload complex may largely differ with respect to the compounds alone and affect the distribution, selectivity, and bioavailability, different antibodies and payloads are tested to identify the optimal combination for a specific target.
Antibody-drug conjugation is another aspect to consider. Indeed, in nonspecific, conventional conjugation, cytotoxin binding to lysines or cysteines, which are abundant in antibody structure, can result in more off-target side effects. By contrast, site-specific conjugation is built on engineered specific sites, therefore increasing the therapeutic index.
Linker properties are another point to evaluate to build a good ADC. The presence of a stable linker is required to ensure that the payload is only released in the target cells and not in normal cells, and a specific cleavage of the linker is important to ensure that the payload is effectively released and can exert its therapeutic effect in the TME.16
The choice of cleavage mechanism will affect activity and safety profile of ADC. The cleavage of the linker can affect the pharmacokinetic of the payload by altering the rate and extent of release from the ADC.78 For example, a more efficient cleavage mechanism can result in a more rapid and complete release of the payload, which can increase the therapeutic effect but also increase the risk of toxicity. Cleavage by tumor-enriched enzymes, such as cathepsin B for T-DXd, can help to increase the specificity of the ADC for cancer cells.79
Beyond the efforts to optimize the selection of the most appropriate mAb-cytotoxic payload-linker composition for each ADCs, research is moving toward novel approaches and payload selection. These include the use of bispecific antibodies for enhanced internalization and/or improved tumor specificity,80 the use of small-molecule drug conjugates—instead of the antibody backbone—to increase tumor tissue penetration including CNS,81 or the use of alternative payloads.82 ADCs that contain a microtubule inhibitor as the cytotoxic payload (such as MMAE) have been associated with treatment-related neuropathy.83 As such alternative cytotoxic payloads, including topoisomerase I inhibitors, may be more desirable to avoid such side effect. Another example is the pyrrolobenzodiazepine payload coupled with monoclonal antibody DLL3, which has shown unacceptable toxicity despite its high potency.84 The development of a variety of payloads can provide a range of options for ADCs with different mechanism of action, potency, and toxicity profiles. Moreover, noncytotoxic payloads offer potential advantages over traditional cytotoxic ADCs, including reduced toxicity to healthy cells and increased specificity in targeting cancer cells. Some examples of noncytotoxic payloads in ADCs include
1. Radioisotopes, therefore with ADCs delivering radiation directly to cancer cells85;
2. Enzymes: ADCs carrying enzymes can be used to target and degrade specific proteins in the cancer cells, leading to cell death86;
3. Small molecules, which can be used to inhibit specific targets in the cancer cells, leading to cell death or altering cancer cell behavior87;
4. Peptides: ADCs with peptides as payloads can be used to target and activate immune cells, leading to an immune response against cancer cells.88
However, these strategies are still in early stages of development and require further research and clinical testing.
Finally, DAR optimization is an important aspect of ADC development. A higher DAR typically results in a higher dose of the therapeutic payload delivered to the target cancer cells, leading to increased efficacy. However, it can also result in increased toxicity to normal cells, which can limit the therapeutic window. Therefore, it is important to carefully evaluate the DAR to optimize the balance between efficacy and safety for each ADC. This can be achieved through various methods, such as adjusting the number of drugs attached to each antibody, modifying the linker technology, or selecting a different payload.89
Combination Strategies
The different results obtained with T-DM1 and T-DXd, two ADCs sharing same mAb and epitope recognition, suggest that improved efficacy can be obtained by using different payloads. The sequential use of ADCs targeting the same receptor could possibly overcome payload-related toxicities. As demonstrated in HER2-positive breast cancer, the sequential use of ADCs with the same target but different payload might be a strategy to overcome resistance,37 especially if the resistance is not target-dependent.
Besides sequential approach, the combination of ADCs with different payloads and/or with different coexisting targets could be evaluated as a novel polychemotherapy strategy to improve treatment efficacy, despite requiring particular attention on potential overlapping toxicities.
In addition, combinatorial strategies are under investigation to assess the safety and efficacy of ADCs delivered in association with partner drugs that can modulate the target antigen dynamics (eg, the combination with TKIs directed against the same ADC target to increase internalization, or other pathway regulators to upregulate target expression),19,43 drugs that can modify the TME composition and ADC penetration (eg, antiangiogenetics),90 immunotherapeutic agents for potential synergistic effect in immunologically cold tumors,91 or even systemic cytotoxic agents with alternative mechanism of action.92 Of note, the combination of ADCs with prior TKIs could also be evaluated as a strategy to overcome TKI resistance not mediated by on-target resistance.93
With regards to the combination with ICIs, ADCs work by triggering various processes in cancer and immune cells, including immunogenic cell death, antibody-dependent cell-mediated cytotoxicity, and dendritic cell activation, which can complement immunotherapy.91 The synergistic potential of an ADC with ICIs can depend on factors such as the antibody used (IgG1 mediating higher ADCC than other IgG subtypes), the target antigen, the linker, and the payload (and subsequent tumor cell killing through bystander effect).94 In a future perspective, ADC results in the advanced setting are proof of concept for transferring drug evaluation in the early disease. As such, clinical trials are being envisaged in the adjuvant/neoadjuvant setting, where ADCs, alone or in combination with ICIs, are envisaged to replace conventional chemotherapy.
Principles of ADC Resistance
On the basis of the complex and dynamic mechanism of action of ADCs, resistance to ADCs might be attributed to multiple factors, that can also co-occur in vivo (Fig 2).
Primary lack of activity might be attributed to pharmacodynamic properties, primarily related to inadequate tumor penetration of the mAb-payload complex, as well as to the heterogeneity of target expression, especially in those ADCs with noncleavable linkers that have limited bystander effect activity.95
Acquired resistance mechanisms are instead related to the dynamic of the tumor cells and their microenvironment and might be categorized according to the three major steps of ADC functioning: target binding, intracellular trafficking of the mAb-payload complex, and payload activity.96
Indeed, chronic exposure to a target-directed ADC leads to downregulation of the target expression, with subsequently less ADC-binding and internalization in tumor cells.97 The effectiveness of an ADC can depend on whether the target antigen has undergone any mutations that affect the binding site for the antibody (epitope), or if the internalization motif has changed, which can affect the rate at which the ADC is taken up into the cell. If either of these components is altered, the ADC may not bind effectively or internalize efficiently, leading to decreased efficacy.
This aspect might have less impact in ADCs with pH-dependent cleavable linkers, that retain the possibility for the payload to be released in the tumor stroma, according to the hypoxic and acidic conditions of the TME.98
In parallel, decreased endosomal/lysosomal acidification and proteolytic activity can occur, reducing the payload intracellular release.99 In addition, upregulation of drug efflux pumps has been observed, in particular for those payloads that are ABC transporter substrates, with subsequent payload ejection.100
In conclusion, the use of ADCs for lung cancer treatment has demonstrated encouraging results. Several target antigens (HER2, HER3, TROP2, c-MET, CEACAM5, and B7-H3) have been evaluated with their specific ADCs, and some of these agents (eg, anti-HER2) are already available in clinical practice. Promising results have been obtained not only in NSCLC, but also in SCLC. Other target antigens of interest are under investigation with novel ADCs currently in early-phase clinical trials.
Appropriate patient selection and drug development approaches will help improve toxicity profiles, as well as strategies to overcome acquired ADC resistance.
Authors' Disclosures of Potential Conflicts of Interest
Antibody-Drug Conjugates in Lung Cancer: Recent Advances and Implementing Strategies
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
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Antonio Passaro
Consulting or Advisory Role: Roche/Genentech, Bristol Myers Squibb, AstraZeneca, MSD Oncology, Pfizer, Boehringer Ingelheim, Johnson & Johnson/Janssen, Novartis, Daiichi Sankyo Europe GmbH, Bayer
Speakers' Bureau: AstraZeneca, Johnson & Johnson/Janssen, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, MSD Oncology
Pasi A. Jänne
Stock and Other Ownership Interests: Gatekeeper Pharmaceuticals, Loxo
Consulting or Advisory Role: Pfizer, Boehringer Ingelheim, AstraZeneca, Merrimack, Chugai Pharma, Roche/Genentech, LOXO, Mirati Therapeutics, Araxes Pharma, Ignyta, Lilly, Takeda, Novartis, Biocartis, Voronoi Health Analytics, SFJ Pharmaceuticals Group, Sanofi, Biocartis, Daiichi Sankyo, Silicon Therapeutics, Nuvalent, Inc, Eisai, Bayer, Syndax, AbbVie, Allorion Therapeutics, Accutar Biotech, Transcenta, Monte Rosa Therapeutics, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotech, Duality Biologics
Research Funding: AstraZeneca, Astellas Pharma, Daiichi Sankyo, Lilly, Boehringer Ingelheim, Puma Biotechnology, Takeda, Revolution Medicines
Patents, Royalties, Other Intellectual Property: I am a co-inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp I receive post-marketing royalties from this invention
Solange Peters
Honoraria: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), MSD (Inst), AstraZeneca (Inst), Takeda (Inst), Illumina (Inst), medscape (Inst), Prime Oncology (Inst), RMEI Medical Education (Inst), Research to Practice (Inst), PER (Inst), Imedex (Inst), Ecancer (Inst), Ecancer (Inst), OncologyEducation (Inst), Fishawack Facilitate (Inst), Peerview (Inst), Medtoday (Inst), Mirati Therapeutics (Inst), Sanofi (Inst), Incyte (Inst)
Consulting or Advisory Role: Roche/Genentech (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst), MSD (Inst), Amgen (Inst), AstraZeneca (Inst), Janssen (Inst), Regeneron (Inst), Merck Serono (Inst), Boehringer Ingelheim (Inst), Takeda (Inst), Lilly (Inst), AbbVie (Inst), Bayer (Inst), Biocartis (Inst), Debiopharm Group (Inst), Illumina (Inst), PharmaMar (Inst), Sanofi (Inst), Seagen (Inst), Blueprint Medicines (Inst), Daiichi Sankyo (Inst), Incyte (Inst), Bioinvent (Inst), Clovis Oncology (Inst), Vaccibody (Inst), Phosplatin Therapeutics (Inst), Foundation Medicine (Inst), Arcus Biosciences (Inst), F-Star Biotechnology (Inst), Genzyme (Inst), Gilead Sciences (Inst), GlaxoSmithKline (Inst), Vaccibody (Inst), ITeos Therapeutics (Inst)
Research Funding: roche (Inst), BMS (Inst), MSD (Inst), Amgen (Inst), Lilly (Inst), AstraZeneca (Inst), Pfizer (Inst), Illumina (Inst), Merck Serono (Inst), Novartis (Inst), Biodesix (Inst), Boehringer Ingelheim (Inst), Boehringer Ingelheim (Inst), Boehringer Ingelheim (Inst), Iovance Biotherapeutics (Inst), Phosplatin Therapeutics (Inst)
Travel, Accommodations, Expenses: Roche, Bristol Myers Squibb, MSD, Sanofi, Incyte
Uncompensated Relationships: Annals of Oncology, ESMO, ETOP Scientific chair, JTO Past Deputy Editor, SAMO President
No other potential conflicts of interest were reported.
Appendix 1. Other Potential Targets for Antibody-Drug Conjugates in Lung Cancer
Carcinoembryonic Antigen–Related Cell Adhesion Molecule 5
The cell surface glycoprotein carcinoembryonic antigen–related cell adhesion molecule 5 (CEACAM5) is highly expressed across several cancer types compared with normal tissues.101 In nonsquamous non–small-cell lung cancer (NSCLC), about 20% of tumors have high CEACAM5 expression as defined by IHC (≥50%).102
SAR408701 (tusamitamab ravtansine) consists of a humanized monoclonal antibody (mAb) targeting CEACAM5 and a maytansinoid DM4 payload attached through a cleavable SPDB linker (Fig 1; drug-to-antibody ratio 3.8). In the first-in-human study, 92 patients with NSCLC were included. Overall response rate (ORR) was 20.3% and 7.1% in patients with high (n = 64) and moderate (n = 28) expression, with grade ≥3 TEAEs occurring in 47.8% of patients (15.2% drug-related).103 Reversible microcystic keratopathy, identified as dose-limiting toxicity, occurred in 25.8% of patients, and more in general corneal adverse events occurred in 29% of cases, including keratopathy, keratitis, and punctate keratitis.103 The randomized phase III trial versus docetaxel in previously treated nonsquamous NSCLC with high CEACAM5 expression is currently ongoing.104
B7-H3 (Cd276)
The transmembrane glycoprotein B7-H3 was found overexpressed in many cancer types, with limited expression on normal tissues, and was therefore considered as a potential antibody-drug conjugate (ADC) target.105
DS-7300a is an ADC composed by a humanized B7-H3 IgG1 mAb and the topoisomerase I inhibitor payload DXd with a tetrapeptide-based cleavable linker (Fig 1).106 The phase I/II first-in-human study enrolled 147 patients with tumors unselected for B7-H3 expression at doses of 4.8 mg/kg to 16.0 mg/kg once every 3 weeks (81 patients in dose escalation, 66 in 12.0 mg/kg dose expansion).107 In the overall population, with a median of five prior treatment lines, ORR was 32% and DCR was 71.4%. More patients in the highest-dose cohort had grade ≥3 TEAEs. The most common grade ≥3 TEAEs were anemia (19%) and neutropenia (4%). Among 19 patients with small-cell lung cancer (SCLC) evaluable, ORR 58% was observed, with an mDOR of 5.5 months; in patients with squamous NSCLC (n = 5 evaluable), ORR was 40%.108
MGC018 is an ADC composed by a humanized B7-H3 IgG1 mAb and duocarmycin-based DNA-alkylating payload with a valine-citrulline protease cleavable linker (Fig 1).109 Preliminary results of phase I cohort expansion in solid tumors were presented. 48 patients (55.8%) had grade ≥3 TEAEs. In the NSCLC cohort, 13 of 16 patients had reductions in target lesion sums, with four unconfirmed partial responses.110
Specific ADC targets in SCLC
DLL3 and CD56
Notch ligand DLL3 is highly expressed in 80% SCLCs and therefore has represented a potential target to increase therapeutic options in this poor prognosis disease.111
Rovalpituzumab tesirine (Rova-T) is a DLL-3 targeting ADC composed of an anti-DLL3 mAb, pyrrolobenzodiazepine (PBD), and a protease-cleavable linker. The results from the phase II trial were encouraging, with an ORR of 38% in patients with high DLL-3 expression.84 Grade 3 or higher TEAEs occurred in 64% of patients; the most frequent were hematologic toxicity, and pleural and pericardial effusion.84 Unfortunately, the phase III randomized comparing Rova-T with topotecan in second-line setting of SCLC-ED with high DLL3 expression was negative.112 Rova-T efficacy results were also negative in the maintenance setting of SCLC-ED,113 whereas activity was observed in combination with ICIs but with high toxicity likely because of nonspecific cleavage of the linker leading to systemic exposure of the chemotherapy payload.114
Novel compounds beyond ADCs, including bispecific T-cell engager or adoptive cellular therapy, are being developed to target DLL-3.115,116
CD56 is a cell surface protein also known as neural cell adhesion molecule, expressed in 70%-80% of SCLC.117 Lorvotuzumab mertamsine, a CD56-directed ADC with DM1, was evaluated in phase I/II trial in combination with first-line carboplatin-etoposide in SCLC-ED. In this study, no difference was observed in median progression-free survival compared with chemotherapy alone, and 19% grade 5 events occurred.118
Others
Several other transmembrane proteins or membrane receptors have been identified as potential targets for development of ADCs that are currently in early-phase clinical trials in lung cancer (Table 2).
AXL, a transmembrane RTK member of TAM family, is commonly expressed in multiple tumors, and is commonly associated with resistance to EGFR-TKIs.119 Enapotamab vedotin is an ADC composed of anti-AXL mAb AXL-107, monomethyl auristatin E (MMAE), and a protease cleavable linker.120 Of note, ORR was 19% and DCR 50% in 26 patients with pretreated NSCLC included in a phase II expansion trial.121 Grade≥ 3 TRAEs occurred in 12 of 26 patients. BA3011 (CAB-AXL-ADC), also in early-phase clinical trials, is composed of an anti-AXL mAb with MMAE through cleavable linker, with the specific of being a conditionally active biologic, binding to the target only on cancer cells under unique cancer microenvironment, and not on normal tissues, on the basis of the glycolytic tumor metabolism (including Warburg effect leading to extracellular pH and oxygen concentration decrease as moving away from the vasculature into the tumor space).122
PTK7 is an RTK, frequently upregulated in many cancers, including NSCLC.123 Cofetuzumab pelidotin, a PTK7-targeted ADC, showed an ORR of 19% in preliminary data on 31 patients with NSCLC and moderate-high PTK IHC expression, with grade ≥3 neutropenia occurring in 25% of patients.124
PVRL4 (Nectin4) is an Ig-like transmembrane adhesion molecule, overexpressed in up to 60% of NSCLC, and the ADC enfortumab vedotin is currently under evaluation.125
Tissue factor (TF) is a transmembrane glycoprotein responsible for the coagulation cascade, which is widely expressed in many cancers.126 Tisotumab vedotin, an ADC composed of anti-TF mAb TF-011 and MMAE with cleavable linker, showed an ORR of 13.3% in 15 patients with NSCLC enrolled in the first-in-human study of 147 patients, with phase II trial ongoing.127
Mesothelin (MSLN) is a membrane glycoprotein, commonly overexpressed in tumors, including malignant mesothelioma and lung cancer128. Anetumab ravtansine is an ADC composed of the anti-MSLN MF-T and DM4 with disulfide cleavable linker.129 Of note, an ORR of 31% was observed in patients with mesothelioma enrolled in the first-in-human trial involving 148 patients with metastatic solid tumors.130 A phase II randomized trial failed to demonstrate a higher activity for anetumab ravtansine over vinorelbine in pretreated patients with malignant pleural mesothelioma.131
EGFR is a very well-known therapeutic target in NSCLC.132 The MRG003 ADC consists of an anti-EGFR mAb conjugated to MMAE via a cleavable linker, and is under evaluation in a phase II trial in patients with pretreated EGFR-mutant NSCLC (ClinicalTrials.gov identifier: NCT04838548).133
ROR2, a transmembrane receptor interacting with the noncanonical Wnt pathway, is also frequently expressed in several tumors including NSCLC,135 and trials are currently ongoing to evaluate ROR2-targeted ADC (BA3021).
References
1.
Tolcher AW: Antibody drug conjugates: Lessons from 20 years of clinical experience. Ann Oncol 27:2168-2172, 2016
2.
Tarantino P, Carmagnani Pestana R, Corti C, et al: Antibody-drug conjugates: Smart chemotherapy delivery across tumor histologies. CA Cancer J Clin 72:165-182, 2022
3.
Tsuchikama K, An Z: Antibody-drug conjugates: Recent advances in conjugation and linker chemistries. Protein Cell 9:33-46, 2018
4.
Jain N, Smith SW, Ghone S, et al: Current ADC linker chemistry. Pharm Res 32:3526-3540, 2015
5.
Beck A, Goetsch L, Dumontet C, et al: Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov 16:315-337, 2017
6.
Hamblett KJ, Senter PD, Chace DF, et al: Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res 10:7063-7070, 2004
7.
Sun X, Ponte JF, Yoder NC, et al: Effects of drug-antibody ratio on pharmacokinetics, biodistribution, efficacy, and tolerability of antibody-maytansinoid conjugates. Bioconjug Chem 28:1371-1381, 2017
8.
Minchinton AI, Tannock IF: Drug penetration in solid tumours. Nat Rev Cancer 6:583-592, 2006
9.
Matsumura Y: Cancer stromal targeting therapy to overcome the pitfall of EPR effect. Adv Drug Deliv Rev 154-155:142-150, 2020
10.
Lu G, Nishio N, van den Berg NS, et al: Co-administered antibody improves penetration of antibody-dye conjugate into human cancers with implications for antibody-drug conjugates. Nat Commun 11:5667, 2020
11.
Alley SC, Zhang X, Okeley NM, et al: The pharmacologic basis for antibody-auristatin conjugate activity. J Pharmacol Exp Ther 330:932-938, 2009
12.
Thurber GM, Dane Wittrup K: A mechanistic compartmental model for total antibody uptake in tumors. J Theor Biol 314:57-68, 2012
13.
Acchione M, Kwon H, Jochheim CM, et al: Impact of linker and conjugation chemistry on antigen binding, Fc receptor binding and thermal stability of model antibody-drug conjugates. MAbs 4:362-372, 2012
14.
Redman JM, Hill EM, AlDeghaither D, et al: Mechanisms of action of therapeutic antibodies for cancer. Mol Immunol 67:28-45, 2015
15.
Tai YT, Mayes PA, Acharya C, et al: Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood 123:3128-3138, 2014
16.
Drago JZ, Modi S, Chandarlapaty S: Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat Rev Clin Oncol 18:327-344, 2021
17.
Moasser MM: The oncogene HER2: Its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26:6469-6487, 2007
18.
Damelin M, Zhong W, Myers J, et al: Evolving strategies for target selection for antibody-drug conjugates. Pharm Res 32:3494-3507, 2015
19.
Li BT, Michelini F, Misale S, et al: HER2-Mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers. Cancer Discov 10:674-687, 2020
20.
Jedema I, Barge RM, van der Velden VH, et al: Internalization and cell cycle-dependent killing of leukemic cells by gemtuzumab ozogamicin: Rationale for efficacy in CD33-negative malignancies with endocytic capacity. Leukemia 18:316-325, 2004
21.
Sutherland MS, Sanderson RJ, Gordon KA, et al: Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J Biol Chem 281:10540-10547, 2006
22.
Kovtun YV, Goldmacher VS: Cell killing by antibody-drug conjugates. Cancer Lett 255:232-240, 2007
23.
Erickson HK, Lewis Phillips GD, Leipold DD, et al: The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol Cancer Ther 11:1133-1142, 2012
24.
Ogitani Y, Hagihara K, Oitate M, 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. Cancer Sci 107:1039-1046, 2016
25.
Li F, Emmerton KK, Jonas M, et al: Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res 76:2710-2719, 2016
26.
Staudacher AH, Brown MP: Antibody drug conjugates and bystander killing: Is antigen-dependent internalisation required? Br J Cancer 117:1736-1742, 2017
27.
Coats S, Williams M, Kebble B, et al: Antibody-drug conjugates: Future directions in clinical and translational strategies to improve the therapeutic index. Clin Cancer Res 25:5441-5448, 2019
28.
Jebbink M, de Langen AJ, Boelens MC, et al: The force of HER2—A druggable target in NSCLC? Cancer Treat Rev 86:101996, 2020
29.
Del Re M, Cucchiara F, Petrini I, et al: erbB in NSCLC as a molecular target: current evidences and future directions. ESMO Open 5:e000724, 2020
30.
Wang Z: ErbB receptors and cancer. Methods Mol Biol 1652:3-35, 2017
31.
Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012
32.
Li BT, Shen R, Buonocore D, et al: Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: Results from a phase II basket trial. J Clin Oncol 36:2532-2537, 2018
33.
Peters S, Stahel R, Bubendorf L, et al: Trastuzumab emtansine (T-DM1) in patients with previously treated HER2-overexpressing metastatic non-small cell lung cancer: Efficacy, safety, and biomarkers. Clin Cancer Res 25:64-72, 2019
34.
Jebbink M, Langen AD, Monkhorst K, et al: MA02.07 T-DM1 and osimertinib (TRAEMOS) to target HER2 bypass track resistance in EGFRm+ NSCLC: Interim analysis of a phase II trial. J Thorac Oncol 16:S891-S892, 2021
35.
Ogitani Y, Aida T, Hagihara K, 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. Clin Cancer Res 22:5097-5108, 2016
36.
Shitara K, Bang YJ, Iwasa S, et al: Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 382:2419-2430, 2020
37.
Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382:610-621, 2020
38.
Li BT, Smit EF, Goto Y, et al: Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med 386:241-251, 2022
39.
Passaro A, Peters S: Targeting HER2-mutant NSCLC—The light is on. N Engl J Med 386:286-289, 2022
40.
Goto K, Sang-We K, Kubo T, et al: LBA55 Trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutant metastatic non-small cell lung cancer (NSCLC): Interim results from the phase 2 DESTINY-Lung02 trial. Ann Oncol 33:S1422, 2022
41.
Jänne PA, Baik C, Su WC, et al: Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer. Cancer Discov 12:74-89, 2022
42.
Alam SK, Zhang Y, Wang L, et al: DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma. Oncogene 41:83-98, 2022
43.
Yonesaka K, Takegawa N, Watanabe S, et al: An HER3-targeting antibody-drug conjugate incorporating a DNA topoisomerase I inhibitor U3-1402 conquers EGFR tyrosine kinase inhibitor-resistant NSCLC. Oncogene 38:1398-1409, 2019
44.
Steuer CE, Hayashi H, Su W-C, et al: Efficacy and safety of patritumab deruxtecan (HER3-DXd) in advanced/metastatic non-small cell lung cancer (NSCLC) without EGFR-activating mutations. J Clin Oncol 40, 2022 (suppl 16; abstr 9017)
45.
Goldenberg DM, Stein R, Sharkey RM: The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget 9:28989-29006, 2018
46.
Okajima D, Yasuda S, Maejima T, et al: Datopotamab deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Mol Cancer Ther 20:2329-2340, 2021
47.
Spira A, Lisberg A, Sands J, et al: OA03.03 Datopotamab deruxtecan (Dato-DXd; DS-1062), a TROP2 ADC, in patients with advanced NSCLC: Updated results of TROPION-PanTumor01 phase 1 study. J Thorac Oncol 16:S106-S107, 2021
48.
Garon E, Johnson M, Lisberg A, et al: MA03.02 TROPION-PanTumor01: Updated results from the NSCLC cohort of the phase 1 study of datopotamab deruxtecan in solid tumors. J Thorac Oncol 16:S892-S893, 2021
49.
Meric-Bernstam F, Spira AI, Lisberg AE, 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). J Clin Oncol 39, 2021 (suppl 15; abstr 9058)
50.
Garon EB, Johnson ML, Lisberg AE, et al: LBA49 Efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC) and actionable genomic alterations (AGAs): Preliminary results from the phase I TROPION-PanTumor01 study. Ann Oncol 32:S1326-S1327, 2021
51.
Yoh K, Goto Y, Thomas M, et al: A randomized, phase 3 study of datopotamab deruxtecan (Dato-DXd; DS-1062) versus docetaxel in previously treated advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (TROPION-Lung01). J Clin Oncol 39, 2021 (suppl 15; abstr TPS9127)
52.
Levy BP, Reck M, Yang JC-H, et al: Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab in treatment-naive advanced/metastatic (adv/met) non–small cell lung cancer (NSCLC) with PD-L1 ≥ 50% and without actionable genomic alterations. J Clin Oncol 40, 2022 (suppl 15; abstr TPS3162)
53.
Levy B, Paz-Ares L, Rixe O, et al: MA13.07 TROPION-lung02: Initial results for datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy in advanced NSCLC. J Thorac Oncol 17:S91, 2022
54.
Goldenberg DM, Sharkey RM: Sacituzumab govitecan, a novel, third-generation, antibody-drug conjugate (ADC) for cancer therapy. Expert Opin Biol Ther 20:871-885, 2020
55.
Heist RS, Guarino MJ, Masters G, et al: Therapy of advanced non-small-cell lung cancer with an SN-38-anti-Trop-2 drug conjugate, sacituzumab govitecan. J Clin Oncol 35:2790-2797, 2017
56.
Bardia A, Messersmith WA, Kio EA, 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. Ann Oncol 32:746-756, 2021
57.
Gray JE, Heist RS, Starodub AN, et al: Therapy of small cell lung cancer (SCLC) with a topoisomerase-I-inhibiting antibody-drug conjugate (ADC) targeting trop-2, sacituzumab govitecan. Clin Cancer Res 23:5711-5719, 2017
58.
Lee JK, Madison R, Classon A, et al: Characterization of non–small-cell lung cancers with MET exon 14 skipping alterations detected in tissue or liquid: Clinicogenomics and real-world treatment patterns. JCO Precis Oncol 5:1354-1376, 2021
59.
Sabari JK, Leonardi GC, Shu CA, et al: PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers. Ann Oncol 29:2085-2091, 2018
60.
Kron A, Scheffler M, Heydt C, et al: Genetic heterogeneity of MET-aberrant NSCLC and its impact on the outcome of immunotherapy. J Thorac Oncol 16:572-582, 2021
61.
Schmid S, Früh M, Peters S: Targeting MET in EGFR resistance in non-small-cell lung cancer-ready for daily practice? Lancet Oncol 21:320-322, 2020
62.
Wang J, Anderson MG, Oleksijew A, 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. Clin Cancer Res 23:992-1000, 2017
63.
Strickler JH, Weekes CD, Nemunaitis J, 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. J Clin Oncol 36:3298-3306, 2018
64.
Waqar SN, Redman MW, Arnold SM, 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). Clin Lung Cancer 22:170-177, 2021
65.
Camidge DR, Barlesi F, Goldman JW, et al: Phase Ib study of telisotuzumab vedotin in combination with erlotinib in patients with c-Met protein-expressing non-small-cell lung cancer. J Clin Oncol 41:1105-1115, 2023
66.
Camidge DR, Bar J, Horinouchi H, et al: Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met–overexpressing (OE) advanced non-small cell lung cancer (NSCLC). J Clin Oncol 40, 2022 (suppl 16; abstr 9016)
67.
Goldman J, Moiseenko F, Cicin I, et al: P47.03 Telisotuzumab vedotin monotherapy in patients with previously treated c-Met+ advanced non-small cell lung cancer: Stage 2. J Thorac Oncol 16:S1097, 2021
68.
Goldman JW, Horinouchi H, Cho BC, et al: Phase 1/1b study of telisotuzumab vedotin (Teliso-V) + osimertinib (Osi), after failure on prior Osi, in patients with advanced, c-Met overexpressing, EGFR-mutated non-small cell lung cancer (NSCLC). J Clin Oncol 40, 2022 (suppl 16; abstr 9013)
69.
Donaghy H: Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. mAbs 8:659-671, 2016
70.
Masters JC, Nickens DJ, Xuan D, et al: Clinical toxicity of antibody drug conjugates: A meta-analysis of payloads. Investig New Drugs 36:121-135, 2018
71.
Eaton JS, Miller PE, Mannis MJ, et al.: Ocular adverse events associated with antibody–drug conjugates in human clinical trials. J Ocul Pharmacol Ther 31:589-604, 2015
72.
Powell CA, Modi S, Iwata H, et al: Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies☆. ESMO Open 7:100554, 2022
73.
Tarantino P, Modi S, Tolaney SM, et al: Interstitial lung disease induced by anti-ERBB2 antibody-drug conjugates: A review. JAMA Oncol 7:1873-1881, 2021
74.
Abuhelwa Z, Alloghbi A, Alqahtani A, et al: Trastuzumab deruxtecan-induced interstitial lung disease/pneumonitis in ERBB2-positive advanced solid malignancies: A systematic review. Drugs 82:979-987, 2022
75.
Swain SM, Nishino M, Lancaster LH, et al: Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)–related interstitial lung disease/pneumonitis—focus on proactive monitoring, diagnosis, and management. Cancer Treat Rev 106:102378, 2022
76.
Tarantino P, Curigliano G, Tolaney SM: Navigating the HER2-low paradigm in breast oncology: New standards, future horizons. Cancer Discov 12:2026-2030, 2022
77.
Bardia A, Mayer IA, Diamond JR, et al: Efficacy and safety of anti-trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol 2017:2141-2148, 2017
78.
Nolting B: Linker technologies for antibody-drug conjugates. Methods Mol Biol 1045:71-100, 2013
79.
Gikanga B, Adeniji NS, Patapoff TW, et al: Cathepsin B cleavage of vcMMAE-based antibody-drug conjugate is not drug location or monoclonal antibody carrier specific. Bioconjug Chem 27:1040-1049, 2016
80.
de Goeij BE, Vink T, Ten Napel H, et al: Efficient payload delivery by a bispecific antibody-drug conjugate targeting HER2 and CD63. Mol Cancer Ther 15:2688-2697, 2016
81.
Zhuang C, Guan X, Ma H, et al: Small molecule-drug conjugates: A novel strategy for cancer-targeted treatment. Eur J Med Chem 163:883-895, 2019
82.
Dovgan I, Koniev O, Kolodych S, et al: Antibody-oligonucleotide conjugates as therapeutic, imaging, and detection agents. Bioconjug Chem 30:2483-2501, 2019
83.
Best RL, LaPointe NE, Azarenko O, et al: Microtubule and tubulin binding and regulation of microtubule dynamics by the antibody drug conjugate (ADC) payload, monomethyl auristatin E (MMAE): Mechanistic insights into MMAE ADC peripheral neuropathy. Toxicol Appl Pharmacol 421:115534, 2021
84.
Blackhall F, Jao K, Greillier L, et al: Efficacy and safety of rovalpituzumab tesirine compared with topotecan as second-line therapy in DLL3-high SCLC: Results from the phase 3 TAHOE study. J Thorac Oncol 16:1547-1558, 2021
85.
Martiniova L, Zielinski RJ, Lin M, et al: The role of radiolabeled monoclonal antibodies in cancer imaging and ADC treatment. Cancer J 28:446-453, 2022
86.
Mohit E, Rafati S: Chemokine-based immunotherapy: Delivery systems and combination therapies. Immunotherapy 4:807-840, 2012
87.
Tolcher AW, Carneiro BA, Dowlati A, et al: A first-in-human study of mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose escalation results. J Clin Oncol 39, 2021 (suppl 15; abstr 3015)
88.
Alas M, Saghaeidehkordi A, Kaur K: Peptide-drug conjugates with different linkers for cancer therapy. J Med Chem 64:216-232, 2021
89.
Yurkovetskiy AV, Bodyak ND, Yin M, et al: Dolaflexin: A novel antibody-drug conjugate platform featuring high drug loading and a controlled bystander effect. Mol Cancer Ther 20:885-895, 2021
90.
O'Malley DM, Matulonis UA, Birrer MJ, et al: Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol 157:379-385, 2020
91.
Nicolò E, Giugliano F, Ascione L, et al: Combining antibody-drug conjugates with immunotherapy in solid tumors: Current landscape and future perspectives. Cancer Treat Rev 106:102395, 2022
92.
Cardillo TM, Sharkey RM, Rossi DL, et al: Synthetic lethality exploitation by an anti-trop-2-SN-38 antibody-drug conjugate, IMMU-132, plus PARP inhibitors in BRCA1/2-wild-type triple-negative breast cancer. Clin Cancer Res 23:3405-3415, 2017
93.
Boshuizen J, Koopman LA, Krijgsman O, et al: Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors. Nat Med 24:203-212, 2018
94.
Yu J, Song Y, Tian W: How to select IgG subclasses in developing anti-tumor therapeutic antibodies. J Hematol Oncol 13:45, 2020
95.
Singh AP, Sharma S, Shah DK: Quantitative characterization of in vitro bystander effect of antibody-drug conjugates. J Pharmacokinet Pharmacodyn 43:567-582, 2016
96.
Loganzo F, Sung M, Gerber HP: Mechanisms of resistance to antibody-drug conjugates. Mol Cancer Ther 15:2825-2834, 2016
97.
Loganzo F, Tan X, Sung M, et al: Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments. Mol Cancer Ther 14:952-963, 2015
98.
Vasan N, Baselga J, Hyman DM: A view on drug resistance in cancer. Nature 575:299-309, 2019
99.
Ríos-Luci C, García-Alonso S, Díaz-Rodríguez E, et al: Resistance to the antibody-drug conjugate T-DM1 is based in a reduction in lysosomal proteolytic activity. Cancer Res 77:4639-4651, 2017
100.
Chen R, Hou J, Newman E, et al: CD30 downregulation, MMAE resistance, and MDR1 upregulation are all associated with resistance to brentuximab vedotin. Mol Cancer Ther 14:1376-1384, 2015
101.
Thompson JA, Grunert F, Zimmermann W: Carcinoembryonic antigen gene family: Molecular biology and clinical perspectives. J Clin Lab Anal 5:344-366, 1991
102.
Gazzah A, Ricordel C, Cousin S, 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). J Clin Oncol 38, 2020 (suppl 15; abstr 9505)
103.
Gazzah A, Bedard PL, Hierro C, et al: Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: First-in-human dose-escalation study. Ann Oncol 33:416-425, 2022
104.
Johnson ML, Chadjaa M, Yoruk S, et al: Phase III trial comparing antibody-drug conjugate (ADC) SAR408701 with docetaxel in patients with metastatic non-squamous non-small cell lung cancer (NSQ NSCLC) failing chemotherapy and immunotherapy. J Clin Oncol 38, 2020 (suppl 15; abstr TPS9625)
105.
Nygren MK, Tekle C, Ingebrigtsen VA, et al: B7-H3 and its relevance in cancer; immunological and non-immunological perspectives. Front Biosci E3:989-993, 2011
106.
Yamato M, Hasegawa J, Maejima T, et al: DS-7300a, a DNA topoisomerase I inhibitor, DXd-based antibody-drug conjugate targeting B7-H3, exerts potent antitumor activities in preclinical models. Mol Cancer Ther 21:635-646, 2022
107.
Bendell JC, Doi T, Patel MR, et al: A phase I/II, two-part, multicenter, first-in-human study of DS-7300a in patients with advanced solid malignant tumors. J Clin Oncol 38, 2020 (suppl 15; abstr TPS3646)
108.
Doi T, Patel M, Falchook GS, et al: 453O DS-7300 (B7-H3 DXd antibody-drug conjugate [ADC]) shows durable antitumor activity in advanced solid tumors: Extended follow-up of a phase I/II study. Ann Oncol 33:S744-S745, 2022
109.
Scribner JA, Brown JG, Son T, et al: Preclinical development of MGC018, a duocarmycin-based antibody–drug conjugate targeting B7-H3 for solid cancer. Mol Cancer Ther 19:2235-2244, 2020
110.
Jang S, Powderly JD, Spira AI, et al: Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors. J Clin Oncol 39, 2021 (suppl 15; abstr 2631)
111.
Saunders LR, Bankovich AJ, Anderson WC, et al: A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med 7:302ra136, 2015
112.
Morgensztern D, Besse B, Greillier L, et al: Efficacy and safety of rovalpituzumab tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell lung cancer: Results from the phase II TRINITY study. Clin Cancer Res 25:6958-6966, 2019
113.
Johnson ML, Zvirbule Z, Laktionov K, et al: Rovalpituzumab tesirine as a maintenance therapy after first-line platinum-based chemotherapy in patients with extensive-stage-SCLC: Results from the phase 3 MERU study. J Thorac Oncol 16:1570-1581, 2021
114.
Malhotra J, Nikolinakos P, Leal T, et al: A phase 1-2 study of rovalpituzumab tesirine in combination with nivolumab plus or minus ipilimumab in patients with previously treated extensive-stage SCLC. J Thorac Oncol 16:1559-1569, 2021
115.
Giffin MJ, Cooke K, Lobenhofer EK, et al: AMG 757, a half-life extended, DLL3-targeted bispecific T-cell engager, shows high potency and sensitivity in preclinical models of small-cell lung cancer. Clin Cancer Res 27:1526-1537, 2021
116.
Liu M, Huang W, Guo Y, et al: CAR NK-92 cells targeting DLL3 kill effectively small cell lung cancer cells in vitro and in vivo. J Leukoc Biol 112:901-911, 2022
117.
Van Acker HH, Capsomidis A, Smits EL, et al: CD56 in the immune system: More than a marker for cytotoxicity?. Front Immunol 8:892, 2017
118.
Socinski MA, Kaye FJ, Spigel DR, et al: Phase 1/2 study of the CD56-targeting antibody-drug conjugate lorvotuzumab mertansine (IMGN901) in combination with carboplatin/etoposide in small-cell lung cancer patients with extensive-stage disease. Clin Lung Cancer 18:68-76.e2, 2017
119.
Zhu C, Wei Y, Wei X: AXL receptor tyrosine kinase as a promising anti-cancer approach: Functions, molecular mechanisms and clinical applications. Mol Cancer 18:153, 2019
120.
Ameratunga M, Harvey RD, Mau-Sørensen 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. J Clin Oncol 37, 2019 (suppl 15; abstr 2525)
121.
Ramalingam S, Lopez J, Mau-Sorensen M, et al: OA02.05 First-in-human phase 1/2 trial of anti-AXL antibody–drug conjugate (ADC) enapotamab vedotin (EnaV) in advanced NSCLC. J Thorac Oncol 14:S209, 2019
122.
Rodon Ahnert J, Taylor MH, O'Reilly EM, 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. J Clin Oncol 36(15_suppl):TPS12126, 2018 (suppl 15; abstr TPS12126)
123.
Gärtner S, Gunesch A, Knyazeva T, et al: PTK 7 is a transforming gene and prognostic marker for breast cancer and nodal metastasis involvement. PLOS One 9:e84472, 2014
124.
Maitland ML, Sachdev JC, Sharma MR, et al: First-in-Human study of PF-06647020 (cofetuzumab pelidotin), an antibody–drug conjugate targeting protein tyrosine kinase 7, in advanced solid tumors. Clin Cancer Res 27:4511-4520, 2021
125.
Challita-Eid PM, Satpayev D, Yang P, et al: Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 76:3003-3013, 2016
126.
Goldin-Lang P, Tran QV, Fichtner I, et al: Tissue factor expression pattern in human non-small cell lung cancer tissues indicate increased blood thrombogenicity and tumor metastasis. Oncol Rep 20:123-128, 2008
127.
de Bono JS, Concin N, Hong DS, et al: Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): A first-in-human, multicentre, phase 1–2 trial. Lancet Oncol 20:383-393, 2019
128.
Hassan R, Thomas A, Alewine C, et al: Mesothelin immunotherapy for cancer: Ready for prime time? J Clin Oncol 34:4171-4179, 2016
129.
Golfier S, Kopitz C, Kahnert A, et al: Anetumab ravtansine: A novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther 13:1537-1548, 2014
130.
Hassan R, Blumenschein GR, Moore KN, 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. J Clin Oncol 38:1824-1835, 2020
131.
Kindler HL, Novello S, Bearz A, et al: Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): A randomised, open-label phase 2 trial. Lancet Oncol 23:540-552, 2022
132.
Passaro A, Leighl N, Blackhall F, et al: ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer. Ann Oncol 33:466-487, 2022
133.
Qiu MZ, Zhang Y, Guo Y, et al: Evaluation of safety of treatment with anti-epidermal growth factor receptor antibody drug conjugate MRG003 in patients with advanced solid tumors: A phase 1 nonrandomized clinical trial. JAMA Oncol 8:1042-1046, 2022
134.
Xu R-H, Qiu M-Z, Zhang Y, et al: First-in-human dose-escalation study of anti-EGFR ADC MRG003 in patients with relapsed/refractory solid tumors. J Clin Oncol 38, 2020 (suppl 15; abstr 3550)
135.
Debebe Z, Rathmell WK: Ror2 as a therapeutic target in cancer. Pharmacol Ther 150:143-148, 2015
136.
Xu H, Bai L, Collins JF, et al: Molecular cloning, functional characterization, tissue distribution, and chromosomal localization of a human, small intestinal sodium-phosphate (Na+-Pi) transporter (SLC34A2). Genomics 62:281-284, 1999
137.
Bodyak ND, Mosher R, Yurkovetskiy AV, et al: The dolaflexin-based antibody–drug conjugate XMT-1536 targets the solid tumor lineage antigen SLC34A2/NaPi2b. Mol Cancer Ther 20:896-905, 2021
138.
Lin K, Rubinfeld B, Zhang C, et al: Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. Clin Cancer Res 21:5139-5150, 2015
139.
Gerber DE, Infante JR, Gordon MS, et al: Phase ia study of anti-NaPi2b antibody-drug conjugate Lifastuzumab vedotin DNIB0600A in patients with non-small cell lung cancer and platinum-resistant ovarian cancer. Clin Cancer Res 26:364-372, 2020
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© 2023 by American Society of Clinical Oncology.
History
Published online: May 24, 2023
Published in print: July 20, 2023
Authors
Author Contributions
Conception and design: All authors
Collection and assembly of data: Antonio Passaro, Solange Peters
Data analysis and interpretation: Antonio Passaro, Solange Peters
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
Disclosures
Antonio Passaro
Consulting or Advisory Role: Roche/Genentech, Bristol Myers Squibb, AstraZeneca, MSD Oncology, Pfizer, Boehringer Ingelheim, Johnson & Johnson/Janssen, Novartis, Daiichi Sankyo Europe GmbH, Bayer
Speakers' Bureau: AstraZeneca, Johnson & Johnson/Janssen, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, MSD Oncology
Pasi A. Jänne
Stock and Other Ownership Interests: Gatekeeper Pharmaceuticals, Loxo
Consulting or Advisory Role: Pfizer, Boehringer Ingelheim, AstraZeneca, Merrimack, Chugai Pharma, Roche/Genentech, LOXO, Mirati Therapeutics, Araxes Pharma, Ignyta, Lilly, Takeda, Novartis, Biocartis, Voronoi Health Analytics, SFJ Pharmaceuticals Group, Sanofi, Biocartis, Daiichi Sankyo, Silicon Therapeutics, Nuvalent, Inc, Eisai, Bayer, Syndax, AbbVie, Allorion Therapeutics, Accutar Biotech, Transcenta, Monte Rosa Therapeutics, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotech, Duality Biologics
Research Funding: AstraZeneca, Astellas Pharma, Daiichi Sankyo, Lilly, Boehringer Ingelheim, Puma Biotechnology, Takeda, Revolution Medicines
Patents, Royalties, Other Intellectual Property: I am a co-inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp I receive post-marketing royalties from this invention
Solange Peters
Honoraria: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), MSD (Inst), AstraZeneca (Inst), Takeda (Inst), Illumina (Inst), medscape (Inst), Prime Oncology (Inst), RMEI Medical Education (Inst), Research to Practice (Inst), PER (Inst), Imedex (Inst), Ecancer (Inst), Ecancer (Inst), OncologyEducation (Inst), Fishawack Facilitate (Inst), Peerview (Inst), Medtoday (Inst), Mirati Therapeutics (Inst), Sanofi (Inst), Incyte (Inst)
Consulting or Advisory Role: Roche/Genentech (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst), MSD (Inst), Amgen (Inst), AstraZeneca (Inst), Janssen (Inst), Regeneron (Inst), Merck Serono (Inst), Boehringer Ingelheim (Inst), Takeda (Inst), Lilly (Inst), AbbVie (Inst), Bayer (Inst), Biocartis (Inst), Debiopharm Group (Inst), Illumina (Inst), PharmaMar (Inst), Sanofi (Inst), Seagen (Inst), Blueprint Medicines (Inst), Daiichi Sankyo (Inst), Incyte (Inst), Bioinvent (Inst), Clovis Oncology (Inst), Vaccibody (Inst), Phosplatin Therapeutics (Inst), Foundation Medicine (Inst), Arcus Biosciences (Inst), F-Star Biotechnology (Inst), Genzyme (Inst), Gilead Sciences (Inst), GlaxoSmithKline (Inst), Vaccibody (Inst), ITeos Therapeutics (Inst)
Research Funding: roche (Inst), BMS (Inst), MSD (Inst), Amgen (Inst), Lilly (Inst), AstraZeneca (Inst), Pfizer (Inst), Illumina (Inst), Merck Serono (Inst), Novartis (Inst), Biodesix (Inst), Boehringer Ingelheim (Inst), Boehringer Ingelheim (Inst), Boehringer Ingelheim (Inst), Iovance Biotherapeutics (Inst), Phosplatin Therapeutics (Inst)
Travel, Accommodations, Expenses: Roche, Bristol Myers Squibb, MSD, Sanofi, Incyte
Uncompensated Relationships: Annals of Oncology, ESMO, ETOP Scientific chair, JTO Past Deputy Editor, SAMO President
No other potential conflicts of interest were reported.
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Antibody-Drug Conjugates in Lung Cancer: Recent Advances and Implementing Strategies. JCO 41, 3747-3761(2023).
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Antonio Passaro, Pasi A. Jänne, Solange Peters
Journal of Clinical Oncology 2023 41:21, 3747-3761
Antonio Passaro, Pasi A. Jänne, Solange Peters
Journal of Clinical Oncology 2023 41:21, 3747-3761
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References
1.
Tolcher AW: Antibody drug conjugates: Lessons from 20 years of clinical experience. Ann Oncol 27:2168-2172, 2016
2.
Tarantino P, Carmagnani Pestana R, Corti C, et al: Antibody-drug conjugates: Smart chemotherapy delivery across tumor histologies. CA Cancer J Clin 72:165-182, 2022
3.
Tsuchikama K, An Z: Antibody-drug conjugates: Recent advances in conjugation and linker chemistries. Protein Cell 9:33-46, 2018
4.
Jain N, Smith SW, Ghone S, et al: Current ADC linker chemistry. Pharm Res 32:3526-3540, 2015
5.
Beck A, Goetsch L, Dumontet C, et al: Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov 16:315-337, 2017
6.
Hamblett KJ, Senter PD, Chace DF, et al: Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res 10:7063-7070, 2004
7.
Sun X, Ponte JF, Yoder NC, et al: Effects of drug-antibody ratio on pharmacokinetics, biodistribution, efficacy, and tolerability of antibody-maytansinoid conjugates. Bioconjug Chem 28:1371-1381, 2017
8.
Minchinton AI, Tannock IF: Drug penetration in solid tumours. Nat Rev Cancer 6:583-592, 2006
9.
Matsumura Y: Cancer stromal targeting therapy to overcome the pitfall of EPR effect. Adv Drug Deliv Rev 154-155:142-150, 2020
10.
Lu G, Nishio N, van den Berg NS, et al: Co-administered antibody improves penetration of antibody-dye conjugate into human cancers with implications for antibody-drug conjugates. Nat Commun 11:5667, 2020
11.
Alley SC, Zhang X, Okeley NM, et al: The pharmacologic basis for antibody-auristatin conjugate activity. J Pharmacol Exp Ther 330:932-938, 2009
12.
Thurber GM, Dane Wittrup K: A mechanistic compartmental model for total antibody uptake in tumors. J Theor Biol 314:57-68, 2012
13.
Acchione M, Kwon H, Jochheim CM, et al: Impact of linker and conjugation chemistry on antigen binding, Fc receptor binding and thermal stability of model antibody-drug conjugates. MAbs 4:362-372, 2012
14.
Redman JM, Hill EM, AlDeghaither D, et al: Mechanisms of action of therapeutic antibodies for cancer. Mol Immunol 67:28-45, 2015
15.
Tai YT, Mayes PA, Acharya C, et al: Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood 123:3128-3138, 2014
16.
Drago JZ, Modi S, Chandarlapaty S: Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat Rev Clin Oncol 18:327-344, 2021
17.
Moasser MM: The oncogene HER2: Its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26:6469-6487, 2007
18.
Damelin M, Zhong W, Myers J, et al: Evolving strategies for target selection for antibody-drug conjugates. Pharm Res 32:3494-3507, 2015
19.
Li BT, Michelini F, Misale S, et al: HER2-Mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers. Cancer Discov 10:674-687, 2020
20.
Jedema I, Barge RM, van der Velden VH, et al: Internalization and cell cycle-dependent killing of leukemic cells by gemtuzumab ozogamicin: Rationale for efficacy in CD33-negative malignancies with endocytic capacity. Leukemia 18:316-325, 2004
21.
Sutherland MS, Sanderson RJ, Gordon KA, et al: Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J Biol Chem 281:10540-10547, 2006
22.
Kovtun YV, Goldmacher VS: Cell killing by antibody-drug conjugates. Cancer Lett 255:232-240, 2007
23.
Erickson HK, Lewis Phillips GD, Leipold DD, et al: The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol Cancer Ther 11:1133-1142, 2012
24.
Ogitani Y, Hagihara K, Oitate M, 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. Cancer Sci 107:1039-1046, 2016
25.
Li F, Emmerton KK, Jonas M, et al: Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res 76:2710-2719, 2016
26.
Staudacher AH, Brown MP: Antibody drug conjugates and bystander killing: Is antigen-dependent internalisation required? Br J Cancer 117:1736-1742, 2017
27.
Coats S, Williams M, Kebble B, et al: Antibody-drug conjugates: Future directions in clinical and translational strategies to improve the therapeutic index. Clin Cancer Res 25:5441-5448, 2019
28.
Jebbink M, de Langen AJ, Boelens MC, et al: The force of HER2—A druggable target in NSCLC? Cancer Treat Rev 86:101996, 2020
29.
Del Re M, Cucchiara F, Petrini I, et al: erbB in NSCLC as a molecular target: current evidences and future directions. ESMO Open 5:e000724, 2020
30.
Wang Z: ErbB receptors and cancer. Methods Mol Biol 1652:3-35, 2017
31.
Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012
32.
Li BT, Shen R, Buonocore D, et al: Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: Results from a phase II basket trial. J Clin Oncol 36:2532-2537, 2018
33.
Peters S, Stahel R, Bubendorf L, et al: Trastuzumab emtansine (T-DM1) in patients with previously treated HER2-overexpressing metastatic non-small cell lung cancer: Efficacy, safety, and biomarkers. Clin Cancer Res 25:64-72, 2019
34.
Jebbink M, Langen AD, Monkhorst K, et al: MA02.07 T-DM1 and osimertinib (TRAEMOS) to target HER2 bypass track resistance in EGFRm+ NSCLC: Interim analysis of a phase II trial. J Thorac Oncol 16:S891-S892, 2021
35.
Ogitani Y, Aida T, Hagihara K, 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. Clin Cancer Res 22:5097-5108, 2016
36.
Shitara K, Bang YJ, Iwasa S, et al: Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 382:2419-2430, 2020
37.
Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382:610-621, 2020
38.
Li BT, Smit EF, Goto Y, et al: Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med 386:241-251, 2022
39.
Passaro A, Peters S: Targeting HER2-mutant NSCLC—The light is on. N Engl J Med 386:286-289, 2022
40.
Goto K, Sang-We K, Kubo T, et al: LBA55 Trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutant metastatic non-small cell lung cancer (NSCLC): Interim results from the phase 2 DESTINY-Lung02 trial. Ann Oncol 33:S1422, 2022
41.
Jänne PA, Baik C, Su WC, et al: Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer. Cancer Discov 12:74-89, 2022
42.
Alam SK, Zhang Y, Wang L, et al: DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma. Oncogene 41:83-98, 2022
43.
Yonesaka K, Takegawa N, Watanabe S, et al: An HER3-targeting antibody-drug conjugate incorporating a DNA topoisomerase I inhibitor U3-1402 conquers EGFR tyrosine kinase inhibitor-resistant NSCLC. Oncogene 38:1398-1409, 2019
44.
Steuer CE, Hayashi H, Su W-C, et al: Efficacy and safety of patritumab deruxtecan (HER3-DXd) in advanced/metastatic non-small cell lung cancer (NSCLC) without EGFR-activating mutations. J Clin Oncol 40, 2022 (suppl 16; abstr 9017)
45.
Goldenberg DM, Stein R, Sharkey RM: The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget 9:28989-29006, 2018
46.
Okajima D, Yasuda S, Maejima T, et al: Datopotamab deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Mol Cancer Ther 20:2329-2340, 2021
47.
Spira A, Lisberg A, Sands J, et al: OA03.03 Datopotamab deruxtecan (Dato-DXd; DS-1062), a TROP2 ADC, in patients with advanced NSCLC: Updated results of TROPION-PanTumor01 phase 1 study. J Thorac Oncol 16:S106-S107, 2021
48.
Garon E, Johnson M, Lisberg A, et al: MA03.02 TROPION-PanTumor01: Updated results from the NSCLC cohort of the phase 1 study of datopotamab deruxtecan in solid tumors. J Thorac Oncol 16:S892-S893, 2021
49.
Meric-Bernstam F, Spira AI, Lisberg AE, 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). J Clin Oncol 39, 2021 (suppl 15; abstr 9058)
50.
Garon EB, Johnson ML, Lisberg AE, et al: LBA49 Efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC) and actionable genomic alterations (AGAs): Preliminary results from the phase I TROPION-PanTumor01 study. Ann Oncol 32:S1326-S1327, 2021
51.
Yoh K, Goto Y, Thomas M, et al: A randomized, phase 3 study of datopotamab deruxtecan (Dato-DXd; DS-1062) versus docetaxel in previously treated advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (TROPION-Lung01). J Clin Oncol 39, 2021 (suppl 15; abstr TPS9127)
52.
Levy BP, Reck M, Yang JC-H, et al: Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab in treatment-naive advanced/metastatic (adv/met) non–small cell lung cancer (NSCLC) with PD-L1 ≥ 50% and without actionable genomic alterations. J Clin Oncol 40, 2022 (suppl 15; abstr TPS3162)
53.
Levy B, Paz-Ares L, Rixe O, et al: MA13.07 TROPION-lung02: Initial results for datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy in advanced NSCLC. J Thorac Oncol 17:S91, 2022
54.
Goldenberg DM, Sharkey RM: Sacituzumab govitecan, a novel, third-generation, antibody-drug conjugate (ADC) for cancer therapy. Expert Opin Biol Ther 20:871-885, 2020
55.
Heist RS, Guarino MJ, Masters G, et al: Therapy of advanced non-small-cell lung cancer with an SN-38-anti-Trop-2 drug conjugate, sacituzumab govitecan. J Clin Oncol 35:2790-2797, 2017
56.
Bardia A, Messersmith WA, Kio EA, 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. Ann Oncol 32:746-756, 2021
57.
Gray JE, Heist RS, Starodub AN, et al: Therapy of small cell lung cancer (SCLC) with a topoisomerase-I-inhibiting antibody-drug conjugate (ADC) targeting trop-2, sacituzumab govitecan. Clin Cancer Res 23:5711-5719, 2017
58.
Lee JK, Madison R, Classon A, et al: Characterization of non–small-cell lung cancers with MET exon 14 skipping alterations detected in tissue or liquid: Clinicogenomics and real-world treatment patterns. JCO Precis Oncol 5:1354-1376, 2021
59.
Sabari JK, Leonardi GC, Shu CA, et al: PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers. Ann Oncol 29:2085-2091, 2018
60.
Kron A, Scheffler M, Heydt C, et al: Genetic heterogeneity of MET-aberrant NSCLC and its impact on the outcome of immunotherapy. J Thorac Oncol 16:572-582, 2021
61.
Schmid S, Früh M, Peters S: Targeting MET in EGFR resistance in non-small-cell lung cancer-ready for daily practice? Lancet Oncol 21:320-322, 2020
62.
Wang J, Anderson MG, Oleksijew A, 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. Clin Cancer Res 23:992-1000, 2017
63.
Strickler JH, Weekes CD, Nemunaitis J, 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. J Clin Oncol 36:3298-3306, 2018
64.
Waqar SN, Redman MW, Arnold SM, 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). Clin Lung Cancer 22:170-177, 2021
65.
Camidge DR, Barlesi F, Goldman JW, et al: Phase Ib study of telisotuzumab vedotin in combination with erlotinib in patients with c-Met protein-expressing non-small-cell lung cancer. J Clin Oncol 41:1105-1115, 2023
66.
Camidge DR, Bar J, Horinouchi H, et al: Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met–overexpressing (OE) advanced non-small cell lung cancer (NSCLC). J Clin Oncol 40, 2022 (suppl 16; abstr 9016)
67.
Goldman J, Moiseenko F, Cicin I, et al: P47.03 Telisotuzumab vedotin monotherapy in patients with previously treated c-Met+ advanced non-small cell lung cancer: Stage 2. J Thorac Oncol 16:S1097, 2021
68.
Goldman JW, Horinouchi H, Cho BC, et al: Phase 1/1b study of telisotuzumab vedotin (Teliso-V) + osimertinib (Osi), after failure on prior Osi, in patients with advanced, c-Met overexpressing, EGFR-mutated non-small cell lung cancer (NSCLC). J Clin Oncol 40, 2022 (suppl 16; abstr 9013)
69.
Donaghy H: Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. mAbs 8:659-671, 2016
70.
Masters JC, Nickens DJ, Xuan D, et al: Clinical toxicity of antibody drug conjugates: A meta-analysis of payloads. Investig New Drugs 36:121-135, 2018
71.
Eaton JS, Miller PE, Mannis MJ, et al.: Ocular adverse events associated with antibody–drug conjugates in human clinical trials. J Ocul Pharmacol Ther 31:589-604, 2015
72.
Powell CA, Modi S, Iwata H, et al: Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies☆. ESMO Open 7:100554, 2022
73.
Tarantino P, Modi S, Tolaney SM, et al: Interstitial lung disease induced by anti-ERBB2 antibody-drug conjugates: A review. JAMA Oncol 7:1873-1881, 2021
74.
Abuhelwa Z, Alloghbi A, Alqahtani A, et al: Trastuzumab deruxtecan-induced interstitial lung disease/pneumonitis in ERBB2-positive advanced solid malignancies: A systematic review. Drugs 82:979-987, 2022
75.
Swain SM, Nishino M, Lancaster LH, et al: Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)–related interstitial lung disease/pneumonitis—focus on proactive monitoring, diagnosis, and management. Cancer Treat Rev 106:102378, 2022
76.
Tarantino P, Curigliano G, Tolaney SM: Navigating the HER2-low paradigm in breast oncology: New standards, future horizons. Cancer Discov 12:2026-2030, 2022
77.
Bardia A, Mayer IA, Diamond JR, et al: Efficacy and safety of anti-trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol 2017:2141-2148, 2017
78.
Nolting B: Linker technologies for antibody-drug conjugates. Methods Mol Biol 1045:71-100, 2013
79.
Gikanga B, Adeniji NS, Patapoff TW, et al: Cathepsin B cleavage of vcMMAE-based antibody-drug conjugate is not drug location or monoclonal antibody carrier specific. Bioconjug Chem 27:1040-1049, 2016
80.
de Goeij BE, Vink T, Ten Napel H, et al: Efficient payload delivery by a bispecific antibody-drug conjugate targeting HER2 and CD63. Mol Cancer Ther 15:2688-2697, 2016
81.
Zhuang C, Guan X, Ma H, et al: Small molecule-drug conjugates: A novel strategy for cancer-targeted treatment. Eur J Med Chem 163:883-895, 2019
82.
Dovgan I, Koniev O, Kolodych S, et al: Antibody-oligonucleotide conjugates as therapeutic, imaging, and detection agents. Bioconjug Chem 30:2483-2501, 2019
83.
Best RL, LaPointe NE, Azarenko O, et al: Microtubule and tubulin binding and regulation of microtubule dynamics by the antibody drug conjugate (ADC) payload, monomethyl auristatin E (MMAE): Mechanistic insights into MMAE ADC peripheral neuropathy. Toxicol Appl Pharmacol 421:115534, 2021
84.
Blackhall F, Jao K, Greillier L, et al: Efficacy and safety of rovalpituzumab tesirine compared with topotecan as second-line therapy in DLL3-high SCLC: Results from the phase 3 TAHOE study. J Thorac Oncol 16:1547-1558, 2021
85.
Martiniova L, Zielinski RJ, Lin M, et al: The role of radiolabeled monoclonal antibodies in cancer imaging and ADC treatment. Cancer J 28:446-453, 2022
86.
Mohit E, Rafati S: Chemokine-based immunotherapy: Delivery systems and combination therapies. Immunotherapy 4:807-840, 2012
87.
Tolcher AW, Carneiro BA, Dowlati A, et al: A first-in-human study of mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose escalation results. J Clin Oncol 39, 2021 (suppl 15; abstr 3015)
88.
Alas M, Saghaeidehkordi A, Kaur K: Peptide-drug conjugates with different linkers for cancer therapy. J Med Chem 64:216-232, 2021
89.
Yurkovetskiy AV, Bodyak ND, Yin M, et al: Dolaflexin: A novel antibody-drug conjugate platform featuring high drug loading and a controlled bystander effect. Mol Cancer Ther 20:885-895, 2021
90.
O'Malley DM, Matulonis UA, Birrer MJ, et al: Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol 157:379-385, 2020
91.
Nicolò E, Giugliano F, Ascione L, et al: Combining antibody-drug conjugates with immunotherapy in solid tumors: Current landscape and future perspectives. Cancer Treat Rev 106:102395, 2022
92.
Cardillo TM, Sharkey RM, Rossi DL, et al: Synthetic lethality exploitation by an anti-trop-2-SN-38 antibody-drug conjugate, IMMU-132, plus PARP inhibitors in BRCA1/2-wild-type triple-negative breast cancer. Clin Cancer Res 23:3405-3415, 2017
93.
Boshuizen J, Koopman LA, Krijgsman O, et al: Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors. Nat Med 24:203-212, 2018
94.
Yu J, Song Y, Tian W: How to select IgG subclasses in developing anti-tumor therapeutic antibodies. J Hematol Oncol 13:45, 2020
95.
Singh AP, Sharma S, Shah DK: Quantitative characterization of in vitro bystander effect of antibody-drug conjugates. J Pharmacokinet Pharmacodyn 43:567-582, 2016
96.
Loganzo F, Sung M, Gerber HP: Mechanisms of resistance to antibody-drug conjugates. Mol Cancer Ther 15:2825-2834, 2016
97.
Loganzo F, Tan X, Sung M, et al: Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments. Mol Cancer Ther 14:952-963, 2015
98.
Vasan N, Baselga J, Hyman DM: A view on drug resistance in cancer. Nature 575:299-309, 2019
99.
Ríos-Luci C, García-Alonso S, Díaz-Rodríguez E, et al: Resistance to the antibody-drug conjugate T-DM1 is based in a reduction in lysosomal proteolytic activity. Cancer Res 77:4639-4651, 2017
100.
Chen R, Hou J, Newman E, et al: CD30 downregulation, MMAE resistance, and MDR1 upregulation are all associated with resistance to brentuximab vedotin. Mol Cancer Ther 14:1376-1384, 2015
101.
Thompson JA, Grunert F, Zimmermann W: Carcinoembryonic antigen gene family: Molecular biology and clinical perspectives. J Clin Lab Anal 5:344-366, 1991
102.
Gazzah A, Ricordel C, Cousin S, 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). J Clin Oncol 38, 2020 (suppl 15; abstr 9505)
103.
Gazzah A, Bedard PL, Hierro C, et al: Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: First-in-human dose-escalation study. Ann Oncol 33:416-425, 2022
104.
Johnson ML, Chadjaa M, Yoruk S, et al: Phase III trial comparing antibody-drug conjugate (ADC) SAR408701 with docetaxel in patients with metastatic non-squamous non-small cell lung cancer (NSQ NSCLC) failing chemotherapy and immunotherapy. J Clin Oncol 38, 2020 (suppl 15; abstr TPS9625)
105.
Nygren MK, Tekle C, Ingebrigtsen VA, et al: B7-H3 and its relevance in cancer; immunological and non-immunological perspectives. Front Biosci E3:989-993, 2011
106.
Yamato M, Hasegawa J, Maejima T, et al: DS-7300a, a DNA topoisomerase I inhibitor, DXd-based antibody-drug conjugate targeting B7-H3, exerts potent antitumor activities in preclinical models. Mol Cancer Ther 21:635-646, 2022
107.
Bendell JC, Doi T, Patel MR, et al: A phase I/II, two-part, multicenter, first-in-human study of DS-7300a in patients with advanced solid malignant tumors. J Clin Oncol 38, 2020 (suppl 15; abstr TPS3646)
108.
Doi T, Patel M, Falchook GS, et al: 453O DS-7300 (B7-H3 DXd antibody-drug conjugate [ADC]) shows durable antitumor activity in advanced solid tumors: Extended follow-up of a phase I/II study. Ann Oncol 33:S744-S745, 2022
109.
Scribner JA, Brown JG, Son T, et al: Preclinical development of MGC018, a duocarmycin-based antibody–drug conjugate targeting B7-H3 for solid cancer. Mol Cancer Ther 19:2235-2244, 2020
110.
Jang S, Powderly JD, Spira AI, et al: Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors. J Clin Oncol 39, 2021 (suppl 15; abstr 2631)
111.
Saunders LR, Bankovich AJ, Anderson WC, et al: A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med 7:302ra136, 2015
112.
Morgensztern D, Besse B, Greillier L, et al: Efficacy and safety of rovalpituzumab tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell lung cancer: Results from the phase II TRINITY study. Clin Cancer Res 25:6958-6966, 2019
113.
Johnson ML, Zvirbule Z, Laktionov K, et al: Rovalpituzumab tesirine as a maintenance therapy after first-line platinum-based chemotherapy in patients with extensive-stage-SCLC: Results from the phase 3 MERU study. J Thorac Oncol 16:1570-1581, 2021
114.
Malhotra J, Nikolinakos P, Leal T, et al: A phase 1-2 study of rovalpituzumab tesirine in combination with nivolumab plus or minus ipilimumab in patients with previously treated extensive-stage SCLC. J Thorac Oncol 16:1559-1569, 2021
115.
Giffin MJ, Cooke K, Lobenhofer EK, et al: AMG 757, a half-life extended, DLL3-targeted bispecific T-cell engager, shows high potency and sensitivity in preclinical models of small-cell lung cancer. Clin Cancer Res 27:1526-1537, 2021
116.
Liu M, Huang W, Guo Y, et al: CAR NK-92 cells targeting DLL3 kill effectively small cell lung cancer cells in vitro and in vivo. J Leukoc Biol 112:901-911, 2022
117.
Van Acker HH, Capsomidis A, Smits EL, et al: CD56 in the immune system: More than a marker for cytotoxicity?. Front Immunol 8:892, 2017
118.
Socinski MA, Kaye FJ, Spigel DR, et al: Phase 1/2 study of the CD56-targeting antibody-drug conjugate lorvotuzumab mertansine (IMGN901) in combination with carboplatin/etoposide in small-cell lung cancer patients with extensive-stage disease. Clin Lung Cancer 18:68-76.e2, 2017
119.
Zhu C, Wei Y, Wei X: AXL receptor tyrosine kinase as a promising anti-cancer approach: Functions, molecular mechanisms and clinical applications. Mol Cancer 18:153, 2019
120.
Ameratunga M, Harvey RD, Mau-Sørensen 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. J Clin Oncol 37, 2019 (suppl 15; abstr 2525)
121.
Ramalingam S, Lopez J, Mau-Sorensen M, et al: OA02.05 First-in-human phase 1/2 trial of anti-AXL antibody–drug conjugate (ADC) enapotamab vedotin (EnaV) in advanced NSCLC. J Thorac Oncol 14:S209, 2019
122.
Rodon Ahnert J, Taylor MH, O'Reilly EM, 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. J Clin Oncol 36(15_suppl):TPS12126, 2018 (suppl 15; abstr TPS12126)
123.
Gärtner S, Gunesch A, Knyazeva T, et al: PTK 7 is a transforming gene and prognostic marker for breast cancer and nodal metastasis involvement. PLOS One 9:e84472, 2014
124.
Maitland ML, Sachdev JC, Sharma MR, et al: First-in-Human study of PF-06647020 (cofetuzumab pelidotin), an antibody–drug conjugate targeting protein tyrosine kinase 7, in advanced solid tumors. Clin Cancer Res 27:4511-4520, 2021
125.
Challita-Eid PM, Satpayev D, Yang P, et al: Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 76:3003-3013, 2016
126.
Goldin-Lang P, Tran QV, Fichtner I, et al: Tissue factor expression pattern in human non-small cell lung cancer tissues indicate increased blood thrombogenicity and tumor metastasis. Oncol Rep 20:123-128, 2008
127.
de Bono JS, Concin N, Hong DS, et al: Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): A first-in-human, multicentre, phase 1–2 trial. Lancet Oncol 20:383-393, 2019
128.
Hassan R, Thomas A, Alewine C, et al: Mesothelin immunotherapy for cancer: Ready for prime time? J Clin Oncol 34:4171-4179, 2016
129.
Golfier S, Kopitz C, Kahnert A, et al: Anetumab ravtansine: A novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther 13:1537-1548, 2014
130.
Hassan R, Blumenschein GR, Moore KN, 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. J Clin Oncol 38:1824-1835, 2020
131.
Kindler HL, Novello S, Bearz A, et al: Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): A randomised, open-label phase 2 trial. Lancet Oncol 23:540-552, 2022
132.
Passaro A, Leighl N, Blackhall F, et al: ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer. Ann Oncol 33:466-487, 2022
133.
Qiu MZ, Zhang Y, Guo Y, et al: Evaluation of safety of treatment with anti-epidermal growth factor receptor antibody drug conjugate MRG003 in patients with advanced solid tumors: A phase 1 nonrandomized clinical trial. JAMA Oncol 8:1042-1046, 2022
134.
Xu R-H, Qiu M-Z, Zhang Y, et al: First-in-human dose-escalation study of anti-EGFR ADC MRG003 in patients with relapsed/refractory solid tumors. J Clin Oncol 38, 2020 (suppl 15; abstr 3550)
135.
Debebe Z, Rathmell WK: Ror2 as a therapeutic target in cancer. Pharmacol Ther 150:143-148, 2015
136.
Xu H, Bai L, Collins JF, et al: Molecular cloning, functional characterization, tissue distribution, and chromosomal localization of a human, small intestinal sodium-phosphate (Na+-Pi) transporter (SLC34A2). Genomics 62:281-284, 1999
137.
Bodyak ND, Mosher R, Yurkovetskiy AV, et al: The dolaflexin-based antibody–drug conjugate XMT-1536 targets the solid tumor lineage antigen SLC34A2/NaPi2b. Mol Cancer Ther 20:896-905, 2021
138.
Lin K, Rubinfeld B, Zhang C, et al: Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. Clin Cancer Res 21:5139-5150, 2015
139.
Gerber DE, Infante JR, Gordon MS, et al: Phase ia study of anti-NaPi2b antibody-drug conjugate Lifastuzumab vedotin DNIB0600A in patients with non-small cell lung cancer and platinum-resistant ovarian cancer. Clin Cancer Res 26:364-372, 2020
