Trop-2 Directed Antibody-Drug Conjugates for the Treatment of Solid Tumors

Supplements and Featured Publications, Trop-2 Directed Antibody-Drug Conjugates for the Treatment of Solid Tumors ,

This article provides an overview of antibody-drug conjugates for the treatment of solid tumors and examines emerging evidence demonstrating Trop-2 as a potential target in breast and lung cancers.


The oncology treatment landscape has evolved with the clinical development of precision-based therapeutic approaches and the growing availability of targeted agents.1,2 Over the last decade, targeted therapeutics have increasingly become an attractive method for improving tumor selectivity and reducing the systemic toxicity associated with traditional chemotherapy.3 Monoclonal antibodies (mAbs) specifically recognize and target cellular surface antigens, which is a valuable mechanism for the delivery of drugs to tumor cells while minimizing off-target toxicity to normal tissues.1 Antibody-drug conjugates (ADCs) allow for improved drug delivery and reduced toxicity. They are designed to combine the targeting ability of mAbs with the cell damaging effects of potent cytotoxic agents.1,4 ADCs, in particular, represent a rapidly expanding therapeutic drug class specifically designed to overcome these shortfalls associated with chemotherapeutic agents.3,4

ADC Design

The clinical success achieved with a particular ADC is contingent upon several key factors including the target antigen, antibody framework, cytotoxic payload, type of linker, method of conjugation, and target indication.4

Target Antigen

Target antigens should be preferentially and homogeneously expressed at high levels on the surface of tumor cells relative to normal tissues, rapidly internalize upon antibody binding, and be minimally present in the circulation.1,4,5 Antigens expressed exclusively on the surface of tumor cells are ideal targets for ADCs.6 Lineage-specific antigens expressed by hematological malignancies have been investigated to a large extent as ideal targets for ADC development.6 Solid tumors express mostly tumor-associated antigens rather than those that are tumor- or lineage-specific, which can lead to an increased potential for off-target toxicity and decrease the level of intratumoral drug delivery.6

ADC targets for the treatment of solid tumors with United States Food and Drug Administration (FDA)-approved options include HER2, poliovirus receptor-related protein 4 (nectin-4), and trophoblast cell-surface antigen 2 (Trop-2). Additional potential ADC targets for solid tumors that are under investigation include HER3, carcinoembryonic antigen-related cell adhesion molecule (CEACAM), mesenchymal-epithelial transition factor (c-Met), mesothelin, LIV-1, folate receptor α, and tissue factor.6

Antibody Framework

Since the advent of mAb-associated technologies, the continued pursuit to improve tissue penetration and uptake has led to the development of a variety of antibody frameworks.1,4,7 The type and size of antibody utilized can affect multiple ADC-associated properties including cross-linking capabilities, complement-dependent cytotoxicity effector functions, cellular uptake, clearance rates, structure, and overall biological activity.4 ADC-associated mAbs should possess a strong binding affinity for the target antigen with low immunogenicity and cross-reactivity.1

Cytotoxic Payload

While the target antigen and corresponding mAb are important factors contributing to tumor selectivity, the cytotoxic payload is essential in eliciting a cell apoptotic effect.4 It is estimated that 1% to 2% of ADC payloads reach their cellular target, which has led to the utilization of more potent agents, including those with anti-tubulin polymerization and DNA-damaging activity.4 Agents with high plasma stability, low immunogenicity, a smaller molecular weight, and a longer drug half-life are preferred characteristics for ADC-associated payloads.1

Chemical Linkers

Essential in connecting the ADC-associated mAb and payload, chemical linkers are classified as either cleavable or noncleavable based on their mechanism of drug release.4,5 Cleavable linkers allow the payload to be cleaved from the parent antibody structure in the presence of acid, proteases, or reducing agents such as glutathione.1,4 Glutathione-sensitive disulfide linkers have greater plasma stability and can be advantageous for oncology applications due to the high glutathione concentration present in the intracellular compartment of cancer cells.1 Conversely, noncleavable linkers form stable, nonreducible bonds with amino acid residues of their mAb counterparts, which may contribute to greater plasma stability, a longer half-life, and decreased potential for off-target toxicity.1 Linker chemistry may also be used to balance hydrophobicity between the mAb and drug payload to help reduce potential aggregation.4 Selection of the ADC-associated linker can be influenced by the mechanism of action (MOA) sought in the end drug design.4

Method of Conjugation

In addition to the linker, the conjugation method used to attach payloads to their respective mAb framework plays a crucial role in controlling the potency and homogeneity of the end drug product.4 Conventional methods have used lysine and interchain cysteines sites for conjugation.4 However, conjugation with these methods occurs randomly and leads to heterogeneous drug-to-antibody ratios (DARs) associated with variability in pharmacokinetics, efficacy, and safety profiles.1 The abundance of lysine and inability to control conjugation at these sites can result in lower binding efficiency and cytotoxicity of the ADC.1 While higher DARs can lead to more potent ADCs, they may also decrease stability and increase the potential for aggregation, off-target toxicity, and greater drug clearance.1 Novel site-specific strategies involve installing natural or unnatural amino acids, carbohydrate moieties, or aldehyde tags for drug conjugation to overcome these shortfalls and achieve a more homogeneous product.4

ADCs in the Solid Tumor Treatment Landscape

As of February 2022, 4 ADCs targeting 1 of 3 specific biomarker are FDA approved for the treatment of solid tumors: ado-trastuzumab emtansine (HER2), trastuzumab deruxtecan (HER2), enfortumab vedotin (Nectin-4), and sacituzumab govitecan (Trop-2).6,8-10

HER2-Directed ADCs

HER2 overexpression is present in approximately 25% to 30% of breast cancer (BC) and has been further identified in other types of malignancy including gastric and gastroesophageal junction (GEJ) cancers, biliary tract cancer, colorectal cancer (CRC), non–small cell lung cancer (NSCLC), bladder cancer, and uterine cancer.11,12

Ado-trastuzumab emtansine (T-DM1)

Ado-trastuzumab emtansine (T-DM1) received FDA approval in 2013 for the treatment ofpatients with HER2-positive (HER2+) metastatic BC who have been previously treated with trastuzumab and a taxane.6,13 T-DM1 employs a noncleavable thioether linker to bind the anti-HER2 antibody trastuzumab to a potent anti-tubulin payload with an associated DAR of 3.5:1.9,13 While T-DM1 has demonstrated favorable efficacy, some HER2+ BCs are nonresponsive or are minimally responsive to T-DM1.14 Multiple mechanisms of resistance to T-DM1 have been identified, and patients can eventually experience disease progression following treatment.14 In addition to elucidating the mechanisms of resistance to T-DM1, there is a need to identify other targetable biomarkers for the development of additional treatment options.14

Trastuzumab deruxtecan (T-DXd)

Another anti-HER2 ADC, trastuzumab deruxtecan (T-DXd), received FDA approval in 2019 for the treatment of patients with unresectable or metastatic HER2+ BC who have previously received 2 or more anti-HER2–based regimens in a metastatic setting.15 T-DXd is also indicated for the treatment of locally advanced or metastatic HER2+ gastric or GEJ adenocarcinoma in patients who have received a prior trastuzumab-based therapy.15 T-DXd shares the same anti-HER2 targeting vehicle present in T-DM1 for drug delivery, but it uses a cleavable linker design to attach a topoisomerase I inhibitor. Cysteine conjugation methods employed in T-DXd drug design also allow for a more homogeneous product with a higher associated DAR (8:1).9,16 During the process of internalization, T-DXd undergoes intracellular cleavage via lysosomal enzymes, releasing the membrane-permeable cytotoxic payload.9,15 Consequently, T-DXd elicits a greater bystander killing effect, which may allow for increased cytotoxic effects on proximal antigen-negative cells and improve clinical activity in patients with low or heterogeneous HER2 expression.9,16

Nectin-4–Directed ADC

Nectin-4 is an immunoglobulin-like adhesion molecule that is involved in calcium-independent cell-to-cell adhesion.10,17 High levels of nectin-4 expression have been reported in approximately 70% to 90% of urothelial cancers with higher levels more commonly seen in non-invasive subtypes.10

Enfortumab vedotin is an ADC composed of an anti-tubulin payload attached to an anti–nectin-4 IgG1 antibody via a protease cleavable linker.18 It received FDA approval in 2019 indicated for the treatment of patients with locally advanced or metastatic urothelial cancer who have previously received treatment with a PD-1 or PD-L1 inhibitor and platinum chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting.18

Trop-2–Directed ADCs

The cell surface glycoprotein Trop-2 is thought to serve an important role in cell proliferation and transformation.8,19 Trop-2 overexpression accelerates the cancer cell cycle and drives tumor progression.20 Trop-2 is overexpressed in many epithelial solid tumors versus normal tissue, including BC and lung cancer as well as gynecological, urothelial, and gastrointestinal carcinomas among others, which has led to the investigation of anti–Trop-2 agents in other malignancies.6,8,19-23 In some cancers, Trop-2 overexpression has been shown to be associated with increased tumor aggressiveness, metastases, and poor prognosis, which highlights Trop-2 as a valid target for ADC development that will expand treatment options and fill unmet needs within the current treatment landscape.22,24,25

Therapeutic resistance continues to be an ongoing challenge in the management of solid tumors, and there remain unmet needs in the current treatment landscape.26-29 Among BC subtypes, triple-negative BC (TNBC) continues to demonstrate the worst outcomes with an associated median overall survival of approximately 13 months.27 Although some patients with TNBC initially respond to standard systemic treatment with chemotherapy, nearly half of these patients will develop resistance to treatment.27,30 The lack of well-defined molecular targets for TNBC further highlights the need to identify biomarkers that can be utilized in the development of novel targeted therapeutics.27 Lung cancer continues to be the leading cause of cancer-related death in the United States, and it is the second most common cancer among American men and women.31 NSCLC is the most commonly diagnosed type of lung cancer, representing approximately 80% to 85% of all diagnoses.32 Many patients (40%) are diagnosed in metastatic stages, and the associated 5-year survival rate remains low (roughly 20% to 30%); systemic chemotherapy continues to be the standard of care for most patients.33 However, only 20% to 30% of patients respond to chemotherapy due to a high rate of intrinsic or acquired drug resistance.33 Although advances in targeted agents for patients with NSCLC have led to improvements in survival, durable remissions remain limited due to the growing resistance to targeted therapies.29 The emergence of Trop-2–directed ADCs provide a potential opportunity to improve survival outcomes and address therapeutic resistance for patients with TNBC and NSCLC. Key details of several ongoing clinical trials that are currently evaluating the use of novel anti-Trop-2 ADCs for the treatment of solid tumors are summarized in the table.1,34-54

Sacituzumab govitecan (SG)

In 2020 sacituzumab govitecan received FDA approval with an indication for the treatment of unresectable locally advanced or metastatic TNBC in patients who have received 2 or more prior systemic therapies (at least 1 for metastatic disease).55 Prior to that FDA approval, in May 2015, sacituzumab govitecan received fast-track designation for the treatment of patients with metastatic NSCLC who have failed 2 prior lines of therapy.56 In April of 2021, based on the results of the TROPHY trial (NCT03547973), the FDA granted accelerated approval to sacituzumab govitecan for the treatment of locally advanced or metastatic urothelial cancer in patients who have previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.6,57

Sacituzumab govitecan comprises a humanized mAb and the topoisomerase inhibitor SN-38 (the active metabolite of irinotecan), coupled via a novel polyethylene glycol (PEG)-based, pH-sensitive, hydrolysable linker (CL2A) using cysteine conjugation.7,58,59 Utilization of the ADC design results in a relatively high DAR of approximately 7.6, and the addition of short PEG groups help to increase solubility and minimize aggregation.58,59 Moreover, the cleavable linker and high hydrophobicity are thought to contribute to the bystander killing effect associated with sacituzumab govitecan and may suggest a greater potential for improved clinical activity in heterogeneous biomarker expression.9,58-60

Datopotamab deruxtecan (dato-DXd)

Anti–Trop-2 ADCs differ with respect to the payload-associated MOA, payload potency, and linker design. Payloads in investigational and FDA-approved Trop-2–targeted ADCs inhibit topoisomerase I (eg, irinotecan-derived SN-38 and exatecan-derived DXd/MAAA-1181a) or microtubule activity (eg, TUB196).4,34,58,59 In terms of potency, the DXd payload is said to be approximately 10 times as potent as SN-38.59 Other cytotoxic payloads used in anti–Trop-2 investigational ADCs include a belotecan-derived payload SKB-264) and an auristatin microtubule inhibitor (RN927C).1,44,59 Noncleavable linkers are generally thought to be more stable in the bloodstream, allow for extracellular release of payload, and enable a greater bystander killing effect.1,58

The investigational anti–Trop-2 ADC datopotamab deruxtecan (dato-DXd, DS-1062a) design comprises a topoisomerase I inhibitor payload (an exatecan derivative) attached to a humanized immunoglobulin G (IgG1) mAb via a cleavable peptide linker and cysteine conjugation using thioether bonds.61-63 The unique tetrapeptide linker of dato-DXd is designed to allow selective cleavage of the payload by cancer cell lysosomes while avoiding cleavage in normal cells following internalization.63 The ADC-associated design of dato-DXd also contributes to high plasma stability, a short systemic payload half-life, and similar to sacituzumab govitecan, a bystander killing effect.62,63 Moreover, dato-Dxd achieves an average DAR of 4, which is thought to maximize the DXd-associated therapeutic window and potentially minimize drug-associated toxicity.62,64

The TROPION clinical trials are currently investigating the safety and efficacy of dato-Dxd in multiple tumor types including TNBC and NSCLC.34,65 The open-label phase I TROPION-PanTumor01 trial (NCT03401385) is an ongoing, open-label, 2-part study investigating the safety, tolerability, and preliminary efficacy of dato-Dxd in patients with advanced solid tumors, including populations with unresectable advanced NSCLC and TNBC who are relapsed or refractory to treatment following standard treatment or for which no standard treatment is available.34,61 At the European Society for Medical Oncology Congress 2021 annual meeting, interim data was presented from a cohort of 34 patients with advanced or metastatic NSCLC and actionable genomic alterations that was treated with dato-DXd at doses of 4 mg/kg (n = 8), 6 mg/kg (n = 10), or 8 mg/kg (n = 16).66,67 Approximately 82% of patients had received at least 3 prior regimens with 85% having received a prior tyrosine kinase inhibitor.66,67 Additionally, 69% of patients with EGFR mutations had previously received therapy with osimertinib.66,67 Safety end points for the trial include dose limiting toxicities and serious adverse events (AEs); efficacy end points include, but are not limited to, overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR).61 Resultant data demonstrated an ORR of 35% (95% CI, 19.7-53.5) as confirmed by blinded independent central review across all doses with a median DOR of 9.5 months.66,67 The most common any-grade AEs included stomatitis (56%) and nausea (62%).66,67 Drug-related hematological toxicities were infrequent.66,67 Investigators reported 1 incident of grade 5 interstitial lung disease (ILD) thatoccurred at the 8 mg/kg dosing level; this dose has since been discontinued.66,67

Interim trial data from a cohort of 44 patients with advanced or metastatic TNBC were presented at the annual San Antonio Breast Cancer Symposium on December 7, 2021.61 The median number of previous therapies in the metastatic setting was 3 (range, 1-10) with 41 patients having received at least 2 prior regimens (taxanes, 91%; platinum-based chemotherapy, 52%), immunotherapy (43%), PARP inhibitors (16%), and Topo I inhibitor-based ADC (30%).61 In patients treated with dato-DXd resultant data reported an ORR by BICR of 34% (15 of 44) and a disease control rate (DCR) of 77% (34 of 44).61,68 A subgroup analysis that included 27 patients who had not received prior therapy with a topoisomerase I inhibitor ADC revealed an ORR of 52% (14 of 27) following treatment with dato-DXd with a disease control rate (DCR) of 81% (22 of 27).61,68 Approximately 95% of patients experienced at least 1 treatment-emergent AE (TEAE), with 35% of patients experiencing a grade 3 or higher TEAE.68 TEAEs most commonly experienced among patients included nausea, stomatitis, alopecia, vomiting, and fatigue.69 Furthermore, dose reductions due to AEs were required in 18% of patients, 14% of patients experienced treatment interruption due to an AE, and no cases of ILD or fatal TEAEs were reported.61

Conclusion

Targetable biomarkers have improved the ability to selectively target tumor cells and have been a key factor in the development of novel ADCs.1,4 There is a growing interest in Trop-2 as a targetable biomarker in TNBC and NSCLC with the thought that Trop-2 inhibition may help improve outcomes for these patients.8,70,71 Emerging data from trials investigating the use of the novel anti-Trop-2 ADC dato-Dxd in solid tumors (eg, triple-negative breast cancer [TNBC] and non–small cell lung cancer [NSCLC]) demonstrated its potential to address unmet needs of FDA-approved sacituzumab govitecan by providing a tumor-selective delivery of a more potent payload, which resulted in favorable response rates and safety signals in heavily pretreated TNBC and NSCLC patient populations.20,55,61,66,68 These promising results warrant further investigation of dato-DXd in these patient populations and other solid tumors.


References

  1. Hafeez U, Parakh S, Gan HK, Scott AM. Antibody-drug conjugates for cancer therapy. Molecules. 2020;25(20):4764. doi:10.3390/molecules25204764
  2. Chae YK, Pan AP, Davis AA, et al. Path toward precision oncology: review of targeted therapy studies and tools to aid in defining "actionability" of a molecular lesion and patient management support. Mol Cancer Ther. 2017;16(12):2645-2655. doi:10.1158/1535-7163.MCT-17-0597
  3. LoRusso PM, Weiss D, Guardino E, Girish S, Sliwkowski MX. Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res. 2011;17(20):6437-6447. doi:10.1158/1078-0432.CCR-11-0762
  4. Dean AQ, Luo S, Twomey JD, Zhang B. Targeting cancer with antibody-drug conjugates: promises and challenges [published correction appears in MAbs. 2021 Jan-Dec;13(1):1966993]. MAbs. 2021;13(1):1951427. doi:10.1080/19420862.2021.1951427
  5. Trail PA, Dubowchik GM, Lowinger TB. Antibody drug conjugates for treatment of breast cancer: novel targets and diverse approaches in ADC design. Pharmacol Ther. 2018;181:126-142. doi:10.1016/j.pharmthera.2017.07.013
  6. Criscitiello C, Morganti S, Curigliano G. Antibody-drug conjugates in solid tumors: a look into novel targets. J Hematol Oncol. 2021;14(1):20. doi:10.1186/s13045-021-01035-z
  7. Jin S, Sun Y, Liang X, et al. Emerging new therapeutic antibody derivatives for cancer treatment. Signal Transduct Target Ther. 2022;7(1):39. doi:10.1038/s41392-021-00868-x
  8. Goldenberg DM, Stein R, Sharkey RM. The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget. 2018;9(48):28989-29006. doi:10.18632/oncotarget.25615
  9. Eiger D, Agostinetto E, Saúde-Conde R, de Azambuja E. The exciting new field of HER2-low breast cancer treatment. Cancers (Basel). 2021;13(5):1015. doi:10.3390/cancers13051015
  10. Hoffman-Censits JH, Lombardo KA, Parimi V, et al. Expression of nectin-4 in bladder urothelial carcinoma, in morphologic variants, and nonurothelial histotypes. Appl Immunohistochem Mol Morphol. 2021;29(8):619-625. doi:10.1097/PAI.0000000000000938
  11. Carlsson J, Nordgren H, Sjöström J, et al. HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review. Br J Cancer. 2004;90(12):2344-2348. doi:10.1038/sj.bjc.6601881
  12. Oh DY, Bang YJ. HER2-targeted therapies - a role beyond breast cancer. Nat Rev Clin Oncol. 2020;17(1):33-48. doi:10.1038/s41571-019-0268-3
  13. Kadcyla. Prescribing information. Genentech, Inc; 2013. Accessed January 13, 2022. https://www.gene.com/download/pdf/kadcyla_prescribing.pdf
  14. Barok M, Joensuu H, Isola J. Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Res. 2014;16(2):209. doi:10.1186/bcr3621
  15. Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2019. Accessed January 13, 2022. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true
  16. Kang MS, Kong TWS, Khoo JYX, Loh TP. Recent developments in chemical conjugation strategies targeting native amino acids in proteins and their applications in antibody-drug conjugates. Chem Sci. 2021;12(41):13613-13647. doi:10.1039/d1sc02973h
  17. O’Neill MJF. Nectin cell adhesion molecule 4; Nectin4. Online Mendelian Inheritance of Man. Updated May 8, 2017. Accessed February 4, 2022. https://www.omim.org/entry/609607
  18. Padcev. Prescribing information. Seagen Inc.; 2021. Accessed February 15, 2022. https://astellas.us/docs/PADCEV_label.pdf
  19. Shvartsur A, Bonavida B. Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer. 2015;6(3-4):84-105. doi:10.18632/genesandcancer.40
  20. Zaman S, Jadid H, Denson AC, Gray JE. Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther. 2019;12:1781-1790. doi:10.2147/OTT.S162447
  21. Strop P, Tran TT, Dorywalska M, et al. RN927C, a site-specific Trop-2 antibody-drug conjugate (ADC) with enhanced stability, is highly efficacious in preclinical solid tumor models. Mol Cancer Ther. 2016;15(11):2698-2708. doi:10.1158/1535-7163.MCT-16-0431
  22. Lin H, Huang JF, Qiu JR, et al. Significantly upregulated TACSTD2 and cyclin D1 correlate with poor prognosis of invasive ductal breast cancer. Exp Mol Pathol. 2013;94(1):73-78. doi:10.1016/j.yexmp.2012.08.004
  23. Kluger HM, Kluger Y, Gilmore-Hebert M, et al. cDNA microarray analysis of invasive and tumorigenic phenotypes in a breast cancer model. Lab Invest. 2004;84(3):320-331. doi:10.1038/labinvest.3700044
  24. King GT, Eaton KD, Beagle BR, et al. A phase 1, dose-escalation study of PF-06664178, an anti-Trop-2/Aur0101 antibody-drug conjugate in patients with advanced or metastatic solid tumors. Invest New Drugs. 2018;36(5):836-847. doi:10.1007/s10637-018-0560-6
  25. Ambrogi F, Fornili M, Boracchi P, et al. Trop-2 is a determinant of breast cancer survival. PLoS One. 2014;9(5):e96993. doi:10.1371/journal.pone.0096993
  26. Lei JT, Anurag M, Haricharan S, Gou X, Ellis MJ. Endocrine therapy resistance: new insights. Breast. 2019;48(suppl 1):S26-S30. doi:10.1016/S0960-9776(19)31118-X
  27. Li Y, Zhan Z, Yin X, Fu S, Deng X. Targeted therapeutic strategies for triple-negative breast cancer. Front Oncol. 2021;11:731535. doi:10.3389/fonc.2021.731535
  28. 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. 2017;35(24):2790-2797. doi:10.1200/JCO.2016.72.1894
  29. Meador CB, Hata AN. Acquired resistance to targeted therapies in NSCLC: updates and evolving insights. Pharmacol Ther. 2020;210:107522. doi:10.1016/j.pharmthera.2020.107522
  30. Resistance to chemotherapy in triple-negative breast cancer. Oncology Times. 2018;40(10):19. doi:10.1097/01.COT.0000534132.18270.c0
  31. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021 [published correction appears in CA Cancer J Clin. 2021 Jul;71(4):359]. CA Cancer J Clin. 2021;71(1):7-33. doi:10.3322/caac.21654
  32. Duma N, Santana-Davila R, Molina JR. Non-small cell lung cancer: epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc. 2019;94(8):1623-1640. doi:10.1016/j.mayocp.2019.01.013
  33. Min HY, Lee HY. Mechanisms of resistance to chemotherapy in non-small cell lung cancer. Arch Pharm Res. 2021;44:146-164. doi:10.1007/s12272-021-01312-y
  34. First-in-human study of DS-1062a in subjects with advanced solid tumors (TROPION-PanTumor01). ClinicalTrials.gov identifier: NCT03401385. Updated November 26, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT03401385
  35. A phase-3, open-label, randomized study of Dato-DXd versus investigator's choice of chemotherapy (ICC) in participants with inoperable or metastatic HR-positive, HER2-negative breast cancer who have been treated with one or two prior lines of systemic chemotherapy (TROPION-Breast01). ClinicalTrials.gov identifier: NCT05104866. Updated December 23, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT05104866
  36. Study of DS-1062a in advanced or metastatic non-small cell lung cancer with actionable genomic alterations (TROPION-Lung05). ClinicalTrials.gov identifier: NCT04526691. Updated December 20, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04484142
  37. Datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab with or without platinum chemotherapy in subjects with advanced or metastatic non-small cell lung cancer (TROPION-Lung02). ClinicalTrials.gov identifier: NCT04526691. Updated December 7, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04526691
  38. Datopotamab deruxtecan (Data-DXd) in combination with durvalumab with or without carboplatin in subjects with advanced or metastatic non-small cell lung cancer (TROPION-Lung04). ClinicalTrials.gov identifier: NCT751. Updated December 20, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04612751
  39. Study of DS-1062a versus docetaxel in previously treated advanced or metastatic non-small cell lung cancer without actionable genomic alterations (TROPION-LUNG01). ClinicalTrials.gov identifier: NCT04656652. Updated January 10, 2022. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04656652
  40. Datopotamab (DS-1062a) in Advanced and/or Unresectable Non-Small Cell Lung Cancer (ICARUS-LUNG01) ClinicalTrials.gov identifier: NCT04940325. Updated June 25, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04940325
  41. Clinical trials appendix Q3 2021 results update. AstraZeneca. Accessed February 15, 2022. https://www.astrazeneca.com/content/dam/az/PDF/2021/q3/Year-to-date_and_Q3_2021_results_clinical_trials_appendix.pdf
  42. A study of FDA018-ADC in patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT05174637. Updated January 3, 2022. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT05174637
  43. Shanghai Fudan-Zhangjiang’s FDA018-ADC enters phase I clinical trials. ADC Review. Accessed February 10, 2022. https://www.adcreview.com/uncategorized/shanghai-fudan-zhangjiangs-fda018-adc-enters-phase-i-clinical-trials/
  44. A phase I study of JS108 in patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT04601285. Updated April 22, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04601285
  45. Study of Sacituzumab Govitecan-hziy versus treatment of physician's choice in participants with HR+/HER2- metastatic breast cancer (TROPiCs-02). ClinicalTrials.gov identifier: NCT03901339. Updated November 11, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT03901339
  46. A study of sacituzumab govitecan (IMMU-132) in endometrial carcinoma. ClinicalTrials.gov identifier: NCT04251416. Updated December 28, 2020. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04251416
  47. Sacituzumab govitecan in primary HER2-negative breast cancer. ClinicalTrials.gov identifier: NCT04595565. Updated November 17, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04595565
  48. Asian study of sacituzumab govitecan (IMMU-132) in HR+/ HER2- MBC. ClinicalTrials.gov identifier: NCT04639986. Updated February 25, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04639986
  49. Testing sacituzumab govitecan therapy in patients with HER2-negative breast cancer and brain metastases. ClinicalTrials.gov identifier: NCT04647916. Updated November 9, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04647916
  50. Sacituzumab govitecan in patients with solid tumor. ClinicalTrials.gov identifier: NCT05119907. Updated November 15, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT05119907
  51. Alpelisib and sacituzumab govitecan for treatment of breast cancer (ASSET). ClinicalTrials.gov identifier: NCT05143229. Updated December 3, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT05143229
  52. Phase I-II, FIH, trop2 ADC, advanced unresectable/metastatic solid tumors, refractory to available standard therapies (A264). ClinicalTrials.gov identifier: NCT04152499. Updated January 11, 2022. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT04152499
  53. Liu Y, Lian W, Zhao X, et al. SKB264 ADC: A first-in-human study of SKB264 in patients with locally advanced unresectable/metastatic solid tumors who are refractory to available standard therapies [TPS3659]. Presented at: 2020 American Society of Clinical Oncology (ASCO) Annual Meeting I. Accessed January 13, 2022. https://ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.TPS3659
  54. Study to assess an anti-Trop2 antibody drug conjugate in relapsed or refractory solid tumors. ClinicalTrials.gov identifier: NCT05060276. Updated September 29, 2021. Accessed January 13, 2022. https://clinicaltrials.gov/ct2/show/record/NCT05060276
  55. Trodelvy. Prescribing information. Gilead Sciences, Inc; 2020. Accessed January 13, 2022. https://www.gilead.com/-/media/files/pdfs/medicines/oncology/trodelvy/trodelvy_pi.pdf
  56. Immunomedics awarded fast track designation by FDA for sacituzumab govitecan for non-small cell lung cancer therapy. Press release. Global News Wire. May 15, 2015. Accessed February 18, 2021. https://www.globenewswire.com/news-release/2015/05/15/736408/10134743/en/Immunomedics-Awarded-Fast-Track-Designation-by-FDA-for-Sacituzumab-Govitecan-for-Non-Small-Cell-Lung-Cancer-Therapy.html
  57. FDA grants accelerated approval to sacituzumab govitecan-hziy for advanced urothelial cancer News release. U.S. Food & Drug Administration. April 13, 2021. Accessed February 18, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-advanced-urothelial-cancer
  58. Adams E, Wildiers H, Neven P, Punie K. Sacituzumab govitecan and trastuzumab deruxtecan: two new antibody-drug conjugates in the breast cancer treatment landscape. ESMO Open. 2021;6(4):100204. doi:10.1016/j.esmoop.2021.100204
  59. Goldenberg DM, Sharkey RM. Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: a case study of anti-TROP-2 sacituzumab govitecan. MAbs. 2019;11(6):987-995. doi:10.1080/19420862.2019.1632115
  60. Menichetti R, Kanekal KH, Bereau T. Drug-membrane permeability across chemical space. ACS Cent Sci. 2019;5(2):290-298. doi:10.1021/acscentsci.8b00718
  61. Datopotamab deruxtecan continues to show promising durable response and disease control in patients with metastatic triple negative breast cancer. Press Release. Daiichi-Sankyo. December 7, 2021. Accessed February 18, 2022. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202112/20211207_E2.pdf
  62. 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. 2021;20(12):2329-2340. doi:10.1158/1535-7163.MCT-21-0206
  63. Shaffer, C. Trop2 deal heats up antibody–drug conjugate space in cancer. Nat Biotechnol. 2021;39:128-130. https://doi.org/10.1038/s41587-021-00824-8
  64. Helwick C. Datopotamab deruxtecan shows activity in advanced triple-negative breast cancer. The ASCO Post. February 10, 2022. Accessed February 15, 2022. https://ascopost.com/issues/february-10-2022/datopotamab-deruxtecan-shows-activity-in-advanced-triple-negative-breast-cancer/
  65. Clinical trials, study results and plain language results summaries. Daiichi Sankyo. Accessed February 15, 2022. https://www.daiichisankyo.com/rd/clinical_trials/list/
  66. Dobkowski D. Datopotamab deruxtecan shows safe antitumor activity in advanced NSCLC with genomic alterations. Cancer Network. Accessed February 5, 2021. https://www.cancernetwork.com/view/datopotamab-deruxtecan-shows-safe-antitumor-activity-in-advanced-nsclc-with-genomic-alterations
  67. Garon E. 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. Abstract presented at: The European Society for Medical Oncology Congress 2021; September 19, 2021; Paris, France, Virtual. Accessed February 21, 2022. https://oncologypro.esmo.org/meeting-resources/esmo-congress/efficacy-of-datopotamab-deruxtecan-dato-dxd-in-patients-pts-with-advanced-metastatic-adv-met-non-small-cell-lung-cancer-nsclc-and-actionabl
  68. Ryan C. Datopotamab deruxtecan produces encouraging clinical activity in advanced TNBC. OncLive®. December 8, 2021. Accessed February 15, 2022. https://www.onclive.com/view/datopotamab-deruxtecan-produces-encouraging-clinical-activity-in-advanced-tnbc
  69. Krop I, Juric D, Shimizu T, et al. Datopotamab deruxtecan in advanced/metastatic HER2- breast cancer: results from the phase 1 TROPION-PanTumor01 study. Abstract presented at: The San Antonio Breast Cancer Symposium; December 7-10, 2021. San Antonio, TX. Accessed February 15, 2022. https://www.abstractsonline.com/pp8/#!/10462/presentation/2164
  70. Vidula N, Bardia A. Targeted therapy for metastatic triple negative breast cancer: The next frontier in precision oncology. Oncotarget. 2017;8(63):106167-106168. doi:10.18632/oncotarget.22580
  71. Huang H, Groth J, Sossey-Alaoui K, Hawthorn L, Beall S, Geradts J. Aberrant expression of novel and previously described cell membrane markers in human breast cancer cell lines and tumors. Clin Cancer Res. 2005;11(12):4357-4364. doi:10.1158/1078-0432.CCR-04-2107

Related Content:

Expert Perspectives on Trop-2 Biomarker Expression in Lung Cancer and the Potential Role of Dato-DXd
Clinical Advancements of Targeted Antibody-Drug Conjugates in Breast and Lung Cancer