TROP2

  • Tumor-associated calcium signal transducer 2 (TROP2 or TACSTD2)
  • Gene Location: Chromosome 1p32.1

Biology

  • TROP2 is a transmembrane glycoprotein encoded by the TACSTD2 gene that plays a role in calcium signaling and the maintenance of epithelial integrity.1
  • TROP2 is commonly overexpressed in a broad range of epithelial tumors, including non‒small cell lung cancer (NSCLC).1,2
  • Overexpression of TROP2 has been correlated with invasive tumor behavior, increased proliferation, and worse survival in patients with NSCLC.2,3
  • TROP2 may function as both a prognostic biomarker and antibody-drug conjugate (ADC)target.2,3
  • Inepidermal growth factor receptor(EGFR)-mutant NSCLC, high baseline TROP2 expression has been linked to EGFR tyrosine kinase inhibitor (TKI) resistance through activation of the IGF2/IGF1R–AKT signaling pathway.4
  • Elevated TROP2 expression has been associated with resistance to immune checkpoint inhibitors in NSCLC, potentially by promoting an immunosuppressive tumor microenvironment and impairing antitumor immune responses.5

Etiology and Epidemiology

  • TROP2 is expressed in approximately 40% to 85% of NSCLC cases, with the highest levels seen in squamous cell carcinoma.2,3
  • In adenocarcinoma, higher TROP2 expression correlates with more advanced stage and higher tumor grade.2
  • In EGFR-mutated NSCLC, increased baseline TROP2 correlates with TKI resistance.5

Testing

When to Test:

  • Testing may be considered in advanced or treatment-refractory NSCLC, particularly for clinical trial consideration for TROP2-targeted therapy.6,7
  • TROP2 testing may be especially useful in patients with no actionable driver mutations, where it may help inform treatment selection as emerging assessment tools, such as quantitative immunohistochemistry and normalized membrane ratio (NMR), enhance biomarker precision. However, these testing methods remain investigational and are not yet standardized across laboratories.8

Testing Methodologies:

  • Immunohistochemistry remains the primary method to assess TROP2 protein expression.3
  • Tumors expressing 2+/3+ intensity in greater than or equal to 10% of cells are defined as TROP2-high and suitable for investigative agents.2,3
  • Quantitative continuous scoring (QCS) is an emerging investigational approach that employs digital pathology algorithms to calculate the NMR, enabling more precise differentiation of membrane-specific vs cytoplasmic TROP2 staining and improving biomarker quantification.8
  • Data from the TROPION-LUNG01 (NCT04656652)trial indicate that NMR-based scoring can effectively identify patients with high TROP2 membrane expression, which correlates with better clinical responses to datopotamabderuxtecan (Dato-DXd).8,9
  • While higher TROP2 membrane expression correlates with improved response to Dato-DXd, clinical responses have also been observed across a range of expression levels.
  • This scoring method is being further explored in ongoing clinical studies to validate its predictive utility across broader NSCLC populations.8

Guideline Recommendations

  • As of 2024, routine TROP2 testing is not yet part of NCCN or ASCO guidelines, and testing remains focused on established driver alterations (e.g., EGFR, ALK, ROS1).
  • However, TROP2 assessment is increasingly important for clinical trial eligibility, and emerging QCS methods may soon provide more insight into TROP NMR as a tool to guide treatment decision making.3,4,9

Targeted Therapy

Approved Agents

  • On June 23, 2025, the US Food and Drug Administration granted accelerated approval to datopotamabderuxtecan-dlnk (Dato-DXd) for the treatment of adults with locally advanced or metastatic NSCLC harboring EGFR mutations who have previously received both an EGFR-targeted therapy and platinum-based chemotherapy.
  • Approval was based on pooled data from the TROPION-LUNG01 (NCT04656652) and TROPION-Lung05 (NCT04484142) trials, which demonstrated clinically meaningful antitumor activity, durable responses, and a manageable safety profile in patients with previously treated EGFR-mutated NSCLC.10-12
  • Approval is contingent on confirmatory evidence from the ongoing TROPION-Lung15 (NCT06417814)trial, a randomized phase 3study evaluating Dato-DXd vs investigator’s choice of chemotherapy in the same EGFR-mutant, post-TKI setting.13

Datopotamab deruxtecan-dlnk3,10

  • FDA-Approved Indication:
    • Adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non‒small cell lung cancer (NSCLC) who have received prior EGFR-directed therapy and platinum-based chemotherapy.
    • This indication is approved under accelerated approval based on objective response rate and duration of response.
    • Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.
  • Mechanism of Action:
    • Dato-DXd is a TROP2-directed ADC composed of a humanized IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload.
    • Dato-DXd binds to TROP2 on the surface of tumor cells, internalizes, and delivers the cytotoxic payload within lysosomes.
    • The payload induces DNA damage, leading to tumor cell death; antitumor activity is generally greater in tumors with higher TROP2 expression, although responses can occur across expression levels.
    • Off-target toxicity is relatively limited; however, some normal tissues express TROP2 at low levels, which can contribute to certain adverse events such as stomatitis and ocular toxicity.
  • Drug Information:
  • Patient Resources:

References

  1. 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
  2. Kuo P, Elboudwarej E, Zavodovskaya M, et al. Trop-2 expression in non-small cell lung cancer. PLoS One. 2025;20(4):e0321555. Published April 15, 2025. doi:10.1371/journal.pone.0321555
  3. Pak MG, Shin DH, Lee CH, Lee MK. Significance of EpCAM and TROP2 expression in non-small cell lung cancer. World J Surg Oncol.2012;10:53. doi:10.1186/1477-7819-10-53
  4. Sun X, Jia L, Wang T, Zhang Y, et al. Trop2 binding IGF2R induces gefitinib resistance in NSCLC by remodeling the tumor microenvironment. J Cancer. 2021;12(17):5310-5319. doi:10.7150/jca.57711
  5. Bessede A, Peyraud F, Besse B, et al. TROP2 is associated with primary resistance to immune checkpoint inhibition in patients with advanced non-small cell lung cancer. Clin Cancer Res. 2024;30(4):779-785. doi:10.1158/1078-0432.CCR-23-2566
  6. Novel Computational Pathology-Based TROP2 Biomarker for DatopotamabDeruxtecan Was Predictive of Clinical Outcomes in Patients with Non-Small Cell Lung Cancer in TROPION-Lung01 Phase 3 Trial. Press release.Daiichi-Sankyo and AstraZeneca. September 8, 2024. Accessed June 24, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202409/20240908_E.pdf 
  7. DatopotamabDeruxtecan Granted Priority Review in the US for Patients with Previously Treated Advanced EGFR-Mutated Non-Small Cell Lung Cancer. Press release. Daiichi-Sankyo and AstraZeneca. January 13,2025. Accessed June 24, 2025. https://daiichisankyo.us/press-releases/-/article/datopotamab-deruxtecan-granted-priority-review-in-the-u-s-for-patients-with-previously-treated-advanced-egfr-mutated-non-small-cell-lung-cancer 
  8. Garassino MC, Sands J, Paz-Ares L, et al. Normalized membrane ratio of TROP2 by quantitative continuous scoring is predictive of clinical outcomes in TROPION-Lung01. 2024 World Conference on Lung Cancer. Abstract PL02.11. Presented September 8, 2024. Accessed June 26, 2025. https://www.jto.org/article/S1556-0864(24)00889-X/abstract 
  9. Study of DS-1062a versus docetaxel in previously treated advanced or metastatic non-small cell lung cancer with or without actionable genomic alterations (TROPION-LUNG01). Clinicaltrials.gov. Updated March 30, 2025. Accessed June 24, 2025. https://clinicaltrials.gov/study/NCT04656652
  10. Garon E, Johnson M, Lisberg A, et al. MA03.02 TROPION-PanTumor01: Updated results from the NSCLC cohort of the phase 1 study of datopotamabderuxtecan in solid tumors. J Thoracic Oncol. 2021;16(10):S892-S893. https://www.jto.org/article/S1556-0864(21)02541-7/fulltext
  11. Study of DS-1062a in advanced or metastatic non-small cell lung cancer with actionable genomic alterations (TROPION-Lung05). ClinicalTrials.gov. Updated June 3, 2025. Accessed June 26, 2025. https://clinicaltrials.gov/study/NCT04484142 
  12. Ahn MJ, Sands J, Lisberg AE, et al. Efficacy and safety of datopotamabderuxtecan (Dato-DXd) in patients (pts) with previously-treatedEGFR-mutated advanced non-small cell lung cancer (NSCLC): a pooled analysis of TROPION-Lung01 and TROPION-Lung05. Ann Oncol. 2024;35(suppl 4):S1630-S1631.
  13. A study to investigate the efficacy and safety of dato-DXd with or without osimertinib compared with platinum based doublet chemotherapy in participants with EGFR-mutated locally advanced or metastatic non-small cell lung cancer (TROPION-Lung15). ClinicalTrials.gov. Updated June 5, 2025. Accessed June 26, 2025. https://clinicaltrials.gov/study/NCT06417814