Datopotamab deruxtecan: Expanding treatment options for patients with EGFR-positive non-small cell lung cancer

Despite significant advances in the treatment of patients with EGFR-positive metastatic non-small cell lung cancer (NSCLC), a number of unanswered questions remain. EGFR tyrosine kinase inhibitors (EGFR TKIs), both monotherapy and in combination regimens, are undoubtedly the optimal first-line therapy and can significantly improve long-term outcomes. After disease progression with targeted therapy, we typically use standard platinum-based therapy or a quadruple regimen (atezolizumab, paclitaxel, carboplatin, and bevacizumab), which limits our options. Further treatment is limited to cytostatics, typically used alone, with expectedly low efficacy. Thus, there is an unmet need for subsequent lines of therapy for these patients. The objective of this study was to present the results of clinical and preclinical studies of datopotamab deruxtecan to confirm its benefit in patients with metastatic EGFR-positive NSCLC. The phase I clinical trials TROPION-PanTumor01 and TROPION-PanTumor02 demonstrated encouraging results and satisfactory tolerability in a cohort of patients with NSCLC. In the randomized TROPION LUNG01 study, datopotamab deruxtecan, administered at a dose of 6 mg/kg intravenously every 3 weeks, was compared with docetaxel in a population of previously treated patients with non-small cell lung cancer. The clear advantage of datopjtamab over docetaxel, especially in patients with EGFR mutations, led to its further study in this cohort of patients in the Phase II TROPION LUNG 05 trial. Subsequently, a pooled analysis of the efficacy of datopotamab deruxtecan was conducted in EGFR-positive patients participating in the TROPION LUNG01/05 trials. Datopotamab demonstrated the best results to date in terms of immediate efficacy, progression-free survival, and overall survival in pretreated EGFR-positive patients. The drug was well-tolerated. These results led to the approval of datopotamab deruxtecan for clinical use in patients with EGFR-positive NSCLC following progression on EGFR-TKIs and platinum-based chemotherapy, opening the door to further personalized therapy.

1. Laktionov KK, Artamonova EV, Breder VV, Gorbunova VA, Demidova IA, Dengina NV et al. Non-small cell lung cancer. Malignant Tumours. 2024;14(3s2-1):65–104. (In Russ.) https://doi.org/10.18027/2224-5057-2024-14-3s2-1.1-04.

2. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113–125. https://doi.org/10.1056/NEJMoa1713137.

3. Jänne PA, Planchard D, Kobayashi K, Yang JC, Liu Y, Valdiviezo N et al. Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2025. https://doi.org/10.1056/NEJMoa2510308.

4. Nogami N, Barlesi F, Socinski MA, Reck M, Thomas CA, Cappuzzo F et al. IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain. J Thorac Oncol. 2022;17(2):309–323. https://doi.org/10.1016/j.jtho.2021.09.014.

5. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22(9):1589–1597. https://doi.org/10.1200/JCO.2004.08.163.

6. Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000;18(12):2354–2362. https://doi.org/10.1200/JCO.2000.18.12.2354.

7. Gadgeel S, Wang E, Phani S, Wu C, Salas M, Meng J et al. EP12.01-64 Metastatic Non-Small Cell Lung Cancer With EGFR Mutations: Treatment Pattern and Outcomes From a Systematic Literature Review. J Thorac Oncol. 2023;18(11 Suppl.):S667. https://doi.org/10.1016/j.jtho.2023.09.1280.

8. Inamura K, Yokouchi Y, Kobayashi M, Ninomiya H, Sakakibara R, Subat S et al. Association of tumor TROP2 expression with prognosis varies among lung cancer subtypes. Oncotarget. 2017;8(17):28725–28735. https://doi.org/10.18632/oncotarget.15647.

9. Abuhelwa Z, Alloghbi A, Nagasaka M. A comprehensive review on antibody-drug conjugates (ADCs) in the treatment landscape of non-small cell lung cancer (NSCLC). Cancer Treat Rev. 2022;106:102393. https://doi.org/10.1016/j.ctrv.2022.102393.

10. Okajima D, Yasuda S, Maejima T, Karibe T, Sakurai K, Aida 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. https://doi.org/10.1158/1535-7163.MCT-21-0206.

11. Kaplon H, Crescioli S, Chenoweth A, Visweswaraiah J, Reichert JM. Antibodies to watch in 2023. MAbs. 2023;15(1):2153410. https://doi.org/10.1080/19420862.2022.2153410.

12. Nakada T, Sugihara K, Jikoh T, Abe Y, Agatsuma T. The Latest Research and Development into the Antibody-Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy. Chem Pharm Bull. 2019;67(3):173–185. https://doi.org/10.1248/cpb.c18-00744.

13. Shimizu T, Sands J, Yoh K, Spira A, Garon EB, Kitazono S et al. First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01. J Clin Oncol. 2023;41(29):4678–4687. https://doi.org/10.1200/JCO.23.00059.

14. Sun Y, Xio Z, Cheng Y, Li J, Tu H-Y, Long J et al. Datopotamab deruxtecan (Dato-DXd) in Chinese patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): results from the phase 1/2 TROPION-pantumor02 study. J Clin Oncol. 2024;42(16 Suppl.):8548. https://doi.org/10.1200/JCO.2024.42.16_suppl.8548.

15. Ahn M-J, Lisberg AE, Paz-Ares L, Cornelissen R, Girard N, Pons-Tostivint E et al. LBA12 Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): Results of the randomized phase III study TROPION-Lung01. Ann Oncol. 2023;34(Suppl. 2):S1305–S1306. https://doi.org/10.1016/j.annonc.2023.10.061.

16. Ahn MJ, Tanaka K, Paz-Ares L, Cornelissen R, Girard N, Pons-Tostivint E et al. Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study. J Clin Oncol. 2025;43(3):260–272. https://doi.org/10.1200/JCO-24-01544.

17. Pons-Tostivint E, Okamoto I, Ahn M-J, Girard N, Cornelissen R, Hong M-H et al. OA10.01 Intracranial Efficacy of Datopotamab Deruxtecan (Dato-DXd) in Patients With Advanced/Metastatic NSCLC in TROPION-Lung01. J Thorac Oncol. 2025;20(10):S30–S31. https://doi.org/10.1016/j.jtho.2025.09.061.

18. Planchard D, Cozic N, Wislez M, Chouaid, C, Curcio H, Cousin S et al. ICARUS-LUNG01: a phase 2 study of datopotomab deruxtecan (Dato-DXd) in patients with previously treated advanced non-small cell lung cancer (NSCLC), with sequential tissue biopsies and biomarkers analysis to predict treatment outcome. J Clin Oncol. 2024;42(16 Suppl.):8501. https://doi.org/10.1200/JCO.2024.42.16_suppl.8501.

19. Sands J, Ahn MJ, Lisberg A, Cho BC, Blumenschein G Jr, Shum E et al. Datopotamab Deruxtecan in Advanced or Metastatic Non-Small Cell Lung Cancer With Actionable Genomic Alterations: Results From the Phase II TROPION-Lung05 Study. J Clin Oncol. 2025;43(10):1254–1265. https://doi.org/10.1200/JCO-24-01349.

20. Lisberg A, Ahn M-Ju, Kitazono S, Cho B, Blumenschein G, Shum E et al. Intracranial efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously treated advanced/metastatic non-small cell lung cancer (a/m NSCLC) with actionable genomic alterations (AGA): Results from TROPION-Lung05. J Clin Oncol. 2024;42(16 Suppl.):8593. https://doi.org/10.1200/JCO.2024.42.16_suppl.8593.

21. Ahn MJ, Lisberg A, Goto Y, Sands J, Hong MH, Paz-Ares L et al. A Pooled Analysis of Datopotamab Deruxtecan in Patients With EGFR-Mutated NSCLC. J Thorac Oncol. 2025;20(11):1669–1682. https://doi.org/10.1016/j.jtho.2025.06.002.

22. Jones K, Suksomboon M, Rosenthal SA, Gordon J, Reimer C, Sung M, Rane Ch. Abstract 1911: Dato-DXd mediates anti-tumor activity in preclinical TROP2-expressing intracranial tumor model. Cancer Res. 2024;84(6 Suppl.):1911. https://doi.org/10.1158/1538-7445.AM2024-1911.

23. Cho BC, Lu S, Felip E, Spira AI, Girard N, Lee JS et al. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med. 2024;391(16):1486–1498. https://doi.org/10.1056/NEJMoa2403614.

24. Nadal E, Cheema PK, Wu Y-L, Ahn M-J,∙Tanizaki J, Gharagoozloo S et al. 124TiP: TROPION-Lung15: A phase III study of datopotamab deruxtecan (Dato-DXd) ± osimertinib vs platinum doublet chemotherapy in patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) and disease progression on prior osimertinib. J Thorac Oncol. 2025;20(3 Suppl. 1):S87–S88. https://doi.org/10.1016/s1556-0864(25)00319-3.

25. Goldberg SB, Provencio Pulla M, Lisberg AE, Mascarenhas E, Tanizaki J, Cheng Y et al. 123TiP: TROPION-Lung14: A phase III study of osimertinib ± datopotamab deruxtecan (Dato-DXd) as first-line (1L) treatment for patients with EGFR-mutated locally advanced or metastatic (LA/M) non-small cell lung cancer (NSCLC). J Thorac Oncol. 2025;20(3 Suppl. 1):S86–S87. https://doi.org/10.1016/S1556-0864(25)00318-1.

26. Paz-Ares LG, Juan-Vidal O, Mountzios GS, Felip E, Reinmuth N, de Marinis F et al. Sacituzumab Govitecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III EVOKE-01 Study. J Clin Oncol. 2024;42(24):2860–2872. https://doi.org/10.1200/JCO.24.00733.

27. Yu HA, Goto Y, Hayashi H, Felip E, Chih-Hsin Yang J, Reck M et al. HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy. J Clin Oncol. 2023;41(35):5363–5375. https://doi.org/10.1200/JCO.23.01476.

28. Mok T, Jänne PA, Nishio M, Novello S, Reck M, Steuer C et al. HERTHENA-Lung02: phase III study of patritumab deruxtecan in advanced EGFR-mutated NSCLC after a third-generation EGFR TKI. Future Oncol. 2024;20(15):969–980. https://doi.org/10.2217/fon-2023-0602.