Trophoblast cell-surface antigen 2-targeted “sacituzumab tirumotecan”: a new approach for epidermal growth factor receptor-tyrosine kinase inhibitor-resistant non-small cell lung cancer

In non-small-cell lung cancer (NSCLC), anticancer drug therapy is typically personalized based on targetable driver gene mutations (1,2). Activating mutations in the epidermal growth factor receptor (EGFR) gene occur in approximately 30% of patients with NSCLC in East Asian countries and 10‒15% of those in Western countries and are generally mutually exclusive with other driver mutations (3). The FLAURA2 trial demonstrated that first-line treatment with osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI), in combination with pemetrexed plus platinum-based chemotherapy significantly improved progression-free survival (PFS) and overall survival (OS) compared with osimertinib monotherapy [hazard ratio (HR) for death, 0.77; 95% confidence interval (CI): 0.61–0.96; P=0.02; median OS, 47.5 vs. 37.6 months] (4). Similarly, the combination of lazertinib, a third-generation EGFR-TKI, and amivantamab, an EGFR/MET bispecific antibody, demonstrated superior PFS and OS compared with osimertinib alone (HR for death, 0.75; 95% CI: 0.61–0.92; P=0.005; median OS, not estimable vs. 36.7 months) (5). Following the emergence of resistance to EGFR-TKIs, pemetrexed plus platinum-based chemotherapy has been widely adopted in clinical practice. Alternatively, in patients with non-central nervous system progression after osimertinib monotherapy, continuation on osimertinib with pemetrexed plus platinum-based chemotherapy markedly prolonged PFS compared with placebo and pemetrexed plus platinum-based chemotherapy in the COMPEL trial (HR, 0.43; 95% CI: 0.27–0.70; median PFS, 8.4 vs. 4.4 months) (6). However, the efficacy of immune checkpoint inhibitors (ICIs) in EGFR-mutant NSCLC remains limited, and outcomes in the second-line and later settings are suboptimal (7). In the phase 3 OptiTROP-Lung04 trial, sacituzumab tirumotecan (sac-TMT) demonstrated superior efficacy compared with pemetrexed plus platinum-based chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC with resistance to EGFR-TKIs (8).

Sac-TMT is an antibody-drug conjugate (ADC) targeting trophoblast cell-surface antigen 2 (Trop-2) and conjugated with a belotecan-derived topoisomerase I inhibitor (9). Trop-2 is highly expressed in EGFR-mutated NSCLC cells and is associated with EGFR-TKI resistance (10). Notably, EGFR mutations have been shown to markedly enhance internalization and lysosomal uptake of sac-TMT in NSCLC cells (11). In the phase 3 OptiTROP-Lung04 study, 376 patients were randomly assigned (1:1) to receive sac-TMT monotherapy (administered intravenously at 5 mg/kg body weight on days 1 and 15 of each 28-day cycle) or pemetrexed plus platinum-based chemotherapy (8). The primary endpoint was PFS, as assessed by a blinded independent review committee. The trial was adequately powered to evaluate PFS, with OS as a key secondary endpoint tested hierarchically (8).

In the interim analysis of PFS, sac-TMT monotherapy met the prespecified significance criterion (two-sided P<0.0001). The report presents the final PFS analysis and the planned interim OS analysis (8). After a median follow-up of 18.9 months, median PFS was 8.3 months in the sac-TMT group and 4.3 months in the chemotherapy group (HR for disease progression or death, 0.49; 95% CI: 0.39–0.62). The PFS benefit of sac-TMT was consistent across prespecified subgroups, including those defined by sex, age, smoking history, or type of EGFR mutation. In patients with brain metastases, the HR was 0.73 (95% CI: 0.43–1.21). Despite the limited sample size (n=69), the HR for disease progression or death favored sac-TMT in patients with brain metastases (8). However, the difference was not statistically significant, and the wide CIs preclude definitive conclusions regarding the efficacy of sac-TMT in this subgroup.

Nevertheless, the findings should be interpreted with caution, as the study population was limited to Asians in China. Consequently, the generalizability of these results to other populations remains uncertain, and regional differences in healthcare systems may influence study outcomes. Furthermore, current National Comprehensive Cancer Network (NCCN) and other guidelines recommend third-generation EGFR-TKIs as first-line treatment for EGFR-mutated NSCLC (12-14). Notably, approximately 30% of patients in this trial received third-generation EGFR-TKIs as second-line therapy after acquisition of the T790M mutation, a treatment pattern that differs from the current standard of care in many regions. Therefore, caution is warranted when extrapolating these findings to populations outside China.

In phase 3 clinical trials of other novel therapies for patients with EGFR-mutant NSCLC previously treated with EGFR-TKIs, prolonged PFS has been reported compared with that achieved with standard chemotherapy (15-18) (Table 1). However, differences in patient characteristics, treatment lines, and control-group regimens preclude reliable cross-trial comparisons, and randomized head-to-head studies are necessary to eliminate bias. Although several novel therapeutic approaches, including bispecific antibodies, ICIs, and ADCs, have demonstrated promising clinical activity, only ivonescimab has been shown to improve OS compared with standard chemotherapy (19). Meanwhile, sac-TMT demonstrated an OS benefit in the prespecified interim analysis of the phase 3 OptiTROP-Lung04 trial (Table 1). Compared with standard chemotherapy, sac-TMT reduced the risk of death by 40% (HR, 0.60; 95% CI: 0.44–0.82; two-sided P=0.001), with 18-month OS rates of 65.8% and 48.0%, respectively (8). Improvement in OS may be an advantage of sac-TMT over other novel therapeutics. Patritumab deruxtecan (HER3-DXd), a HER3-targeted ADC, is another ADC developed for the treatment of EGFR-mutated NSCLC. HER3 is highly expressed in EGFR-mutant NSCLC, and its expression has been shown to increase following EGFR-TKI therapy (15,20). Although HER3-DXd markedly prolonged PFS compared with standard platinum-based chemotherapy in a phase 3 clinical trial of patients with EGFR-mutated NSCLC after progression on third-generation EGFR-TKI therapy, it did not improve OS (15). Therefore, even with ADC therapy, clinical outcomes are not necessarily superior to those achieved with conventional chemotherapy, and further advances in biomarker research are needed to elucidate the mechanisms underlying the efficacy of sac-TMT.

To date, multiple large-scale comparative clinical trials have evaluated three Trop-2-targeting ADCs, namely, datopotamab deruxtecan (Dato-DXd), sacituzumab govitecan, and sac-TMT, in NSCLC (Table 2) (9,21,22). Sac-TMT demonstrated an OS benefit not only in this phase 3 clinical trial but also in a randomized phase 2 trial comparing it with docetaxel as a third-line treatment for EGFR-mutated NSCLC (8,23). In contrast, the ADCs Dato-DXd and sacituzumab govitecan failed to demonstrate an OS benefit in phase 3 clinical trials comparing them with docetaxel in a third-line setting for NSCLC (24,25). Both ADCs demonstrated efficacy against Trop-2-expressing cancers and have been shown to yield superior efficacy compared with chemotherapy in phase 3 clinical trials for breast cancer (22). The favorable clinical outcomes observed with sac-TMT in NSCLC may be attributable not only to its antitumor efficacy but also to the selection of patients with EGFR-mutated NSCLC (8). Interestingly, preclinical studies demonstrated enhanced internalization and lysosomal trafficking of sac-TMT in cells transfected with EGFR 19del or L858R mutations compared with cells expressing wild-type EGFR (11). The positive results observed in the phase 3 clinical trial may be attributable to its unique ability to undergo internalization and trafficking in EGFR-mutated NSCLC cells. Alternatively, elevated Trop-2 expression in EGFR-mutated lung cancer may contribute to the efficacy of Trop-2-targeting ADCs (10). However, biomarker analyses from previous clinical trials of Trop-2-targeting ADCs in lung cancer have not identified Trop-2 expression as a reliable predictor of treatment efficacy (26). In contrast, the anticancer activity of Dato-DXd has been associated with the normalized membrane ratio (NMR), defined as the ratio of membrane-to-cytoplasmic Trop-2 expression in tumor cells (27,28). Specifically, a study using multiple NSCLC cell lines revealed that intracellular uptake of datopotamab was more strongly associated with TROP2 NMR than with the level of cell-surface Trop-2 expression (27). In addition, TROP2-NMR was associated with the anticancer activity of Dato-DXd (27). In a clinical trial involving patients with NSCLC, Dato-DXd was associated with a favorable PFS HR compared with docetaxel in the Quantitative Continuous Scoring (QCS)-NMR (+) subgroup (HR, 0.57; 95% CI: 0.41–0.79) (28). However, this benefit was not observed in the QCS-NMR (−) subgroup (PFS HR,1.16; 95% CI: 0.79–1.70) (28). These findings suggest that the efficacy of Trop-2-targeting ADCs may be influenced more by ADC internalization than by the level of cell-surface Trop-2 expression.

Sac-TMT may be associated with a more favorable safety and tolerability profile than chemotherapy. In the phase 3 clinical trial, treatment-related serious adverse events occurred less frequently with sac-TMT than with chemotherapy (9.0% vs. 17.6%) (8), and no treatment-related adverse events led to treatment discontinuation in the sac-TMT group (8). However, neutropenia was the most common grade ≥3 treatment-related adverse event and occurred more frequently with sac-TMT than with chemotherapy (39.9% vs. 33.0%, respectively) (8). Specifically, stomatitis occurred more frequently with sac-TMT than with chemotherapy (64.4% vs. 4.9%, respectively). Dose reductions due to stomatitis were required in 10.1% of patients receiving sac-TMT. Stomatitis is also a common adverse event associated with other Trop-2-targeting ADCs (24). Trop-2 is expressed not only in tumor cells but also in normal salivary gland epithelium, suggesting that on-target toxicity to normal epithelial cells may contribute to Trop-2-ADC-associated stomatitis (29,30). Ocular surface toxicities, including dry eye syndrome, increased lacrimation, and keratitis, occurred in 9.6% of patients receiving sac-TMT and in 0.5% of those receiving chemotherapy; no grade ≥3 events were reported (8). Similarly, ocular surface toxicities have been reported with Dato-DXd, another Trop-2-targeting ADC (24). Although stomatitis and ocular surface toxicities associated with sac-TMT are generally not severe, they may substantially affect quality of life owing to reduced food intake and pain.

In conclusion, sac-TMT may represent a novel therapeutic option for patients with EGFR-mutant NSCLC following EGFR-TKI treatment. The observed OS benefit in the interim analysis may be an advantage, and the treatment was generally well-tolerated. However, the phase 3 OptiTROP-Lung04 trial was conducted exclusively in China and enrolled only Asian patients (8). Accordingly, the results should be interpreted with caution when extrapolated to other populations. To facilitate the broader adoption of sac-TMT in clinical practice for EGFR-mutant NSCLC, global clinical trials involving more diverse patient populations are needed. In addition, biomarker research may help identify patient subgroups most likely to benefit from this treatment. Beyond EGFR-mutant cases, sac-TMT may also have therapeutic potential in combination with ICIs. In the OptiTROP-Lung05 trial, sac-TMT plus pembrolizumab significantly improved PFS compared with pembrolizumab alone in patients with programmed death ligand-1 (PD-L1)-positive advanced NSCLC (HR, 0.35; 95% CI: 0.26–0.47; P<0.0001) (31). Although this trial was also conducted exclusively in an Asian population, the findings suggest that sac-TMT may have broader clinical applicability beyond EGFR-mutated NSCLC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0584/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0584/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Tang FH, Wong HYT, Tsang PSW, et al. Recent advancements in lung cancer research: a narrative review. Transl Lung Cancer Res 2025;14:975-90. [Crossref] [PubMed]
2. Tahayneh K, Idkedek M, Abu Akar F. NSCLC: Current Evidence on Its Pathogenesis, Integrated Treatment, and Future Perspectives. J Clin Med 2025;14:1025. [Crossref] [PubMed]
3. Gibson AJW, D'Silva A, Elegbede AA, et al. Impact of Asian ethnicity on outcome in metastatic EGFR-mutant non-small cell lung cancer. Asia Pac J Clin Oncol 2019;15:343-52. [Crossref] [PubMed]
4. Jänne PA, Planchard D, Kobayashi K, et al. Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med 2026;394:27-38. [Crossref] [PubMed]
5. Yang JC, Lu S, Hayashi H, et al. Overall Survival with Amivantamab-Lazertinib in EGFR-Mutated Advanced NSCLC. N Engl J Med 2025;393:1681-93. [Crossref] [PubMed]
6. Peled N, Tufman A, Sequist LV, et al. COMPEL: osimertinib plus platinum-based chemotherapy in patients with EGFR-mutated advanced NSCLC and progression on first-line osimertinib. ESMO Open 2025;10:105807.
7. Zhou F, Guo H, Xia Y, et al. The changing treatment landscape of EGFR-mutant non-small-cell lung cancer. Nat Rev Clin Oncol 2025;22:95-116. [Crossref] [PubMed]
8. Fang W, Wu L, Meng X, et al. Sacituzumab Tirumotecan in EGFR-TKI-Resistant, EGFR-Mutated Advanced NSCLC. N Engl J Med 2026;394:13-26. [Crossref] [PubMed]
9. Cheng Y, Yuan X, Tian Q, et al. Preclinical profiles of SKB264, a novel anti-TROP2 antibody conjugated to topoisomerase inhibitor, demonstrated promising antitumor efficacy compared to IMMU-132. Front Oncol 2022;12:951589. [Crossref] [PubMed]
10. Baldacci S, Brea EJ, Facchinetti F, et al. Eradicating Drug-tolerant Persister Cells in EGFR-Mutated Non-Small Cell Lung Cancer by Targeting TROP2 with CAR-T Cellular Therapy. Cancer Discov 2025;15:2235-50. [Crossref] [PubMed]
11. Zhao S, Cheng Y, Wang Q, et al. Sacituzumab tirumotecan in advanced non-small-cell lung cancer with or without EGFR mutations: phase 1/2 and phase 2 trials. Nat Med 2025;31:1976-86. [Crossref] [PubMed]
12. Ganti AKP, Loo BW Jr, Badiyan S, et al. NCCN Guidelines® Insights: Small Cell Lung Cancer, Version 2.2026. J Natl Compr Canc Netw 2026;24:e260002. [Crossref] [PubMed]
13. Hendriks LE, Cortiula F, Mariamidze E, et al. ESMO Oncogene-Addicted Metastatic Non-Small-Cell Lung Cancer Living Guideline, v1.3 - February 2026. Available online: https://www.esmo.org/guidelines/living-guidelines/esmo-living-guideline-oncogene-addicted-metastatic-non-small-cell-lung-cancer
14. Puri S, Leighl NB, Ismaila N, et al. Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, 2026.3.0. J Clin Oncol 2026;44:e15-e55. [Crossref] [PubMed]
15. Mok TS, Yu HA, Lim SM, et al. Patritumab deruxtecan (HER3-DXd) in resistant EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) after a third-generation EGFR TKI: The phase 3 HERTHENA-Lung02 study. J Clin Oncol 2025;43:8506.
16. HARMONi-A Study Investigators. Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial. JAMA 2024;332:561-70.
17. Lu S, Wu L, Jian H, et al. Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med 2023;11:624-36. [Crossref] [PubMed]
18. Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol 2024;35:77-90. [Crossref] [PubMed]
19. Zhang L, Wenfeng F, Yuanuan Z, et al. 1348 Final overall survival analysis of HARMONi-A study comparing ivonescimab plus chemotherapy to chemotherapy alone in patients with EGFR+ NSCLC progressed on EGFR-TKI treatment. J Immunother Cancer 2025;13:A1592.
20. Yonesaka K, Tanizaki J, Maenishi O, et al. HER3 Augmentation via Blockade of EGFR/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non-Small Cell Lung Cancer. Clin Cancer Res 2022;28:390-403. [Crossref] [PubMed]
21. 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;20:2329-40. [Crossref] [PubMed]
22. Nelson BE, Meric-Bernstam F. Leveraging TROP2 Antibody-Drug Conjugates in Solid Tumors. Annu Rev Med 2024;75:31-48. [Crossref] [PubMed]
23. Fang W, Li X, Wang Q, et al. Sacituzumab tirumotecan versus docetaxel for previously treated EGFR-mutated advanced non-small cell lung cancer: multicentre, open label, randomised controlled trial. BMJ 2025;389:e085680. [Crossref] [PubMed]
24. Ahn MJ, Tanaka K, Paz-Ares L, 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;43:260-72. [Crossref] [PubMed]
25. Paz-Ares LG, Juan-Vidal O, Mountzios GS, 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;42:2860-72. [Crossref] [PubMed]
26. Sands J, Ahn MJ, Lisberg A, 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;43:1254-65. [Crossref] [PubMed]
27. Sung MS, Wilson M, Vonficht D, et al. Abstract 7149: The role of TROP2 in the MoA of Dato-DXd and how it underpins the biologic rationale of the novel AI-guided biomarker TROP2 normalized membrane ratio. Cancer Res 2025;85:7149.
28. Garassino MC, Sands J, Paz-Ares L, et al. PL02.11 normalized membrane ratio of TROP2 by quantitative continuous scoring is predictive of clinical outcomes in TROPION-lung 01. J Thorac Oncol 2024;19:S2-S3.
29. Stepan LP, Trueblood ES, Hale K, et al. Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. J Histochem Cytochem 2011;59:701-10. [Crossref] [PubMed]
30. Siqueira JM, Mitani Y, Marques-Piubelli ML, et al. TROP2 Expression in Salivary Gland Adenoid Cystic Carcinoma (ACC) According to Histologic Subtype: Therapeutic Implications. J Oral Pathol Med 2025;54:658-66. [Crossref] [PubMed]
31. Xiong A, Yao W, Zheng W, et al. Sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab in PD-L1-positive advanced non-small-cell lung cancer (OptiTROP-Lung05): interim analysis of a randomised, open-label, phase 3 trial. Lancet 2026;407:2607-19. [Crossref] [PubMed]