HER2-targeted therapy in non–small-cell lung cancer has rapidly evolved from an area of unmet clinical need to a field

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, spanning 4 journals. Those papers have been cited 1 times in total.

Supporting evidence — 4 representative gaps

• Evolving treatment strategies for HER2-altered non–small-cell lung cancer: the rise of TKIs and ADCs (2026) · Frontiers in Oncology · cited 1× · doi

  HER2-targeted therapy in non–small-cell lung cancer has rapidly evolved from an area of unmet clinical need to a field with multiple effective treatment options. The development of HER2-selective tyrosine kinase inhibitors and antibody–drug conjugates has substantially improved outcomes for patients with HER2-mutant NSCLC and established HER2 as a clinically actionable oncogenic driver. Despite these advances, several challenges remain. The optimal sequencing of HER2-targeted agents has not yet been defined, and prospective data are needed to clarify how best to integrate TKIs, ADCs, and other systemic therapies across treatment lines. Acquired resistance is expected to become increasingly relevant as improves, underscoring the importance of patient survival understanding resistance mechanisms and developing rational strategies to overcome them. In parallel, refinement of predictive biomarkers beyond HER2 mutation status may help better individualize treatment selection and avoid unnecessary toxicity.

  generalfuture work
  Keywords: treatment targeted resistance therapy small cell lung cancer rapidly evolved area unmet clinical need multiple
• Current Status and Progress of Targeted and Immunotherapy for DSRCT (2026) · Cancers · doi

  In conclusion, in terms of targeted therapy, TKIs remain an important component of DSRCT treatment, and drugs targeting different molecular targets can complement each other. Among these targets, precise targeted therapy against HER2 has attracted increasing attention in recent years. Downstream targets regulated by EWSR1-WT1, such as NTRK3 and MERTK, have initially shown potential therapeutic value in preclinical studies, which still require further in-depth research. As a gender-differentiated tumor, the mechanism of action of the AR in DSRCT and the corresponding targeted therapy have long been a focus of attention, and we have reason to believe that key breakthroughs will be achieved in this field in the future. In the field of immunotherapy, as a “cold tumor”, DSRCT has encountered bottlenecks in the application of traditional immune checkpoint inhibitors. However, radioimmunotherapy and cellular immunotherapy targeting B7H3, HER2, and GD2 are gradually gaining attention, with multiple clinical trials focusing on these strategies. In addition, neogenes and neopeptides induced by EWSR1-WT1, as tumor-specific antigens, hold great prospects for immunotherapy. Finally, the DDR is an important participant in the occurrence of DSRCT; the significant upregulation of markers such as PARP1, SLFN11, and CHK1 may indicate that drugs inhibiting DDR, such as PARPi and trabectedin, can exert certain therapeutic effects. Despite significant progress in understanding the pathogenesis and therapeutic strate- gies of DSRCT, challenges remain, and the path ahead is not smooth. Future research should focus on clarifying the precise molecular mechanisms of EWSR1-WT1-mediated tumorigenesis, identifying novel actionable targets, optimizing multimodal treatment regi- mens, and conducting large-scale prospective clinical trials to improve the prognosis of patients with this devastating disease. Author Contributions: T.W.: Draft writing, data collection, and figure preparation. Y.L. (correspond- ing author): Idea and design, manuscript revision. Q.Z. (second author): Review and revision of the manuscript, literature collection. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Data Availability Statement: No new data were created or analyzed in this study. Conflicts of Interest: The authors declare that they have no competing interests.

  generalfuture work
  Keywords: dsrct targets targeted therapy attention ewsr therapeutic tumor immunotherapy author manuscript remain important treatment drugs
• Clinical Efficacy, Safety and Future Horizons of Trastuzumab Deruxtecan (T-Dxd) in Her2 – Driven Tumors (2026) · Zenodo (CERN European Organization for Nuclear Research) · doi

  Trastuzumab deruxtecan (T-DXd) is transforming HER2 targeted therapy with future directions focused on expanding clinical impact and improving patient outcomes. Ongoing trials are exploring its use in earlier treatment lines for HER2 positive breast cancer and in HER2-low or other HER2-expressing tumors potentially broadening its indications beyond traditional cohorts.21 Combination strategies with immune checkpoint inhibitors, other HER2 targeted agents and DNA damage repair inhibitors aim to enhance efficacy and overcome resistance mechanisms. Research into molecular drivers of resistance including HER2 downregulation and drug efflux pathways may guide more durable treatment approaches. Safety optimization remains crucial particularly regarding interstitial lung disease with efforts focusing on predictive biomarkers, risk mitigation and individualized dosing. Overall, these advances indicate a future where T-DXd offers more personalized, versatile and effective treatment options across multiple HER2 driven malignancies.22 CONCLUSION Trastuzumab deruxtecan (T-DXd; DS-8201, Enhertu®) represents a significant advancement in the treatment of HER2-expressing malignancies demonstrating robust anti tumor activity in both HER2-positive and HER2-low tumors. By combining a humanized anti-HER2 monoclonal antibody with a potent topoisomerase I inhibitor via a cleavable linker T-DXd delivers cytotoxic therapy selectively to cancer cells while limiting systemic exposure. Its membrane-permeable payload enables a bystander effect allowing T-DXd to exert efficacy even in tumors with heterogeneous HER2 expression which is particularly relevant for patients who traditionally had limited treatment options. Clinical trials have consistently shown that T-DXd improves key outcomes including progression free survival and objective response rates even in heavily pretreated populations. Pivotal studies such as DESTINY-Breast01, DESTINY-Breast04, and DESTINY-Gastric01 have established its efficacy in metastatic breast and gastric cancers and real-world data further confirm these durable responses, reinforcing the relevance of T-DXd in routine clinical practice. These findings demonstrate that T-DXd not only achieves tumor control but also provides meaningful survival benefit across diverse patient populations. Safety remains an important consideration with gastrointestinal toxicities, hematologic adverse events and interstitial lung disease (ILD) being the most clinically significant. Vigilant monitoring, early recognition and proactive management of adverse events are critical to optimizing the risk-benefit profile. Despite these challenges, the overall tolerability of T-DXd is manageable and its therapeutic benefits outweigh the potential risks when administered with appropriate precautions. Looking forward, ongoing research is expanding the therapeutic potential of T-DXd. Combination strategies with immune checkpoint inhibitors, oth

  generalfuture work
  Keywords: treatment breast clinical tumors inhibitors efficacy destiny trastuzumab deruxtecan targeted therapy future expanding patient outcomes
• Current Treatment Options Guided by Molecular Classification in Endometrial Cancer (2026) · Current Treatment Options in Oncology · doi

  Molecular classification is reshaping treatment stratifica- tion for high-risk endometrial cancer. HER2 expression is not limited to serous carcinoma and is enriched in high-risk phenotypes such as p53abn tumors, supporting broader HER2 testing beyond conventional pathological categories [38]. p53abn/CNH represents a shared high-risk phenotype characterized by chromosomal instability, replication stress, and aggressive behavior, within which HER2-targeted ther- apy, WEE1 inhibition, PARP inhibition, and antibody-drug conjugates may be rationally integrated [25, 27, 39]. Molec- ularly designed studies such as RAINBO reflect a shift from single-drug matching toward combination pathways for high-risk molecular phenotypes; until evidence matures, these strategies should preferably be evaluated in clinical trials or rigorously stratified real-world studies [27, 39]. No Specific Molecular Profile/Copy-Number- Low Tumors: From an Exclusionary Category to Restratified Treatment

  generalfuture work
  Keywords: high risk molecular treatment phenotypes tumors inhibition drug classification reshaping stratifica tion endometrial cancer expression

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