HER-2 exon 20 mutation

Patients with all nodules classified as low risk demonstrated significantly improved disease-free survival (DFS) (P=0.04). The 14-gene RNA expression assay may help prioritize high-risk lesions requiring clinical intervention, and provide guidance for postoperative adjuvant therapy and surveillance strategies, thereby optimizing treatment for MPLC.

Concerning treatment, in advanced HER2-positive, Non-Squamous NSCLC tumors, the first-line treatment is Platinum-based + Pemetrexed chemotherapy, with or without immunotherapy, because no HER2-targeted antibody therapy has yet been approved for initial treatment. After progression, HER2-targeted antibody-drug conjugates like Trastuzumab-Deruxtecan and Ado Trastuzumab-Emtansine may offer patients clinical benefits. New HER2-selective tyrosine kinase inhibitors, such as zongertinib and sevabertinib, have shown promising results, including patients previously treated with antibody-drug conjugates (ADCs). Recent advances, including next-generation ADCs such as SHR-A1811 and A166, and bispecific antibodies, such as zenocutuzumab for NRG1 fusion-positive disease, which are also expanding treatment options. Overall, advances in diagnostics and new targeted therapies are changing how HER2-altered NSCLC is treated and are helping to make care more personalized.

P2, N=152, Not yet recruiting, The Third Xiangya Hospital of Central South University

DS-8201 demonstrates potential as one of the effective salvage therapies following RC48 failure in HER2 altered solid tumors, showing significantly better disease control and a distinct, manageable toxicity profile. These findings highlight the importance of selecting personalized ADCs based on molecular subtypes and toxicity factors and provide a basis for future, larger-scale prospective studies.

In this small case series, T-DXd demonstrated encouraging antitumor activity and manageable safety in heavily pretreated patients with HER2 mutated, metastatic NSCLC. Although selected patients had durable benefits, the findings are anecdotal and should be interpreted with caution. Larger real‑world cohorts and prospective studies are needed to validate the consistency, durability, and safety of T‑DXd in routine clinical practice.

This study enriches the current volume of evidence on histopathologic, genetic, immunologic correlates of PD-L1 expression and, to our knowledge, is the first comprehensive analysis of arm-level alterations. Further studies are warranted to validate these finding and to determine their associations with clinical outcomes.

In contrast, such changes in CD8 + T cell infiltration and PD-1 expression were not evident in another HER2 20ins patient who received conventional chemotherapy. These findings suggest that neoadjuvant T-DXd may represent a promising therapeutic option for locally advanced HER2-mutant NSCLC, warranting further investigation in larger cohorts.

Progression-free survival was longer with targeted therapies compared with immunotherapy ± chemotherapy, although overall survival remained similar. This study provides the first integrated clinical and molecular characterization of lung adenocarcinoma in the French West Indies and highlights the urgent need to improve early diagnosis, molecular testing access, and treatment initiation in underserved island populations.

The second case involves a patient with metastatic micropapillary urothelial carcinoma with HER2 expression, refractory to platinum chemotherapy, avelumab maintenance, and enfortumab vedotin. These two observations illustrate the capacity of T-DXd to induce deep and complete metabolic remissions in distinct HER2-altered solid tumors. They support further development of HER2-targeted ADCs beyond traditional indications and highlight the value of FDG-PET/CT for assessing the depth of response to these agents.

She enrolled in a clinical trial of the selective HER2 tyrosine kinase inhibitor zongertinib (60 mg twice daily) in February 2025 and tolerated therapy well, with mild diarrhea, lactose intolerance, brittle nails, and intermittent muscle cramps...As of January 2026, she has maintained lung-confined disease control for over 11 months without extrapulmonary progression and remains fully functional without symptoms. This case highlights the clinical benefit and tolerability of selective HER2-targeted therapy in HER2-mutant NSCLC and adds to emerging evidence supporting consideration of risk-based lung cancer screening strategies in high-risk never-smoking populations.

The study underscores the importance of integrating NGS-based molecular testing with PD-L1 evaluation for personalised management of NSCLC. Distinct patterns of PD-L1 expression across molecular subtypes, particularly lower in EGFR-mutated tumours and higher in KRAS-mutated tumours, underscore the need for tailored therapeutic strategies and informed sequencing of targeted therapies and immunotherapies.

This case is the first to elucidate the putative resistance mechanisms to zongertinib in HER2-mutant lung adenocarcinoma might be transformation of adenosquamous with giant-cell carcinoma and acquired HER2 amplification through integrated histological and molecular analyses. These findings highlight the necessity of post-progression biopsy and genomic profiling to characterize resistance evolution and guide subsequent therapy selection.