P1, N=6, Active, not recruiting, Carisma Therapeutics Inc | Recruiting --> Active, not recruiting

P2, N=87, Completed, Nancy Lin, MD | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Aug 2024

P1, N=21, Recruiting, West China Hospital

One twentieth of lung cancer patients diagnosed in 2016 in Germany received at least one EGFR, ALK, or BRAF inhibitor during follow-up. The proportion was higher in East than in West Germany. As the development and availability of new cancer drugs is a dynamic area, regularly updated utilization studies-ideally as cross-country-comparisons-are required.

In our real-world study, afatinib showed encouraging effectiveness in Vietnamese patients with EGFR-mutant NSCLC and brain metastases at baseline.

We used BC cell line data from the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases and single-cell RNA sequencing (scRNA-seq) information that established afatinib as an efficacious candidate demonstrating superior IC50 values...The promising candidates underwent computational structural biology assessments for their molecular interactions and conformational dynamics. Our findings indicate that compounds ChEMBL233324, ChEMBL233325, ChEMBL234580, and ChEMBL372692 exhibit potent repressive action against EGFR, underscoring their potential as active antibreast cancer agents.

TRPC6 expression correlated strongly with immune cell infiltration, immune checkpoint genes, and sensitivity to therapies such as Lapatinib, anti-CTLA4, and anti-PD1 treatments...This study highlights the prognostic significance of TRPC6 in STAD and its potential as a therapeutic target. TRPC6's involvement in immune regulation and cancer cell progression underscores its dual role in STAD pathogenesis and treatment, offering new avenues for targeted therapy development.

P1, N=17, Completed, Dizal Pharmaceuticals | Recruiting --> Completed | Trial completion date: May 2024 --> Oct 2024

P2, N=610, Recruiting, Henan Cancer Hospital | Trial completion date: May 2026 --> Dec 2026 | Trial primary completion date: May 2025 --> Dec 2025

P2, N=71, Recruiting, Henan Cancer Hospital | Not yet recruiting --> Recruiting

We visualized these interactions using Cytoscape to generate individual and combined drug-gene networks, focusing on frequently used drugs such as Erlotinib, Gefitinib, Lapatinib, and Cetuximab...Combined drug networks, such as those for Cetuximab with Lapatinib, Cetuximab with Erlotinib, and Erlotinib with Lapatinib, revealed potential synergies that could enhance therapeutic efficacy by simultaneously influencing multiple genes and pathways. Our findings suggest that a network-based approach to analyzing drug combinations provides valuable insights into the molecular mechanisms of HER2+ breast cancer and offers promising strategies for overcoming drug resistance and improving treatment outcomes.

We identified that histone deacetylases (HDACs) were prominent candidates, and subsequently identified that the HDAC inhibitors mocetinostat and pracinostat, as well as the combined HDAC-epidermal growth factor receptor inhibitor CUDC-101, were effective at radiosensitising cell models of HNSCC (FaDu, A253, UMSCC11b) through their impact on both spheroid growth and clonogenic survival assays. We also demonstrated that this combinatorial strategy leads to inhibition of the repair of DNA double-strand breaks through the neutral comet assay and γH2AX foci analysis using immunofluorescence microscopy, providing a mechanism of action through which HDAC inhibition functions in HNSCC radiosensitisation. We believe that this approach should be further investigated in preclinical models, in order to realise the full therapeutic potential of HDAC inhibition for the radiosensitisation of HNSCC, eventually leading to improved patient treatment efficacy and outcomes.

We believe that FGFR4 overexpression and complex formation with HER2 can serve as molecular markers to assist clinicians in identifying trastuzumab-resistant tumors. Our results suggest that FGF401 combined with trastuzumab as adjuvant therapy for patients with trastuzumab-resistant breast cancer may be a potential new treatment strategy.

The patient, now on combination therapy for exceeding 12 months, exhibits further decreased tumor size and a high quality of life. This case underscores the importance of precise molecular diagnosis in guiding therapeutic strategies and provides a valuable reference for clinical decision-making in EGFR-positive NSCLC cases with atypical mutations.

These findings provide preliminary evidence for the involvement of the CREB3L4/RASEF signaling pathway in LUAD pathogenesis and suggest its potential as a novel biomarker for accurate diagnosis and targeted therapy.

Notably, the half-maximal inhibitory concentration (IC50) of commonly used chemotherapeutic drugs, such as lapatinib and mitomycin, was inversely associated with TRAF3IP3 expression in HCC patients. TRAF3IP3 may be as a novel and promising biomarker for prognosis prediction and immunological evaluation of HCC.

We synthesized Fc-PLG-Mal, conjugated DM1 through a "click" reaction, and subsequently bound the resultant compound with the HER2 antibody trastuzumab...HER2-PLG-DM1 significantly inhibited tumor growth in NCI-N87 tumor-bearing mice, achieving a 90.8% tumor inhibition rate, and displayed dose-dependent effects without significant liver and kidney toxicity. These studies offer an efficient and stable method for the preparation of antibody-coupled drugs.

Tumors with lower IFNG SHAP values exhibited higher IFNG expression and better overall survival, which were linked to more abundant presence of M1 macrophages and activated CD4+ and CD8+ T cells in the tumor microenvironment. The association of the IFNG pathway with overall survival was validated in the trastuzumab arm of the NCCTG-N9831 trial, an independent breast cancer study.

No abstract available

P3, N=812, Recruiting, Hoffmann-La Roche | Trial completion date: Sep 2032 --> Dec 2030 | Trial primary completion date: Aug 2026 --> Mar 2027

P2, N=23, Not yet recruiting, Guangzhou Women and Children's Medical Center

The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is widely used as a first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC). In three cases of EGFR-L858R+V834L, other co-mutations, including TP53, CTNNB1, and RB1, were detected either before or after afatinib resistance. These results suggested that V834L cooperates with other coexisting mutations to influence the therapeutic efficacy of EGFR-TKIs.

P2, N=25, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Jul 2025 --> Oct 2025

Cardiotoxicity was not associated with DFS or OS. Clinical stage III, Suspension and permanent interruption of treatment regardless of the cause were associated with worse DFS and OS in breast cancer patients.

We aimed to dynamically monitor serum adenosine levels in patients with HER2-positive metastatic breast cancer (MBC) patients and to explore its predictive significance in trastuzumab therapy...The dynamic change of adenosine is a predictive biomarker for monitoring disease progression. The adenosine metabolism-based signature has the potential application in the prognosis of HER2-positive MBC patients.

P1/2, N=40, Recruiting, Centre de recherche du Centre hospitalier universitaire de Sherbrooke

P1, N=25, Completed, Dizal Pharmaceuticals | Recruiting --> Completed | Trial primary completion date: Aug 2024 --> May 2024

Tumor growth was significantly inhibited by [225Ac]Ac-DOTA-trastuzumab IgG, F(ab')2 or Fab but [225Ac]Ac-DOTA-trastuzumab F(ab')2 was most effective for increasing median survival (46 d vs 22 d for IgG and 29 d for Fab). We conclude that [111In]In- and [225Ac]Ac-DOTA-trastuzumab F(ab')2 exhibited superior properties for theranostic imaging and α-particle RIT of HER2-positive human BC xenografts in NRG mice.

The introduction of antibody-drug conjugates, in specific trastuzumab deruxtecan, has resulted in the best progression-free survival among patients with this subtype of breast cancer...Tucatinib, capecitabine, and trastuzumab combination represent one such promising strategy. With the increasing longevity of these patients, important clinical questions include optimal treatment sequencing, the role of de-escalation of treatment in excellent responders, and the associated financial toxicity. Despite the aggressive nature of this subtype of breast cancer, the outcomes continue to improve for these patients with the evolving treatments.

P1, N=40, Recruiting, Baptist Health South Florida | Trial completion date: Nov 2025 --> Feb 2029 | Trial primary completion date: Nov 2024 --> Feb 2028

Third-generation TKIs, such as osimertinib, almonertinib and furmonertinib, are effective for the treatment of NSCLC that is EGFR-sensitizing mutation-positive and T790M-positive. To the best of our knowledge, the present report describes the first case of a patient with lung adenocarcinoma who had multiple co-existing EGFR resistance mutations, including EGFR L718Q, EGFR C797S, EGFR C797G, EGFR L792H, EGFR V802F and EGFR V689L. These mutations conferred resistance to almonertinib, whilst maintaining sensitivity to afatinib.

Specifically, over 50% of patients either do not respond to or develop resistance against trastuzumab.The specific mechanisms of resistance to trastuzumab are currently unclear. This paper aims to review the existing research on the resistance mechanisms of trastuzumab, based on its target, from aspects such as genetic loci, molecular structure, signaling pathways, and the tumor microenvironment and to outline current research progress and new strategies.

Preclinical studies illustrated that tumor regression induced by HER2 antibodies requires T cell involvement, and the combination of immune checkpoint inhibitors with trastuzumab augments HER2-specific T cell responses, promotes immune cell recruitment, and induces the expansion of peripheral memory T cells, which showed synergistic rationales for a combination of pembrolizumab and trastuzumab. The observed synergy between pembrolizumab and trastuzumab highlights a promising treatment avenue that warrants further investigation.

P2, N=120, Active, not recruiting, University of California, Irvine | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P1, N=43, Completed, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine | Recruiting --> Completed

Additionally, among patients with ERBB2 mutations and treated with pyrotinib, the HER2-low group may experience superior prognosis when compared to the HER2-0 group...Moreover, we classified HER2-low MBC into three clusters, providing a reference for subsequent treatment with enhanced precision. Our study offers valuable insights into the biology of HER2-low MBC and may provide reference for personalized treatment strategies.

For HER2-positive tumours, preoperative systemic therapy with trastuzumab may be considered as it demonstrates a significantly higher number of pathological complete remissions and offers the possibility of achiev-ing a higher R0 resection rate. In oligometastatic disease, surgical management of the primary tumour and metastases may be considered in individual cases in patients who respond to systemic therapy. However, an impact on overall survival has only been documented in patients with retroperitoneal involvement and no peritoneal metastases.

Finding suggests that immune checkpoint inhibitors combined with chemotherapy could enrich patients with benefits regardless of CPS grades, though subtle efficacy in low CPS subgroups. This study compared the efficacy of different immunotherapies combined with chemotherapy in patients with gastric cancer, but we acknowledge some differences between reconstructed and original data. Hopefully there will be more research investigating comparisons between current therapies rather than with chemotherapy only in the future.

This suggests its potential as a viable therapeutic option for trastuzumab-resistant gastric cancers. In summary, compound 10 could be a novel alternative therapeutic strategy for HER2-overexpressing cancers, overcoming the limitations of trastuzumab.

Afatinib is a viable treatment option for tissue or ctDNA-detected EGFR mutant NSCLC comorbid patients, with a proportion achieving long-term clinical benefit. Plasma ctDNA testing improved EGFR mutant identification and its clearance predicted improved PFS and OS.

P1/2, N=34, Active, not recruiting, US Oncology Research | N=26 --> 34 | Trial completion date: Jun 2024 --> Jan 2025 | Trial primary completion date: Jun 2024 --> Jan 2025

Collectively, our results indicate that afatinib induces intestinal epithelial barrier dysfunction via mechanisms involving NF-κB-iNOS-MLCK pathways. This finding may pave the way for developing therapeutic strategies to reduce adverse effects and enhance efficacy of TKI in cancer patients.