P2, N=30, Active, not recruiting, First Affiliated Hospital of Zhejiang University | Recruiting --> Active, not recruiting | Trial completion date: Sep 2025 --> Dec 2026

Despite profound genomic instability, targeting DNA repair or replication stress pathways was ineffective, whereas sensitivity to platinum-based chemotherapy was retained across clades. Collectively, these findings indicate that recurrent senescence escape drives osimertinib resistance through widespread genomic instability and is most effectively treated by cytotoxic strategies rather than pathway-targeted approaches.

Here, we found that exosomes secreted by lung cancer cells that had acquired epidermal growth factor receptor tyrosine kinase inhibitor resistance and undergone epithelial-mesenchymal transition (osimertinib- and WZ4002-resistant H1975) exhibited enhanced brain-specific distribution and a concomitant increase in BrM compared with exosomes from parental H1975 cells. Clinically, exosomal L1CAM demonstrated diagnostic potential for BrM (area under the curve [AUC] = 0.80), and a combined exosomal L1CAM/ITGB3 panel significantly improved diagnostic accuracy (AUC = 0.98). Collectively, these findings identify exosomal L1CAM as a key regulator of brain-specific metastasis and support the clinical utility of the L1CAM/ITGB3 panel as a noninvasive biomarker for BrM in lung cancer.

With a primary EGFR p.L858R-mutant NSCLC, osimertinib was administered, resulting in a partial response within 10 months. In addition, given the synchronous primary pancreatic adenocarcinoma, germline testing was performed, revealing a CDKN2A p.I49T variant consistent with melanoma-pancreatic cancer syndrome, prompting comprehensive cancer surveillance and familial testing. This case illustrates how ctDNA testing enabled a comprehensive evaluation by clarifying the diagnosis, identifying actionable biomarkers, and facilitating genetic risk assessment, ultimately having a significant impact on the patient's clinical management.

P2, N=29, Active, not recruiting, Tianjin Medical University Cancer Institute and Hospital | Recruiting --> Active, not recruiting

The translation potential of this scaffold is also supported by the clinical success of indole-based EGFR inhibitors, including the third-generation drug osimertinib. This paper summarizes the relevant literature of indole EGFR inhibitors published between 2021 and 2025, which may include mechanistic insights, biological screening, and therapeutic potential. The indole scaffold can be a useful starting point to push forward the next generation of targeted cancer therapies.

Taiho Pharmaceutical Co. Ltd.

In vivo, anlotinib reduced tumor growth in Sh-PD-L1-OR models (P < 0.01), with decreased expression of EGFR, PD-L1, YAP, and β-catenin. These findings suggest that high PD-L1 expression promotes osimertinib resistance through activation of YAP and Wnt/β-catenin, and that anlotinib combined with osimertinib can reverse resistance by restoring GSK3β activity, activating the Hippo pathway, and inhibiting β-catenin signaling.

P2, N=37, Active, not recruiting, Washington University School of Medicine | Recruiting --> Active, not recruiting | N=72 --> 37 | Trial completion date: Apr 2031 --> Jun 2030 | Trial primary completion date: Apr 2028 --> Jun 2027

The primary endpoint is the objective response rate, which is assessed by a blinded independent central review. Translational research is planned to explore the predictive biomarkers and mechanisms of resistance to bemarituzumab by sequencing tumor DNA (PleSSiSion-Neo) and circulating tumor DNA (Guardant360), which are collected at multiple time points.

Patients were treated in first-line (1L) with osimertinib or other TKIs (non-osimertinib). This study demonstrates that real-world treatment patterns and outcomes of TKIs are comparable with those found in both clinical trials and other real-world studies. RWE studies can support clinicians in investigating the best treatment strategy and decision makers to drive new health policies.

An elderly male diagnosed with Stage IV LUAD achieved sustained stable disease (SD) and symptomatic improvement through a sequential therapeutic strategy, including platinum-based chemotherapy followed by the PD-1 inhibitor sintilimab combined with anti-angiogenic agents (apatinib or anlotinib). This case demonstrates that while ICIs can provide exceptional long-term benefits in advanced NSCLC, particularly in patients with highly immunogenic mutation profiles, they may also trigger late-onset fatal irAEs. Our findings underscore the imperative for close, long-term metabolic surveillance throughout the course of immunotherapy, regardless of treatment duration or radiological stability.