Tagrisso (osimertinib)

P1/2, N=253, Not yet recruiting, Beijing Pearl Biotechnology Limited Liability Company

Additionally, we found that the copper ionophore disulfiram (DSF) overcame osimertinib resistance by augmenting YTHDC2 expression. Collectively, our findings elucidate a novel YTHDC2-SLC31A1-cuproptosis axis as a key mechanism underlying EGFR-TKI resistance and propose new therapeutic strategies for its reversal.

Noteworthily, ERB-2 could promote ROS accumulation, mitochondrial dysfunction, cell apoptosis and restore Osimertinib sensitivity in Osimertinib-resistant NSCLC cells, eventually lead to effective reversal of Osimertinib resistance in vivo. Collectively, this study identifies ERB-2 as a potent first-in-class ERβ degrader capable of overcoming Osimertinib resistance in NSCLC, putting forward potential solution for clinical unmet need in NSCLC treatment.

When binding to osimertinib, ASV- and SVD-EGFR still revealed two energy minima on their free energy landscapes, but with considerably less conformational probability distribution at collective variable 2 >1.00 Å. In contrast, mobocertinib eliminated the energy minima at collective variable 2 >1.00 Å while decreasing the K745-E762 salt bridge formation rates.ConclusionsMobocertinib outperforms osimertinib in targeting specific subtypes of EGFR exon 20 insertions, highlighting its ability to restore the inactive state of this protein.

PIK3CA mutant-mediated cachexia can be overcome by osimertinib (Osi) treatment in Osi-sensitive GEMM. PIK3CA mutant-driven cachexia is mediated through NF-κB activation and can be dampened by combined aspirin treatment. This work provides insights into PIK3CA mutant biological function and mechanisms behind its clinical impacts, and proposes a potential strategy for clinical management.

We outline mechanisms of action, clinical efficacy, and limitations of FDA-approved tyrosine kinase inhibitors (TKIs) and emerging agents, with emphasis on resistance pathways, both on-target and bypass-mediated, observed during treatment with drugs such as osimertinib, crizotinib, sotorasib, and entrectinib. The role of next-generation sequencing (NGS), liquid biopsy, and comprehensive biomarker profiling in guiding personalized therapy selection is also discussed, along with strategies for sequential therapy and rational combination approaches.

Among the 12 patients treated with escalating doses of quaratusugene ozeplasmid and standard doses of osimertinib there were 3 patients with prolonged time to progression, including 1 with continuing PR. Quaratusugene ozeplasmid administration was associated with a delayed infusion-related reaction managed with prophylactic steroids, acetaminophen and diphenhydramine. There were no DLTs. The recommended phase II dose of quaratusugene ozeplasmid in combination with osimertinib in patients with NSCLC progressing after osimertinib treatment is 0.12 mg/kg.

P2, N=140, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Oct 2025 --> May 2026

P4, N=100, Not yet recruiting, AstraZeneca

Case 1 received osimertinib combined with savolitinib, had 33 months of follow-up, and achieved a partial response. Case 2 received furmonertinib and achieved a complete response. NTRK2 fusion coexisting with EGFR mutations is a rare molecular characteristic of non-small cell lung cancer, accompanied by positive PD-L1 expression, and may serve as a promising biomarker for targeted therapy.

Reference inhibitors (osimertinib-EGFR, ibrutinib-BTK, THZ1-CDK7, and THZ531-CDK12) reproduced the expected geometries and served as internal controls. Although no quantitative affinity was inferred, the consistent geometric feasibility supports their potential as structural templates for covalent-binding natural scaffolds. These results provide a qualitative, structure-based rationale for further chemoproteomic and enzymatic validation of NP-derived or hybrid compounds as potential leads in cancer therapy, expanding covalent chemical space beyond existing synthetic scaffolds.

Eugenol can effectively overcome osimertinib resistance in NSCLC by regulating glycolysis through the TRIM59/ERK signaling pathway. Eugenol could serve as a promising adjunctive therapy to improve chemotherapy efficacy and overcome drug resistance in NSCLC.