Mouse Anti-Human EGFR monoclonal antibody, clone 22I8

Purpose: Small-molecule inhibitors have had a major impact on cancer care. While treatments have demonstrated clinically promising results, they suffer from dose-limiting toxicities and the emergence of refractory disease. Considerable efforts made to address these issues have more recently focused on strategies implementing particle-based probes that improve drug delivery and accumulation at target sites, while reducing off-target effects. Experimental Design: Ultrasmall (<8 nm) core-shell silica nanoparticles, C' dots, were molecularly engineered to function as multivalent drug delivery vehicles for significantly improving key in vivo biological and therapeutic properties of a prototype epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib. Novel surface chemical components were used to conjugate gefitinibdipeptide drug-linkers and deferoxamine (DFO) chelators for therapeutic delivery and PET imaging labels, respectively. Results: Gefitinib-bound C' dots (DFO-Gef-C' dots), synthesized using the gefitinib analogue, APdMG, at a range of drugto-particle ratios (DPR; DPR = 11-56), demonstrated high stability for DPR values <= 40, bulk renal clearance, and enhanced in vitro cytotoxicity relative to gefitinib (LD50 = 6.21 nmol/L vs. 3 mmol/ L, respectively). In human non-small cell lung cancer mice, efficacious Gef-C' dot doses were at least 200-fold lower than that needed for gefitinib (360 nmoles vs. 78 mmoles, respectively), noting fairly equivalent tumor growth inhibition and prolonged survival. Gef-C' dot-treated tumors also exhibited low phosphorylated EFGR levels, with no appreciable wildtype EGFR target inhibition, unlike free drug. Conclusions: Results underscore the clinical potential of DFOGef-C' dots to effectively manage disease and minimize off-target effects at a fraction of the native drug dose.

Background There are few studies that directly compare the effects of osimertinib on patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) T790M mutation between the generation of prior EGFR tyrosine kinase inhibitors (TKIs). Methods We retrospectively reviewed clinical data from the medical records of consecutive patients with advanced NSCLC who had developed resistance to first- or second-generation EGFR-TKIs due to EGFR T790M mutation and were subsequently treated with osimertinib at Juntendo University Hospital. In patients with available tumor samples, target amplicon sequencing analyses were performed to explore the genetic biomarkers. Results A total of 38 patients with NSCLC harboring EGFR T790M mutation were treated with osimertinib. Eight patients were classified into group A (afatinib followed by osimertinib) and 30 patients were classified into group B (first-generation EGFR-TKI followed by osimertinib). Progression-free survival (PFS) was significantly longer in group A than in group B (median PFS; not reached vs. 11.0 months, P = 0.018). Fourteen patients had available tissue samples collected before osimertinib treatment for target sequencing. In group A we found no additional mutations, other than EGFR T790M mutation. On the other hand, there were three samples in which other mutations emerged, in addition to EGFR T790M mutation, in group B. Conclusions PFS of osimertinib was significantly longer in patients with NSCLC harboring EGFR T790M mutation after treatment with afatinib than in patients after treatment with first generation EGFR-TKIs. Additional mutations other than EGFR T790M may affect the efficacy of osimertinib treatment. Key points Significant findings of the study: PFS of osimertinib was significantly longer in patients with NSCLC harboring EGFR T790M mutation after treatment with afatinib than in patients after treatment with first generation EGFR-TKIs. What this study adds: Additional mutations other than EGFR T790M may affect the efficacy of osimertinib treatment.