LY2875358 + gefitinib

LY2875358 + gefitinib is a combination therapy that has been studied in clinical trials, particularly for patients with advanced non-small cell lung cancer (NSCLC). This combination pairs LY2875358, a bivalent monoclonal antibody targeting MET (mesenchymal-epithelial transition factor), with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)[1][2]. ## Pharmacological Profile LY2875358 is designed to target the MET receptor, which is involved in the regulation of cell proliferation and migration. MET has been identified as a potential mechanism of resistance to EGFR-TKI therapy in NSCLC patients[5]. By combining LY2875358 with gefitinib, the treatment aims to address this resistance mechanism while maintaining EGFR inhibition[1][2]. In a phase I dose-escalation study conducted in Japanese patients with advanced malignancies, LY2875358 at doses up to 2000 mg demonstrated a favorable safety and tolerability profile when administered in combination with gefitinib[1][2]. Three patients received LY2875358 2000 mg in combination with gefitinib in this study[1]. ## Safety and Efficacy The combination therapy showed an acceptable safety profile. The most frequently reported adverse events considered possibly drug-related in patients receiving LY2875358 in combination with erlotinib or gefitinib included dermatitis acneiform (4 patients), hypoalbuminemia (3 patients), diarrhea (3 patients), fatigue (3 patients), and paronychia (3 patients)[1]. One patient experienced peripheral edema considered possibly related to LY2875358[1]. In terms of efficacy, a best response of stable disease was achieved by 4 out of 6 patients who received LY2875358 in combination with either erlotinib or gefitinib, resulting in a disease control rate of 35%[1][2]. ## Development Context This combination therapy represents an approach to targeting multiple pathways in cancer treatment. MET remains a valid target in the treatment of EGFR-mutated NSCLC, as MET amplification or overexpression has been identified as a mechanism of acquired resistance to EGFR-TKIs[5]. The combination of MET inhibitors with EGFR-TKIs has been explored as a strategy to overcome or delay resistance to EGFR-TKI monotherapy[5]. The clinical development of this specific combination was part of broader efforts to improve outcomes for patients with advanced NSCLC, particularly those who develop resistance to EGFR-TKI therapy.