afatinib + xentuzumab

The combination of afatinib + xentuzumab is an investigational therapy that has been studied in clinical trials for patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Afatinib is an EGFR tyrosine kinase inhibitor (TKI), while xentuzumab is an insulin-like growth factor (IGF)-ligand neutralizing monoclonal antibody[1][2]. ## Mechanism and Development This combination was specifically investigated because insulin-like growth factor signaling has been implicated in acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC[1]. The phase 1b trial (NCT02191891) was designed to determine if combining these agents could overcome resistance mechanisms and provide clinical benefit to patients whose disease had progressed on prior EGFR TKI therapy[1][3]. The trial established that the maximum tolerated dose was xentuzumab 1000 mg/week (administered intravenously) plus afatinib 40 mg/day (administered orally)[1][2]. While the combination could be safely administered together without new safety concerns, it demonstrated only modest clinical activity in patients with EGFR mutation-positive, T790M-negative NSCLC after progression on afatinib[1][2]. ## Safety Profile The most common drug-related adverse events observed in the clinical trial included: - Part A: diarrhea (75%), paronychia (69%), and rash (69%) - Part B: diarrhea (31%), rash (19%), paronychia (19%), and fatigue (19%)[1][2][6] No dose-limiting toxicities were reported at the established dosing regimen, indicating the combination had a manageable safety profile[1][2]. ## Clinical Efficacy In the phase 1b trial, no patients in part B had an objective response, though 10 patients achieved stable disease with a median duration of disease control of 2.3 months (range 0.8-10.9 months)[1][2]. This suggests the combination had limited efficacy in the studied patient population. The trial was sponsored by Boehringer Ingelheim and was completed, with results published in 2021[1][3][6]. While the combination demonstrated an acceptable safety profile, its modest clinical activity suggests it may not be pursued further for this specific indication without additional modifications or patient selection strategies.

Brand names

Gilotrif (afatinib)

Other names

BI 836845 + afatinibxentuzumab + afatinib