In preclinical studies, insulin-like growth factor (IGF) signaling has been implicated in acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). This trial evaluates BI 836845, an IGF ligand-neutralizing antibody that binds to both IGF-1 and IGF-2 and neutralizes growth-promoting signaling, combined with afatinib in patients (pts) with EGFR-mutated NSCLC.
This open-label, dose-escalation trial in Korea, Taiwan and Singapore (NCT02191891; 1280.16) consists of a dose confirmation part (Part A) followed by an expansion part (Part B). Eligible pts are aged ≥18 years with advanced and/or metastatic NSCLC progressing during prior treatment with EGFR TKI or platinum-based chemotherapy (Part A) or prior EGFR TKIs (Part B), with a documented activating EGFR mutation and no EGFR T790M mutation (Part B only). Pts with prior afatinib therapy below assigned dose level (Part A only) or <30 mg/day (Parts A and B), or progressive disease (PD) on an insufficient dose of EGFR TKI prior to study in investigator's opinion, or >2 (Part B only) prior EGFR TKI regimens for relapsed/metastatic NSCLC are excluded. Part A uses a 3 + 3 design to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BI 836845 plus afatinib (starting dose: BI 836845 1000 mg/week 1-hour intravenous infusion plus oral afatinib 30 mg/day in 4-week courses). Pts receive treatment until PD, intolerability or study discontinuation. In Part A, pts are entered sequentially into escalating/de-escalating dose tiers (3–6 pts/cohort) to determine the MTD based on dose-limiting toxicities (DLTs) during Course 1; 6 additional pts will be enrolled in an extension cohort at the RP2D. In Part B, two expansion cohorts of 18 pts previously treated with irreversible EGFR TKIs (e.g. afatinib, dacomitinib; Cohort 1) or reversible EGFR TKIs (gefitinib or erlotinib; Cohort 2) will receive the RP2D determined in Part A. Primary endpoints are MTD and DLTs during Course 1 (Part A) and objective response (OR; Part B). Secondary endpoints include disease control, time to OR, duration of OR, and pharmacokinetics. All analyses will be descriptive and exploratory.
Clinical trial identification
NCT02191891; Study 1280.16
D. Chin-Lun Huang, H. Jung, T. Bogenrieder: employment: Boehringer Ingelheim. HK. Park: Advisory board: Astellas, AZ, BI, Clovis, Eli Lilly, Hanmi, KHK, Novartis, ONO, Roche. All other authors have declared no conflicts of interest.
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