A Phase I/II Study of Erlotinib in Combination with the Anti-Insulin-Like Growth Factor-1 Receptor Monoclonal Antibody IMC-A12 (Cixutumumab) in Patients with Advanced Non-small Cell Lung Cancer

Abstract

Introduction This phase I/II study evaluated the safety and anti-tumor effect of the combination of erlotinib with cixutumumab, a recombinant fully humanized anti-insulin-like growth factor-1 receptor IgG1 monoclonal antibody, in advanced non-small cell lung cancer (NSCLC). Methods Patients with advanced NSCLC were treated in an initial safety-lead and drop-down cohorts using erlotinib 150 mg/d with cixutumumab 6 or 5 mg/kg on days 1, 8, 15, and 22 in 28-day cycles (cohorts 1 and 2). Emerging pharmacokinetic data led to an additional cohort (3 + 3 design) with cixutumumab at 15 mg/kg on day 1 in 21-day cycles (cohort 3). Results Eighteen patients entered the study (6 at 6 mg/kg, 8 at 5 mg/kg, and 4 at 15 mg/kg), with median age of 65 years. Four of six patients at 6 mg/kg experienced dose-limiting toxicities (DLTs), whereas at 5 mg/kg, one of eight patients experienced DLT but three of eight patients still required a dose delay during cycle 1. At 15 mg/kg every 21 days, two of four patients experienced DLTs. In all cohorts, DLTs were either G3 rash or fatigue. Five patients had stable disease as best response and 14 patients had progressive disease. The median progression-free survival was 39 days (range 21–432+ days). Biomarkers analyses showed a trend toward better progression-free survival seen with higher free baseline insulin-like growth factor-1 levels as seen with other insulin-like growth factor-1R inhibitors. Conclusions The combinations of cixutumumab at 6 mg/kg every 7 days and 15 mg/kg every 21 days and full-dose erlotinib are not tolerable in unselected patients with NSCLC, as measured by DLT. Cixutumumab at 5 mg/kg every 7 days was tolerable per DLT, but dose delays were common. Efficacy in unselected patients with NSCLC seems to be low.

The Role of Molecular Pathology in Non-Small-Cell Lung Carcinoma—Now and in the Future

“…The development of a potential therapeutic strategy targeting igf-1r was initiated by the development of a human antibody that binds the receptor with high affinity, consequently inhibiting ligand attachment, and preventing downstream signalling of the mapk/pi3k/Akt pathways. However, the association of a monoclonal antibody to igf-1r and erlotinib in unselected nsclc patients did not appear beneficial, likely because of high drug toxicity, which prevented optimal dosage [92][93][94] .…”

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

“…Specifically, at the time of progression many drug sensitive clones may still be suppressed and can be documented to flare up when the TKI is stopped. 72 Consequently, although traditionally progression has prompted discontinuation of the drug, if isolated areas in the CNS or even outside the CNS progress and most of the rest of the disease is still under control with the targeted therapy, local treatment, such as with radiation of the progressing disease and continuation of the TKI may be associated with many months of benefit before a new progressive site develops 73 .…”

Instability of IGF–IGFBP complex as a cause of the different performance of serum and EDTA-plasma after storage: EDTA-plasma is preferable for evaluating bioactive IGF especially in the mouse

“…Free IGF in its bioactive form is recognized as being critical for activation of the IGF system [4][5][6]. Some studies using data from clinical trials targeting IGF-1R have suggested that pretreatment levels of circulating free IGFs have potential as predictive biomarkers of the response to anti-IGF-1R antibodies [7][8][9]. In these clinical studies, commercially available immunoassays were used to evaluate the level of circulating free IGF [5][6][7][8][9].…”