Pre-treatment levels of circulating free IGF-1 identify NSCLC patients who derive clinical benefit from figitumumab

Abstract

Background: Phase III trials of the anti-insulin-like growth factor type 1 receptor (IGF-IR) antibody figitumumab (F) in unselected non-small-cell lung cancer (NSCLC) patients were recently discontinued owing to futility. Here, we investigated a role of free IGF-1 (fIGF-1) as a potential predictive biomarker of clinical benefit from F treatment.

Materials and method: Pre-treatment circulating levels of fIGF-1 were tested in 110 advanced NSCLC patients enrolled in a phase II study of paclitaxel and carboplatin given alone (PC) or in combination with F at doses of 10 or 20 mg kg(-1) (PCF10, PCF20).

Results: Cox proportional hazards model interactions were between 2.5 and 3.5 for fIGF-1 criteria in the 0.5-0.9 ng ml(-1) range. Patients above each criterion had a substantial improvement in progression-free survival on PCF20 related to PC alone. Free IGF-1 correlated inversely with IGF binding protein 1 (IGFBP-1, ρ=-0.295, P=0.005), and the pre-treatment ratio of insulin to IGFBP-1 was also predictive of F clinical benefit. In addition, fIGF-1 levels correlated with tumour vimentin expression (ρ=0.594, P=0.021) and inversely with E-cadherin (ρ=-0.389, P=0.152), suggesting a role for fIGF-1 in tumour de-differentiation.

Conclusion: Free IGF-1 may contribute to the identification of a subset of NSCLC patients who benefit from F therapy.

Figure 1

Receiver-operating characteristic curves for fIGF-1 as a predictive maker for PFS benefit at 3–6 months in PCF-treated patients (10–20 mg kg⁻¹ F).

Figure 2

(A) Hazard ratio of Study 1002 patients receiving treatment with PCF (10 or 20 mg kg⁻¹) vs PC alone according to baseline fIGF-1 levels. (B) A hazard ratio of patients receiving treatment with PCF (10 or 20 mg kg⁻¹) vs PC alone according to baseline insulin to IGFBP-1 ratio.

Figure 3

Kaplan–Meier plots of PFS in Study 1002 patients. (A) All patients with available baseline fIGF-1 level data (N=110). (B and C) Patients with baseline fIGF-1 ⩽0.7 (B, N=64) or >0.7 ng ml⁻¹ (C, N=46). (D) All patients with available baseline insulin/IGFBP-1 ratio data (N=82). (E and F) Patients with baseline insulin/IGFBP-1 ratio ⩽0.7 (E, N=34) or >0.7 ng ml⁻¹ (F, N=48).

Figure 4

Progression-free survival of PC, PCF10 and PCF20 patients by fIGF-1 quartile. The central box represents the values from the lower to upper quartile (25–75 percentile). In the box plots, the middle line represents the median. A line extends from the minimum to the maximum value, excluding ‘outside’ values that are displayed as separate points. An outside value is defined as a value that is smaller than the lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range (inner fences). These values are plotted with a square marker.

Figure 5

Cyanine-5 fluorescence images representative of vimentin and E-cadherin expression in tumours from Study 1002 patients. Insets show cytokeratin (green) and DAPI (blue) fluorescence sample stainings.