Randomized Phase II Study of Erlotinib in Combination With Placebo or R1507, a Monoclonal Antibody to Insulin-Like Growth Factor-1 Receptor, for Advanced-Stage Non–Small-Cell Lung Cancer

Abstract

PurposeR1507 is a selective, fully human, recombinant monoclonal antibody (immunoglobulin G1 subclass) against insulin-like growth factor-1 receptor (IGF-1R). The strong preclinical evidence supporting coinhibition of IGF-1R and epidermal growth factor receptor (EGFR) as anticancer therapy prompted this study.Patients and MethodsPatients with advanced-stage non–small-cell lung cancer (NSCLC) with progression following one or two prior regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and measurable disease were eligible. Patients were randomly assigned to receive erlotinib (150 mg orally once a day) in combination with either placebo, R1507 9 mg/kg weekly, or R1507 16 mg/kg intravenously once every 3 weeks. Treatment cycles were repeated every 3 weeks. The primary end point was comparison of the 12-week progression-free survival (PFS) rate.ResultsIn all, 172 patients were enrolled: median age, 61 years; female, 33%; never-smokers, 12%; and performance status 0 or 1, 88%. The median number of R1507 doses was six for the weekly arm and 3.5 for the every-3-weeks arm. Grades 3 to 4 adverse events occurred in 37%, 44%, and 48% of patients with placebo, R1507 weekly, and R1507 every 3 weeks, respectively. The 12-week PFS rates were 39%, 37%, and 44%, and the median overall survival was 8.1, 8.1, and 12.1 months for the three groups, respectively, with statistically nonsignificant hazard ratios. The 12-week PFS rate in patients with KRAS mutation was 36% with R1507 compared with 0% with placebo.ConclusionThe combination of R1507 with erlotinib did not provide PFS or survival advantage over erlotinib alone in an unselected group of patients with advanced NSCLC. Predictive biomarkers are essential for further development of combined inhibition of IGF-1R and EGFR.

MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors

“…The IGF-IR and ErbB3 signaling pathways have been implicated as potential escape pathways in cancers exhibiting resistance to targeted therapies and chemotherapies (18)(19)(20)(21)(41)(42)(43)(44)(45). We demonstrate that the IGF-IR pathway is often coactivated with ErbB3, another nonoverexpressed receptor.…”

“…We have previously shown that direct targeting of ErbB3 is optimal for blocking the ErbB3-PI3K cascade (32). Recent clinical strategies have combined IGF-IR inhibitors with EGFR-based therapies resulting in disappointing outcomes (19)(20)(21). We propose that the simultaneous blockade of IGF-IR and ErbB3 is necessary to maximize the potency of PI3K/ AKT/mTOR inhibition.…”

“…Addition of the IGF-I ligand has been shown to protect trastuzumab-sensitive cells from cell death (17), and patients treated with trastuzumab who also express IGF-IR have shorter progression-free survival (18). Not surprisingly, IGF-IR and EGFR/ErbB2 therapies were combined in multiple clinical trials (19)(20)(21). However, recent late-stage clinical failures have delayed proof-ofconcept that IGF-IR inhibitors, alone or in combination with EGFR-targeted agents, can be effective (19)(20)(21)(22).…”

[99mTc(CO)3]+-(HE)3-ZIGF1R:4551, a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours

“…Pre-treatment concentration of IGF-1 in serum [12,13], expression of IGF-1R in tumours, the level of circulating IGF-2 and IGF-binding proteins [12] have all been evaluated as predictors for response to IGF-1R targeting therapy in clinical trials. It was found that the level of membranous IGF-1R expression has a correlation with response rate to therapy using the antibody CP-751,871 [15].…”

“…Reports from clinical trials emphasize that identification of predictive biomarkers and careful patient stratification are required for successful IGF-1R-targeted treatment [11][12][13]. Pre-clinical data demonstrated that a higher level of membranous IGF-1R is associated with response to IGF-1R inhibitors [14].…”