Figitumumab combined with carboplatin and paclitaxel in treatment-naïve Japanese patients with advanced non-small cell lung cancer

Abstract

SummaryObjectives The insulin-like growth factor (IGF) signaling pathway has been implicated in the pathogenesis of numerous tumor types, including non-small cell lung cancer (NSCLC). Figitumumab is a fully human IgG2 monoclonal antibody against IGF-1 receptor (IGF-1R). Methods This phase I, open-label, dose-escalation study (ClinicalTrials.gov: NCT00603538) assessed the safety and tolerability of figitumumab (6, 10 and 20 mg/kg) in combination with carboplatin (area under the curve: 6 mg·min/mL) and paclitaxel (200 mg/m2) in Japanese patients (N = 19) with chemotherapy-naïve, advanced NSCLC. Treatments were administered intravenously on day 1 of a 21-day cycle for four to six cycles. Pharmacokinetics, biomarkers, and antitumor activity were also evaluated. Results Figitumumab in combination with carboplatin and paclitaxel was well tolerated at doses up to 20 mg/kg; no dose-limiting toxicities were observed at this dose level. When given in combination, figitumumab plasma exposure increased in an approximately dose-proportional manner. The approximate 2-fold accumulation following repeated administration supported the 21-day regimen as appropriate for figitumumab administration. Serum total IGF-1 and IGF binding protein-3 concentrations increased following figitumumab dosing, but a clear dose-dependent relationship was not demonstrated. Seven of 18 evaluable patients experienced a partial response. Conclusions Figitumumab 20 mg/kg in combination with carboplatin and paclitaxel was well tolerated in chemotherapy-naïve Japanese patients with NSCLC. Further analysis of biomarker data is necessary for the development of figitumumab therapy.

Phase II Randomized Study of Figitumumab plus Docetaxel and Docetaxel Alone with Crossover for Metastatic Castration-Resistant Prostate Cancer

“…The relatively poor tolerability of the figitumumab combination may also account, at least in part, for the inferior efficacy observed in Arm A because of undertreatment with docetaxel; adverse event-related treatment interruptions or delays with this agent were more than twice as common in Arm A than in Arm B1, and more patients needed a docetaxel dose reduction in Arm A compared with Arm B1. In other respects, safety findings in the current study were similar to those known to be class effects for IGF-1R inhibitors and previously reported figitumumabassociated adverse events (25,39). Hyperglycemia, a known class effect of IGF-1R inhibitors, was reported in approximately one third of the patients in this study, and is likely related to impaired homeostatic control of insulin and blood glucose levels following abrogation of IGF-1R signaling (40).…”

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

“…These findings were corroborated with respect to levels of free or total circulating IGFs in additional clinical trials [63,80–82]. Circulating markers present obvious advantages over tissue biomarkers: testing is minimally invasive and amenable to serial monitoring.…”

“…There is as yet little consistent evidence regarding candidate tissue biomarkers for response to IGF-1R antibodies and TKIs, and it is not clear at this stage whether the same parameters will influence sensitivity to IGF ligand antibodies, which are still at a relatively early stage of development. However, enough trials have highlighted the association between response to IGF-1R inhibition and circulating IGFs, IGFBPs, and indicators of glycemic control [63,80–82,86,87,155] to support inclusion of these parameters in future trials of agents that remain under active investigation, for example [21,22,51,165]. Even amongst the failed trials, there are subsets of patients who have obtained durable benefit from IGF-1R inhibition.…”

Subsequent Treatment Choices for Patients with Acquired Resistance to EGFR-TKIs in Non-small Cell Lung Cancer: Restore after a Drug Holiday or Switch to another EGFR-TKI?

“…The RR (response rates) were 65% (95% CI, 58 to 72) with Crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001) and 871) have the potential to overcome EGFR resistance and are currently being investigated in clinical trials (Goto et al, 2012).…”