An every 3-week regimen of the anti-IGF-1R monoclonal antibody F at doses up to 20 mg/kg in combination with paclitaxel and carboplatin was well tolerated. Grade 3 events of hyperglycemia, fatigue, diarrhea, GGT elevation, and thrombocytopenia (one case each) were reported as possibly related to F. Hyperglycemia seems to be characteristic of this class of compounds,10
although contributions of comorbid conditions, such as diabetes and steroid premedication for paclitaxel cannot be excluded. Importantly, the event of hyperglycemia was generally manageable with antidiabetic medication. Mild to moderate fatigue and sporadic isolated GGT elevations have been observed in previous studies of F. In contrast, severe thrombocytopenia has been rare when F was given as single agent.6,7
This is important because hematological toxicity has been reported to be dose limiting for other anti-IGF-1R antibodies.11–13
It is possible that differences in IgG subtype may be responsible for some of these differences. F is a fully human IgG2 antibody4
and, consequently, is expected to be a poor activator of antibody mediated cytotoxicity and complement fixation.
The extended effective half-life of F of approximately 3 weeks at 10 and 20 mg/kg doses compares favorably with other monoclonal antibodies in the anti-IGF-1R class.7
Mean terminal half-lives of 4 to 11 days have been reported for other IGF-1R monoclonal antibodies.9
These differences could be due in part to their IgG backbone.14
PK exposure parameters of F given in combination with paclitaxel and carboplatin were similar to those previously observed with single agent F,9
suggesting that the combination with paclitaxel/carboplatin does not significantly alter the PK properties of F. Based on its favorable safety profile and its optimal PK and pharmacodynamic properties, the maximal feasible dose of 20 mg/kg has been selected for further investigation.
CTCs were detected in approximately 40% of the patients, but the number of circulating cells was too low for systematic analysis. CTC counts have been proposed as a novel and noninvasive approach for pharmacodynamic studies in NSCLC and in breast and prostate cancer.5,8,15
Further research would be required to improve the sensitivity of current methodologies in NSCLC. Intriguingly, the median number of CECs increased during the study in a manner independent to F treatment. This finding may reflect a chemotherapy effect or patient selection based on prognosis, with those patients with a higher number of CECs receiving a larger number of treatment cycles. In that respect, it has been previously reported that baseline CEC counts are associated with better patient response and outcome in NSCLC.16
No relationship between CEC counts and response was apparent in this study. Further research should be undertaken to determine the prognostic value of CECs in the treatment of NSCLC.
Finally, we found that IGF-1 bioactivity may be critical for NSCLC response to chemotherapy and that blockade of the IGF-1/IGF-1R interaction by F may translate to clinical benefit, particularly in settings of high IGF-1 bioactivity. These findings should be considered with caution due to the small data set investigated in this study. However, these results are consistent with previous reports associating high-IGFBP-3 levels with longer overall, disease-free, and event-free survival in NSCLC.17,18
Additional research will be needed to determine the predictive value of fIGF-1 and IGFBP-3 levels and their potential use for patient selection or stratification in studies of anti-IGF-1R therapy. Pharmacodynamic measures are currently underway in ongoing studies to validate these provocative observations.19,20