The comprehensive review by Dr. Karen Kelly meticulously outlines the rationale for the study of irinotecan(Drug information on irinotecan) in non-small-cell lung cancer (NSCLC), summarizes results of trials of this agent as monotherapy and as a component of doublet and triplet regimens in previously untreated NSCLC patients, and then reviews its role in previously treated NSCLC patients.
Like the taxanes and gemcitabine(Drug information on gemcitabine), irinotecan is certainly an active drug in NSCLC. Unfortunately, however, it appears a therapeutic plateau has been reached in the treatment of advanced NSCLC with these newer active drugs in combination with a platinum compound. Median survivals of approximately 8 months and 1-year survival rates of approximately 35% are now widely reported in multiple phase III trials from a variety of cooperative groups.[1,2]
Strategies for Using Irinotecan
Despite attempts at varying the active agents studied, their schedules of administration, and sequences/doses of component agents, no recent trial has suggested an appreciable move forward with any such approach. To that end, it is difficult to foresee in what setting irinotecan might be routinely advantageous when used in the untreated NSCLC population. However, a burgeoning understanding of the molecular biology of common solid tumors may provide an opportunity for irinotecan and other agents to be used more creatively in this disease.
One such strategy would be to study drug combinations for tumor types in which the leading candidates for successful targeted therapies and irinotecan both have activity. To date, the most promising classes of agents have been either small molecules (eg, erlotinib [OSI-774, Tarceva], gefitinib(Drug information on gefitinib) [ZD1839, Iressa]) or monoclonal antibodies targeting the HER family (trastuzumab [Herceptin], cetuximab(Drug information on cetuximab) [IMC-C225, Erbitux]).
Given the frequency of perturbations in this signaling pathway in common solid tumors and the activity profile of irinotecan, combination trials could be envisioned in NSCLC as well as colorectal, ovarian, and cervical cancers.[3,4] Moreover, preclinical data suggest that epidermal growth factor receptor (EGFR)-tyrosine kinase (TK) inhibitors may be helpful in diseases that have little EGFR expressionfor example, small-cell lung cancer (SCLC), in which irinotecan is highly active.
Design of Future Trials