LESSONS LEARNED: The combination of irinotecan and etoposide showed modest efficacy in terms of response rate in the refractory setting for patients with metastatic breast cancer.The studied dose and schedule of irinotecan and etoposide is very toxic, with >70% grade 3 or 4 treatment-related adverse events.
BACKGROUND: As single agents, both irinotecan and etoposide have documented activity against breast cancer among patients who have received multiple lines of prior chemotherapy. Irinotecan interacts with topoisomerase I (Topo I) to stabilize its cleavable complex, and etoposide has an analogous interaction with topoisomerase II (Topo II). This stabilization without rapid resealing of the cleavage point results in apoptotic cell death and accounts for the antitumor activity of these agents. Topo II levels may increase after administration of a Topo I inhibitor, thus providing a rationale for combining these agents in practice. Based on preclinical data, we conducted a phase II trial of the Topo I inhibitor irinotecan combined with the Topo II inhibitor etoposide in patients with metastatic breast cancer (MBC).
METHODS: This was a single-arm phase II clinical trial in patients with MBC refractory to prior anthracycline, taxane, and capecitabine therapy. All patients were treated with oral etoposide at 50 mg/day on days 1-14 and intravenous irinotecan at 100mg/m on days 1 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was median time to progression. Secondary end points included overall clinical response rate using RECIST criteria and assessing the toxicity and safety profile associated with this combination regimen.
RESULTS: We enrolled 31 women with refractory MBC to our trial. Median age was 54 (range, 36-84), with the majority (64%) having hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2 neg) MBC. Median number of prior therapies was five (range, 3-14). Efficacy was evaluated in 24 patients. Seventeen percent had a partial response, and 38% had stable disease as best response. Median progression-free survival was 9 weeks (range, 3-59). All 31 patients were evaluable for toxicity assessment, and 22 patients (71 %) experienced treatment-related grade 3 or 4 adverse events (AEs; Table 1). The most common grade 3-4 AE was neutropenia. The study was terminated early based on interim analysis assessment that suggested toxicities outweighed the efficacy.
CONCLUSION: Irinotecan and etoposide demonstrated only modest clinical activity and poor tolerability in patients with MBC refractory to anthracycline, taxane, and capecitabine therapy. Further studies testing a lower dose and/or different schedule could be considered given ease of administration and responses seen.