Biomarker-Driven Trial of Novel Topo-1 Inhibitor Debuted

Edith Perez, MD

An international team of investigators is evaluating the novel topoisomerase-1 inhibitor etirinotecan pegol in patients with metastatic breast cancer, and at the same time evaluating target-specific biomarkers in circulating tumor cells (CTCs). The experimental agent and the novel CTC isolation technique were described at the 2014 San Antonio Breast Cancer Symposium by Edith Perez, MD, of the Mayo Clinic in Jacksonville, Florida.

Etirinotecan pegol is a long-acting topoisomerase-1 inhibitor designed for prolonged tumor cell exposure. Topoisomerase 1 is a nuclear enzyme that plays an essential role in DNA replication, transcription, recombination, and repair. .

“Etirinotecan pegol target-specific pharmacodynamic biomarkers will be measured in CTCs isolated from patients participating in the BEACON trial,” Perez said. The researchers will analyze CTC information obtained at baseline and throughout treatment, and correlate these findings with clinical outcomes, she explained. .

Describing the new compound, Perez noted that the use of the parent compound irinotecan is mostly limited in the United States to colorectal cancer, although it enjoys broader use in Japan. About 10 years ago, Perez led a study of irinotecan in metastatic breast cancer where the response rate was 23%, convincing her that a topoisomerase-1 inhibitor could be useful in breast cancer.

“Nektar Therapeutics has developed a better formulation, a pegylated formulation with a very improved pharmacokinetic profile,” Perez said in an interview. “Instead of high peak levels, like the parent compound produced, etirinotecan pegol produces steady levels of drug so we can expose the tumor cells to continuous levels of the active metabolite [SN38].” .

In a previous phase II trial of 70 patients, the response rate to etirinotecan was 29%, median progression-free survival was 4.7 months, and median overall survival was 10.3 months.2 .

These encouraging results led to the phase III BEACON study, which is comparing single-agent etirinotecan to physicians’ choice of treatment in 852 previously treated patients. Topline results are expected in the first quarter of 2015, according to Perez. .

“We mandated prior treatment with an anthracycline, a taxane, and capecitabine, which means these are truly refractory patients,” Perez said. “And our primary endpoint is overall survival, because we feel we owe it to our patients to strive for an overall survival benefit in our studies. Based on phase II results, we feel we can meet this endpoint.”

Isolation of CTCs via New Technique The study is designed to isolate CTCs and examine them, both for their numbers and for target-specific pharmacodynamic biomarkers. Circulating tumor cells are shed from the tumor and circulate in the peripheral blood. The isolation of CTCs represents an attractive minimally-invasive alternative to tumor biopsies.

BEACON is employing the ApoStream® system for CTC isolation. This technique, which is based on dielectrophoresis and microfluidic technology and is antibody-independent, yields higher numbers of CTCs than the first-generation EpCAM-dependent methods. Patients will be sampled at baseline, before cycle 2, before cycle 4, and at the end of treatment. Changes in these markers will be correlated with tumor response.

“We have as an exploratory endpoint the biomarker analysis, which we will conduct in the CTCs we isolate. We were happy to have access to novel technology that can detect many more CTCs than EpCAM-dependent technology,” Perez said.

Perez and her team have already analyzed samples from 80% of patients. The researchers looked at the number of CTCs, the percentage of cells staining positive for a given biomarker, and mean fluorescence intensity of the biomarker. “We tested for markers that may be correlated with the activity of topoisomerase 1 inhibitors,” she said. These biomarkers include Top1, Top2, Rad51, γH2Ax, Ki67, and ABCG2.

In San Antonio, the researchers described the initial CTC collection. “We made two observations,” Perez stated. “We can detect CTCs in 97% of samples at baseline, and we get high-yield CTCs that allow us to do molecular profiling.”

This reflects a much lower technical failure rate than occurs with older methods, where about 50% of patients yield CTCs, she said. With ApoStream®, the mean number of CTCs was 472 per 7.5-mL sample.

Perez added that the CTCs are “viable,” allowing the researchers to conduct a variety of translational studies on them.

References

1. Perez E, Caygill K, Hannah AL, et al. Etirinotecan pegol target-specific pharmacodynamic biomarkers in circulating tumor cells from patients with metastatic breast cancer in the phase 3 BEACON study. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13
2. Awada A, Garcia AA, Chan S, et al, for the NKRT-102 Study Group. Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study.Lancet Oncology. 2013;14(2):1216-1225.

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