CHICAGO – Etirinotecan pegol is an efficacious treatment option for selected women with heavily pretreated advanced breast cancer, suggests the international phase III BEACON study (Breast Cancer Outcomes With NKTR-102).
Compared with a treatment of the physician’s choice, the novel drug – an encapsulated form of irinotecan that inhibits topoisomerase 1—did not significantly improve overall survival in the trial population as a whole, first author Dr. Edith A. Perez reported at the annual meeting of the American Society of Clinical Oncology. But it reduced the risk of death by nearly half for the subset of women with a history of brain metastases and by more than a quarter for the subset of women with a history of liver metastases, with less toxicity and better quality of life.
Dr. Edith A. Perez
“Etirinotecan pegol … [has] clinical activity and good tolerability in patients with heavily pretreated advanced breast cancer,” summarized Dr. Perez, who is deputy director at large for the Mayo Clinic Cancer Center in Jacksonville, Florida, as well as director of the Mayo Clinic Breast Cancer Translational Genomics Program and chair of the Breast Cancer Specialty Council.
“The 2.1-month improvement in median survival favoring etirinotecan pegol did not reach statistical significance. However, provocative and potentially very important survival results in predefined subgroups of patients deserve further study, specifically, patients with brain metastases or liver metastases,” she said. “Exploration of potential predictive biomarkers is ongoing.”
The findings regarding brain metastases are “an intriguing nugget,” according to invited discussant Dr. Harold J. Burstein, a senior physician at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston. “I think these data and the growing literature on the effectiveness of systemic therapy for brain metastases … suggest that it’s time for us to be doing trials where we are comparing standards of care of radiotherapy against chemotherapy, trying to optimize our chemotherapy regimens for the palliation of metastatic disease of the brain.”
He pointed to a set of trials in patients with advanced lung cancer testing the benefits of early palliative care on outcomes and finding improvements in overall survival or in quality of life with no detriment to overall survival.
“I used to look at these and think this didn’t really speak to the breast cancer population. But when you start to see data in the heavily refractory patients as we have observed today, it turns out that their survival is unfortunately essentially the same as for all the patients who participated in these trials,” he said. “So when we think about what direction we should go for advanced breast cancer that’s heavily refractory to chemotherapy, in addition to exploring a variety of exciting new immunologic therapies, and targeted therapies … I think we need to begin to lean more on our palliation care specialists and colleagues to help us truly take optimal care of these patients.”
The 852 women studied in the BEACON trial had experienced progression after anthracycline, taxane, and capecitabine therapy and had received two to five prior therapies for their advanced disease. The trial, sponsored by Nektar Therapeutics, was unusual in that it allowed patients with stable brain metastases to enroll and set a high bar of overall survival as its primary endpoint, Dr. Perez noted.
The patients were randomized evenly to receive single-agent etirinotecan pegol or a single agent of the physician’s choice, which was most commonly eribulin.
Main results showed no significant improvement in overall survival among the entire trial population comparing etirinotecan pegol with physician’s choice (12.4 vs. 10.3 months; hazard ratio, 0.87; P = .08).
However, preplanned subgroup analyses showed that in the 8% of women who had a history of brain metastases, median overall survival was 10.0 months with the drug and 4.8 months with physician’s choice (HR, 0.51; P = .0099). The curves began to separate within 3 months of randomization, and the difference in the proportion of women alive at 12 months was “pretty amazing,” Dr. Perez noted, at 44% versus 19%.
There was a similar although smaller survival advantage of etirinotecan pegol among the 53% of patients with a history of liver metastases (10.9 vs. 8.3 months; HR, 0.73; P = .002).
A variety of biomarkers for etirinotecan benefit are still being analyzed, according to Dr. Perez. The most promising signal thus far has been a reduction in the number of topoisomerase 1–positive circulating tumor cells, with patients going from high (above the baseline median) to low (below the baseline median) numbers surviving significantly longer than peers having persistently high numbers (14.9 vs. 10.7 months; HR, 0.54; P = .007).