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Expert Point of View: William Gradishar, MD


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Thoughts on oral taxanes—and in particular, tesetaxel—were provided by William Gradishar, MD, the Betsy Bramsen Professor of Breast Oncology at Northwestern University Feinberg School of Medicine and Deputy Director for the Clinical Network of the Lurie Cancer Center.

Dr. Gradishar commented that tesetaxel would be a beneficial addition to the treatment arsenal for metastatic breast cancer, but perhaps not in the manner by which it was tested in the phase III trial presented by Dr. O’Shaughnessy.1 “This was a trial of capecitabine alone vs with tesetaxel. For those who are questioning why it evaluated a doublet, the design was sort of a registration strategy, and that’s the rationale,” he explained.

“In terms of clinical endpoints, progression-free survival, response rate, and duration of response favored the combination over capecitabine alone, and there were predictable side effects,” he noted. “Not surprisingly,” he noted, dose reductions were required by more patients receiving the combination, including 76% of tesetaxel doses (for neutropenia) and 58% of capecitabine (for neutropenia) vs 61% of capecitabine monotherapy (for hand-foot syndrome). Granulocyte colony-stimulating factor was required by 58% of patients receiving tesetaxel vs 6% of those receiving single-agent capecitabine.

William Gradishar, MD

William Gradishar, MD

“Discontinuations, though rare, were predictably related to hematologic toxicity (4.2%) and neuropathy (5.9%), and alopecia was also rare (8%),” he added. Relative dose intensity remained high at 81% with tesetaxel, 79% with capecitabine (in combination), and 76% with capecitabine monotherapy, he further noted.

A favorable feature of tesetaxel clearly relates to its pharmacokinetics, he added, which allows for dosing every 21 days. It also does not have to be partnered with another drug to prevent efflux, as is the case with oral paclitaxel and encequidar.

“If tesetaxel were magically approved, would the real attraction be to give it in combination? I’m not so sure, but I do think it would provide another palliative option—and would be a treatment that is relatively easy, perhaps given in a manner that does not impair the patient’s quality of life,” Dr. Gradishar concluded. “It may also be a drug that would be attractive to combine with anti-HER2 therapy, even subcutaneous preparations, and that’s getting away from intravenously delivered therapy. The findings are interesting, and I think we may see this drug [in the clinic] sooner rather than later.” 

Editor's note: On March 22, 2021, Odonate Therapeutics announced it was discontinuing the development of tesetaxel and will close the company's operations. Read more here.

DISCLOSURE: Dr. Gradishar disclosed industry relationships with AstraZeneca, Carrick Therapeutics, Celltrion, Genentech, Genomic Health, MacroGenics, Merck, Pfizer, and Seattle Genetics.

REFERENCE

1. O’Shaughnessy J, Schwartzberg L, Piccart M, et al: Results from CONTESSA: A phase 3 study of tesetaxel plus a reduced dose of capecitabine versus capecitabine alone in patients with HER2-negative, hormone receptor-positive metastatic breast cancer who have previously received a taxane. 2020 San Antonio Breast Cancer Symposium. Abstract GS4-01. Presented December 11, 2020.


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