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Oral Taxane Shows Strong Activity and Good Tolerability in Metastatic Breast Cancer


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As first-line treatment for metastatic breast cancer, the oral taxane tesetaxel produced a 45% confirmed response rate and was well tolerated, producing little alopecia or neuropathy, according to Andrew D. Seidman, MD, and colleagues from several cancer centers. Dr. Seidman, of Memorial Sloan Kettering Cancer Center, New York, presented the findings at the 2018 ASCO Annual Meeting.1


We are seeing much less alopecia [with tesetaxel] than with parenteral taxanes, no allergic reactions, and what appears to be less neuropathy.
— Andrew D. Seidman, MD

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“We see a lot of activity with this oral taxane, and the other attractive thing—apart from its convenient oral dosing—is [the toxicity profile]. We are seeing much less alopecia than with parenteral taxanes, no allergic reactions, and what appears to be less neuropathy,” Dr. Seidman told The ASCO Post.

Co-investigator Lee Schwartzberg, MD, of the West Clinic in Memphis, added, “The recent results from the phase II study of tesetaxel as a single agent in HER2-negative hormone receptor–positive metastatic breast cancer are very encouraging. These patients are in need of more options that allow them to maintain their quality of life while on treatment. As the data suggested, tesetaxel offers the benefits of a taxane, but with oral administration, which may help address this unmet need.”

Unique Pharmacologic Properties

In clinical studies, 559 patients have been treated with tesetaxel, including 496 as monotherapy and 63 in combination with capecitabine. In metastatic breast cancer, tesetaxel has shown significant single-agent activity in two multicenter phase II trials, the authors noted on their poster.

Unlike paclitaxel and docetaxel, tesetaxel has potent activity against p-glycoprotein–overexpressing tumors; the p-glycoprotein efflux pump mediates gastrointestinal absorption as well as chemotherapy resistance. Since tesetaxel is not pumped out by p-glycoprotein, it does not need to be given intravenously. The drug also is more bioavailable than other taxanes, is highly soluble (and therefore does not require solubilizing agents such as polyethoxylated castor oil [Kolliphor EL, formerly Cremophor EL] or steroid prophylaxis), and has a half-life of about 8 days (which allows it to be active for the whole 21-day cycle), according to Thomas Wei, Head of Research and Development for Odonate Therapeutics, the manufacturer.

“We are developing a next-generation version of taxanes, but with a lot of unique features,” he said at the poster.

A ‘Resurrected’ Molecule

“There is a long history to this drug,” according to Dr. Seidman, who said he presented early data for tesetaxel at ASCO half a dozen years ago. Tesetaxel was first developed in Japan and tested in a variety of tumor types. The compound was sold to Genta, but the company encountered financial issues that derailed its further development.


As the data suggested, tesetaxel offers the benefits of a taxane, but with oral administration, which may help address this unmet need.
— Lee Schwartzberg, MD

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By that time, it had caught the eye of a number of prominent breast cancer researchers. “We saw this drug had activity as a first-line oral agent given once every 3 weeks and producing remissions in metastatic breast cancer, which is striking,” Dr. Seidman said. “I can’t think of another example where a pill that is taken once every 3 weeks causes metastatic tumors to shrink.”

Ultimately, after languishing on the shelf, the rights to and data for tesetaxel were acquired by Odonate, which has now taken the oral taxane into a phase III registration study.

“We wanted to get the word out that this drug has been resurrected, and these are data informing the phase III registration study,” Dr. Seidman said.

Phase II TOB203 Study

TOB203 enrolled 46 patients with HER2-negative metastatic breast cancer who received tesetaxel as a single agent in the first-line setting. Tesetaxel was administered orally as first-line chemotherapy at 27 mg/m2 on day 1 of a 21-day cycle, with a cohort of patients escalating to 35 mg/m2 in subsequent cycles, depending on tolerability. No antiallergy premedication was given.

TESETAXEL STUDY

  • A phase II study evaluated an oral taxane, tesetaxel, in 38 patients with HER2-negative, hormone receptor–positive metastatic breast cancer.
  • As a first-line single agent, tesetaxel produced confirmed responses in 45% of patients and stable disease in 37%, yielding a clinical benefit rate of 82%.
  • The oral drug is given every 3 weeks and is associated with less alopecia and neuropathy than have historically been reported with parenteral taxanes.
  • The phase III CONTESSA registration study is underway.

The ASCO poster focused on the 38 hormone receptor–positive patients within the study population. Prior adjuvant chemotherapy, including treatment with a taxane, was received by 68% of patients. The population had a median of 2 organ systems involved, and 87% had visceral disease.

The confirmed objective response rate, the study’s primary endpoint, was 45%, and another 37% of patients achieved stable disease, for a clinical benefit rate of 82%. The response rate was consistent across subgroups and, notably, was the same for patients with prior taxane exposure as for taxane-naive patients.

The median duration of response was 10.9 months, and the median progression-free survival was 5.4 months, the investigators reported.

Safety Profile

“The types of side effects with tesetaxel are comparable to those of the other taxanes, but we think the rates are lower. We are particularly intrigued by lower rates of neuropathy and alopecia than have been reported in the literature for the other agents in the class,” Mr. Wei said.

Grade ≥ 3 adverse events occurred less frequently in the 24 patients who were not on dose-escalated regimens. In these patients, neutropenia grade ≥ 3 was the most common toxicity, seen in 25%; febrile neutropenia occurred in 4% (1 patient) and grade 3 neuropathy in 4% (after cycle 12). There were no hypersensitivity reactions, and the incidence of grade 2 alopecia was 18%. For patients in whom the dose was escalated to 35 mg/m2, neutropenia ≥ grade 3 developed in 43% and neuropathy grade ≥ 3, in 29%.

Next Steps

CONTESSA is a multinational randomized phase III registration study of tesetaxel plus a reduced dose of capecitabine vs the approved dose of capecitabine alone in patients with HER2-negative, hormone receptor–positive locally advanced or metastatic breast cancer. The study is underway.

“I’m excited about this drug—the idea that we want to develop an all-oral, well-tolerated regimen that will be more effective than capecitabine alone,” Dr. Seidman said. “Hopefully, the results from CONTESSA will lead to a combination oral chemotherapy regimen that will be kinder and gentler than others.” ■

DISCLOSURE: Dr. Seidman has a consulting or advisory role with Eisai, Genentech, Nektar, Odonate Therapeutics, Eli Lilly, and Pfizer; is on speakers bureaus for Eisai, Genentech, Genomic Health, Novartis, Eli Lilly, and Pfizer; has received honoraria from Eisai, Genentech, Genomic Health, Nektar, Novartis, Odonate Therapeutics, and Pfizer; and has received institutional research funding from Bayer, Nektar, Novartis, and Odonate Therapeutics. Dr. Schwartzberg has received honoraria from Amgen, NanoString Technologies, Novartis, and Pfizer and has a consulting or advisory role with Bristol-Myers Squibb, Caris Life Sciences, Genomic Health, Helsinn Therapeutics, Pfizer, Spectrum Pharmaceuticals, and Tesaro. Mr. Wei is Head of Research and Development for Odonate Therapeutics.

REFERENCE

1. Seidman AD, Schwartzberg LS, Gudena VK, et al: Activity of tesetaxel, an oral taxane, given as a single agent in patients with HER2-negative, hormone receptor-positive locally advanced or metastatic breast cancer in a phase 2 study. 2018 ASCO Annual Meeting. Abstract 1042. Presented June 2, 2018.


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