Tesetaxel Plus Reduced-Dose Capecitabine Significantly Prolongs PFS in Metastatic Breast Cancer

Tesetaxel in combination with a reduced dose of capecitabine led to a significant improvement in progression-free survival (PFS) versus the approved dose of capecitabine alone, meeting the primary end point of the phase 3 CONTESSA trial (NCT03326674).¹

Results showed a median PFS of 9.8 months per independent radiologic review committee (IRC) with the combination versus 6.9 months with capecitabine alone, translating to an improvement of 2.9 months with the investigational regimen and a 28.4 reduction in the risk of disease progression or death (HR, 0.716; 95% CI, 0.573-0.895; P = .003).

“Tesetaxel represents a potential important clinical advance for patients with metastatic breast cancer,” Joyce O’Shaughnessy, MD, Celebrating Women Chair in Breast Cancer Research at Baylor University Medical Center, Texas Oncology, chair of Breast Cancer Research of US Oncology, and a 2016 Giant of Cancer Care^® in Community Outreach, and co-principal investigator of CONTESSA, stated in a press release. “There remains a significant unmet medical need for novel therapies that offer quality-of-life advantages for patients with metastatic breast cancer. This need is underscored by a recent update to the National Comprehensive Cancer Network guidelines recommending oral oncolytics that can reduce the frequency of clinical visits.”

In the international, multicenter, randomized phase 3 trial, investigators set out to compare the efficacy of the investigational, orally administered taxane at 27 mg/m2 on the first day of each 21-day treatment cycle plus a reduced dose of capecitabine versus the regulatory approved dose of oral capecitabine at 2500 mg/m2 daily for 14 days of each 21-day cycle based on PFS as assessed by IRC.

CONTESSA enrolled a total of 685 patients with HER2-negative, hormone receptor (HR)–positive metastatic breast cancer who were previously treated with a taxine in the neoadjuvant or adjuvant setting. Patients will receive treatment until disease progression, evidence of intolerable toxicity, or other decision for treatment discontinuation.

To be eligible for enrollment, patients had to be at least 18 years of age, have histologically or cytologically confirmed breast cancer, HER2-negative disease and HR-positive disease per local testing, measurable disease per RECIST v1.1 criteria, and an ECOG performance status ranging from 0 to 2.² Patients were allowed to have received previous treatment with a taxane-containing regimen in the neoadjuvant or adjuvant settings, previous treatment with an anthracycline-containing regimen in the neoadjuvant, adjuvant, or metastatic settings, and previous endocrine therapy with or without a CDK4/6 inhibitor.

Patients who received 2 or more previous chemotherapy regimens for advanced disease, previous treatment with a taxane in the metastatic setting, or previous therapy with capecitabine at any dose, were not permitted to enroll. Those with current evidence of leptomeningeal disease, known human immunodeficiency virus infection or active hepatitis B or C infection, or neuropathy, among others, were not eligible to participate.

The primary end point of the trial was PFS, and key secondary end points included overall survival, objective response rate per IRC, disease control rate per IRC, central nervous system (CNS) ORR in those with CNS metastases at baseline per IRC, CNS PFS in patients with CNS metastases at baseline or a history of CNS metastases in the intent-to-treat population, and CNS OS in patients with CNS metastases at baseline or a history of CNS metastases.

With regard to safety, the combination of tesetaxel plus reduced-dose capecitabine was found to have a manageable toxicity profile that proved to be consistent with data from previous trials examining the agents. Grade 3 or higher treatment-emergent adverse effects (AEs) that were reported in 5% or more patients included neutropenia (71.2% with the combination and 8.3% with the monotherapy), diarrhea (13.4% vs 8.9%, respectively), hand-foot syndrome (6.8% vs 12.2%), febrile neutropenia (12.8% vs 1.2%), fatigue (8.6% vs 4.5%), hypokalemia (8.6% vs 2.7%), leukopenia (10.1% vs 0.9%), and anemia (8.0% vs 2.1%).

In 1% or more of patients, some AEs with the combination and the monotherapy resulted in treatment discontinuation; these included neutropenia or febrile neutropenia (4.2% vs 1.5%, respectively), neuropathy (3.6% vs 0.3%), diarrhea (0.9% vs 1.5%), and hand-foot syndrome (0.6% vs 2.1%). Treatment discontinuation because of any toxicity was reported in more patients treated with the combination compared with the monotherapy, at 23.1% versus 11.9%, respectively.

Additionally, grade 2 alopecia was reported in 8.0% of patients who received the combination versus 0.3% of patients who received capecitabine alone. Grade 3 or higher neuropathy was observed in 5.9% versus 0.9% of patients who received the combination and the monotherapy, respectively.

Although OS data are not mature, a recent interim analysis of the trial suggested an absence of an adverse effect on OS, according to Odonate Therapeutics, the drug developer. Final OS data from the trial are anticipated to read out in 2022.

“The clinically meaningful PFS improvement observed in CONTESSA, along with the once-every-3-week oral dosing and low rates of clinically significant hair loss and neuropathy, could make tesetaxel an important new treatment option for patients with metastatic breast cancer,” Andrew Seidman, MD, attending physician of Breast Medicine Service in the Department of Medicine and medical director of Bobst International Center at Memorial Sloan Kettering Cancer Center; a professor of medicine at Weill Cornell Medical College, and co-principal investigator of CONTESSA, added in the press release.

Odonate Therapeutics will submit the results from the pivotal phase 3 trial for presentation at an upcoming medical meeting.

References

1. Odonate Therapeutics announces positive top-line results from CONTESSA, a phase 3 study of tesetaxel in patients with metastatic breast cancer. News release. Odonate Therapeutics, Inc. August 24, 2020. Accessed August 24, 2020. https://bwnews.pr/31q9Hij.
2. Tesetaxel plus reduced dose of capecitabine vs capecitabine in HER2 negative, HR positive, LA/MBC (CONTESSA). ClinicalTrials.gov. Updated October 29, 2019. Accessed August 24, 2020. https://clinicaltrials.gov/ct2/show/NCT03326674.