Darlene Dobkowski

Treatment with tesetaxel plus a reduced dose of capecitabine (Xeloda) improved progression-free survival (PFS) in patients with human epidermal growth factor receptor 2-negative (HER2–), hormone receptor-positive (HR+) metastatic breast cancer compared with the FDA-approved dose of capecitabine alone, according to findings from the phase 3 CONTESSA trial presented during the 2020 San Antonio Breast Cancer Symposium.

Tesetaxel, an oral taxane, is a novel drug with several unique properties including oral administration and significant activity against breast cancer cell lines that are resistant to chemotherapy.

“Tesetaxel …is a new chemical entity that, unlike the other taxanes, paclitaxel and docetaxel, is not effluxed by the P-gp pump,” said Joyce O’Shaughnessy, MD, co-chair of breast cancer research and chair of breast cancer prevention research at Baylor-Sammons Cancer Center, during the virtual presentation of the study results. “As a result, [tesetaxel] has the unique feature of being intrinsically orally bioavailable. It is also significantly more soluble than the other taxanes and has a much longer half-life.”

O’Shaughnessy added that tesetaxel also has a low pill burden compared with other treatments. “While the standard regimen of paclitaxel requires weekly IV infusions, tesetaxel is administered as 2 to 5 capsules once every 3 weeks,” she said.

In the phase 3 CONTESSA trial, researchers compared tesetaxel plus capecitabine with capecitabine alone in 685 patients with HER2–, HR+ metastatic breast cancer treated with 1 chemotherapy regimen for advanced disease and received a taxane either in the neoadjuvant or adjuvant setting. Patients assigned to the combination regimen (n = 343; median age, 56 years) received 27 mg/m2 of tesetaxel the first day of a 21-day cycle, then 1,650 mg/m2 per day of capecitabine on days 1 through 14 of the same cycle. Those assigned to capecitabine alone (n = 342; median age, 57 years) received the dose approved by the FDA (2,500 mg/m2 per day on days 1 through 14 of a 21-day cycle).

“The reason for the combination versus monotherapy is because it was designed as a registration trial, very similar to the initial docetaxel plus-minus [capecitabine], paclitaxel plus-minus gemcitabine,” O’Shaughnessy said. “The other thing is that it did allow in a more virulent population, it didn’t have any requirement for at least a year of disease-free interval, so patients could come on within a year of finishing up their taxane.”

The primary end point for this study was PFS. Follow-up was conducted for a median of 13.9 months.

Patients assigned tesetaxel with capecitabine demonstrated a median PFS of 9.8 months, compared with 6.9 months in those assigned capecitabine alone, which led to an improvement of 2.9 months (HR, 0.716; 95% CI, 0.573-0.895; 

“The increment in median PFS is similar certainly to what we had seen in the docetaxel plus-minus [capecitabine],” O’Shaughnessy said. “It was a median improvement of 2 months, albeit there, it was survival. We’ll have to wait and see. Probably we’re going to be using a doublet for patients who have virulent disease who really need a response.”

In addition, the overall response rate was 57% for the tesetaxel plus capecitabine group versus 41% for the capecitabine alone group (

 = .0002). Data on overall survival were immature at the time of this analysis.

Consistent with previous clinical studies, tesetaxel plus capecitabine had a manageable adverse event (AE) profile. Some grade 3 or higher treatment-emergent AEs, which occurred in at least 5% of patients, were observed in more patients assigned tesetaxel plus capecitabine, compared with capecitabine, including diarrhea (13.4% vs 8.9%), neutropenia (71.2% vs 8.3%), fatigue (8.6% vs 4.5%), febrile neutropenia (12.8% vs 1.2%), leukopenia (10.1% vs 0.9%), hypokalemia (8.6% vs 2.7%), and anemia (8% vs 2.1%). In contrast, patients assigned capecitabine alone were more likely to develop hand-foot syndrome compared with those assigned tesetaxel plus capecitabine (6.8% vs 12.2%).

AEs resulting in treatment discontinuation occurred in at least 1% of patients. Some events occurred more often in patients assigned to the combination therapy such as neuropathy (3.6% vs 0.3%) and neutropenia or febrile neutropenia (4.2% vs 1.5%), whereas others were more common in patients assigned capecitabine alone including hand-foot syndrome (0.6% vs 2.1%) and diarrhea (0.9% vs 1.5%). Treatment discontinuation as a result from any AE was observed in 23.1% of patients assigned combination therapy compared with 11.9% of those assigned capecitabine alone.

The combination therapy group experienced several other AEEs more often than the capecitabine alone group, including grade 2 alopecia (8% vs 0.3%) and grade 3 or greater neuropathy (5.9% vs 0.9%).

“Tesetaxel plus a reduced dose of capecitabine is a potential new treatment option for patients with hormone receptor-positive, HER2-negative metastatic breast cancer,” O’Shaughnessy concluded.

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-, hormone receptor + (HR+) metastatic breast cancer (MBC) who have previously received a taxane. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract GS4-01.

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Treatment with tesetaxel plus a reduced dose of capecitabine improved progression-free survival in patients with HER2–, HR+ metastatic breast cancer compared with the FDA-approved dose of capecitabine alone.

Tesetaxel Plus Capecitabine Combo Improves PFS in HR+ Metastatic Breast Cancer

Sustained progression-free survival (PFS) and overall survival (OS) benefit at 5 years was observed in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) treated with the combination of venetoclax (Venclexta) plus rituximab (Rituxan) compared with bendamustine plus rituximab in the MURANO trial (NCT02005471).

Results from a 5-year analysis of the MURANO trial were presented by  Arnon P. Kater, MD, PhD during the American Society of Hematology (ASH) Virtual Annual Meeting and Exposition.

"Overall, sustained undetectable (minimal residual disease), progression-free survival and overall survival benefits provide further support for the use of a fixed duration (Venclexta with rituximab) in patients with relapsed/refractory CLL,” said Kater, leader of tumor immunology at the Cancer Center Amsterdam.

In the MURANO trial, 389 patients with relapsed/refractory CLL were randomly assigned either venetoclax with rituximab (n = 194) or bendamustine with rituximab (n = 195).

After a median follow-up of 59.2 months, the benefit observed in patients assigned venetoclax with rituximab regarding PFS was sustained compared with those assigned bendamustine with rituximab (HR = 0.19; 95% CI, 0.15-0.26). The median PFS in the venetoclax with rituximab group was 53.6 months (95% CI, 48.4-57) compared with 17 months (95% CI, 15.5-21.7) for the bendamustine with rituximab group. Of the 130 patients who completed 2 full years of therapy with venetoclax and rituximab, estimates of PFS at 36 months after treatment completion was 51.1% (95% CI, 40.2-61.9).

Compared with patients assigned bendamustine with rituximab, those assigned venetoclax with rituximab maintained an OS benefit (HR = 0.4; 95% CI, 0.26-0.62), with a five-year OS estimate of 82.1% (95% CI, 76.4-87.8) for the venetoclax with rituximab group vs. 62.2% (95% CI, 54.8-69.6) for the bendamustine with rituximab group. Median OS was not achieved in either group in this study.

Patients assigned venetoclax with rituximab who reached the end of treatment without disease progression and had undetectable minimal residual disease (n = 83) had an improved OS outcome compared with those who had minimal residual disease (n = 35). Survival estimates 3 years after end of treatment was 95.3% (95% CI, 90-100) for those with undetectable minimal residual disease (MRD) and 85% (95% CI, 72.8-97.2) for those with MRD.

In patients with undetectable MRD, 32 did not have disease progression and continued to have undetectable MRD out to 5 years. In addition, 4 patients had disease progression without prior confirmed conversion of MRD, and 47 patients had MRD conversion, with a median conversion time to MRD from the end of treatment of 19.4 months (95% CI, 8.7-28.3). Of the 47 patients who converted to MRD, 19 developed disease progression at a median time of 25.2 months (95% CI, 19.4-30.4). It is important to note that these 19 patients had more rapidly increasing rates of MRD after completing treatment compared with those with MRD but remained free from disease progression.

“The longer undetectable MRD is maintained, the likelihood of conversion to MRD positivity is diminished,” said Kater during the presentation.

Several high-risk factors were associated with an increased risk of disease progression in patients with undetectable MRD at the end of treatment including chromosome 17p deletion, genomic complexity (3 or more subtle genetic abnormalities) and unmutated immunoglobulin heavy chain variable region. Patients without these factors “were more likely to maintained undetectable MRD or experienced MRD conversion without progressive disease at this follow-up,” said Kater.

Researchers also investigated MRD growth rate in this trial in 102 patients assigned venetoclax with rituximab and 104 patients assigned bendamustine with rituximab. The venetoclax with rituximab group had a longer mean doubling time compared with the bendamustine with rituximab group (52 days vs. 72 days). Faster MRD doubling times after the end of treatment was also observed in patients with 17p deletion (44.9 days vs. 85.6 days), genetic complexity (61.6 days vs. 96.4 days) and unmutated immunoglobulin heavy chain variable region (60.2 days vs. 120.3 days) compared with those without these risk factors.


Kater AP. five-year analysis of MURANO study demonstrates enduring undetectable minimal residual disease (UMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia (r/r CLL) patients (pts) following fixed-duration venetoclax-rituximab (venr) therapy (tx). Presented at: the 2020 ASH Annual Meeting and Exposition; December 5-8, 2020. Abstract 125.

Sustained progression-free survival and overall survival benefit at 5 years were observed in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia treated with the combination of venetoclax plus rituximab compared with bendamustine plus rituximab in the MURANO trial.

Darlene Dobkowski | Authors

Articles

Tesetaxel Plus Capecitabine Combo Improves PFS in HR+ Metastatic Breast Cancer

Venetoclax/Rituximab Shows 5-Year Survival Benefit in Relapsed/Refractory CLL