Positive results have now been reported in phase III trials of two oral taxanes in the treatment of metastatic breast cancer. At the 2020 San Antonio Breast Cancer Symposium, treatment with tesetaxel and reduced-dose capecitabine resulted in an improvement in progression-free survival of about 3 months vs standard-dose capecitabine alone, according to Joyce O’Shaughnessy, MD, Chair of Breast Cancer Research and the Celebrating Women Chair in Breast Cancer at Baylor-Sammons Cancer Center, Dallas, and Chair of the Breast Cancer Program in the US Oncology Research Network.¹

“Tesetaxel plus a reduced dose of capecitabine is a potential new treatment option for patients with hormone receptor–positive, HER2-negative breast cancer,” Dr. O’Shaughnessy said. “It gives patients an all-oral option.”

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.

Joyce O’Shaughnessy, MD

Gerardo Umanzor, MD

Other investigators reported a new analysis of secondary endpoints of the phase III KK-ORAX-001 trial of oral paclitaxel plus encequidar (oPac+E). As compared with intravenous paclitaxel given every 3 weeks, the oral taxane resulted in a 26.5% reduction in the risk of death. Median overall survival in the modified intention-to-treat population was 23.3 with oPac+E vs 16.3 months with paclitaxel (hazard ratio [HR] = 0.735; P = .0262), according to Gerardo Umanzor, MD, of Liga Contra el Cancer in San Pedro Sula, Honduras.² At the 2019 San Antonio meeting, Dr. Umanzor reported the primary analysis of KK-ORAX-001, showing superiority in radiologic response rates: 35.8% vs 23.4% (P = .011).³

CONTESSA: Tesetaxel Plus Capecitabine

Tesetaxel’s long half-life enables the maintenance of adequate drug levels with relatively infrequent oral dosing. In preclinical studies, tesetaxel achieved higher intracellular concentrations and greater tumoricidal activity than either paclitaxel or docetaxel. Along with efficacy that is at least equal to that of intravenous taxanes, an oral regimen would be more convenient for patients and potentially offer better quality of life, Dr. O’Shaughnessy said. “Tesetaxel is given once every 3 weeks, and it’s just two to five pills, so the pill burden is very minimal,” she indicated.

The phase III CONTESSA trial evaluated the benefit of oral tesetaxel in 685 patients with hormone receptor–positive, HER2-negative metastatic breast cancer. Patients could have received up to one prior regimen, prior exposure to a taxane in the neoadjuvant or adjuvant setting, and any number of prior endocrine regimens. About half had received an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6).

“Tesetaxel plus a reduced dose of capecitabine is a potential new [all-oral] treatment option for patients with hormone receptor–positive, HER2-negative breast cancer.”

— Joyce O’Shaughnessy, MD

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Patients were randomly assigned to tesetaxel (27 mg/m² on day 1 of 21-day cycles) and reduced-dose capecitabine (1,650 mg/m² on days 1 to 15) or to standard-dose single-agent capecitabine (2,500 mg/m² on days 1 to 15). The primary endpoint, based on 685 patients, was progression-free survival.

Dr. O’Shaughnessy acknowledged that the dose of capecitabine in the control arm is higher than is used in practice today. “This was because of the global nature of the study. Clinicians could dose-reduce at the first sign of grade 2 toxicity,” she explained.

Primary Endpoint Met

“The study achieved its primary endpoint, with an improvement in progression-free survival of 2.9 months,” Dr. ­O’Shaughnessy said. At 13.9 months’ follow-up, median progression-free survival was 9.8 months with tesetaxel/capecitabine vs 6.9 months with capecitabine monotherapy, a difference of 2.9 months (HR = 0.716; P = .003). Neutropenia, the most frequent grade 3 or higher treatment-related adverse event, was generally manageable, primarily with dose reductions and growth factors as needed, she said.

The objective response rate was also higher in the tesetaxel arm, 57% vs 41% (P = .0002), and the 24-week disease control rate was 67% vs 50% (P < .0001). Final overall survival data are expected in 2022.

Although a listener questioned whether a 3-month gain in remission is clinically meaningful, Dr. O’Shaughnessy said the results are similar to those observed in trials of intravenous taxanes in combination with capecitabine or gemcitabine.

The benefits were consistent across prespecified subgroups, including age, performance status, disease-free interval after prior taxane, prior treatment with CDK4/6 inhibitors, presence or absence of visceral or brain metastases, and geographic region.

Safety Profile

Treatment-emergent adverse events were more frequent with tesetaxel and capecitabine, and treatment discontinuations were doubled, with the exception of hand-foot syndrome, which was more common with single-agent capecitabine (66.2% vs 50.7%). Adverse events were primarily grade 1 or 2. Though “rare,” patients receiving tesetaxel/capecitabine were more likely to have grade ≥ 3 neuropathy (5.9%) and grade 2 alopecia (8.0%).

The most common grade ≥ 3 toxicities with tesetaxel were neutropenia (71%, febrile in 13%) and diarrhea (13.1%). Treatment discontinuation due to neutropenia or febrile neutropenia occurred in 4.2% of the combination arm vs 1.5% of the capecitabine arm. There were six treatment-related deaths in the combination arm and three in the capecitabine arm.

Odonate Therapeutics intends to file a U.S. marketing application for tesetaxel in mid-2021.

KK-ORAX-001: Oral Paclitaxel Plus Encequidar

In additional analyses of the phase III KK-ORAX-001 clinical trial, oPac+E achieved superiority in numerous endpoints, including response rate, progression-free survival, and overall survival, according to Dr. Umanzor.²

The study’s 402 patients with metastatic breast cancer were randomly assigned to 205 mg/m² of oral paclitaxel (with 12.9 mg of the P-glycoprotein inhibitor encequidar given 1 hour before each dose of paclitaxel) for 3 consecutive days per week, or 175 mg/m² of intravenous paclitaxel every 3 weeks for 18 weeks. The modified intention-to-treat analysis included 360 patients who had received at least 7 days of oPac+E or one dose of intravenous paclitaxel. The new analysis was based on an additional 14 months of follow-up, showing a 26.5% reduction in the risk of death with oPac+E.

“The responses were of long duration, and strong trends of overall survival superiority were observed in favor of oPac+E in the intention-to-treat population,” Dr. Umanzor said. “These findings support the clinical relevance of the increased tumor response rates observed with oPac+E.”

Amelioration of Gastrointestinal Events

Co-investigator Hope Rugo, MD, FASCO, of the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, also reported that gastrointestinal adverse events associated with this treatment, which were more common than in the control arm, can be managed using 5-HT3 inhibitors and early intervention with loperamide.

After an imbalance in gastrointestinal complaints emerged in the oPac+E arm, patients were asked to take loperamide at the onset of diarrhea and were also given prophylactic antiemetics, primarily ondansetron. (The oral NK1 inhibitor aprepitant was not recommended due to pharmacokinetic interactions with oPac+E.)

Hope Rugo, MD, FASCO

After prophylactic antiemetic therapy and early anti-diarrheal therapy was initiated, there was a marked decrease of grade ≥ 2 vomiting and diarrhea in patients on oPac+E, from 24% to 7% and from 27% to 16%, respectively. The incidence of both adverse events was greater with intravenous paclitaxel.

In a separate poster, Dr. Rugo further reported that neuropathy occurred less often with oPac+E than with intravenous paclitaxel, 36% vs 8% for all grades and 7% vs 1% for grade 3.⁴

A new drug application for oPac+E is currently under Priority Review by the U.S. Food and Drug Administration. The Prescription Drug User Fee Act target action date has been set for February 28, 2021. 

DISCLOSURE: The CONTESSA trial was supported by Odonate Therapeutics, and the KK-ORAX-001 study was funded by Athenex. Dr. O’Shaughnessy disclosed relationships with AbbVie, Agendia, AstraZeneca, Celgene/Bristol Myers Squibb, Eisai, Eli Lilly, Genentech/Roche, Genomic Health, GRAIL, Heron Therapeutics, Immunomedics, Ipsen, Jounce Therapeutics, Novartis, Odonate Therapeutics, Pfizer, Puma Biotechnology, and Seagen. Dr. Umanzor and Dr. Rugo reported no conflicts of interest.

REFERENCES

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.

2. Umanzor G, Rugo HS, Barrios FJ, et al: Oral paclitaxel versus IV paclitaxel (oPac+E) in the treatment of metastatic breast cancer patients (Study KX-ORAX-001): Progression-free survival and overall survival updates. 2020 San Antonio Breast Cancer Symposium. Abstract PD1-08. Presented December 8, 2020.

3. Rugo H, Umanzor G, Barrios FJ, et al: Oral paclitaxel and encequidar (oPac+E) in the treatment of metastatic breast cancer: Management of gastrointestinal adverse events. 2020 San Antonio Breast Cancer Symposium. Abstract PS13-11. Presented December 8, 2020.

4. Rugo HS, Umanzor G, Barrios FJ, et al: Lower rates of neuropathy with oral paclitaxel and encequidar compared to IV paclitaxel in treatment of metastatic breast cancer: Study KX-ORAX-001. 2020 San Antonio Breast Cancer Symposium. Abstract PS13-06. Presented December 8, 2020.