Oral Taxanes Open the Door for New Standards in Metastatic Breast Cancer

Sara A. Hurvitz, MD

Although not yet approved, oral taxanes, such as oral paclitaxel and encequidar, and tesetaxel, have demonstrated activity for patients with metastatic breast cancer, said Sara A. Hurvitz, MD, who added that using these agents alone or in novel combinations could further enhance their utility.

“The 2 oral taxanes we have now may be soon available as standards of care for patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer,” said Hurvitz. “We saw exciting data for encequidar plus oral paclitaxel, as well as for tesetaxel. I’m looking forward to seeing these agents evaluated in other disease subtypes, as single agents rather than [in combinations], and in combination with other targeted therapies.”

During the 2020 San Antonio Breast Cancer Symposium (SABCS), updated findings from the phase 3 KX-ORAX-001 trial demonstrated a 26.5% reduction in the risk of death with oral encequidar plus oral paclitaxel compared with intravenous (IV) paclitaxel in patients with metastatic breast cancer.¹

Moreover, based on previously reported findings from the study, on September 1, 2020, the FDA granted a priority review to a new drug application for encequidar plus oral paclitaxel for use in patients with metastatic breast cancer.²

Additionally, results of the phase 3 CONTESSA trial, which were also presented during the 2020 SABCS, demonstrated improved progression-free survival (PFS) with tesetaxel plus reduced-dose capecitabine (Xeloda) vs standard capecitabine in patients with HR-positive, HER2-negative metastatic breast cancer.³

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on breast cancer, Hurvitz, director of the Breast Cancer Clinical Research Program and co-director of the Santa Monica University of California, Los Angeles (UCLA) Outpatient Hematology/Oncology Practice, as well as an assistant professor of medicine in the Division of Hematology/Oncology of the David Geffen School of Medicine at UCLA, discussed the potential integration of oral taxanes into the treatment paradigm of patients with metastatic breast cancer.

OncLive^®: What data have been observed with encequidar in metastatic breast cancer?

Hurvitz: Currently, we don’t have any oral taxanes available for metastatic HR-positive, HER2-negative breast cancer. However, encequidar, a potent inhibitor of P-glycoprotein, allows paclitaxel to be absorbed more systemically when taken orally. Typically, we give paclitaxel intravenously. [Encequidar] was evaluated in a clinical trial in which patients were treated with the agent in combination with oral paclitaxel vs IV paclitaxel every 3 weeks. In the study, there was a significantly improved objective response rate [ORR] with the oral paclitaxel, as well as a trend toward improved PFS and overall survival [(OS), compared with IV paclitaxel]. [Regarding safety], we saw lower rates of neuropathy and alopecia with the oral strategy; however, higher rates of cytopenias and gastrointestinal [GI] toxicities were also seen.

This was exciting; however, at this point, we don’t have [encequidar] available outside of a clinical trial setting. It will be interesting to see if [encequidar] is ultimately approved.

How has tesetaxel performed in this patient population and what potential strategies could improve upon the agent’s utility?

Tesetaxel is the second single-agent taxane [that is being evaluated in metastatic breast cancer that is given and absorbed orally. Tesetaxel was evaluated in the phase 3 CONTESSA trial, in which tesetaxel was given in combination with low-dose capecitabine and compared with a standard dose of single-agent capecitabine. The study ended up showing that the PFS was improved by about 3 months with oral tesetaxel in patients with HR-positive, HER2-negative metastatic breast cancer who received up to 1 prior line of chemotherapy in the metastatic setting. The ORR and disease control rate were also significantly improved. The toxicity profile of using 2 oral chemotherapies together was not as favorable as using 1 chemotherapy, so we saw more cytopenia, neutropenia, and GI toxicity. [Tesetaxel plus capecitabine] is a regimen that looks promising. Many of us would like to use it as a single agent, not in combination [with capecitabine], but we are all waiting for its approval [nonetheless].

Have any other oral taxanes been investigated?

Entinostat showed a lot of promise in a randomized phase 2 study in patients with estrogen receptor–positive, metastatic breast cancer. [The agent was then] evaluated in the phase 3 confirmatory E2112 trial, which failed to show an improvement in PFS or OS by adding entinostat to endocrine therapy compared with endocrine therapy alone. Those results were a big disappointment.

Beyond oral taxanes, what other agents are you keeping an eye on?

Many of us are excited to see whether fam-trastuzumab deruxtecan-nxki [Enhertu] has efficacy in HER2-low–expressing HR-positive metastatic breast cancer. An ongoing phase 3 clinical trial is comparing trastuzumab deruxtecan with standard chemotherapy. About two-thirds of patients with HR-positive metastatic breast cancer have low HER2 expression. If we had [trastuzumab deruxtecan] available as an agent with good activity and a favorable safety profile [in this patient population], we would be excited to use it.

Looking to the future, what is next for the metastatic breast cancer space?

We aren’t curing HR-positive, HER2-negative metastatic breast cancer. Although patients live a median of 4 to 5 years, they are not able to live out a normal life span in the majority of cases. Certainly, we need therapies for endocrine-resistant disease. We need more oral therapies that have good safety profiles, as well as targeted agents that can improve long-term survival as we go forward.

References

1. Umanzor G, Rugo HS, Barrios FJ, et al. Oral paclitaxel and encequidar (oPac+E) versus IV paclitaxel (IVPac) in the treatment of metastatic breast cancer (mBC) patients (Study KX-ORAX-001): progression free survival (PFS) and overall survival (OS) updates. Cancer Res. 2021;81(4). doi:10.1158/1538-7445.SABCS20-PD1-08
2. Athenex announces FDA acceptance for filing of U.S. NDA for oral paclitaxel and encequidar in metastatic breast cancer with priority review. News release. Athenex, Inc. September 1, 2020. Accessed February 16, 2021. https://bit.ly/2YUOfQE.
3. 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. Cancer Res. 2021;81(4). doi:10.1158/1538-7445.SABCS20-GS4-01