Amended Protocols Allow for Reduced GI Toxicities With Oral Paclitaxel Combo in Metastatic Breast Cancer

Allowing for the use of antiemetic prophylaxis and anti-diarrheal medication in the phase 3 KX-ORAX-001 study reduced study drug-related gastrointestinal adverse events.

Following protocol amendments to the administration of oral paclitaxel plus encequidar, patients with metastatic breast cancer experienced fewer gastrointestinal (GI) adverse events (AEs), resulting in outcomes that were more in line with intravenous (IV) administration of paclitaxel, according to findings presented at the 38th Annual Miami Breast Cancer Conference®, hosted by Physicians’ Education Resource, LLC (PER®).1

“GI adverse events were initially more frequent with [oral paclitaxel plus encequidar] compared to IV [paclitaxel]. However, once the protocol amendments were initiated, with both prophylaxis and treatment of appropriate toxicities in an emergent manner, the incidence of GI adverse events was considerably lower and in line with the levels seen with IV [paclitaxel],” Hope S. Rugo, MD, FASCO, from the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, said during a poster presentation of the findings.

The initial protocol for the international, randomized, phase 3 KX-ORAX-001 study (NCT02594371)—designed to evaluate oral paclitaxel at 205 mg/m2 plus 15 mg of encequidar 3-times-weekly or IV paclitaxel at 175 mg/m2 every 3 weeks in 402 patients with metastatic breast cancer2—did not allow the use of antiemetics in either group. However, the IV paclitaxel group received pretreatment with antihistamines and corticosteroids, which have anti-emetogenic activity.

Therefore, a protocol amendment, which was implemented on April 7, 2017, allowed for the use of antiemetic prophylaxis. An additional amendment, implemented on October 5, 2018, allowed for the use of anti-diarrheal medication.

“During the study, it became apparent that patients with elevated liver function tests at baseline had a higher risk of early-onset [study] AEs,” investigators wrote. “The inclusion criteria were progressively amended to reduce the allowable excursions from normal range for AST/ALT, bilirubin, and [gamma-glutamyl transferase] at baseline.”

Following the amendment, the rates of grade 3 or greater nausea (7% to 3%), vomiting (7% to 4%), and diarrhea (9% to 4%) declined, compared with rates of 1%, 1%, and 2%, respectively, with IV paclitaxel. Treatment discontinuations due to GI AEs in the oral regimen group were diarrhea (1%) and nausea and vomiting (<1%). Moreover, investigators noted that tightening of baseline hepatic function criteria resulted in a decrease in study AEs, including neutropenia.

Lastly, oral administration of aprepitant, a neurokinin-1 (NK1) inhibitor, was associated with an increased incidence of paclitaxel toxicity, “potentially due to inhibition of metabolism of [oral paclitaxel plus encequidar],” the investigators explained.

“Oral chemotherapy offers patients more convenience and studies have shown that patients prefer oral therapies over IV therapies, providing efficacy is not compromised,” Rugo said. “Taxanes are among the most active chemotherapeutic agents in the management of breast cancer that are associated with treatment-limiting toxicities, but we do need more efficacious and less toxic therapies.”

Paclitaxel is known to have poor oral bioavailability due to excretion by gastrointestinal p-glycoprotein. Encequidar is a potent, specific, minimally absorbed p-glycoprotein inhibitor that allows for absorption of oral paclitaxel. The combination of the 2 drugs are a liquid-filled capsule of paclitaxel and a tablet of encequidar and does not contain Cremophor.

“GI AEs in [oral paclitaxel plus encequidar]–treated patients were managed with prophylactic use of antiemetics, primarily 5-HT3 inhibitors, and early intervention with the anti-diarrhea agents, like loperamide,” Rugo said. “The use of the oral NK1 inhibitor aprepitant in combination with [oral paclitaxel plus encequidar is not recommended.”


1. Rugo HS, Umanzor G, Barrios FJ, et al. Oral Paclitaxel and Encequidar in the Treatment of Patients With Metastatic Breast Cancer: Management of Adverse Events. Presented at: 38th Annual Miami Breast Cancer Conference®; March 4-7, 2021; virtual. Poster 24.

2. 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. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD1-08.