In the phase 3 KX-ORAX-001 clinical trial, treatment with paclitaxel in combination with encequidar achieved a 26.5% reduction in the risk of death compared with paclitaxel by intravenous injection in patients with metastatic breast cancer.
In the phase 3 KX-ORAX-001 clinical trial, treatment with paclitaxel in combination with encequidar achieved a 26.5% reduction in the risk of death compared with paclitaxel by intravenous (IV) injection in patients with metastatic breast cancer.1
Results presented during the virtual 2020 San Antonio Breast Cancer Symposium showed that in this modified intent-to-treat (mITT) population, the median overall survival (OS) with the combination was 23.3 months compared with 16.3 months for IV paclitaxel (HR, 0.735; 95% CI, 0.556-0.972; P = .0262).
In this modified intent-to-treat (mITT) population, the median overall survival (OS) with the combination was 23.3 months compared with 16.3 months for IV paclitaxel (HR, 0.735; 95% CI, 0.556-0.972; P = .0262).
Additionally, results showed that, in the mITT population, the median progression-free survival (PFS) was 8.4 months compared with 7.4 months for IV paclitaxel, leading to an estimated 26% reduction in the risk of disease progression or death (HR, 0.739; 95% CI, 0.561-0.974; P = .0223).
“PFS and OS in the modified intent-to-treat population were greater with the oral paclitaxel/encequidar]–treated subjects,” lead study author Gerardo Umanzor, MD, medical oncologist with Centro Oncologico Integral in San Pedro Sula, Honduras, said in a prerecorded poster presentation of the data. “Strong trends of OS superiority were seen with the [combination] vs IV paclitaxel in the ITT population.”
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.
In September 2020, the FDA granted a priority review designation to a new drug application oral paclitaxel and encequidar for use in patients with metastatic breast cancer, based on the phase 3 findings.
Previously, the combination has shown a lower incidence of neuropathy and alopecia; however, there is a higher incidence of infections, low-grade gastrointestinal adverse events (AEs), and grade 4 neutropenia vs the IV formulation.
In the international, randomized, phase 3 KX-ORAX-001 study, women with metastatic breast cancer were randomized 2:1 to receive oral paclitaxel at 205 mg/m2 plus 15 mg of encequidar 3-times-weekly or IV paclitaxel at 175 mg/m2 every 3 weeks until disease progression or unacceptable toxicity.
The ITT population comprised 402 patients who received the combination (n = 265) or IV paclitaxel (n = 137). A total 399 patients received treatment. The mITT population (n = 360) included those with RECIST measurable disease and had received at least 7 days of oral paclitaxel/encequidar treatment (n = 235) or 1 dose of IV paclitaxel (n = 125). Patients had an ECOG performance status of 0 or 1.
The primary end point was confirmed tumor response as assessed by a blinded independent central review on 2 consecutive evaluations; secondary end points included duration of response, PFS, and OS.
Baseline characteristics were similar between the 2 arms, such as median age (56.0 years with the combination vs 60.0 years with IV paclitaxel), prior taxane exposure (31% vs 29%, respectively), prior anthracycline exposure (58% vs 58%), those with visceral metastases (77% vs 77%), and whether the lines of prior chemotherapy were 0 (68% vs 70%), 1 (20% vs 20%), or at least 2 (12% vs 9%).
Compared with the combination or IV paclitaxel, patients were Black (1% vs 2%, respectively), Caucasian (7% vs 8%), Hispanic/Latino (90% vs 89%), or other (1% vs 1%). The receptor status was HER2-negative (estrogen receptor [ER] negative/progesterone receptor [PR] negative; 18% vs 10%, respectively), HER2-negative (ER or PR positive; 53% vs 59%), HER2-positive (ER or PR positive; 9% vs 11%), HER2 unknown (ER and PR unknown; 13% vs 11%), and other (7% vs 8%).
At the 2019 SABCS, the final analysis of the KX-ORAX-001 trial showed that the combination had confirmed responses and early trends toward improved PFS and OS.2 The confirmed tumor response rate was 35.8% with oral paclitaxel/encequidar vs 23.4% with IV paclitaxel in the ITT population (P = .011).
In the mITT population, a statistically significant difference in tumor responses was observed with OPE versus IV paclitaxel at 40.4% and 25.6%, respectively, for an absolute difference of 14.8% (P = .005). This was supported further by tumor responses observed in patients in the ITT population, with corresponding rates of 35.8% versus 23.4%, for a difference of 12.4% (P = .011).
At the 2020 SABCS, updated data of PFS and OS, comprising an additional 14 months of follow-up, were presented.
In the ITT population, the median PFS was 8.4 months and 7.4 months for the combination and IV paclitaxel, respectively (HR, 0.768; 95% CI, 0.584-1.01; P = .0459). Moreover, the median OS was 22.7 months and 16.5 months, respectively (HR, 0.794; 95% CI, 0.607-1.037; P = .0821).
The combination also achieved the primary efficacy end point of the trial, which was superiority in confirmed radiologic response rate versus IV paclitaxel when given at the approved dose and schedule for patients with metastatic breast cancer. The responses were also reported to be of long duration.
“Having previously presented superior efficacy on overall response rate and favorable tolerability versus IV paclitaxel at SABCS 2019, it is gratifying to report that our pivotal phase 3 trial continues to show sustained efficacy and manageable adverse events with oral paclitaxel and encequidar,” Johnson Lau, MD, chairman and chief executive officer of Athenex, the developer of the oral paclitaxel regimen.3 “The updated phase 3 PFS and OS data further support the clinical rationale for oral paclitaxel as an efficacious and tolerable treatment option for people living with metastatic breast cancer.”
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. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD1-08.
2. Umanzor G, Rugo HS, Barrios FJ, et al. Oral paclitaxel with encequidar (OPE): the first orally administered paclitaxel shown to be superior to iv paclitaxel on confirmed response and survival with less neuropathy: a phase III clinical study in metastatic breast cancer. Presented at: 2019 San Antonia Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. Abstract GS6-01.
3. Athenex presents updated phase 3 data on survival and tolerability associated with oral paclitaxel and encequidar in patients with metastatic breast cancer. News release. Athenex. December 9, 2020. Accessed December 9, 2020. https://bit.ly/3gwKYyP