Hope S. Rugo, MD

In a Latin American phase III trial reported in the Journal of Clinical Oncology, Hope S. Rugo, MD, and colleagues found that oral paclitaxel with the P-glycoprotein pump inhibitor encequidar produced a higher response rate and trends toward better survival outcomes vs intravenous (IV) paclitaxel in patients with metastatic breast cancer.

As stated by the investigators, “Intravenous paclitaxel … is complicated by neuropathy and requires premedication to prevent hypersensitivity-type reactions. Paclitaxel is poorly absorbed orally; encequidar, a novel P-glycoprotein pump inhibitor, allows oral absorption.”

Study Details

In the open-label trial, 402 patients with ≥ 1 year since their last taxane treatment from sites in 10 countries in Central/South America and the Caribbean were randomly assigned 2:1 between December 2015 and February 2019 to receive oral paclitaxel at 205 mg/m² plus encequidar methanesulfonate monohydrate at 15 mg for 3 consecutive days per week (n = 265) or IV paclitaxel at 175 mg/m² once every 3 weeks. The primary endpoint was confirmed radiographic objective response on blinded independent central review.

Responses

Confirmed objective response was observed in 95 patients (35.8%; complete response in 3 [1%]) in the oral paclitaxel group vs 34 patients (23.4%; complete response in 1 [< 1%]) in the IV paclitaxel group (P = .01). Median durations of response were 36 weeks (range = 6–111+ weeks) vs 33 weeks (range = 4–84+ weeks). 

Median progression-free survival was 8.4 months vs 7.4 months (hazard ratio [HR] = 0.768, 95.5% confidence interval [CI] = 0.584–1.01, P = .046). Median overall survival was 22.7 months vs 16.5 months (HR = 0.794, 95.5% CI = 0.607–1.037, P = .08).

Adverse Events

Grade 3 or 4 adverse events occurred in 55% of the oral paclitaxel group vs 53% of the IV paclitaxel group. The IV paclitaxel group had higher rates of grade ≥ 2 neuropathy (15% vs 2%) and any grade alopecia (62% vs 49%). The oral paclitaxel group had higher rates of gastrointestinal adverse events (overall = 85% vs 51% any grade, grade 3–4 in 12% vs 4%), including nausea, vomiting, and diarrhea. The incidence of grade ≥ 3 neutropenia was similar in the two groups (36% vs 32%), but grade 4 neutropenia was more common in the oral paclitaxel group (15% vs 9%); treatment was discontinued due to neutropenia in 7% vs 1% of patients.

Adverse events led to death in 8% vs 9% of patients; however, death due to infectious complications considered related to treatment occurred in 9 (3%) vs 0 patients. A post hoc multivariate analysis in the oral paclitaxel group to determine risk of grade 4 or 5 toxicities during the first 10 weeks of therapy showed that increasing baseline bilirubin and gamma-glutamyltransferase and decreasing albumin were associated with increased risk of severe neutropenia and infectious complications.

The investigators concluded: “[Oral paclitaxel plus encequidar] increased the confirmed tumor response versus IV [paclitaxel], with trends in [progression-free survival] and [overall survival]. Neuropathy was less frequent and severe with [oral paclitaxel plus encequidar]; neutropenic serious infections were increased. Elevated liver enzymes at baseline predispose [oral paclitaxel plus encequidar] patients to early neutropenia and serious infections.”

Dr. Rugo, of UCSF Helen Diller Family Comprehensive Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Athenex, Inc. For full disclosures of the study authors, visit ascopubs.org.