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27-07-2022 | Breast cancer | News

Oral paclitaxel plus encequidar tops intravenous paclitaxel for metastatic breast cancer response

Author: Shreeya Nanda

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medwireNews: Oral paclitaxel given alongside encequidar, a P-glycoprotein pump inhibitor, achieves a significantly higher response rate than intravenous paclitaxel in women with metastatic breast cancer, suggest trial data.

The researchers explain in the Journal of Clinical Oncology that intravenous paclitaxel “is complicated by neuropathy and requires premedication to prevent hypersensitivity-type reactions,” but the taxane “is poorly absorbed orally.”

They continue: “Coadministration of [oral paclitaxel] with encequidar, a minimally absorbed, highly specific, and potent P-glycoprotein pump inhibitor, facilitates absorption of orally administered paclitaxel.”

Noting that the combination has shown promise in earlier randomized crossover and phase 2 studies, the team conducted a phase 3 trial in Central America, South America, and the Caribbean that comprised 402 postmenopausal women with stage IV disease, 69% of whom had not received prior treatment in the metastatic setting.

The primary endpoint of tumor response rate by independent review was 36% for the 265 participants who were randomly assigned to receive oral paclitaxel 205 mg/m2 plus encequidar methanesulfonate monohydrate 15 mg on three consecutive days each week.

This was significantly higher than the rate of 23% among the 137 patients who instead received intravenous paclitaxel 175 mg/m2 once every 3 weeks.

There were also trends toward improved progression-free and overall survival with the oral combination relative to intravenous paclitaxel, say the study authors, with median times of 8.4 versus 7.4 months and 22.7 versus 16.5 months, respectively, and corresponding nonsignificant hazard ratios of 0.768 and 0.794.

Turning to the safety profile, Hope Rugo (UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA) and co-investigators note that a comparable proportion of patients in the oral combination and intravenous paclitaxel groups experienced adverse events of grade 3 or 4, at 55% and 53%, respectively.

However, the incidence of neuropathy of at least grade 2 was nearly fourfold lower with oral paclitaxel plus encequidar than with intravenous paclitaxel, at 8% versus 31%, while the incidence of grade 3 neuropathy was around sevenfold lower, at 2% versus 15%.

Fewer patients in the oral combination group experienced alopecia compared with their counterparts in the intravenous paclitaxel group, with all-grade events observed in a respective 49% and 62% and grade 2 events in 29% and 48%.

By contrast, gastrointestinal toxicity was more common with the oral than intravenous formulation; all-grade events occurred in 85% and 51% of patients, respectively. The rates of grade 3 or 4 diarrhea, vomiting, and nausea in the oral group were 5%, 4%, and 3%, respectively, compared with rates below 1% in the intravenous group.

Rugo and colleagues point out, however, that “[a]fter approximately 50% of patients were enrolled, prophylactic antiemetics (primarily 5-hydroxytryptamine-3 antagonists) and early antidiarrheal therapy were encouraged for [oral paclitaxel plus encequidar] patients, reducing grade ≥ 3 [gastrointestinal] toxicity by approximately half.”

The oral paclitaxel plus encequidar regimen was also associated with a higher rate of grade 4 neutropenia than intravenous paclitaxel (15 vs 9%), “resulting in more infections, use of growth factors, and treatment-related deaths primarily in the first 10 weeks of treatment,” reports the team.

Finally, multivariate analyses revealed that elevated levels of bilirubin and gamma-glutamyltransferase as well as low albumin levels at baseline were significantly associated with an increased risk for grade 4 or 5 toxicities in patients treated with the oral combination.

The authors speculate that “[a]s paclitaxel is metabolized by cytochrome P450 2C8/9 and CYP3A4 in the liver, it is probable that abnormal hepatic function has a greater influence on orally administered paclitaxel, where first-pass metabolism by the liver may play a role.”

And they add: “Careful patient selection and close monitoring for early toxicity are warranted in patients with elevated hepatic enzymes or hepatic dysfunction.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

J Clin Oncol 2022; doi:10.1200/JCO.21.02953



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