Paclitaxel Pill Tops IV Form, but Needs 9-Hour Fast

Nick Mulcahy

December 13, 2019

SAN ANTONIO — In a first of its kind result, an investigational oral form of paclitaxel yielded a higher overall response rate than the IV form of the chemotherapy drug among women with metastatic breast cancer, according to results from a phase 3 trial presented here at the San Antonio Breast Cancer Symposium.

Patients who received the oral form also had better progression-free and overall survival (PFS and OS), which were secondary endpoints, and less neuropathy, a potentially debilitating adverse event associated with the chemotherapy.

But the oral form is taken with encequidar, which facilitates absorption in the gut, and has a time-consuming administration that requires 9 consecutive hours of fasting. The process was called a limitation by multiple experts, including one who said that it was "a full-time job."

The challenges associated with the pill form were not discouraging to women, said lead study author Gerardo Antonio Umanzor Funez, MD, Centro Oncologico Integral, San Pedro, Honduras. "Patients were so excited they were getting an oral treatment," he told reporters at a meeting press briefing.

Paclitaxel is the most common chemotherapy used in the treatment of breast cancer, and the IV administration requires a time commitment of its own — travel to and attendance at an infusion clinic.

In the randomized trial, the oral paclitaxel group (n = 265) had a superior overall response rate, which was the primary outcome, compared with the IV group (n = 137; 35.8% vs 23.4%; P = .011) for the intent-to-treat population.

Responses were confirmed at two consecutive evaluations by a blinded, independent radiology company at 45 study sites in Central and South America.

The study design called for patients to receive either 205 mg/m² of oral paclitaxel plus encequidar for 3 days a week or 175 mg/m² of paclitaxel intravenously every 3 weeks. The treatment period was 18 weeks before the first scheduled imaging scan, with an ongoing extension period.

Responses were durable, said the trialists. Confirmed responses of > 150 days were recorded in 51% of responders for the oral group vs 38% of responders for the IV group. There was a higher percentage of oral subjects receiving ongoing treatment at the time of the study endpoint compared to IV subjects: 19% vs 13%.

Notably, there was a lower incidence and severity of neuropathy with the oral formulation compared with the IV version. Specifically, as of week 23, only 17% of the oral group reported neuropathy (all grades) vs 57% of the IV group. Also, only 1% of the oral group reported grade 3 neuropathy vs 8% of the IV group.

Rowan T. Chlebowski, MD, PhD, Harbor-UCLA Medical Center, Torrance, California, who attended the press event, observed that 25% of women who receive IV paclitaxel are "left with permanent disability" due to neuropathy.

The neuropathy reduction with the oral form "would be a big selling point."

After being prompted by a reporter, Umanzor Funez described the oral administration, which can involve as many as 11 pills. First, a patient fasts for 4 hours and then takes one capsule of encequidar. Next, the patient waits another hour and takes 10 paclitaxel pills (more or less, depending on body size). Finally, the patient must wait another 4 hours before eating, for safety reasons.

According to Umanzor Funez, the process was not off-putting to women in the trial. "We didn't have any trouble with adherence," he said. He also emphasized that oral administration is especially important in areas where patients have difficulty accessing infusion clinics regularly.

Chlebowski was doubtful about feasibility of the time-intensive administration, even if was only 3 days a week. "It is a full-time job to take this," he said. The California medical oncologist agreed with press event moderator Virginia Kaklamani, MD, UT Health Science Center San Antonio, that the process was a "limitation."

Still Chlebowski ultimately encouraged a wait-and-see attitude, commenting that trial participants sometimes defy expectations: "I think we would like to see how easy it is for people to do it."

Kaklamani also observed that another limitation of the clinical trial is that a 3-weekly dose of IV paclitaxel was used as the comparator. "There are several other trials that show the weekly [IV] dose [of paclitaxel] is more efficacious," she said.

Modified Study Population

The investigators also reported on a protocol-defined modified intent-to-treat (mITT) population. This data reflected patients who had baseline evaluable scans and received a first cycle of dosing. The confirmed response rates were 40.4% for the oral group vs 25.5% for the IV group (P = .005)

Ongoing analysis of PFS shows a strong trend in the protocol prespecified mITT population with a median of 8.5 and 6.9 months (P = .065) for the oral and IV groups, respectively.

In addition, ongoing analysis of OS in the mITT population favors the pill, with a median of 27.9 months vs 16.5 months for the oral and IV groups, respectively (P = .02).

The toxicity profile of the two treatment groups was similar, with some exceptions including neuropathy. But the oral group also had a lower incidence of alopecia. Higher rates of neutropenia, infection, and gastrointestinal adverse events were also observed in the oral group. Also, notably, pretrial pharmacokinetics studies showed that total exposure of the two drugs in patients was "comparable."

The study was funded by Athenex, the maker of the oral form of paclitaxel. Kaklamani is an unpaid scientific adviser to Athenex. Umanzor Funez and Chlebowski have disclosed no relevant financial relationships.

San Antonio Breast Cancer Symposium 2019: GS6-01. Presented December 13, 2019.

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