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Oral Paclitaxel Outperforms Intravenous Formulation in Phase III Trial


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In the first reported phase III study of an oral taxane, an investigational oral form of paclitaxel yielded a higher overall response rate and produced less neuropathy than standard intravenous paclitaxel, researchers reported at the 2019 San Antonio Breast Cancer Symposium.1

“Oral paclitaxel [combined with encequidar] is the first oral taxane in a phase III trial to demonstrate a significant improvement in confirmed overall response rate compared to intravenous (IV) paclitaxel,” said Gerardo Antonio Umanzor Funez, MD, of Centro Oncologico Integral of San Pedro Sula, Honduras. He added that the treatment represents “a meaningful improvement in the clinical profile of paclitaxel.”

Gerardo Antonio Umanzor Funez, MD

Gerardo Antonio Umanzor Funez, MD

The drug was developed based on the hypothesis that high peak concentrations of IV paclitaxel may be responsible for peripheral neuropathy. An oral formulation of paclitaxel was made bioavailable by combining it with the minimally absorbed p-glycoprotein pump inhibitor encequidar. The pharmacokinetic exposure matches that of IV paclitaxel at 80 mg/m2, with peak concentrations that are approximately one-tenth those of IV paclitaxel, the investigators noted.

Not a Simple Administration Schedule

Administration of this oral taxane, however, is not as simple as it sounds. The drug is taken with encequidar, which facilitates absorption in the gut but requires long periods of fasting and intermittent dosing of an average 11 pills per day for 3 consecutive days per week. The patient must first fast for 4 hours and then take one capsule of encequidar. The patient waits another hour and then, based on body size, takes an average of 10 paclitaxel pills. This is followed by another 4-hour fast.


I think we would like to see how easy it is for patients to [comply with the oral regimen].
— Rowan T. Chlebowski, MD, PhD

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Several experts saw the administration schedule as a limitation for oral paclitaxel. “It’s a full-time job to take this medication,” observed Rowan T. Chlebowski, MD, PhD, Chief of the Division of Medical Oncology and Hematology at Harbor-UCLA Medical Center, but he acknowledged is potential benefit. “Neuropathy is a big factor, as 25% or more of women taking [IV] paclitaxel are left with permanent disability. That’s a big selling point,” he said.

“I think we would like to see how easy it is for patients to [comply with the oral regimen],” Dr. Chlebowski commented. “When I’m doing lifestyle intervention trials, often I hear comments that no one would ‘do that,’ and yet 19,000 subjects did [maintained a low-fat diet in the Women’s Health Initiative]. We’ll have to see what happens.”

Study Details

The trial enrolled 402 patients with metastatic breast cancer from 45 sites in Central and South America, randomly assigning them 2:1 to either 205 mg/m2 of oral paclitaxel plus encequidar for 3 days a week, or 175 mg/m2 of IV paclitaxel every 3 weeks for 18 weeks. Tumors were evaluated by blinded, independent radiologists.

The primary endpoint was independently reviewed, radiologically confirmed tumor response by week 19 in the prespecified modified intent-to-treat population, which reflected patients who had baseline evaluable scans and received a first cycle of dosing. Secondary endpoints included progression-free survival and overall survival in the modified intent-to-treat population.

In the modified intent-to-treat population, a statistically significant difference in tumor response was observed with OPE (40.4%) vs IV paclitaxel (25.6%), for an absolute difference of 14.8% (P = .005). The difference was mirrored by the intent-to-treat population, whose corresponding response rates were 35.8% vs 23.4%, respectively, for a difference of 12.4% (P = .011).

“Tumor response in all clinically important subgroups was consistent with the overall confirmed response profiles,” Dr. Umanzor Funez said.

Responses were maintained past 100 days in 75% of patients, beyond 200 days in 34%, and for 300 days or longer in 13%.

Survival and Toxicity

At the time of the analysis, data collection for progression-free survival and overall survival were ongoing. A numerical trend favoring OPE was observed for progression-free survival, with a median of 9.3 months vs 8.3 months with IV paclitaxel (hazard ratio [HR] = 0.760, P = .077). The improvement seen in overall survival was statistically significant: 27.9 months vs 16.9 months, respectively (HR = 0.684, P = .035). Again, this was mirrored in the intent-to-treat analysis, where median overall survival was 27.7 months and 16.9 months, respectively (P = .114), he reported.

Importantly, rates of peripheral neuropathy were considerably lower with the oral regimen. Grade ≥ 2 neuropathy was observed in 7.6% of the oral paclitaxel plus encequidar arm vs 31.3% of the standard paclitaxel arm. Alopecia of grade ≥ 2 was seen in 28.0% vs 48.1%, respectively.

KEY POINTS

  • The first phase III data have been reported for an oral taxane: paclitaxel plus encequidar, a minimally absorbed p-glycoprotein pump inhibitor that aids absorption of the taxane.
  • Compared to IV paclitaxel, oral paclitaxel plus encequidar improved response rates from 26% to 40% and was associated with significantly less grade ≥ 2 neuropathy, 8% vs 31%.
  • Administration of the treatment requires, on average, 11 pills and intermittent fasting, which some experts have expressed concern about in terms of patient compliance.

“The reduction in chemotherapy-induced peripheral neuropathy between the two arms is quite dramatic…, and the rate of alopecia was about 50% lower,” said Dr. Umanzor Funez.

Journalists at a press briefing and some attendees at the oral presentation raised concerns about the administration schedule for oral paclitaxel plus encequidar, but Dr. Umanzor said the experience of patients seemed positive. “Patients were excited to get an oral treatment, and we had good compliance. They managed pretty well,” he said. He pointed out that oral administration of drugs is especially important in areas where patients have difficulty accessing infusion clinics regularly. 

DISCLOSURE: The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported no conflicts of interest. Dr. Chlebowski served in a consulting or advisory role for Amgen, AstraZeneca, Genentech, Immunomedics, Novartis, and Pfizer; and has participated in a speakers bureau for AstraZeneca and Novartis.

REFERENCE

1. Umanzor G, Cutler DL, Barrios FJ, et al: Oral paclitaxel with encequidar: 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. 2019 San Antonio Breast Cancer Symposium. Abstract GS6-01. Presented December 13, 2019.


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