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SAN ANTONIO -- An oral formulation of paclitaxel significantly improved objective response rate in patients with metastatic breast cancer as compared with the intravenous formulation, a randomized trial showed.

Oral paclitaxel with encequidar (OPE) led to objective responses in 40.4% of patients versus 25.5% of patients treated with IV paclitaxel. A preliminary analysis of progression-free survival (PFS) and overall survival (OS) yielded trends in favor of OPE.

Patients treated with OPE had substantially less peripheral neuropathy, including severe neuropathy, reported Gerardo Umanzor, MD, of Centro Oncologico Integral in San Pedro Sula, Honduras, at the San Antonio Breast Cancer Symposium (SABCS).

"Paclitaxel is one of the most widely used drugs in oncology, and it is a pillar of treatment in breast cancer," Umanzor told MedPage Today. "But you have all these problems with IV paclitaxel, like neuropathy and alopecia, and you cannot use it for a long time because these side effects are going to compromise the quality of care of the patient.

"What we found especially interesting is that the (oral formulation) is active, it's performing better [than IV paclitaxel] but we have less toxicity and we can give it orally, which is much more convenient."

The administration schedule for the oral drug could prove to be the principal downside of the drug. The drug is dosed weekly on 3 consecutive days, and the patient consumes a total of 11 capsules on each dosing day. The dosing schedule is repeated weekly.

Encequidar, an inhibitor of P-glycoprotein, increases absorption of oral paclitaxel, and is taken first, after a 4-hour fast. Following encequidar dosing, the patient must wait another hour before taking the paclitaxel capsules, followed by an 4-hour fast before the patient can eat.

During an SABCS press briefing, Virginia Kaklamani, MD, of UT Health San Antonio, mused about potential issues with patient adherence. In response, Umanzor said, "We had some doubts at the beginning, but there were no [patient] complaints at all. Patients were so excited that they were getting an oral treatment, and we had very good compliance. We had to give the patients a crash course in how to take the capsules, but no problems after that."

Kaklamani said she thinks the regimen will be problematic for at least some patients in clinical practice. That view was seconded by Rowan Chlebowski, MD, of City of Hope in Duarte, California.

"It really is a full-time job to take this," said Chlebowski. "The neuropathy thing is a big factor, though, because 25% or more of women who take paclitaxel are left with permanent disability."

"I think we'd like to see how easy it is for people to do it," Chlebowski continued. "When I'm doing lifestyle interventions, a lot of people look at it and say, 'Nobody would do that,' and 19,000 people did [in the Women's Health Initiative]. I think we just have to see what happens."

The trial reported by Umanzor was preceded by a , which demonstrated the equivalence of the weekly oral regimen to weekly IV paclitaxel. In a involving patients with previously treated metastatic breast cancer, OPE produced partial responses in 43% of the study population and stable disease in another 46.2%.

Umanzor reported results from a phase III randomized trial comparing weekly OPE and IV paclitaxel, which was administered once every 3 weeks. Eligible patients had histologically or cytologically confirmed metastatic breast cancer with no central nervous system involvement and no taxane therapy within the past 12 months. Investigators randomized the patients 2:1 to OPE or IV paclitaxel. The primary endpoint was objective response, confirmed radiologically at consecutive time points 3-6 weeks apart.

Data analysis included 402 patients. The primary analysis yielded a statistically significant 14.8% absolute difference in response rate in favor of the OPE arm (P=0.005). An additional 23.8% of patients in the OPE had stable disease, as did 39.5% of patients randomized to IV paclitaxel.

Survival analyses are ongoing, but preliminary data showed a median OS of 27.9 months with OPE and 16.5 months with IV paclitaxel. Median PFS was 9.3 versus 8.3 months.

An analysis of treatment-emergent adverse events showed lower rates of grade ≥2 neuropathy, alopecia, and pain in the OPE arm. Hematologic and gastrointestinal events tended to occur more often with OPE:

• Neuropathy: 7.6% (1.3% grade 3) vs 31.1% (14.9%)
• Alopecia: 28.8% vs 48.1%
• Pain: 14.8% vs 33.3%
• Asthenia: 10.6% vs 7.4%
• Neutropenia: 38.3% vs 33.3%
• Anemia: 19.7% vs 10.4%
• Urinary tract infection: 18.9% vs 11.9%
• Diarrhea: 24.2% vs 8.1%
• Nausea: 23.1% vs 5.2%
• Vomiting: 17.0% vs 4.4%
• Abdominal pain: 13.6% vs 4.4%

Kaklamani noted that a limitation of the trial was the use of q3w dosing for IV paclitaxel, as weekly dosing of the taxane has proven to be superior. The pharmacokinetics studies of OPE used weekly IV dosing for comparison.

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