SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.
The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.
In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.
Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.
Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.
Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.
Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”
The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.
Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.
Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.
Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m2 of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m2 over a 3-hour infusion every 3 weeks.
Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.
The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.
The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.
“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.
Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m2, but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.
In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.
The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.
“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.
He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”
The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.
During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”
“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.
The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.