In phase 3 trial results presented at the San Antonio Breast Cancer Symposium in San Antonio, Texas, oral paclitaxel with encequidar, the first orally administered paclitaxel, was shown to exhibit superior confirmed response and survival with less neuropathy for patients with metastatic breast cancer compared with intravenous (IV) paclitaxel.
Paclitaxel is a widely used chemotherapy treatment for patients with metastatic breast cancer, and is typically administered intravenously. The administration of the drug solely through IV can create barriers to access for patients and further lead to the risk of infusion hypersensitivity reactions and need for prophylactic corticosteroids. Lead study author Gerardo Antonio Umanzor Funez, MD, medical oncologist with Centro Oncologico Integral, stressed that “as an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” said Umanzor.
Researchers sought to address these issues by creating an oral formulation of the drug, which Umanzor highlighted can improve availability and overall patient convenience. “Oral administration of cancer chemotherapy is very important for cancer patients, especially in areas where patients have difficulty accessing infusion clinics regularly,” said Umanzor.
While IV paclitaxel directly reaches the bloodstream, an oral formulation of the drug would not, as it is excreted by the P-glycoprotein (P-gp) pump. To combat this, researchers added encequidar, a highly specific, potent inhibitor of P-glycoprotein that increases absorption. In the phase 3 trial, 402 patients with metastatic breast cancer were enrolled and randomly assigned in a 2:1 ratio to be given either 205 mg/m2 of oral paclitaxel with encequidar (OPE) for 3 days a week, or 175 mg/m2 IV paclitaxel every 3 weeks:
Study results from the study showed that patients administered OPE had a confirmed tumor RR of 35.8%, a statistically significant difference of 12.4% (P = .011) greater than patients of the IV paclitaxel group (23.4%). After evaluating the pre-specified modified intention to treat population (n = 360; OPE = 240; IV paclitaxel = 120), which excludes patients that did not have target tumors that could be evaluated by the central radiologist per RECIST or who did not receive sufficient treatments, the RR was shown as 40.4% for OPE versus 25.6% for IV paclitaxel, a statistically significant difference of 14.8% (P = .0005).
For the secondary endpoints, ongoing analysis of PFS exhibited a median of 9.3 months for patients administered OPE and 8.3 months for those given IV paclitaxel (P = .077), while OS was also heightened in the OPE group compared to the IV paclitaxel group (27.9 months vs 16.9 months; P = .035). OPE was additionally shown to significantly limit neuropathic risk as it had lower incidence (17%) compared to IV paclitaxel (57%), with lower severity observed in OPE as only 1% of patients experienced grade 3 neuropathic symptoms compared to 8% of the IV paclitaxel group.
Patients in OPE group did report higher rates of neutropenia, infection, and gastrointestinal side effects, but Umanzor noted these symptoms were low grade and manageable. Responses to OPE were also shown to be more durable than IV pacliaxel based off the ongoing analysis of confirmed response median durations (OPE = 39.0 weeks; IV paclitaxel = 30.1 weeks).
“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,” said Umanzor.
Limitations to drug were highlighted at a press briefing of the study results on Friday at SABCS, which included the process of administering OPE. The treatment involves having to fast for 4 hours before taking the encequidar, waiting 1 hour to take the oral paclitaxel, and then waiting 4 hours before eating, with 11 capsules taken in that time frame.
While these issues could prove difficult for adherence, patients were still reportedly committed to the therapy. “No complaints at all--patients were excited they were getting an oral treatment and we had a very good compliance,” said Umanzor.
Further studies were noted by Umanzor, incuding plans to test the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, and potentially expanding studies on the oral formulation for other cancers, either as a monotherapy or in combination with other agents.
Umanzor G, Rugo HS, 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. Presented at the San Antonio Breast Cancer Symposium, San Antonio, Texas; December 10-14. Abstract: GS6-01.