Oral paclitaxel with encequidar in metastatic breast cancer
Dr Gerardo Umanzor - Hospital del Valle, San Pedro Sula, Honduras
On behalf of my co-authors and the OPE team thank you for asking us to present OPE, which is oral paclitaxel with encequidar, a phase III clinical trial of oral paclitaxel with encequidar compared to IV paclitaxel in patients with metastatic breast cancer. I do not have any disclosures.
Taxanes remain a foundation of breast cancer treatment with several IV dosing regimens that are used in clinical practice. As an oncologist it has been very frustrating to have an effective chemotherapy like paclitaxel which a lot of patients cannot tolerate. So the therapy used in this phase III study, oral paclitaxel and encequidar, was designed to overcome this issue. There are multiple benefits associated with oral administration, including patient convenience, a lack of need of IV access, a lack of infusion hypersensitivity reactions. So paclitaxel is a substrate of the intestinal efflux pump P-glycoprotein or P-gp and that results in a low oral bioavailability. But encequidar is a minimally absorbed highly specific potent inhibitor of P-gp which increases the absorption of the paclitaxel. OPE is a combination of oral solubilized paclitaxel and the P-gp inhibitor encequidar.
I want to introduce the dose justification for OPE. Pharmacogenetic studies, a phase I study comparing OPE 205mg/m2 per day for three days to IV paclitaxel 80mg/m2 showed that total exposure to paclitaxel was comparable between the two arms with a lower peak concentration of OPE compared with the IPE formulation. We hypothesised that the lower peak concentration of the OPE might result in lower systemic toxicity.
In a phase II study 26 patients with heavily pre-treated metastatic breast cancer were treated with the OPE, 205mg/m2 daily for three consecutive days repeated weekly and demonstrated encouraging clinical activity with a partial response of 42%.
Now, moving to the phase III study of OPE in metastatic breast cancer, this pivotal phase III open label randomised patients with any type of metastatic breast cancer in a two to one ratio to receive OPE for three consecutive days each week to IV paclitaxel according to the labelled dose of IV paclitaxel 175mg/m2 every three weeks. The primary endpoint is blinded, independently reviewed, radiologically confirmed tumour response including complete and partial responders at two consecutive time points 3-6 weeks apart using the RECIST criteria. Imaging was performed in weeks 10, 16 and 19 and in patients with a complete or partial response at week 19 a confirmatory scan was completed at week 22. The primary endpoint of final analysis was defined as the date that the last enrolled patient had their last scan within the 22 week study period. Patients with stable or responding disease could continue on study therapy for the extension period of this trial. Additional endpoints were safety and tolerability, progression free survival and overall survival.
I want to say also that the study was powered based on the modified intent to treat population which included 360 evaluable patients for a p-value of 0.045 which would confirm tumour response rate and was considered significant. The study was conducted in 45 sites in South and Central America.
Inclusion criteria included patients with a diagnosis of metastatic breast cancer with measurable disease at least one year from last adjuvant or metastatic taxane and an ECOG 0 or 1. Patients with central nervous system metastasis were excluded. Looking at two of the pre-specified analysis populations we have the primary endpoint was based on the pre-specified modified intent to treat population consisting of all patients with a baseline evaluable scan and who received at least seven doses of OPE or one dose of IV paclitaxel. These 360 patients comprised the primary efficacy population. The intent to treat population included 402 randomised patients. The patient demographics were balanced between the two treatment arms and a similar percentage of subjects in each treatment group received prior taxane therapy.
Now, introducing the dosing regimen of OPE, OPE is comprised of one 50mg tablet of encequidar given by mouth prior to the oral paclitaxel, 205mg/m2 for three consecutive days each week for three weeks without a break. Nine doses of OPE represent one cycle or three weeks. No prophylactic corticosteroid or antihistamine pre-medication was allowed for the OPE arm and IV paclitaxel was administered at 175mg/m2 over a three hour infusion every three weeks representing one cycle.
To look at the study’s primary endpoint, overall response rate in the pre-specified MITT population, treatment with OPE resulted in a significantly improved, centrally confirmed, response rate of 40.4% compared with 25.6% with IV paclitaxel with a p-value equal to 0.005 and representing an absolute improvement of 14.8%. These results were further supported by a significant improvement in overall response with OPE in the ITT population with an absolute improvement of 12.4% and a p-value of 0.011. In addition, tumour response in all clinically important subgroups was consistent with the oral confirmed response profiles.
For the study’s secondary endpoints at the time of the data cut for the primary endpoint PFS and OS data collection remained ongoing. A non-significant numerical trend was seen for median PFS favouring OPE, median 9.3 months for OPE and 8.3 months for IV paclitaxel in the MITT population. Also in the MITT population an early analysis of overall survival was significantly improved with OPE at 27.9 months versus IV paclitaxel at 16.9 months with a p-value of 0.035.
Regarding the safety profile, I would like to highlight the chemotherapy induced peripheral neuropathy in particular as this is a highly debilitating side effect of IV and the difference between the arms is quite dramatic. OPE is associated with a lower incidence of severity of neuropathy compared to the IV paclitaxel. For neuropathy overall 57% was presented in the IV paclitaxel versus 17% in the OPE group. The incidence of grade 3 neuropathic symptoms in the OPE group was only 1% versus 8% in the IV paclitaxel group. The toxicity profile of OPE was generally similar to IV paclitaxel, there were higher rates of neutropenia, infection and gastrointestinal AEs but these were low grade and were manageable.
In summary, oral paclitaxel and encequidar is the first oral taxane to demonstrate improved and durable confirmed overall response compared with IV paclitaxel given every three weeks. Oral paclitaxel and encequidar significantly improved overall survival in the modified intent to treat population compared with IV paclitaxel. In addition, responses were durable for oral paclitaxel and encequidar. Oral paclitaxel and encequidar was associated with a lower incidence of clinically meaningful neuropathy and alopecia and a higher incidence of low grade gastrointestinal events. 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.
In conclusion, on behalf of my co-investigators I would like to thank the patients, families and investigators who made this study possible.