Intravenous paclitaxel (IV Pac) is an efficacious chemotherapeutic agent against multiple cancers including metastatic breast cancer (mBC). We hypothesized that the high peak concentration with IV Pac may be responsible for peripheral neuropathy. We have developed an orally administered Pac made bioavailable through the combination with the minimally absorbed P-glycoprotein pump inhibitor encequidar (Pac+E). The pharmacokinetic exposure (AUC) matches that of IV Pac 80 mg/m2 with peak concentrations that are approximately 1/10 of IV Pac.Objective: To determine the efficacy and safety profile of oral Pac+E vs IV Pac in patients with mBC.Patients/Methods: This is a pivotal, Phase 3, open-label, randomized study of oral 205mg/m2 Pac+E for 3 days/week vs IV Pac at the labeled dose of 175mg/m2 q3weeks (NCT02594371). Subjects were randomized 2:1 to Pac+E vs IV Pac. The primary endpoint is radiologically confirmed tumor response rate (CR and PR) at two consecutive timepoints, 3-6 weeks apart, by study Day 160 using RECIST v1.1 criteria, as assessed by the blinded, independent central radiology company (Intrinsic Imaging). Progression-free survival (PFS) and overall survival (OS) were secondary endpoints.Results: A total of 402 mBC patients were enrolled (Pac+E 265 vs IV Pac 137); demographics were balanced. A similar percentage of subjects in each treatment group received prior taxane therapy (Pac+E, 28%; IV Pac, 31%). For the ITT population, final analysis of the primary endpoint of confirmed tumor response demonstrated a statistically significant difference between treatments; Pac+E 35.8% vs IV Pac 23.4%, a difference of 12.4%, p=0.011, favoring Pac+E. For the protocol defined mITT population (baseline evaluable scans and received at least 75% of the first cycle of dosing) the confirmed response rates were 40.4% for Pac+E vs 25.6% for IV Pac (p=0.005). For the population with evaluable post-baseline scan, the confirmed response rates were 50.3% for Pac+E vs 29.6% for IV Pac (p=0.0005). Tumor response in all clinically important subgroups was consistent with the overall confirmed response profiles. Responses were durable. Ongoing analysis of duration of confirmed response showed the median durations were39.0 weeks for Pac+E vs 30.1 weeks for IV Pac. Ongoing analysis of OS in the prespecified mITT population favors Pac+E (p=0.035) with a median of 27.9 months vs 16.9 months for Pac+E and IV Pac, respectively. Ongoing analysis of PFS in the prespecified mITT population shows a strong trend favoring Pac+E (p=0.077) with a median of 9.3 months vs 8.3 months. The Pac+E group had a lower incidence of alopecia and a lower incidence and severity of neuropathic AEs compared to IV Pac (17% versus 57% respectively to Week 23), with Grade 3 neuropathic symptoms observed in 1% for Pac+E vs 8% for IV Pac. The toxicity profile of Pac+E was generally similar to IV Pac. However higher rates of neutropenia, infection and gastrointestinal AEs were observed in Pac+E group. The risk of serious AEs on both treatments was highest among subjects with pre-treatment evidence of hepatic impairment and the protocol was amended to address this issue.

Conclusion: Oral paclitaxel + encequidar is the first orally administered paclitaxel shown to be superior to IV paclitaxel for confirmed response, progression-free survival, and overall survival, with minimal clinically meaningful neuropathy.

Citation Format: Gerardo Umanzor, David L Cutler, Francisco J Barrios, Rosa H Vassallo, Marco A Chivalan, Suyapa A Bejarano, Julio R Ramirez, Luis Fein, E Douglas Kramer, Rubio D Kowalyszyn, Hui Wang, John Goldfinch, Taryn Moore, Rudolf MF Kwan. 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 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS6-01.