Abstract PS13-11: Oral paclitaxel and encequidar (oPac+E) in the treatment of metastatic breast cancer (mBC): Management of gastrointestinal adverse events (GI AE). Study KX-ORAX-001
Authors: Rugo H S , Umanzor G , Barrios F J , Vasallo R H , Chivalan M A , Bejarano S , Ramirez J R , Fein L , Kowalyszyn R D , Cutler D L , Kramer D , Goldfinch J , Wang H , Moore T , Kwan R MF 
Published: February 2021

Background: There is a need for more effective and less toxic treatments for patients with mBC. Patients may prefer oral vs IV cytotoxic therapies to avoid frequent hospital visits. In addition, oral therapies allow frequent or metronomic dosing regimens which may alter the toxicity or activity profile of agents vs infrequent IV administration. oPac+E is oral paclitaxel combination with Encequidar, a specific, minimally absorbed, oral p-glycoprotein inhibitor that facilitates the absorption of oral paclitaxel. mBC patients who received oPac+E had significantly greater confirmed tumor response and longer survival with lower rates and severity of neuropathy but increased GI AE compared to IV paclitaxel (IVPac) (Study KX-ORAX-001 presented at SABCS, 2019, Abstract # GS6-01).

Methods: Study KX-ORAX-001 was a phase III, randomized, study in women with mBC for whom treatment with IVPac was recommended. Patients were randomized 2:1 to receive oPac+E or IVPac. Patients continued treatment until discontinuation due to progressive disease or toxicity. oPac 205 mg/m2 was given once daily for 3 days weekly. E 12.9 mg was given 1 hour before each dose of oPac. IVPac 175 mg/m2 was infused over 3 hours every 3 weeks. The primary endpoint was efficacy defined as tumor response confirmed by BICR at two consecutive evaluations. Key secondary endpoints included PFS, OS. Safety was monitored throughout the study.

Results: All IVPac patients received high-dose dexamethasone and antihistamine premedication, which have significant anti-emetic activity and may have received additional anti-emetic agents as needed. The protocol did not allow any prophylaxis for GI AE for oPac+E patients nor were they to receive predose corticosteroids, nor antihistamines.

The protocol was amended after approximately 30% of patients were enrolled to allow prophylactic anti-emetic medications for patients randomized to oPac+E. Patients were also given loperamide to take at home and were instructed to initiate loperamide with the onset of diarrhea. The rates of Grade ≥2, vomiting and diarrhea for patients treated with IVPac, the patients treated with oPac+E prior to after the amendment are summarized in the table below.

Prophylactic anti-emetic therapy and early use of loperamide markedly decreased the incidence of ≥Grade 2 vomiting and diarrhea although there was a greater incidence than IVPac.

The most frequently prescribed anti-emetic agents for oPac+E treated patients were ondansetron (54%), metoclopramide (21%), domperidone (4%) and aprepitant (3%). For patients randomized to IVPac, the most frequently prescribed agents were ondanesteron (59%), granisetron (24%), palenosetron (7%) and aprepitant (2%). Oral administration of the oral NK1 inhibitor aprepitant appeared to be associated with increased incidence of oral paclitaxel systemic toxicity, potentially due to inhibition of metabolism of oPac by cytochrome P450 3A4.

Conclusions: oPac+E was associated with greater efficacy in the treatment of mBC and lower rates and severity of peripheral neuropathy, but increased GI AE compared to IVPac 175mg/m2. GI AE in oPac+E treated patients can be managed by prophylactic use of anti-emetics, primarily 5-HT3 inhibitors and early intervention with the anti-diarrhea agent loperamide. The use of the oral NK1 inhibitor aprepitant in combination with oPac+E is not recommended.(NTC02594371)

IVPacoPac+E Pre-AmendmentoPac+E Post AmendmentGrade 2Grade 3Grade 4Grade 2Grade 3Grade 4Grade 2Grade 3Grade 4Vomiting4%1%0%24%7%0%7%4%0%Diarrhea7%1%0%27%9%0%16%3%0.5%

Citation Format: H S Rugo, G Umanzor, F J Barrios, R H Vasallo, M A Chivalan, S Bejarano, J R Ramirez, L Fein, R D Kowalyszyn, D L Cutler, D Kramer, J Goldfinch, H Wang, T Moore, R MF Kwan. Oral paclitaxel and encequidar (oPac+E) in the treatment of metastatic breast cancer (mBC): Management of gastrointestinal adverse events (GI AE). Study KX-ORAX-001 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-11.