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Background: IVPac is widely used to treat patients with breast cancer. oPac+E is oral paclitaxel in combination with Encequidar, an oral, minimally absorbed, specific p-glycoprotein inhibitor that enables the absorption of oral paclitaxel. Results of the phase III trial, KX-ORAX-001, were presented at SABCS, 2019, Abstract # GS6-01. At the time of the database lock for the final analysis of the primary endpoint of confirmed tumor response rate, analyses of PFS and OS were performed. The confirmed tumor response rate was significantly higher in the oPac+E group vs IVPac (35.8% vs 23.4%, p=0.011 ITT, population). The median overall survival, as of Sept 2020 presented at SABCS 2020, Abstract# PD1-08 was 22.7 months vs 16.5 months, respectively favoring oPac. Analysis of safety data demonstrated that patients with elevated liver tests (at screening or baseline), were at increased risk of serious and early complications of neutropenia including sepsis, septic shock, febrile neutropenia which could be fatal. A post hoc, subgroup analysis of survival for patients with elevated liver tests was conducted. Methods: Study KX-ORAX-001 was a phase III, randomized, international study in women with mBC for whom treatment with IVPac was recommended. Eligible patients were randomized 2:1 to receive oPac+E or IVPac. Patients received 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: A total of 402 mBC patients were randomized (oPac+E 265: IVPac 137) and represent the ITT population of which 399 subjects were dosed. 122 patients (oPac+E 74, IVPac 48) had elevated AST, or bilirubin (NCI ODWG mild category) at screening or predose/baseline. The subjects were generally balanced between treatment groups for mean age (55 vs 57 years), extent of tumor metastases, and tumor markers ER/PR+ HER2- (62% vs 63%), ER/PR- HER2- (11% vs 15%). For subjects receiving OPac+E, the median survival was 18.9 months vs 10.1 months for subjects receiving IVPac; with a hazard ratio of 0.593 (95.5% CI 0.382 - 0.921) favoring OPac+E.Greater than 65% of subjects had a survival event at the time of this analysis. Conclusion: Although patients with mBC and mild hepatic dysfunction at baseline are at increased risk of early serious neutropenic and infectious/septic complications after treatment with oPAC+E, this risk is counterbalanced by an increase in overall survival. (NCT 02594371) Citation Format: Gerardo Umanzor, Hope S Rugo, Francisco J Barrios, R H Vasallo, Marco A Chivalan, S Bejarano, Julio Roberto Ramirez, Luis Fein, R D Kowalyszyn, D L Cutler, D Kramer, H Wang, R MF Kwan. Oraxol + Encequidar (OPac+E) vs IV paclitaxel (IVPac) in the treatment of patients with metastatic breast cancer (mBC) (Study KX-ORAX-001): Subgroup survival analysis of patients with hepatic dysfunction [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-05.

Background: IVPac is widely used to treat patients with breast cancer. oPac+E is oral paclitaxel in combination with Encequidar, an oral, minimally absorbed, specific p-glycoprotein inhibitor that enables the absorption of oral paclitaxel. Results of the phase III trial, KX-ORAX-001, were presented at SABCS, 2019, Abstract # GS6-01. At the time of the database lock for the final analysis of the primary endpoint of confirmed tumor response rate, analyses of PFS and OS were performed. The confirmed tumor response rate was significantly higher in the oPac+E group vs IVPac (35.8% vs 23.4%, p=0.011 ITT, population). The median overall survival was 27.7 months vs 16.7 months, respectively favoring oPac. An update of the duration of response, PFS and OS data comprising an additional 14 months follow-up will be presented. At the time of the update it is projected that approximately 60% of subjects will have had a survival event. Methods: Study KX-ORAX-001 was a phase III, randomized, international study in women with mBC for whom treatment with IVPac was recommended. Eligible 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: A total of 402 mBC patients were randomized (oPac+E 265: IVPac 137) and represent the ITT population of which 399 subjects were dosed. Updated data for duration of response, PFS and OS for the ITT and prespecified mITT populations will be presented. (NCT 02594371) Citation Format: G Umanzor, H S Rugo, 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) versus IV paclitaxel (IVPac) in the treatment of metastatic breast cancer (mBC) patients (study KX-ORAX-001): Progression free survival (PFS) and overall survival (OS) updates [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 PD1-08.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity associated with IVPac. Primarily sensory, CIPN is an often irreversible condition primarily affecting the hands and feet associated with pain, numbness, tingling, and sensitivity to cold and has a significant impact on quality of life and treatment tolerance. Risk of CIPN increases with age, dose intensity, cumulative dose, and preexisting conditions including diabetes. Methods: Study KX-ORAX-001 was a phase III, randomized, international study in women with mBC for whom treatment with IVPac was recommended. Eligible 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: A total of 402 mBC patients were enrolled, 265 randomized to oPac+E and 137 to IVPac (ITT population). 399 patients were treated and comprise the safety population. The confirmed response rate was significantly greater in the oPac+E group vs IVPac (35% vs 23%) for the ITT population. Median overall survival was (27.7 vs 16.7 months, ITT) at the time of the analysis. Long-term follow up for final determination of PFS and OS is ongoing.Incidence of neuropathy-related TEAEs were lower in patients receiving oPac+E vs IVPac: Overall (21% vs 64%; all grades), grade ≥3 (2% vs 15%). Cumulative risk for neuropathy with IVPac was >50% by week 8 and was 83% at week 88. In contrast, the cumulative risk of neuropathy with oPac+E rose slowly and plateaued at 34% at week 88. Treatment discontinuations due to neuropathy occurred only in the IVPac arm (8%). Dose reductions due to neuropathy were reported in 8% of IVPac treated patients and in 2% of oPac+E treated patients. In agreement with the lower rates of peripheral neuropathy in patients treated with oPac+E, there was lower use of medications used for the treatment of neuropathic symptoms. Use of gabapentin or pregabalin was 12% for patients receiving oPac+E vs 40% for IVPac treated patients. Conclusions: oPac+E was associated with greater efficacy in the treatment of patients with mBC and a lower incidence of neuropathy, slower onset and lesser severity of neuropathic events compared to IVPac 175mg/m2 administered every three weeks. Fewer patients receiving oPac+E required dose reduction due to neuropathy and no patients receiving oPac+E discontinued treatment due to neuropathy. Reduction in neuropathy may improve quality of life and allow longer administration of effective therapy while maintaining dose intensity. 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. Lower rates of neuropathy with oral paclitaxel and encequidar (oPac+E) compared to IV paclitaxel (IVPac) in treatment of metastatic breast cancer (mBC): 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 PS13-06.

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.