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.

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.

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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. Triple-negative (TNBC) is the most aggressive subtype of breast cancer and represents 12% of all cases in the US. In the Mexican population, the prevalence of TNBC is 23%. The prognosis is poor for most of these women, with a higher risk of locoregional recurrence, lower disease-free survival, and lower cancer-specific survival. The sociodemographic characteristics of Central American women, such as indigenous, afro descendants, and Hispanic descent, have been associated with factors such as high nuclear grade, high proliferation index, aggressive clinical presentation with advanced stages, high recurrence rates, and an increased risk of cancer fatality rate. Yet, no epidemiological characterization of women treated for TNBC in specialized hospitals in Central American countries exists to this date. Therefore, we describe the characteristics of women diagnosed with TNBC in three specialized hospitals in Guatemala and Honduras. Methods. We identify 1,501 women with breast cancer who attended three specialized hospitals, two in Guatemala and one in Honduras, from 2015 to 2021. Self-reported sociodemographic and clinical characteristics were determined, as well as pathologic data from medical records. Results. Of the 1,501 women, 272 (18.12%) were diagnosed with triple-negative phenotype. The median age was 49.5 years, with 25% under 40.5 years of age, 95.2% reported mestizo race, 51.5% were pre-menopausal, 49.6% had a high histologic grade (grade 3), and 98.8 had locally advanced disease (Table 1). Conclusions: The characteristics described in our sample were similar to those in other Hispanic populations. The prevalence of TNBC in our sample was lower than in Mexico but higher than that of the US. Our sample was made of primarily young women with locally advanced disease and pathologic factors associated with aggressive cancer behavior, such as high grade, lymphovascular invasion, and high Ki67 index. This first report is the product of a multidisciplinary team with interest in breast cancer subtypes. Our objectives include expanding the collaboration of clinical researchers to all the Central American and Caribbean countries and contributing to the understanding of molecular behavior of TNBC and support advances in treatment. Table 1.Characterization of women diagnosed with TNBC in three hospitals in Central AmericanCHARACTERISTIC% (95% CI)n = 272RaceMestizo95.2 (91.9 - 97.2)Indigenous4.8 (2.8 - 8.1)AgeMean (SD)49.5 years (11.7)IQR40.5 - 57Tobacco useYes3.7 (2.0 – 6.7)Number of pregnanciesMean (SD)1.5 (0.5)IQR1 – 2MenopauseYes48.5 (42.6 – 54.5)Use of contraceptivesYes14.0 (10.3 – 18.7)MulticentricYes19.2 (14.9 – 24.5)HypertensionYes8.4 (5.7 – 12.4)DiabetesYes8.8 (6.0 – 12.9)IMCLess than 3042.3 (36.5 – 48.3)Family history of cancerYes12.9 (9.4 – 17.5)Histologic grade15.5 (3.3 – 9.0)244.8 (39.0 – 50.8)349.6 (43.7 – 55.6)Lymphovascular invasionYes44.5 (38.6 – 50.5)Clinical stageI1.1 (0.3 – 3.4)II40.4 (34.7 – 46.4)III54.4 (48.4 – 60.8)IV4.0 (2.2 – 7.2)KI 67Mean (SD)46.9 (24.1)IQR30 - 70TherapyNeoadjuvant chemotherapy29.2 (21.3 – 38.7)RPC32.1 (23.9 – 41.6)Surgery97.4 (94.5 – 98.7)Adjuvant chemotherapy55.0 (49.0 – 60.8)Radiotherapy94.4 (90.8 – 96.6)MetastasisYes4.0 (2.2 – 7.2)BRCAMutated0.4 (0.0 – 2.6)WT2.2 (1.0 – 4.8) Citation Format: Agatha Reyes-Morales, Juan Francisco Alvarado-Muñoz, Suyapa Bejarano, Hugo Castro, Victor Puac-Polanco, Marco Chivalan, Silvana Torselli. Characterization of triple-negative breast cancer in two Central American countries [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 P3-12-23.