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.

PURPOSE Intravenous paclitaxel (IVpac) is complicated by neuropathy and requires premedication to prevent hypersensitivity-type reactions. Paclitaxel is poorly absorbed orally; encequidar (E), a novel P-glycoprotein pump inhibitor, allows oral absorption. METHODS A phase III open-label study comparing oral paclitaxel plus E (oPac + E) 205 mg/m2 paclitaxel plus 15 mg E methanesulfonate monohydrate 3 consecutive days per week versus IVpac 175 mg/m2 once every 3 weeks was performed. Women with metastatic breast cancer and adequate organ function, at least 1 year from last taxane, were randomly assigned 2:1 to oPac + E versus IVpac. The primary end point was confirmed radiographic response using RECIST 1.1, assessed by blinded independent central review. Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS Four hundred two patients from Latin America were enrolled (265 oPac + E, 137 IVpac); demographics and prior therapies were balanced. The confirmed response (intent-to-treat) was 36% for oPac + E versus 23% for IVpac ( P = .01). The PFS was 8.4 versus 7.4 months, respectively (hazard ratio, 0.768; 95.5% CI, 0.584 to 1.01; P = .046), and the OS was 22.7 versus 16.5 months, respectively (hazard ratio, 0.794; 95.5% CI, 0.607 to 1.037; P = .08). Grade 3-4 adverse reactions were 55% with oPac + E and 53% with IVpac. oPac + E had lower incidence and severity of neuropathy (2% v 15% > grade 2) and alopecia (49% v 62% all grades) than IVpac but more nausea, vomiting, diarrhea, and neutropenic complications, particularly in patients with elevated liver enzymes. On-study deaths (8% oPac + E v 9% IVpac) were treatment-related in 3% and 0%, respectively. CONCLUSION oPac + E increased the confirmed tumor response versus IVpac, with trends in PFS and OS. Neuropathy was less frequent and severe with oPac + E; neutropenic serious infections were increased. Elevated liver enzymes at baseline predispose oPac + E patients to early neutropenia and serious infections (funded by Athenex, Inc; ClinicalTrials.gov identifier: NCT02594371 ).

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.

PURPOSE The HOLA COVID-19 study sought to evaluate the impact of COVID-19 on oncology practices across Latin America (LATAM), challenges faced by physicians, and how practices and physicians adapted while delivering care to patients with cancer. METHODS This international cross-sectional study of oncology physicians in LATAM included a 43-item anonymous online survey to evaluate changes and adaptations to clinical practice. Multivariable logistic regression analyses were used to evaluate the association of caring for patients with COVID-19 and changes to clinical practice. RESULTS A total of 704 oncology physicians from 19 countries completed the survey. Among respondents, the most common specialty was general oncology (34%) and 56% of physicians had cared for patients with COVID-19. The majority of physicians (70%) noted a decrease in the number of new patients evaluated during the COVID-19 pandemic when compared with prepandemic, and 73% reported adopting the use of telemedicine in their practice. More than half (58%) of physicians reported making changes to the treatments that they offered to patients with cancer. In adjusted models, physicians who had cared for patients with COVID-19 had higher odds of changing the type of chemotherapy or treatments that they offered (adjusted odds ratio 1.81; 95% CI, 1.30 to 2.53) and of delaying chemotherapy start (adjusted odds ratio 2.05; 95% CI, 1.49 to 2.81). Physicians identified significant delays in access to radiation and surgical services, diagnostic tests, and supportive care. CONCLUSION The COVID-19 pandemic has significantly disrupted global cancer care. Although changes to health care delivery are a necessary response to this global crisis, our study highlights the significant disruption and changes to the treatment plans of patients with cancer in LATAM resulting from the COVID-19 health care crisis.

We appreciate the comments from McCaw et al 1 regarding the statistical analysis of end points in our study. 2 The primary end point of the study was response rate, but we agree that the estimate of absolute value by median improvement in progression-free survival using Kaplan-Meier can be misleading and may underestimate the true value of new treatment approaches.Using a time-based (t-year) approach to estimate benefit in mean event-free (survival) time to summarize the survival curve is interesting and may provide clinically meaningful results. The t-year mean survival time is the area under the Kaplan-Meier curve. The higher the curve, the larger the area under the curve. The group difference between two treatments can then be quantified by the difference or ratio of two mean survival times. It is interesting that the results using this new summary measure have similar statistical conclusions as those via the hazard ratio estimates in terms of P values. We agree that with such a time scale summary, the quantification of the treatment effect could be easier to interpret and could potentially help with a more accurate estimate of clinical impact for both providers and patients.