Open-Label, Randomized, Multicenter, Phase III Study Comparing Oral Paclitaxel Plus Encequidar Versus Intravenous Paclitaxel in Patients With Metastatic Breast Cancer
Hope S Rugo, Gerardo A Umanzor, Francisco J Barrios, Rosa H Vasallo, Marco A Chivalan, Suyapa Bejarano, Julio R Ramírez, Luis Fein, Ruben D Kowalyszyn, E Douglas Kramer, Hui Wang, Min-Fun R Kwan, David L Cutler, Oraxol Study Consortium Investigators, Hope S Rugo, Gerardo A Umanzor, Francisco J Barrios, Rosa H Vasallo, Marco A Chivalan, Suyapa Bejarano, Julio R Ramírez, Luis Fein, Ruben D Kowalyszyn, E Douglas Kramer, Hui Wang, Min-Fun R Kwan, David L Cutler, Oraxol Study Consortium Investigators
Abstract
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).
Conflict of interest statement
David L. Cutler
Employment: Athenex
Stock and Other Ownership Interests: Merck Sharp & Dohme, Athenex
No other potential conflicts of interest were reported.
Figures
References
- Gradishar WJ: Taxanes for the treatment of metastatic breast cancer. Breast Cancer (Auckl) 6:159-171, 2012
- Rivera E, Cianfrocca M: Overview of neuropathy associated with taxanes for the treatment of metastatic breast cancer. Cancer Chemother Pharmacol 75:659-670, 2015
- Panday VRN, Huizing MT, Ten Bokkel Huinink WW, et al. : Hypersensitivity reactions to the taxanes paclitaxel and docetaxel. Clin Drug Invest 14:418-427, 1997
- Seidman AD, Berry D, Cirrincione C, et al. : Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: Final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26:1642-1649, 2008
- Sparano JA, Wang M, Martino S, et al. : Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663-1671, 2008
- Loprinzi CL, Reeves BN, Dakhil SR, et al. : Natural history of paclitaxel-associated acute pain syndrome: Prospective cohort study NCCTG N08C1. J Clin Oncol 29:1472-1478, 2011
- Bandos H, Melnikow J, Rivera DR, et al. : Long-term peripheral neuropathy in breast cancer patients treated with adjuvant chemotherapy: NRG Oncology/NSABP B-30. J Natl Cancer Inst 110:djx162, 2018
- Fujiwara Y, Mukai H, Saeki T, et al. : A multi-national, randomised, open-label, parallel, phase III non-inferiority study comparing NK105 and paclitaxel in metastatic or recurrent breast cancer patients. Br J Cancer 120:475-480, 2019
- Dodd MJ, Miaskowski C, Paul SM: Symptom clusters and their effect on the functional status of patients with cancer. Oncol Nurs Forum 28:465-470, 2001
- Pachman DR, Barton DL, Swetz KM, et al. : Troublesome symptoms in cancer survivors: Fatigue, insomnia, neuropathy, and pain. J Clin Oncol 30:3687-3696, 2012
- Eek D, Krohe M, Mazar I, et al. : Patient-reported preferences for oral versus intravenous administration for the treatment of cancer: A review of the literature. Patient Prefer Adherence 10:1609-1621, 2016
- Sparreboom A, van Asperen J, van Asperen J, et al. : Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA 94:2031-2035, 1997
- Jackson C, Deva S, Bayston K, et al. : An international randomized cross-over bio-equivalence study of oral paclitaxel + HM30181 compared with weekly intravenous (IV) paclitaxel in patients with advanced solid tumours. Ann Oncol 30:v180-v181, 2019
- Dai M-S, Chao T-C, Chiu C-F, et al. : Oral paclitaxel in the treatment of metastatic breast cancer (MBC) patients. J Clin Oncol 37:1084-1084, 2019
- Gradishar WJ, Tjulandin S, Davidson N, et al. : Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 23:7794-7803, 2005
Source: PubMed