A multi-national, randomised, open-label, parallel, phase III non-inferiority study comparing NK105 and paclitaxel in metastatic or recurrent breast cancer patients

Yasuhiro Fujiwara, Hirofumi Mukai, Toshiaki Saeki, Jungsil Ro, Yung-Chang Lin, Shigenori E Nagai, Keun Seok Lee, Junichiro Watanabe, Shoichiro Ohtani, Sung Bae Kim, Katsumasa Kuroi, Koichiro Tsugawa, Yutaka Tokuda, Hiroji Iwata, Yeon Hee Park, Youngsen Yang, Yoshihiro Nambu, Yasuhiro Fujiwara, Hirofumi Mukai, Toshiaki Saeki, Jungsil Ro, Yung-Chang Lin, Shigenori E Nagai, Keun Seok Lee, Junichiro Watanabe, Shoichiro Ohtani, Sung Bae Kim, Katsumasa Kuroi, Koichiro Tsugawa, Yutaka Tokuda, Hiroji Iwata, Yeon Hee Park, Youngsen Yang, Yoshihiro Nambu

Abstract

Background: NK105 is a novel nanoparticle drug delivery formulation that encapsulates paclitaxel (PTX) in polymeric micelles. We conducted an open-label phase III non-inferiority trial to compare the efficacy and safety of NK105 and PTX in metastatic or recurrent breast cancer.

Methods: Patients were randomly assigned in a 1:1 ratio to receive either NK105 (65 mg/m2) or PTX (80 mg/m2) on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS), with a non-inferiority margin of 1.215.

Results: A total of 436 patients were randomised and 211 patients in each group were included in the efficacy analysis. The median PFS was 8.4 and 8.5 months for NK105 and PTX, respectively (adjusted hazard ratio: 1.255; 95% confidence interval: 0.989-1.592). The median overall survival and overall response rates were 31.2 vs. 36.2 months and 31.6% vs. 39.0%, respectively. The two groups exhibited similar safety profiles. The incidence of peripheral sensory neuropathy (PSN) was 1.4% vs. 7.5% (≥Grade 3) for NK105 and PTX, respectively. The patient-reported outcomes of PSN were significantly favourable for NK105 (P < 0.0001).

Conclusions: The primary endpoint was not met, but NK105 had a better PSN toxicity profile than PTX.

Clinical trial registration: ClinicalTrials.gov: NCT01644890.

Conflict of interest statement

Y.F. reports grants and other from Japan Agency for Medical Research and Development, grants and other from The Ministry of Health Labor and Welfare, Japan, during the conduct of the study; other from Astra Zeneca KK, other from Eisai Co., Ltd, other from Daiichi Sankyo Co., Ltd, other from Taiho Pharmaceutical Co., Ltd, grants from Takeda Pharmaceutical Co., Ltd, grants and other from Chugai Pharmaceutical Co., Ltd, other from Eli Lilly Japan KK, other from Novartis Pharma KK, outside the submitted work. H.M. received honoraria from Nippon Kayaku Co., Ltd. T.S. received honoraria and research funding from Nippon Kayaku Co., Ltd. J.R. received consulting fees from Nippon Kayaku Co., Ltd. Y.-C.L. received consulting fees from Nippon Kayaku Co., Ltd. Y.T. received research funding from Nippon Kayaku Co., Ltd. Y.N. is an executive officer of Nippon Kayaku Co., Ltd. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Kaplan–Meier curves for progression-free survival in full analysis set
Fig. 2
Fig. 2
Kaplan–Meier curves for overall survival in full analysis set
Fig. 3
Fig. 3
Cumulative incidence of peripheral sensory neuropathy
Fig. 4
Fig. 4
Patient-reported outcomes of peripheral sensory neuropathy assessed by FACT/GOG-NTX subscale

References

    1. Ferlay J, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer. 2015;136:349–386. doi: 10.1002/ijc.29210.
    1. Hamaguchi T, et al. NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumor activity and reduce the neurotoxicity of paclitaxel. Br. J. Cancer. 2005;92:1240–1246. doi: 10.1038/sj.bjc.6602479.
    1. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46:6387–6392.
    1. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control Release. 2000;65:271–284. doi: 10.1016/S0168-3659(99)00248-5.
    1. Mukai H, et al. Phase I study of NK105, a nanomicellar paclitaxel formulation, administered on a weekly schedule in patients with solid tumors. Invest. New Drugs. 2016;34:750–759. doi: 10.1007/s10637-016-0381-4.
    1. Kato K, et al. Phase II study of NK105, a paclitaxel-incorporating micellar nanoparticle, for previously treated advanced or recurrent gastric cancer. Invest. New Drugs. 2012;30:1621–1627. doi: 10.1007/s10637-011-9709-2.
    1. Smith TJ, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J. Clin. Oncol. 2006;24:3187–3205. doi: 10.1200/JCO.2006.06.4451.
    1. Seidman AD, 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. 2008;26:1642–1649. doi: 10.1200/JCO.2007.11.6699.
    1. Sato K, et al. Multicenter Phase II trial of weekly paclitaxel for advanced or metastatic breast cancer: The Saitama Breast Cancer Clinical Study Group (SBCCSG-01) Jpn. J. Clin. Oncol. 2003;33:371–376. doi: 10.1093/jjco/hyg075.
    1. Perez EA, Vogel CL, Irwin DH, Kirishner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J. Clin. Oncol. 2001;19:4216–4223. doi: 10.1200/JCO.2001.19.22.4216.
    1. Nishimura R, et al. Weekly Paclitaxel in the treatment of advanced or metastatic breast cancer previously treated or not treated with Docetaxel: a phase II study. Chemotherapy. 2005;51:126–131. doi: 10.1159/000085620.
    1. Miller K, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 2007;357:2666–2676. doi: 10.1056/NEJMoa072113.
    1. Gray R, Bhattacharya S, Bowden C, Miller K, Comis RL. Independent review of E2100: A phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J. Clin. Oncol. 2009;27:4966–4972. doi: 10.1200/JCO.2008.21.6630.
    1. Militao M. S. & Saad E. D. Noninferiority (NI) phase III trials in oncology: what is the basis for choosing the NI margin? J. Clin. Oncol.29 (Suppl 15), abstr e13070 (2011).
    1. ten Tije AJ, et al. Weekly paclitaxel as first-line chemotherapy for elderly patients with metastatic breast cancer. A multicentre phase II trial. Eur. J. Cancer. 2004;40:352–357. doi: 10.1016/j.ejca.2003.08.013.
    1. Miles D, et al. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur. J. Cancer. 2017;70:146–155. doi: 10.1016/j.ejca.2016.09.024.
    1. Bernstein V, et al. A randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast cancer: final analysis of Canadian Cancer Trials Group IND.213. Breast Cancer Res. Treat. 2018;167:485–493. doi: 10.1007/s10549-017-4538-4.
    1. Decker T, et al. A randomized phase II study of paclitaxel alone versus paclitaxel plus sorafenib in second- and third-line treatment of patients with HER2-negative metastatic breast cancer (PASO) BMC Cancer. 2017;17:499. doi: 10.1186/s12885-017-3492-1.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir