title: Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.
abstract: BACKGROUND
  Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours.
  
  
  METHODS
  This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer.
  
  
  RESULTS
  Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m(-2) on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1-147.3 weeks). Common treatment-emergent adverse events (all grades/grade ≥3) included diarrhoea (92%/29%; none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9-81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan-Meier median progression-free survival was 57.0 weeks (95% CI: 47.7-81.6 weeks). Pharmacokinetic analyses indicated no interaction between neratinib and paclitaxel.
  
  
  CONCLUSIONS
  The combination of neratinib and paclitaxel was associated with higher toxicity than that of neratinib as a single agent, but was manageable with antidiarrhoeal agents and dose reductions in general. The combination therapy also demonstrated a high rate of response in patients with HER2-positive breast cancer. A phase III trial is ongoing to assess the benefit and risk of this combination in the first-line setting.
authors: UNIMED Medical Institute, Comprehensive Centre for Breast Diseases, Hong Kong, China. lwcchow@ootr.org
authors: L W-C
authors: LW
authors: Chow
authors: B
authors: B
authors: Xu
authors: S
authors: S
authors: Gupta
authors: A
authors: A
authors: Freyman
authors: Y
authors: Y
authors: Zhao
authors: R
authors: R
authors: Abbas
authors: M-L
authors: ML
authors: Vo Van
authors: I
authors: I
authors: Bondarenko
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D017239:Paclitaxel; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C487932:neratinib
references: Ann Oncol. 2008 Jun;19(6):1068-74
references: 18283035
references: Anticancer Res. 2009 Feb;29(2):517-24
references: 19331197
references: Br J Cancer. 2009 Nov 17;101(10):1676-82
references: 19844234
references: J Clin Oncol. 2010 Dec 1;28(34):5110-5
references: 20975068
references: Breast Cancer Res Treat. 2007 Mar;101(3):355-65
references: 16850247
references: Mol Cancer Ther. 2006 May;5(5):1154-65
references: 16731747
references: J Clin Oncol. 2010 Mar 10;28(8):1301-7
references: 20142587
references: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references: 20610543
references: J Clin Oncol. 2008 Apr 1;26(10):1642-9
references: 18375893
references: N Engl J Med. 2001 Mar 15;344(11):783-92
references: 11248153
references: Proc Natl Acad Sci U S A. 2005 May 24;102(21):7665-70
references: 15897464
references: J Clin Oncol. 2006 Jun 20;24(18):2786-92
references: 16782917
references: Cancer. 2007 Sep 1;110(5):965-72
references: 17614302
references: J Clin Oncol. 2011 Jan 20;29(3):264-71
references: 21149659
references: J Med Chem. 2005 Feb 24;48(4):1107-31
references: 15715478
references: Drugs Aging. 1998 Apr;12(4):305-34
references: 9571394
references: Science. 1987 Jan 9;235(4785):177-82
references: 3798106
references: Clin Cancer Res. 2009 Apr 1;15(7):2552-8
references: 19318484
references: J Clin Oncol. 2010 Mar 1;28(7):1124-30
references: 20124187
references: Oncology. 2010;79(1-2):129-35
references: 21088439
references: Breast Cancer. 2006;13(4):329-33
references: 17146157
references: J Clin Oncol. 2004 Jul 15;22(14):2918-26
references: 15254061
references: Ann Oncol. 2013 Jan;24(1):109-16
references: 22967996
references: J Clin Oncol. 2005 Jul 1;23(19):4265-74
references: 15911866
references: Cancer Res. 2004 Jun 1;64(11):3958-65
references: 15173008
references: Breast Cancer Res Treat. 2008 Dec;112(3):533-43
references: 18188694
references: Ann Oncol. 2001;12 Suppl 1:S57-62
references: 11521723
references: N Engl J Med. 2006 Dec 28;355(26):2733-43
references: 17192538
references: Clin Breast Cancer. 2005 Dec;6(5):425-32
references: 16381626
references: Clin Cancer Res. 2000 Dec;6(12):4885-92
references: 11156248
references: J Clin Oncol. 2014 Jan 10;32(2):68-75
references: 24323026
references: J Korean Med Sci. 2009 Oct;24(5):910-7
references: 19794992
references: J Clin Oncol. 2008 Dec 1;26(34):5544-52
references: 18955454