A phase I/II study of epertinib plus trastuzumab with or without chemotherapy in patients with HER2-positive metastatic breast cancer.
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Brain Neoplasms
/ drug therapy
Breast Neoplasms
/ drug therapy
Capecitabine
/ administration & dosage
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Humans
Male
Middle Aged
Quinazolines
/ administration & dosage
Receptor, ErbB-2
/ antagonists & inhibitors
Trastuzumab
/ administration & dosage
Treatment Outcome
Vinorelbine
/ administration & dosage
EGFR
Epertinib
HER2
HER2-positive breast cancer
Trastuzumab
Journal
Breast cancer research : BCR
ISSN: 1465-542X
Titre abrégé: Breast Cancer Res
Pays: England
ID NLM: 100927353
Informations de publication
Date de publication:
31 12 2019
31 12 2019
Historique:
received:
29
01
2019
accepted:
26
07
2019
entrez:
2
1
2020
pubmed:
2
1
2020
medline:
6
6
2020
Statut:
epublish
Résumé
Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-positive metastatic breast cancer (MBC). Eligible patients, with or without brain metastases, had received prior HER2-directed therapy. A dose-escalation phase determined the tolerability of each combination and established a dose for further study. Further, patients were recruited to expansion cohorts in each of the 3 arms to further explore efficacy and safety. The recommended doses of epertinib were 600 mg, 200 mg and 400 mg in arms A, B and C, respectively. The most frequent grade 3/4 adverse event (AE) was diarrhoea in all arms, which was manageable with medical intervention and dose modification. The objective response rate (complete response [CR] plus partial response [PR]) in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with trastuzumab was 67% (N = 9), with trastuzumab plus vinorelbine was 0% (N = 5) and with trastuzumab plus capecitabine was 56% (N = 9). Notably, 4 of 6 patients previously treated with T-DM1 responded in the arm A expansion cohort (epertinib plus trastuzumab). In the arm C expansion cohort (epertinib plus trastuzumab plus capecitabine), 4 of 7 patients responded despite previous exposure to capecitabine. Measurable regression of brain metastases was observed in patients with CNS target lesions treated in both arms A and C. We observed safety, tolerability and encouraging antitumour activity of epertinib combined with trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in patients with pre-treated HER2-positive MBC, with or without brain metastases. EudraCT Number: 2013-003894-87; registered 09-September-2013.
Sections du résumé
BACKGROUND
Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-positive metastatic breast cancer (MBC).
METHODS
Eligible patients, with or without brain metastases, had received prior HER2-directed therapy. A dose-escalation phase determined the tolerability of each combination and established a dose for further study. Further, patients were recruited to expansion cohorts in each of the 3 arms to further explore efficacy and safety.
RESULTS
The recommended doses of epertinib were 600 mg, 200 mg and 400 mg in arms A, B and C, respectively. The most frequent grade 3/4 adverse event (AE) was diarrhoea in all arms, which was manageable with medical intervention and dose modification. The objective response rate (complete response [CR] plus partial response [PR]) in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with trastuzumab was 67% (N = 9), with trastuzumab plus vinorelbine was 0% (N = 5) and with trastuzumab plus capecitabine was 56% (N = 9). Notably, 4 of 6 patients previously treated with T-DM1 responded in the arm A expansion cohort (epertinib plus trastuzumab). In the arm C expansion cohort (epertinib plus trastuzumab plus capecitabine), 4 of 7 patients responded despite previous exposure to capecitabine. Measurable regression of brain metastases was observed in patients with CNS target lesions treated in both arms A and C.
CONCLUSION
We observed safety, tolerability and encouraging antitumour activity of epertinib combined with trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in patients with pre-treated HER2-positive MBC, with or without brain metastases.
TRIAL REGISTRATION
EudraCT Number: 2013-003894-87; registered 09-September-2013.
Identifiants
pubmed: 31892325
doi: 10.1186/s13058-019-1178-0
pii: 10.1186/s13058-019-1178-0
pmc: PMC6938617
doi:
Substances chimiques
Quinazolines
0
S-222611
0
Capecitabine
6804DJ8Z9U
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Trastuzumab
P188ANX8CK
Vinorelbine
Q6C979R91Y
Banques de données
EudraCT
['2013-003894-87']
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1Subventions
Organisme : Department of Health
Pays : United Kingdom
Références
J Clin Oncol. 2016 Mar 20;34(9):945-52
pubmed: 26834058
J Clin Oncol. 2011 Jan 20;29(3):264-71
pubmed: 21149659
J Clin Oncol. 2017 Sep 10;35(26):3030-3038
pubmed: 28437161
Breast Cancer Res Treat. 1998;52(1-3):65-77
pubmed: 10066073
Clin Cancer Res. 2009 Feb 15;15(4):1452-9
pubmed: 19228746
Sci Rep. 2018 Jan 10;8(1):343
pubmed: 29321587
Science. 1989 May 12;244(4905):707-12
pubmed: 2470152
Eur J Cancer. 2015 Jan;51(2):137-45
pubmed: 25434923
Lancet Oncol. 2013 May;14(6):461-71
pubmed: 23602601
J Clin Oncol. 2019 May 1;37(13):1081-1089
pubmed: 30860945
J Clin Oncol. 2015 May 10;33(14):1564-73
pubmed: 25605838
Lancet Oncol. 2017 Jun;18(6):732-742
pubmed: 28526536
J Clin Oncol. 2009 Apr 20;27(12):1999-2006
pubmed: 19289619
J Clin Oncol. 2010 Mar 1;28(7):1124-30
pubmed: 20124187
Eur J Cancer. 2018 Nov;103:17-23
pubmed: 30196106
N Engl J Med. 2006 Dec 28;355(26):2733-43
pubmed: 17192538
J Natl Cancer Inst. 2014 Apr 28;106(5):null
pubmed: 24777111
Cancer Sci. 2014 Aug;105(8):1040-8
pubmed: 24837299