Eribulin for the treatment of metastatic breast cancer: an update on its safety and efficacy

Figures & data

Figure 1 Mechanisms of action of eribulin mesylate.

Figure 2 Binding sites of microtubule-targeting chemotherapy agents.

Table 1 Summary of Phase I studies of eribulin mesylate

References	Year of publication	Schedule	Patients (n)	Most common primaries†	MTD (mg/m^2)	DLT	Responses
Synold et al^Citation16	2005	Bolus d1, 8, 15 q28	40	Lung (23%) Breast (10%)	1.4 mg/m^2	G3 febrile neutropenia	2 PR
Goel et al^Citation17	2009	1 hour infusion d1, 8, 15 q28	32	Colorectal (25%) Ovarian (19%)	1.0 mg/m^2	G3 fatigue (0.5 mg/m^2) G4 neutropenia, G3 fatigue (1.4 mg/m^2)	1 PR (NC)
Tan et al^Citation19	2009	1 hour infusion d1 q21	21	Lung (29%) Kidney (19%)	2.0 mg/m^2	G4 febrile neutropenia	1 PR (NC)
Mukohara et al^Citation18	2012	5 min infusion d1, 8 q21	15	Lung (20%) Breast (13%)	1.4 mg/m^2	G3 febrile neutropenia G4 neutropenia	3 PR

Note:

† Values rounded to nearest percentage.

Abbreviations: MTD, maximum tolerated dose; DLT, dose-limiting toxicity; q28, every 28 days; q21, every 21 days; G3, grade 3 by NCI CTCAE; G4, grade 4 by NCI CTCAE; PR, partial response; NC, not confirmed; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.

Table 2 Phase II studies of eribulin mesylate in metastatic breast cancer

References	Year of publication	Schedule	Median prior chemotherapy Patients (n)	Median prior chemotherapy regimens	ORR	PFS	OS	G3/4 neutropenia	G3/4 neuropathy
Vahdat et al^Citation21	2009	1.4 mg/m^2 d1, 8, 15 q28;	103	4	11.5%	2.6	9	64%	5%
Cortes et al^Citation22	2010	1.4 mg/m^2 d1, 8 q21	299	4	9.3%	2.6	10.4	54%	6.9%
Aogi et al^Citation23	2012	As above	81	3	21.3%	3.7	11.1	95%	3.7%
McIntyre et al^Citation24	2014	As above	56	0	28.6%	6.8	NR	50%	20%
Vahdat et al^Citation28	2013	As above	101	NR	15.4%	3.1	NR	31%	10%
Wilks et al^Citation25	2014	1.4 mg/m^2 d1, 8 q21 + trastuzumab 6 mg/kg q21	52	0	71.2%	11.6	NR	26.9%	38.5%

Abbreviations: ORR, objective response rate; PFS, progression-free survival (months); OS, overall survival (months); G3/4, grade 3 to 4 by NCI CTCAE; q28, every 28 days; q21, every 21 days; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse events; NR, not reported.

Table 3 Selected toxicities reported from Phase III studies of eribulin

	EMBRACE study (n=508)			301 Study (n=544)
	Any grade%	Grade 3%	Grade 4%	Any grade%	Grade 3%	Grade 4%
Hematologic toxicities
Neutropenia	52	21	24	54	25	21
Leukopenia	23	12	2	31	13	2
Anemia	19	2	<1	19	2	0
Thrombocytopenia	NR	NR	NR	5	<1	0
Nonhematologic toxicities
Alopecia	45	–	–	35	–	–
Nausea	35	1	0	22	< 1	0
Vomiting	18	4	<1	12	< 1	<1
Diarrhea	18	0	0	14	1	0
Asthenia	54	8	1	15	4	<1
Peripheral neuropathy	35	8	<1	13	4	0
Febrile neutropenia	5	NR	NR	2	2	<1
Hypersensitivity	1	NR	NR	NR	NR	NR

Abbreviations: NR, not reported; EMBRACE, the Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389.

Table 4 Ongoing studies of eribulin in breast cancer

Study design	Treatment setting	Treatment arm(s)	Primary objective	Secondary objectives	Start date
Metastatic breast cancer studies Phase 1
Combination eribulin plus PLX3397 (CSF1 inhibitor)	Pretreated	Dose escalation cohorts of PLX3397	MTD of PLX3397 percentage of patients without progression	Serum studies, safety assessment, immune response, response rate	July 2012
Combination eribulin plus mifepristone (PR antagonist) in triple negative MBC and ovarian cancer	Pretreated	Dose escalation cohorts of mifepristone + eribulin	MTD		January 2014
Combination eribulin plus POL6326 (CXCR4 antagonist) in MBC	Pretreated	Dose escalation cohorts of POL6326, eribulin	Safety/tolerability	Response rate	June 2013
Combination eribulin plus carboplatin in MBC	Pretreated	Dose escalation cohorts of eribulin + carboplatin	MTD	Response rate	February 2013
Combination eribulin plus everolimus in triple-negative MBC	Pretreated TNBC	Dose escalation cohorts of eribulin + everolimus	RP2D of combination Event-free survival	Safety, OS	Due October 2014
Phase II
Combination eribulin, trastuzumab and pertuzumab in HER2-positive MBC	Second line HER2 positive	Eribulin + trastuzumab + pertuzumab	Safety/tolerability Response rate	PFS, OS	August 2013
Efficacy and tolerability of eribulin plus lapatinib in patients with metastatic breast cancer (E-VITA)	Second-line HER2-positive	Lapatinib + eribulin (two dose schedules of eribulin)	TTP Safety/toxicity	ORR, CBR, OS, biomarker analysis	February 2012
Metronomic eribulin in MBC after chemotherapy	Pretreated	Eribulin	PFS	Safety	January 2014
Combination eribulin plus bevacizumab in HER2-negative MBC	First-line HER2-negative	Eribulin + bevacizumab	Disease control rate	Toxicity	November 2013
First-line eribulin in HER2-negative MBC	First-line HER2-negative	Eribulin	TTP	Response rate, CBR, duration of response, safety	June 2013
Eribulin plus gemcitabine versus paclitaxel plus gemcitabine in HER2-negative metastatic breast cancer	First-line HER2-negative	a) Paclitaxel + gemcitabine b) Eribulin + gemcitabine	PFS	OS, neurotoxicity, toxicity, DOR, ORR, CBR	October 2014
First/second-line eribulin in HER2-negative MBC	First/second-line HER2-negative	Eribulin	Response rate	PFS, DOR, safety, neurotoxicity/QOL assessment	June 2013
Combination eribulin plus bevacizumab in MBC	Second-line HER2-negative	Eribulin + bevacizumab	Response rate	PFS, OS, CBR, DOR, safety, QOL	Due September 2014
Trastuzumab plus pertuzumab alone or combined with hormonal therapy or eribulin in patients over 60 years of age with HER2-positive MBC	First/second-line HER2-positive	a) Trastuzumab + pertuzumab b) Trastuzumab + pertuzumab + hormonal therapy c) Trastuzumab + pertuzumab + eribulin	Response rate		December 2013
Phase III
Paclitaxel versus eribulin in HER2-negative MBC	First/second-line HER2-negative	a) Paclitaxel b) Eribulin	OS	Response rate, DOR, TTF, toxicity, PFS	January 2014
Early-stage breast cancer studies Phase II
Pharmacogenomic study of neoadjuvant eribulin in HER2-negative BC	Neoadjuvant HER2-negative	Eribulin	mRNA correlation with pCRB rate	pCR rate, safety, gene expression prediction	August 2012
Neoadjuvant eribulin followed by dose-dense doxorubicin and cyclophosphamide in HER2-negative LABC	Neoadjuvant HER2-negative	Eribulin followed by doxorubicin + cyclophosphamide	pCR rate	Toxicity	November 2011
Neoadjuvant eribulin followed by FAC versus paclitaxel followed by FEC in HER2-negative BC	Neoadjuvant HER2-negative	a) Eribulin followed by FEC/FAC b) Paclitaxel followed by FEC/FAC	pCR rate		August 2012
Eribulin in combination with capecitabine for adjuvant treatment in estrogen receptor-positive early-stage breast cancer	Adjuvant ER-positive HER2-negative	Eribulin + capecitabine	Feasibility/safety (RDI)	Toxicity	August 2011

Abbreviations: MTD, maximum tolerated dose; RP2D, recommended Phase II dose; OS, overall survival; TNBC, triple-negative breast cancer; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PFS, progression-free survival; TTP, time to progression; CBR, clinical benefit rate; DOR, duration of response; QOL, quality of life; TTF, time-to-treatment failure; BC, breast cancer; pCR, pathological complete response; 5-FU, 5-fluorouracil; PR, progesterone receptor; RDI, relative dose intensity; FEC, 5-Fluorouracil, Epirubicin, Cyclophosphamide; FAC, 5-Fluorouracil, Doxorubicin, Cyclophosphamide; pCRB, pathological complete response in breast.

SynoldTWMorganRJNewmanEMA phase I pharmacokinetic, target validation study of the novel anti-tubulin agent E7389: a California Cancer Consortium trialJ Clin Oncol200523Suppl 200 Abstr 3036

 Google Scholar

GoelSMitaACMitaMA Phase I study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced solid tumorsClin Cancer Res2009154207421219509177

 PubMed Web of Science ®Google Scholar

TanARRubinEHWaltonDCPhase I study of eribulin mesylate (E7389) administered once every 21 days in patients with advanced solid tumorsClin Cancer Res2009154213421819509146

 PubMed Web of Science ®Google Scholar

MukoharaTNagaiSMukaiHEribulin mesylate in patients with refractory cancers: a Phase I studyInvest New Drugs2012301926193321887501

 PubMed Web of Science ®Google Scholar

VahdatLTPruittBFabianCJPhase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxaneJ Clin Oncol2009272954296119349550

 PubMed Web of Science ®Google Scholar

CortesJVahdatLBlumJLPhase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabineJ Clin Oncol2010283922392820679609

 PubMed Web of Science ®Google Scholar

AogiKIwataHMasudaNA phase II study of eribulin in Japanese patients with heavily pretreated metastatic breast cancerAnn Oncol2012231441144821989327

 PubMed Web of Science ®Google Scholar

McIntyreKO’ShaughnessyJSchwartzbergLPhase 2 study of eribulin mesylate as first-line therapy for locally recurrent or metastatic human epidermal growth factor receptor 2-negative breast cancerBreast Cancer Res Treat201414632132824699910

 PubMed Web of Science ®Google Scholar

VahdatLGarciaAVogelCEribulin mesylate versus ixabepilone in patients with metastatic breast cancer: a randomized Phase II study comparing the incidence of peripheral neuropathyBreast Cancer Res Treat201314034135123877339

 PubMed Web of Science ®Google Scholar

WilksSPuhallaSO’ShaughnessyJPhase 2, multicenter, single-arm study of eribulin mesylate with trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancerClin Breast Cancer622014 [Epub ahead of print]

 Web of Science ®Google Scholar