Clinical Impact of Eribulin in the Treatment of Breast Cancer

Figures & data

Figure 1.  Eribulin mechanism of action.

(A) Eribulin inhibits microtubule growth. (B) Eribulin has no effect on microtubule shortening. (C) Eribulin causes nonproductive tubulin aggregates.

Image courtesy of EISAI (NJ, USA).

Figure 2.  Kaplan–Meier of EMBRACE overall survival.

TPC: Treatment of physician’s choice.

Reproduced with permission from [9] © Elsevier (2011).

Figure 3.  Eribulin versus capecitabine.

(A) OS. (B) OS in HER2^- subgroup. Data are for the intent-to-treat population.

*HR Cox model including geographic region and HER2 status as strata.

^†p-value from stratified log-rank test based on clinical database.

HR: Hazard ratio; OS: Overall survival.

(A) Reproduced with permission from [33]; (B) Reproduced with permission from [34].

Figure 4.  Effect of eribulin treatment modification on duration of therapy: type and timing of dose modifications.

Reproduced with permission from [41].

Table 1.  Published Phase II trials for eribulin as monotherapy in advanced breast cancers.

Assessments	Vahdat et al. (2009)	Cortes et al. (2010)	Aogi et al. (2010)
Treatment	Eribulin mesylate 1.4 mg/m^2 on days 1, 8 and 15 of 28-day cycle; days 1 and 8 of 21-day cycle	Eribulin mesylate 1.4 mg/m^2 on days 1 and 8 of 21-day cycle	Eribulin mesylate 1.4 mg/m^2 on days 1 and 8 of 21-day cycle
Response category
Populations (n)	87	269	80
ORR^† (%)	11.5	9.3	21.3
CBR^‡ (%)	17.2	17.1	27.5
Median PFS (months)	2.6	2.6	3.7
Median OS (months)	9.0	10.4	11.1
Grade 3/4 toxicities
Safety populations (n)	103	291	81
Neutropenia (%)	64.0	54.0	95.1
Febrile neutropenia (%)	4.0	5.5	13.6
Leukopenia (%)	18.4	14.1	74.1
Fatigue (%)	4.8	10.0	1.0
Peripheral neuropathy (%)	4.8	6.9	3.7

^†Defined as complete response + partial response.

^‡Defined as complete response + partial response + stable disease ≥6 months.

CBR: Clinical benefit rate; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival.

Data taken from [23–25].

Table 2.  Summary of Phase II results: eribulin as first-line treatment in patients with previously untreated advanced HER⁺ and HER^- breast cancer.

Response category	Phase II HER^+†	Phase II HER^-†
	Eribulin/trastuzumab (n = 52)	Eribulin (n = 56)
Treatment	Eribulin mesylate 1.4 mg/m^2 iv. 2–5 min on days 1 and 8 of each 21-day cycle; trastuzumab 8 mg/kg iv. over 90 min on day 1 of cycle 1	Eribulin mesylate 1.4 mg/m^2 iv. 2–5 min on days 1 and 8 of a 21-day cycle
ORR, n (%) (95% CI)	37 (71.2) (56.9–82.9)	16 (28.6) (17.3–42.2)
CR, n (%)	3 (5.8)	0
PR, n (%)	34 (65.4)	16 (28.6)
SD, n (%)	13 (25.0)	26 (46.4)
PD, n (%)	1 (1.9)	11 (19.6)
NE, n (%)	1 (1.9)	3 (5.4)
CBR^‡, n (%) (95% CI)	44 (84.6) (71.9–93.1)	29 (51.8) (38.0–65.3)
DCR^§, n (%) (95% CI)	50 (96.2) (86.8–99.5)	42 (75.0) (61.6–85.6)
PFS, months (95% CI)	11.6 (9.13–13.9)	6.8 (4.44–7.59)
TTR, months (95% CI)	1.3 (1.22–1.38)	1.4 (1.22–2.66)
DOR, months (95% CI)	11.1 (6.70–17.8)	5.8 (4.67–10.6)

^†Locally recurrent or metastatic breast cancer not previously treated with chemotherapy.

^‡Defined as CR + PR + durable SD.

^§Defined as CR + PR + SD.

CBR: Clinical benefit rate; CR: Complete response; DCR: Disease control rate; DOR: Duration of response; iv.: Intravenous; NE: Not estimable; ORR: Objective response rate; PD: Progressive disease; PFS: Progression-free survival; PR: Partial response; SD: Stable disease; TTR: Time to response.

Data taken from [26,27].

Table 3.  Phase II neurotoxicity profile of eribulin.

Adverse event	Vahdat et al. (2009) (n = 103)				Cortes et al. (2010) 21-day schedule (n = 291)		Total (n = 394)
	28-day cohort (n = 70)		21-day cohort (n = 33)
	Grade 1/2 n (%)	Grade 3 n (%)	Grade 1/2 n (%)	Grade 3^† n (%)	Grade 1/2 n (%)	Grade 3^† n (%)	Grade 1/2 n (%)	Grade 3^† n (%)
Overall
Peripheral neuropathy^‡	19 (27.1)	4 (5.7)	8 (24.2)	1 (3.0)	75 (25.8)	20 (6.9)	102 (25.8)	25 (6.3)
Motor neuropathy	–	–	–	–	1 (0.3)	4 (1.4)	1 (0.25)	4 (1.0)
Sensory neuropathy	–	–	–	–	78 (26.8)	17 (5.8)	78 (19.8)	17 (4.3)
Myalgia/arthralgia^¶	–	–	–	–	60 (20.6)	2 (0.7)	60 (15.2)	2 (0.5)
Nervous system disorders
Dizziness	8 (11.4)	0	4 (12.1)	0	14 (4.8)	0	26 (6.6)	0
Dysgeusia	6 (8.5)	0	3 (9.0)	0	40 (14)	0	49 (12)	0
Headache	5 (7.1)	1 (1.4)	6 (18.1)	1 (3.0)	36 (12)	0	47 (12)	2 (0.5)

^†No grade 4 events were reported for the adverse events shown in either study.

^‡Includes MedDRA preferred terms as follows: Sensory neuropathy: neuropathy peripheral, neuropathy, polyneuropathy, peripheral sensory neuropathy, and demyelinating polyneuropathy; Motor neuropathy: peripheral motor neuropathy and peripheral sensori motor neuropathy; Peripheral neuropathy: combination of the above terms.

^¶Myalgia/arthralgia may be a manifestation of neurotoxicity.

Data taken from [23,24].

Reproduced with permission from [30] © Elsevier (2012).

Table 4.  Incidence of neuropathy and sensitivity analysis of neuropathy based on a narrow definition of peripheral neuropathy by Common Terminology Criteria for Adverse Events grade.

	Eribulin (n = 51), n (%)	Ixabepilone (n = 50), n (%)
Neuropathy^†
All grades	17 (33.3)	24 (48.0)
Grade 1/2	12 (23.5)	13 (26.0)
Grade 3	5 (9.8)	11 (22.0)
Grade ≥4	0	0
Peripheral neuropathy^‡
All grades	16 (31.4)	22 (44.0)
Grade1/2	11 (21.6)	12 (24.0)
Grade 3	5 (9.8)	10 (20.0)
Grade ≥4	0	0

^†Combined MedDRA preferred terms based on a broad list of preferred terms defined in standardized MedDRA queries for neuropathy and the following additional preferred terms: neuropathy, hyperesthesia, painful response to normal stimuli, pallanesthesia and allodynia. If a combined term had >1 Common Terminology Criteria grade, the highest Common Terminology Criteria grade was used.

^‡Of those patients with neuropathy (combined term), peripheral neuropathy was based on a narrow list of preferred terms defined in standardized MedDRA queries for neuropathy and included: neuropathy peripheral, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, peripheral sensorimotor neuropathy, demyelinating polyneuropathy and paresthesia.

Reproduced with permission from the American Society of Clinical Oncology [31].

Table 5.  EMBRACE progression-free survival and best overall tumor response by independent review.

Response category n (%)	Eribulin (n = 468)	TPC (n = 214)	p-value
PFS
Median (range), months	3.7 (3.3–3.9)	2.2 (2.1–3.4)	–
Best overall tumor response
CR	3 (1)	0	–
PR	54 (12)	10 (5)	–
SD	208 (44)	96 (45)	–
PD	190 (41)	105 (49)	–
NE	12 (3)	3 (1)	–
Unknown	1 (<1)	0	–
ORR, n (%) (95% CI)	57 (12) (9.4–15.5)	10 (5) (2.3–8.4)	0.002
CBR^†, n (%) (95% CI)	106 (23) (18.9–26.7)	36 (17) (12.1–22.5)	–
DOR, months, (n; 95% CI)	4.2 (57; 3.8–5.0)	6.7 (10; 6.7–7.0)	0.159

^†Defined as CR + PR + durable SD.

CBR: Clinical benefit rate; CR: Complete response; DOR: Duration of response; NE: Not estimable; ORR: Objective response rate; PD: Progressive disease; PR: Partial response; PFS: Progression-free survival; SD: Stable disease; TPC: Treatment of physician’s choice.

Adapted with permission from [9] © Elsevier (2011).

Table 6.  Eribulin versus capecitabine: response rates.

	Independent review		Investigator review
	Eribulin (n = 554)	Capecitabine (n = 548)	Eribulin (n = 554)	Capecitabine (n = 548)
ORR^† (%)	11	12	16	20
p-value	0.849		0.100
SD (%)	57	55	60	51
PD (%)	23	24	18	23
NE (%)	2	1	6	6
Unknown (%)	8	8	0	0
Unconfirmed CR/PR	–	–	4	3
CBR^‡ (%)	26	27	33	34

Data are for the intent-to-treat population.

^†Defined as CR + PR.

^‡Defined as CR + PR + SD ≥6 months.

Independent review: eribulin arm 1 CR; Investigator review: eribulin arm 4 CR, capecitabine arm 10 CR. Unconfirmed CR/PR: confirmed per RECIST, but bone scan missing at confirmation visit as required by protocol amendment.

CBR: Clinical benefit rate; CR: Complete response; NE: Not estimable; PD: Progressive disease; PR: Partial response; ORR: Objective response rate; SD: Stable disease.

Reproduced with permission from [33].

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