Ixabepilone development across the breast cancer continuum: a paradigm shift

Figures & data

Table 1 Pathologic response rates in single-agent neoadjuvant phase II trials for early breast cancer^22,31–35

Reference	Patients, n	Treatment	Dose and schedule	Number of cycles	pCR, %
Baselga et al^Citation22	161	Ixabepilone	40 mg/m^2 IV over 3 hours; every 3 weeks	4	18
Fisher et al^Citation31	1523	Doxorubicin/cyclophosphamide	60 and 600 mg/m^2, respectively; schedule not reported	4	13
Gradishar^Citation32	33	Docetaxel	100 mg/m^2 IV over 1 hour; every 3 weeks	4	3
Buzdar et al^Citation33	87	Paclitaxel	250 mg/m^2 IV over 24 hours; every 3 weeks	4	9
Amat et al^Citation34	80	Docetaxel	100 mg/m^2 IV over 1 hour; every 3 weeks	6	20
Estévez et al^Citation35	56	Docetaxel	40 mg/m^2 IV over 30 minutes; weekly for 6 weeks of an 8-week cycle	12	16

Abbreviation: pCR, pathologic complete response; IV, intravenous.

Table 2 Phase II trials that evaluated single-agent ixabepilone in patients with locally advanced or metastatic breast cancer^23–27

Reference	Patient population	Patients, n	Treatment	ORR, %	Median duration of response, months	Median TTP/PFS, months	Median OS, months	Main grade 3 or 4 toxic effects
Denduluri et al^Citation23	Metastatic breast cancer with no previous exposure to taxanes in the adjuvant or metastatic setting	23	Ixabepilone (6 mg/m^2) as a 1-hour IV infusion on days 1−5 of a 21-day cycle	57	5.6	5.5	Not reported	Fatigue (13%) Nausea (9%) Motor neuropathy (4%) Neutropenia (22%)
Low et al^Citation24	Advanced breast cancer previously treated with taxanes in the neoadjuvant, adjuvant, or metastatic setting	37	Ixabepilone (6 mg/m^2) as a 1-hour IV infusion on days 1−5 of a 21-day cycle	22	3.7	2.5	Not reported	Fatigue (13%) Diarrhea (11%) Neutropenia (35%) Febrile neutropenia (14%) Thrombocytopenia (8%)
Perez et al^Citation25	Advanced breast cancer resistant to anthracyclines, taxanes, and capecitabine	126	Ixabepilone (40 mg/m^2) as a 3-hour IV infusion on day 1 of a 21-day cycle	11.5a 18.3b	5.7	3.1	8.6	Neuropathy (14%) Fatigue/asthenia (14%) Myalgia/arthralgia (8%) Stomatitis/mucositis (7%) Neutropenia (54%) Leukopenia (49%)
Roché et al^Citation26	Metastatic breast cancer previously treated with adjuvant anthracyclines (17% had received taxanes as part of an adjuvant regimen)	65	Ixabepilone (40 mg/m^2) as a 3-hour IV infusion on day 1 of a 21-day cycle	41.5	8.2	4.8	22.0	Sensory neuropathy (20%) Myalgia (8%) Vomiting (7%) Infection with grade 3 or 4 Neutrogena (6%) Neutropenia (58%) Leukopenia (50%)
Thomas et al^Citation27	Metastatic breast cancer resistant to taxanes	49	Ixabepilone (40 mg/m^2) as a 3-hour IV infusion on day 1 of a 21-day cycle	12	10.4	2.2	7.9	Fatigue (27%) Sensory neuropathy (12%) Myalgia (10%) Pain (10%) Infection/febrile Neutrogena (10%) Nausea (6%) Vomiting (6%) Neutropenia (53%)

a Evaluated by an IRR for 113 evaluable patients.

b Evaluated by investigators for all 126 treated patients.

Abbreviations: ORR, objective response rate; TTP, time-to-progression; PFS, progression-free survival; OS, overall survival.

Figure 1 Independent radiology review-assessed PFS durations after treatment with ixabepilone plus capecitabine compared with capecitabine alone in women with locally advanced or metastatic breast cancer that had progressed after anthracycline and taxane treatment.²⁸ Copyright © 2007. Reproduced with permission from Thomas ES, Gomez HL, Li RK, et al. lxabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007;25:5210–5217.

Table 3 Adverse events that occurred in ≥10% of clinical trials of ixabepilone for locally advanced or metastatic breast cancer^23–28

Study	Thomas et al^Citation28		Denduluri et al^Citation23	Roché et al^Citation26	Low et al^Citation24	Thomas et al^Citation27	Perez et al^Citation25
Dose/schedule	Ixabepilone 40 mg/m^2 every 3 weeks + capecitabine 2000 mg/m^2 on days 1–14	Capecitabine 2500 mg/m^2 on days 1–14	Ixabepilone 6 mg/m^2 daily on days 1–5 every 3 weeks	Ixabepilone 40 mg/m^2 every 3 weeks	Ixabepilone 40 mg/m^2 every 3 weeks	Ixabepilone 40 mg/m^2 every 3 weeks	Ixabepilone 40 mg/m^2 every 3 weeks
Number of patients treated	369	368	23	65	37	49	126
Patient population	Pretreated; resistant to anthracyclines and resistant to taxanes		No previous exposure to taxanes in adjuvant or metastatic setting	Previously treated with adjuvant anthracyclines	Previously treated with taxanes in neoadjuvant, adjuvant, or metastatic setting	Resistant to taxanes	Resistant to anthracyclines, taxanes, and capecitabine
Nonhematologic adverse events, % all grades (% grade 3/4)
Peripheral sensory neuropathy	64 (21)	16 (0)	52 (0)	71 (20)	54 (3)	63 (12)	60 (14)
Fatigue/asthenia	64 (16)	30 (4)	78 (13)	68 (6)	65 (14)	76 (27)	50 (14)
Myalgia/arthralgia	53	6	30	97	51	84	49
Alopecia	31	3	87	92	54	43	48
Nausea	53	40	61	54	54	57	42
Stomatitis/mucositis/pharyngitis	33	21	–	32	–	28	29
Vomiting	39	24	39	26	22	41	29
Diarrhea	44	39	48	29	35	31	22
Rash	–	–	–	22	–	12	–
Musculoskeletal pain	–	–	–	–	–	–	20
Anorexia	31	14	–	18	–	18	19
Constipation	22	6	56	20	27	20	16
Nail changes	20	8	56	17	30	8	9
Fever	–	–	–	14	–	16	–
Abdominal pain/cramping	–	–	–	8	–	10	13
Headache	–	–	–	14	–	–	11
Neuropathic pain	–	–	–	12	–	8	–
Pain, other	–	–	–	14	–	65	8
Infection without neutropenia	–	–	–	14	–	12	–
Infection/febrile neutropenia	–	–	0	6	14	6	–
Motor neuropathy	16	0.3	9	6	–	–	10
Taste disturbance/dysgeusia	=	=	65	11	32	–	6
Hand-foot syndrome	64	62	–	–	–	–	–
Hematologic adverse events, % all grades (% grade 3/4)
Neutropenia	89 (67)	43 (11)	87 (22)	89 (58)	68 (35)	N/A (53)	79 (54)
Leukopenia	90 (57)	54 (6)	–	92 (50)	–	6 (2)	90 (49)
Anemia	90 (9)	70 (4)	83 (0)	92 (3)	73 (0)	6 (4)	84 (8)
Thrombocytopenia	54 (8)	31 (4)	52 (4)	40 (0)	41 (8)	–	44 (8)

Figure 2 Resolution of grade 3 or 4 peripheral neuropathy in patients who received ixabepilone plus capecitabine.⁵⁴ Copyright © 2008. Reproduced with permission from Swain SM, Arezzo JC. Neuropathy associated with microtabile-stabilzing agents. Clin Adv Hematol Oncol. 2008;6:455–467.

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