Targeted treatment of advanced and metastaticbreast cancer with lapatinib

Figures & data

Table 1 Kinase inhibition by lapatinib (GW572016) (adapted from Rusnak et al 2001)

Kinase	IC50 with lapatinib (nM)
EGFR	10.8 ± 0.53
HER2	9.2 ± 0.75
HER4	367 ± 4.2
c-src	3500 ± 650
c-RAF, MEK, ERK, VEGFR-2	all >10,000

Table 2 Phase I studies with lapatinib (GW572016)

Study ID (reference)	Setting	MTD/OTR	Cardiac	Diarrhea	Rash	Other
EGF10001 (Bence et al 2005)	Healthy	250 mg (single dose)	NR	4%	8%	Headache (23%)
EGF10003 (Pandite et al 2004)	Solid tumors	1800 mg OD	NR	17%	9%	Nausea (16%)
		900 mg BD	NR	29%	11%	Nausea (11%)
EGF10004 (Burris et al 2005)	Metastatic	500–1600 mg OD	1.5%a	42%	31%	Fatigue (10%); Nausea (13%)
EGF10005 (Chu et al 2007)	Solid tumors	1250 mg OD + C 2000 mg/m^2/d	NR	67%	44%	Nausea (49%)
EGF10009 (GlaxoSmithKline)	Solid tumors	1500 mg OD + P 175 mg/m^2 q3wk	2%b	80%b	73%b	Fatigue (75%)b; Nausea (73%)b
EGF10021 (GlaxoSmithKline)	Solid tumors	1250 mg OD + D 75 mg/m^2 q3wk	2%c	71%	54%	Nausea (31%)
EGF10023 (Storniolo et al 2008)	HER2+ ABC	1000 mg OD + trastuzumab	1.9%d	~ 90%e	~ 40%	Fatigue (52%)
EGF10030 (GlaxoSmithKline)	ER+/PR+ ABC	1500 mg OD + letrozole 2.5 mg	3%	77%	64%	Nausea (49%)

NR: not reported;

a one patient with asymptomatic LVEF decrease;

b adverse side-effects reported are in the group treated with paclitaxel q3wk + lapatinib only;

c one patient with congestive cardiac failure;

d one patient with greater than 20% decrease in left ventricular ejection fraction, which subsequently resolved;

e estimate from published bar graph;

Abbreviations: MTD, maximum tolerated dose; OTD, optimum tolerated dose; OD, once daily; BD, twice daily; C, capecitabine; P, paclitaxel; D, docetaxel; ABC, advanced breast cancer; ER, estrogen receptor; PR, progesterone receptor; LVEF, left ventricular ejection fraction.

Table 3 Phase II trials with lapatinib (GW572016) monotherapy in advanced/metastatic breast cancer

Study ID (reference)	Lapatinib dose	Population	n	Response rate
EGF20002 (GlaxoSmithKline)	1250 mg, amended to 1500 mg	T-refractory ABC/MBC	78	5.1%
EGF105084a (Lin et al 2008a)	750 mg BD	T-refractory/relapsed HER-2+ with brain metastases	39	2.6%
EGF103009 (Kaufman et al 2008)	1500 mg OD	Chemo-/T-refractory/relapsed IBC, HER-2+ (n = 126); EGFR+/HER-2– (n = 15)	141	HER-2+: 40%b EGFR+/HER-2–: 1 PR
EGF100642 (Toi et al 2007)	1500 mg OD	Chemo-/T-refractory LABC/MBC, HER-2+ (n = 45), HER-2- (n = 22)	67	HER-2+: 24% (0 CR, 11 PR) HER-2–: 5% (1 CR, 0 PR)
EGF20008 (Burstein et al 2008)	1500 mg OD	Chemo-refractory ABC/MBC	229	HER-2+: 4.3%; HER-2–: 0.0%c
EGF20009 (Gomez et al 2008)	1500 mg OD or 500 mg BD	First-line HER-2+ LABC/MBC	138	24%

a An extension arm in EGF105084 with lapatinib 1250 mg OD + capecitabine 2000 mg/m²/day is ongoing;

b estimated response rate based on preliminary data;

c by independent review.

Abbreviations: RR, response rate; ORR, overall response rate; OD, once daily; BD, twice daily; T, trastuzumab; Chemo, chemotherapy; LABC, locally advanced breast cancer; MBC, metastatic breast cancer; IBC, inflammatory breast cancer; PR, partial response; CR, complete response.

Table 4 Completed phase II/III combination trials with lapatinib (GW572016) for advanced/metastatic breast cancer

Study ID (reference)	Regimen	Population	Phase	n	Outcome
EGF102580a (GlaxoSmithKline)	L 1500 mg OD x 14 days → L 1500 mg + P 80 mg/m^2/wk x 12 weeks	A: HER-2+ ± EGFR+ (IBC) B: HER-2–/EGFR + (IBC)	II	42 7	A: RR 78.6% (95% CI, 63.2–89.7) B: RR 71.4% (95% CI, 29.0–96.3)
EGF30001 (Di Leo et al 2007)	P 175 mg/m^2 q3wk + L 1500 mg OD, or P + placebo	MBC HER-2– or untested	III	570	TTP: overall no difference, significant in HER2+ subpopulation only (see text)
EGF100151 (Cameron et al 2008)	L 1250 mg OD + C 2000 mg/m^2 vs C 2500 mg/m^2	LABC/MBC HER-2+	III	399	TTP: HR 0.57 (95% CI, 0.43–0.77, p = 0.00013) OS: HR 0.78 (95% CI, 0.55–1.12, p = 0.177)
EGF104900 (O’Shaughnessy et al 2008)	L 1000 mg OD + T vs L 1500 mg OD	T-refractory MBC HER-2+	III	296	PFS: HR 0.77 (95% CI, 0.6–1.0, p = 0.029) OS (median): HR 0.75 (95% CI, 0.5–1.1, p = 0.106)

a neoadjuvant study.

Abbreviations: OD, once daily; RR, response rate; TTP, time to progression; OS, overall survival; PFS, progression-free survival; T, trastuzumab; LABC, locally advanced breast cancer; MBC, metastatic breast cancer; IBC, inflammatory breast cancer; PR, partial response; CR, complete response.

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