A	B	C	D	E	F	G	H	I	J	K	L
1	Main
2		Brand Name	Tykerb, Tyverb in Europe, fka GW572016.
3		Generic Name	lapatinib ditosyle
4		Mechanism	small molecule, selective dual competitive inhibitor of ErbB1 and ErbB2 tyrosine kinases
5		Administration	Oral
6		Competition	Can enter the brain (unlike Herceptin). Oral vs qm infusion (Herceptin). No HF? (Herceptin)
7		Timeline	3/13/2007 US approval. 6/10/2008 EU approval.
8		Clinical Studies
9			Phase III paclitaxel+- Tykerb in 1L HER2-positive mBC
10			27.8m vs 20.5m mOS.
11			9.7m vs. 6.5m PFS.
12			Asian Pacific region.
13
14			Phase III NeoALTTO Tykerb vs Herceptin vs Tykerb+Herceptin
15			pCR of 51.3% for combination versus 24.7% for Tykerb versus 29.5% for Herceptin.
16
17			Phase III "GeparQuinto" n=620 Herceptin versus Lapatinib in HER2-positive neo-adjuvant
18			31.3% PCR for Herceptin versus 21.7% for Tykerb.
19
20			Phase III Tykerb versus Tykerb+Herceptin n=296 ErbB2-positive 4L+
21			HR=0.74, p=0.03, 14 MOS versus 9.5 MOS monotherapy.
22
23			Pivotal III
24			Indication	Herceptin-relapsed, HER2+ mBC
25			Cohorts	lapatinib+capecitabine vs capecitabine alone.
26			Results	8.5m vs 4.5m TTP. Interim analysis halted study 4/2006.
27
28			p1 Lapatinib+Tras - Storniolo, ASCO 05 #559
29			heavily pretreated HER2+ MBC: 2-3+
30			750-1500mg qd with qw tras
31			n=48, 27 evaluable. 1CR 8mo duration. 5PR, 2-7mo duration, 10SD 1-5mo duration. 11 PD
32
33			p1 Lapatinib+Letrozole - Chu ASCO 2005 #3001
34			n=39, 18 breast, 16 ovarian, 5 other. KPS 70% or greater, advanced disease with life expectancy at least 12 weeks
35			3/18 BC with SD >6 months (8, 8, 6 mo). 5, 3, 3 prior chemos
36			1/2 endometrial had PR (SD for 7 mo then PR for 6 mo)
37			1/16 ovarian had SD >6 months w/ 3 prior chemos
38
39			EGF30008 letrozole +- lapatinib phase 3 n=760
40
41			CALGB 40302: fulvestrant +- lapatinib phase 3 n=288
42
43			Lapatinib +- tamoxifen p2
44
45			p2 lapatinib in MBC with brain mets - harvard
46
47			Tykerb in trastuzumab-resistant breast cancer - late-breaking data at ASCO 2006
48			p2 data in brain mets in patients with HER2-positive BC
49			p2 tykerb monotherapy data in relapsed/refractory inflammatory BC
50			cardiac function in n=2812 treated patients. 1.3% had decrease in LVEF.
51			p3 RCC data for patients with high tumor EGFR expression
52			Tykerb failed in RCC??
53			BCIG will run adjuvant study in n=8000???
54
55			EGF104900 - Herceptin+Tykerb vs Tykerb in refractory BC - n=270, started 11/05, results Q2 2007
56			1L mBC Taxol+- Tykerb n=570, start 12/03, results Q406 - EGF30002 - does not differentiate for HER2 status. Data at ASCO 2007?
57			1L mBC Femara+- Tykerb, n=1280, start 11/03, results Q307 - EGF30008
58			1L mBC HER2+ Taxol+Herceptin+-Tykerb, n=740, 11/05, results 2009 - EGF104383
59			1L mBC HER2+ Taxol+-Tykerb, n=460, 1/06 start, results 2008 - EGF104535
60
61				A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy.
62
63
64				Sub-category:	Metastatic Breast Cancer
65
66				Category:	Breast Cancer--Metastatic Breast Cancer
67
68				Meeting:	2008 ASCO Annual Meeting
69
70
71
72
73
74				Abstract No:		1015
75
76				Citation:		J Clin Oncol 26: 2008 (May 20 suppl; abstr 1015)
77
78				Author(s):		J. O'Shaughnessy, K. L. Blackwell, H. Burstein, A. M. Storniolo, G. Sledge, J. Baselga, M. Koehler, S. Laabs, A. Florance, D. Roychowdhury
79
80				Abstract:		Background: Lapatinib (L) is an oral, small-molecule inhibitor of EGFR and HER2 with a mechanism of action distinct from that of trastuzumab (T). Preclinical data suggest synergy between L and T. We studied L alone and in combination with T in pts with HER2+ MBC who progressed on T. Methods: Eligible women had received prior anthracycline and taxane therapy, had MBC with measurable lesions or bone-only disease, and had progressed on prior T-containing therapy. Pts were stratified by hormone receptor status and visceral/nonvisceral disease, then randomized to receive either L (1,500 mg QD) or L (1,000 mg QD) plus T (2 mg/kg weekly after 4 mg/kg loading dose). If pts progressed on the L arm, they could cross over to the L+T arm. The primary endpoint was PFS (investigator assessment), and secondary endpoints were clinical benefit rate (CBR) at 24 wks, RR, and OS. Results: 296 pts were randomized. All pts had received prior T; the median number of prior chemotherapy regimens was 6. Combination therapy significantly improved PFS and CBR; RR and OS were similar in both arms (Table). Both treatment regimens were generally well tolerated. Grade 1/2 diarrhea was higher in the L+T arm (53% vs 41%); acneiform rash was more common in the L-alone arm, likely due to higher L dose. Asymptomatic decline in LVEF (> 20% and below LLN) occurred in 5% of pts in L+T arm and 2% of pts in L-alone arm. 1 death occurred due to cardiac toxicity in the L+T arm. Conclusions: This is the largest study of 2 targeted agents in HER2+ MBC and the first to demonstrate the synergy of L+T in a phase III setting. Improved clinical outcome was achieved with the combination of L+T in pts progressing on T-based therapy and without a substantial change in the side effect profile. The role of combined anti-HER2 therapy, in combination with chemotherapy, in less heavily pretreated patients with early stage disease is ongoing in the ALTTO (Adjuvant L and/or T Treatment Optimization) study.
81
82						Endpoint	L	L + T	Hazard/OR	95% CI	P value
83						PFS (median, wks)*	8.4	12	0.77	0.6, 1.0	0.029
84						CBR (%)*	13.2	25.2	2.1	1.1, 4.2	0.02
85						RR (%)*	6.9	10.3	1.5	0.6, 3.9	0.46
86						OS (median, wks)	39	51.6	0.75	0.5, 1.1	0.106
87						*Intent to treat.
88
89
90
91
92
93
94
95
96				Lapatinib and paclitaxel in HER2-negative, extracellular domain (ECD) positive metastatic breast cancer (MBC) in a randomized phase III study.
97
98
99				Sub-category:	Metastatic Breast Cancer
100
101				Category:	Breast Cancer--Metastatic Breast Cancer
102
103				Meeting:	2008 ASCO Annual Meeting
104
105
106
107
108
109				Abstract No:		1017
110
111				Citation:		J Clin Oncol 26: 2008 (May 20 suppl; abstr 1017)
112
113				Author(s):		R. S. Finn, R. Gagnon, A. Di Leo, M. F. Press, M. Arbushites, M. Koehler
114
115				Abstract:		Background: It has been hypothesized that women with HER2-negative MBC respond to HER2-targeted drugs if the circulating baseline HER2 ECD is >16 ng/ml. Lapatinib, an oral, dual inhibitor of HER2 and EGFR, is effective in women with HER2+ MBC. We retrospectively examined this hypothesis using tissue and serum data from women with MBC who were enrolled in a randomized clinical trial of lapatinib and paclitaxel. Methods: Patients (pts, n=579) with newly diagnosed MBC were randomized to paclitaxel with placebo (P) or lapatinib (L+P). HER2 status was evaluated by fluorescence in situ hybridization or immunohistochemistry in archival tissue. Serum ECD was centrally measured by ELISA in available samples at baseline (bECD, n=473), Week 9, and every 12 weeks thereafter. Pts were stratified by HER2 and bECD status. Results: bECD was positive only in 62% (50/81) of HER2+ pts and in as many as 24% (96/392) of HER2-negative pts. It is known that PFS increased in L+P in HER2+ patients. In HER2-negative pts, bECD status had no effect on response (see Table). PFS within L+P or P was not significantly different across bECD strata. Follow-up median ECD levels were stable in bECD- pts, and decreased (up to 9 ng/mL) in bECD+ pts. Decreases were similar between treatment arms. Additional correlations (response rate, time, tumor burden) and descriptive statistics for HER2+ pts will be reported. Conclusions: This is the largest reported randomized ECD dataset for HER2-negative MBC pts. bECD+ levels were observed in 24% of HER2-negative MBC pts. We conclude that in HER2-negative MBC: (1) bECD is not predictive of benefit of L+P or P, (2) higher bECD may not indicate more refractory tumors as PFS with L+P and P was similar across bECD strata, (3) bECD may not contribute to treatment decisions for pts with HER2-negative MBC since PFS was similar in bECD strata.
116
117							bECD+ (n=96)			bECD- (n=296)
118							L+P	P	p	L+P	P	p
119						Median PFS, wks, HER2-	17.3	24	0.7948	23.9	22.9	0.3598