clinical development in patients with ErbB2+ metastatic breast cancer (MBC). This ... breast cancer patients, brain metastases are a serious unmet medical need.
ARRY-380, a potent, small molecule inhibitor of ErbB2, increases survival in intracranial ErbB2+ xenograft models in mice Victoria Dinkel, Deborah Anderson, Shannon Winski, Jim Winkler, Kevin Koch and Patrice Lee. Array BioPharma Inc., Boulder, CO
Abstract
Brain metastases are a leading cause of death in HER 2+ breast cancer patients Lapatinib shows limited clinical activity in HER2+ breast cancer brain metastases as single-agent and in combination with capecitabine Activity of ARRY-380 investigated in models of intracranial tumors
Comparison of efficacy in SC versus intracranial xenografts Comparison of efficacy versus lapatinib or neratinib
Tumor Volume (mm3)
600 500 400
0 1 1
300
100
100 80
50
4
0
0 0
5
10
15
20
0
25
10
20
30
40
50
Days
Treatment Day
Both ARRY-380 & lapatinib active
Lapatinib inactive
Subcutaneous NCI-N87 gastric carcinoma tumor model in mice; 5 x 106 cell implanted SC; Drugs at MTD
100
80
40
Lapatinib 10000
Brain Concentration (ng/g) Mean + SD
AR00440993
8000
6000
4000
2000
0 0.5
1
2
4
100
50
0 0.5
1
2
4
Time Point (hr)
Time Point (hr)
Lapatinib
ARRY-380
AR00440993*
0.5
0.026
0.048
-
1
0.022
0.048
2.083
2
0.039
0.021
0.480
4
0.038
0.019
1.311
5
5.0xx105 105Cells Cells 5.0
0 25
Day Post-Tumor Cell Implantation
30
35
N=5 per group
Pilot Study (data not shown) using 14C albumin as the tracer, and mannitol as the positive control for blood brain barrier (BBB) disruption, confirmed that the IC inoculation procedure did not mechanically disrupt the BBB.
5
10
15
20
25
30
35
40
45
50
55
60
65
Day Post-Tumor Cell Implantation
Summary
150
Non-tumor-bearing nude mice; compounds dosed at (75 mg/kg, PO, once). Blood and tissue collected at 0.5, 1,2 and 4 hr post-dose. Plasma and tissue processed and drug concentrations measured using LC/MS/MS.
2.5xx105 105Cells Cells 2.5
0
ARRY-380
AR00440993
1.0 1.0xx105 105Cells Cells
0
Lapatinib 200
ARRY-380
AR00440993 is active metabolite of ARRY-380, possessing equivalent in vitro cellular potency Brain penetration of AR00440993 is significantly higher than either lapatinib or ARRY-380
Vehicle
20
ARRY-380 (75 mg/kg. BID, PO)
N=13 per group
ARRY-380 significantly decreases brain pErbB2/tot ErbB; lapatinib less effective
15
Neratinib (40 mg/kg, QD, PO)
BRAIN
60
10
Vehicle
N=9 per group
PLASMA
Brain:Plasma Ratios
5
40
Lapatinib (50 mg/kg, BID, PO)
ARRY-380 Shows Equivalent or Better Brain Exposure than Lapatinib
Brain tumor cell burden associated with decreased survival in NCI-N87 model
0
60
Drugs at MTD
Time Point (hr)
20
100
ARRY-380 shows superior intracranial effects vs. lapatinib
Anesthetized nude NCr female mice (Taconic Laboratories, Inc., Germantown, NY) were inoculated with human tumor cells intracranially at lamba suture. • NCI-N87 (NCI, Bethesda, MD) human gastric carcinoma model: 5 x 105 cells were implanted. For the • BT-474 (ATCC, Manassas, VA) human breast carcinoma study:17β-estradiol (0.5 mg)/progesterone (10 mg) pellets (35-day release) were implanted 1 day prior to BT474 tumor cell inoculation (1 x 106 cells) Mice were monitored twice daily for general health and behavioral/neurological effects; body weights (BW) determined twice weekly. At first sign of neurological problem or BW loss >20%, animals were euthanized animals by CO2 inhalation. Brain and plasma were collected for analyses in the NCI-N87 study. In efficacy studies, treatment with vehicle or drugs began 2 days post-tumor cell implantation
HER2-positive: 1-2 years TNBC: 3-5 months Whole brain radiotherapy (WBRT) Stereotactic radio-surgery (SRS) Surgical resection
#PRs 0
lapatinib 100 mg/k g, BID, PO
Vehicle lapatinib 50 mg/kg, BID, PO ARRY-380 75 mg/kg, BID, PO
20
Intracranial (IC) model
25-40% for HER2- positive metastatic disease 15% for other types of metastatic breast cancer
Current treatment options (with significant side effects):
ARRY-380 100 mg/k g, QD, PO lapatinib 50 mg/k g, BID, PO
700
• Inhibitor of trastuzumab-resistant p95 truncated HER2 (IC50 =7 nM) ~30% of Stage III/IV patients • No activity against ~100 other kinases at 1 mM • Minimal activity against other kinases at 10 mM
Time to progression (i.e., ‘brain failure’)
150
ARRY-380 50 mg/k g, QD, PO
800
p=0.015
4 3 2 1 0 Vehicle
ARRY-380
Group
• ARRY-380 treatment significantly enhances survival in two ErbB2driven intracranial tumor xenograft models in mice; with superior activity compared to other lapatinib and neratinib in these studies. • ARRY-380 forms an active metabolite which maintains sustained brain levels after oral dosing of ARRY-380 and may contribute to enhanced activity versus other ErbB2 agents • Additionally, ARRY-380 has demonstrated durable clinical activity in heavily pre-treated patients with ErbB2+ MBC6 • These preclinical and clinical data suggest that ARRY-380 may provide benefit to patients with ErbB2+ MBC with brain metastases and warrants further study.
References
25
phos/tot ErbB2
Brain is most common site for CNS metastases (15,000 new cases in US/year) Increasing incidence as women are living longer due to better treatments for systemic disease
Vehicle
200
Survival (%)
• Estimated Ki for ErbB receptors • HER2: 1.8 nM • EGFR: 72 nM • ErbB4: 276 nM
900
ARRY-380 treatment yields superior survival vs. lapatinib or neratinib
NCI-N87: Intracranial tumor implantation
NCI-N87: Subcutaneous tumor implantation
phos/tot ErbB2
Introduction1-5
ARRY-380 Increases Survival
• ARRY-380 is ATP-competitive, reversible and selective for HER2
Plasma Concentration (ng/mL) Mean + SD
ARRY-380 is an orally active, potent small molecule targeting ErbB2 inhibitor currently in clinical development in patients with ErbB2+ metastatic breast cancer (MBC). This compound has shown excellent activity in numerous SC mouse tumor models including breast (BT-474, MDA-MB-453), ovarian (SK-OV-3) and gastric (N87) carcinoma models. In breast cancer patients, brain metastases are a serious unmet medical need. Patients with ErbB2+ breast cancer have a significantly increased incidence of brain metastases following trastuzumab therapy. Here we demonstrate significant single agent activity of ARRY-380 in two ErbB2+ intracranial mouse xenograft models. For these studies, female nude mice received intracranial implantations of tumor cells (either NCI-N87 or BT-474) by direct injection into the brain parenchyma (via the sagittal suture). In pilot studies, we demonstrated that the blood brain barrier was not disrupted by mechanical injections and that increasing tumor burden correlates negatively with neurologic outcome, body weight and survival. In the N87 studies, animals received treatments beginning on Day 2 postimplantation and continuing for up to 6 weeks. Dose groups (n=12/group) were vehicle, ARRY-380 at MTD (75 mg/kg, PO, BID) or lapatinib at MTD (50 mg/kg, PO, BID). All animals in the vehicle- or lapatinib–treated groups did not survive beyond Day 22. In the ARRY-380-treated-group, 75% of the animals were alive on Day 43. Brain PK/PD was also evaluated in the N87 model. ARRY-380 and its active metabolite caused a significant reduction in brain pErbB2 (80%). In the BT-474 model, animals received treatments beginning on Day 2 post-implantation and continuing for up to 8 weeks. Dose groups (n=13/group) were vehicle, ARRY-380 at MTD (75 mg/kg, PO, BID), lapatinib at MTD (50 mg/kg, PO, BID) or neratinib at MTD (40 mg/kg, PO, QD). On Day 56, survival in the ARRY-380 group was 69% while survival rates in the vehicle, lapatinib or neratinib–treated groups were 23%, 8% and 23%, respectively. Thus ARRY-380 treatment significantly enhances survival in two ErbB2 driven intracranial tumor xenograft models, with superior activity compared to other ErbB2 agents in these studies. Additionally, ARRY-380 has demonstrated durable clinical activity in heavily pre-treated patients with ErbB2+ MBC. These preclinical and clinical data suggest that ARRY-380 may provide benefit to patients with ErbB2+ MBC with brain metastases.
BT-474 ErbB2+ breast carcinoma IC xenograft
NCI-N87 ErbB2+ gastric carcinoma IC xenograft
ARRY-380
Survival (%)
Available at www.arraybiopharma.com
Percent survival
Abstract # 852
p=0.118
20 15 10 5 0 Vehicle
Lapatinib
Group
1. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol2004; 22: 3608–3617. 2. Weil RJ, Palmieri DC, Bronder JL et al. Breast cancer metastasis to the central nervous system. Am J Pathol 2005; 167: 913–920. 3. Tham YL, Sexton K, Kramer R et al. Primary breast cancer phenotypes associated with propensity for central nervous system metastases. Cancer 2006;107: 696–704. 4. Pestalozzi BC, Zahrieh D, Price KN et al. Identifying breast cancer patients at risk for central nervous system (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann Oncol 2006; 17: 935–944 5. dos Santos Zimmer and Cameron, D.A. Challenges of brain metastasis in ErbB2 (HER-2-positive) breast cancer and the potential of small molecules, European Oncological Diseases 2007; 14-18 6. Moulder, S.L, Borges, V, Chia, S.K.L., et al. ARRY-380, a Selective HER2 Inhibitor: From Drug Design to Clinical Evaluation. 23rd Annual EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. November, 2011
