Small molecule inhibitor shows promise in trastuzumab-resistant metastatic breast cancer
ORLANDO (June 1, 2009)?Fox Chase Cancer Center researchers report that a
combination of trastuzumab and neratinib (HKI-272) a novel small molecule inhibitor of the HER2 receptor (ErbB2) appears active in women with HER2-positive metastatic breast cancer who have progressed on previous trastuzumab based therapies. More than one-quarter of the women in a phase I/II trial had their tumors shrink on the combination therapy.
"I think this is very promising. Neratinib induces clinically meaningful responses," says Ramona Swaby, M.D., a medical oncologist and attending physician at Fox Chase. Swaby will present the study results on Monday, June 1, at the annual meeting of the American Society of Clinical Oncology.
Trastuzumab is standard therapy for women with HER2-positive metastatic breast cancer and the majority of women respond to the treatment. However, over time some women will develop resistance to the drug and their tumors will start to grow again. For these women, alternative therapies are needed.
Both trastuzumab and neratinib inhibit the HER2 receptor expressed on the surface of HER2-positive breast cancer cells.
Trastuzumab blocks the extracellular portion of the receptor, while neratinib blocks the intracellular portion. Researchers think that the combination may provide the one-two punch necessary to knock out the tumor cells.
Forty-five women with trastuzumab-resistant breast cancer enrolled in the trial. In the phase I portion of the trial, women received either 160 mg or 240 mg neratinib daily plus trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg weekly. None of the patients experienced dose limiting toxicities. The most common grade 3/4 adverse events included diarrhea (13%), nausea (4%) and vomiting (4%). The researchers saw no evidence of cardiac toxicity with the combination.
Of the 33 patients in the phase II portion of the trial who are evaluable for response, nine (27%) had an objective response to the combination therapy. Additionally, 47% were progression-free at 16 weeks, which was the primary endpoint of the trail, and the median progression-free survival was 19 weeks. Seven women continue on therapy at this time. (Updated results will be presented at the meeting.)
"Trastuzumab has certainly made a difference in patient care, but there is still room for improvement," Swaby says. "For example because trastuzumab is an antibody it does not cross the blood-brain barrier so is not effective at treating or preventing brain metastases. It is incredibly heartbreaking to think you are out of the woods and then to have brain metastases occur.
Neratinib, a small molecule drug that can cross the blood-brain barrier, potentially may treat brain metastases. More studies are needed"
"The phase II data are snapshots of what this drug is capable of," Swaby says. "Phase III trials are underway, which I think is the right next step for this medicine. My patients in the study did well."
The current study was supported by Wyeth, which makes neratinib. Wyeth participated in the study design and data analysis.
Fox Chase Cancer Center is one of the leading cancer research and treatments centers in the United States. Founded in 1904 in Philadelphia as one of the nation's first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center's nursing program has received the Magnet status for excellence three consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. For more information, visit Fox Chase's web site at
www.fccc.edu or call 1-888-FOX-CHASE or 1-888-369-2427.
Abstract #1004:
Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: A phase I/II study.
Oral Presentation, Monday, June 1, 10:45 a.m.?Level 2, West Hall D2
ournal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 27, No 15S (May 20 Supplement), 2009: e14554
© 2009
American Society of Clinical Oncology
Safety and efficacy of neratinib (HKI-272) in combination with vinorelbine in patients with solid tumors
S. A. Limentani, A. Awada, L. Dirix, J. Beck, V. Dieras, F. Binlich, C. Germa, V. Agrapart, C. Powell and D. Hershman Carolinas Hematology Oncology Associates, Charlotte, NC; Institut Jules Bordet Unite du Chimiotherapie, Brussels, Belgium; Medische Oncologie, Wilrijk, Belgium; Highlands Oncology Group, Fayetteville, AR; Institut Curie, Unite D’Investigation Clinique, Paris, France; Wyeth Research, Paris, France; Wyeth Research, Cambridge, MA; Columbia Presbyterian Hospital, New York, NY
e14554
Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB
tyrosine kinase inhibitor. Preclinical studies have shown synergistic
antitumor activity with the combination of trastuzumab plus
vinorelbine in metastatic breast cancer.The recommended dose
of neratinib in monotherapy is 240 mg. In this phase 1 study,
a combination dose of neratinib plus vinorelbine that is tolerable
was determined in patients (pts) with solid tumors.
Methods: This is an open-label, 2-part study of ascending multiple daily
oral doses of neratinib (160 mg, 240 mg) in combination with
25 mg/m
2 IV vinorelbine (administered on days 1, 8 every 3 wks).
Tumor measurements were made every 6 wks by modified RECIST
criteria.
Results: 6 pts have been treated at each dose level.
Data for 12 pts (5 pts still ongoing) as of 30 Oct 2008 are
presented (median age [range] of 53.5 [38–75] yrs; 83%
female). The median duration of treatment [range] was 1.9 [1.5–2.7]
m. There was only 1 dose limiting toxicity (DLT) of grade 3
neuropathy (pt had preexisting grade 1 neuropathy) at 160 mg
neratinib-25 mg/m
2 vinorelbine, so the dose was escalated to
240 mg neratinib- 25 mg/m
2 vinorelbine. In this cohort, there
were no DLTs, and since the neratinib and vinorelbine doses
reached full standard doses there was no need for further dose
escalation. AEs, any causality, all grades in
15% of pts included
diarrhea (92%), nausea (67%), constipation (50%), fatigue (42%),
vomiting and anthralgia (33% each), abdominal pain and anorexia,
(25% each), anemia and neutropenia (17% each). Grade
3 AEs that
occurred in
1 pt included neutropenia (2 pts), pneumonia (1
pt) and peripheral neuropathy (2 pts). Preliminary efficacy
data show that 1 pt with stomach cancer had stable disease,
lasting
21 weeks.
Conclusions: The combination of 240 mg neratinib
and 25 mg/m
2 vinorelbine was found to be tolerable and to demonstrate
early evidence of clinical benefit in pts with solid tumors,
to be assessed further in pts with metastatic ErbB-2+ breast
cancer in part 2.
Mol Biosyst. 2011 Jun;7(6):1974-89. Epub 2011 Apr 12.
A genome-wide RNAi screen identifies novel targets of neratinib sensitivity leading to neratinib and paclitaxel combination drug treatments.
Seyhan AA,
Varadarajan U,
Choe S,
Liu Y,
McGraw J,
Woods M,
Murray S,
Eckert A,
Liu W,
Ryan TE.
LINK
Source
Systems Biology, Global Biotherapeutics, Pfizer Inc., 87 Cambridgepark Drive, Cambridge, MA 02140.
attila.seyhan@pfizer.com attila_seyhan@yahoo.com wei.liu@agios.com.
Abstract
ErbB2 is frequently activated in tumors, and influences a wide array of cellular functions, including proliferation, apoptosis, cell motility and adhesion. HKI-272 (neratinib) is a small molecule pan-kinase inhibitor of the ErbB family of receptor tyrosine kinases, and shows strong antiproliferative activity in ErbB2-overexpressing breast cancer cells. We undertook a genome-wide pooled lentiviral RNAi screen to identify synthetic lethal or enhancer (synthetic modulator screen) genes that interact with neratinib in a human breast cancer cell line (SKBR-3). These genes upon knockdown would modulate cell viability in the presence of subeffective concentrations of neratinib. We discovered a diverse set of genes whose depletion selectively impaired or enhanced the viability of SKBR-3 cells in the presence of neratinib. We observed diverse pathways including EGFR, hypoxia, cAMP, and protein ubiquitination that, when co-treated with RNAi and neratinib, resulted in arrest of cell proliferation. Examining the changes of these genes and their protein products also led to a rationale for clinically relevant drug combination treatments. Treatment of cells with either paclitaxel or cytarabine in combination with neratinib resulted in a strong antiproliferative effect. The identification of novel mediators of cellular response to neratinib and the development of potential drug combination treatments have expanded our understanding of neratinib's mode-of-action for the development of more effective therapeutic regimens. Notably, our findings support a paclitaxel and neratinib phase III clinical trial in breast cancer patients.
- PMID:
- 21487605
- [PubMed - in process]
Role for Neratinib in ER/Her crosstalk endocrine resistance?
Breast Cancer Res. 2011 May 20;13(3):106. [Epub ahead of print]
Endocrine resistance in breast cancer: new roles for ErbB3 and ErbB4.
Sutherland RL.
FREE TEXT
Source
Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
r.sutherland@garvan.org.au.
Abstract
ABSTRACT: Endocrine resistance is a major limitation to the successful treatment of estrogen receptor-positive (ER+) breast cancer, and the EGFR (epidermal growth factor receptor) and ErbB-2 receptor tyrosine kinases are involved in this process. A recent study now implicates the other two ErbB family members, ErbB-3 and -4.
Exposure of ER+ breast cancer cells to the pure antiestrogen, fulvestrant, increased levels of ErbB-3 or ErbB-4 and sensitivity to the growth-stimulatory effects of heregulin ݱ, a potent ligand for these receptors. Thus, the initial growth-inhibitory effects of fulvestrant appear compromised by cellular plasticity that allows rapid compensatory growth stimulation via ErbB-3/4. Further evaluation of pan-ErbB receptor inhibitors in endocrine-resistant disease appears warranted.
- PMID:
- 21639949
- [PubMed - as supplied by publisher]
Breast Cancer Res Treat. 2010 Jun;121(3):601-13. Epub 2009 Aug 21.
Breast cancer cells can switch between estrogen receptor alpha and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance.
Sonne-Hansen K,
Norrie IC,
Emdal KB,
Benjaminsen RV,
Frogne T,
Christiansen IJ,
Kirkegaard T,
Lykkesfeldt AE.
LINK
Source
Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, 2100 Copenhagen, Denmark.
Abstract
The majority of breast cancers are estrogen responsive, but upon progression of disease other growth promoting pathways are activated, e.g., the ErbB receptor system. The present study focuses on resistance to the pure estrogen antagonist fulvestrant and strategies to treat resistant cells or even circumvent development of resistance. Limited effects were observed when targeting EGFR and ErbB2 with the monoclonal antibodies cetuximab, trastuzumab, and pertuzumab, whereas the pan-ErbB inhibitor CI-1033 selectively inhibited growth of fulvestrant resistant cell lines. CI-1033 inhibited Erk but not Akt signaling, which as well as Erk is important for antiestrogen resistant cell growth. Accordingly, combination therapy with CI-1033 and the Akt inhibitor SH-6 or the Protein Kinase C inhibitor RO-32-0432 was applied and found superior to single agent treatment. Further, the resistant cell lines were more sensitive to CI-1033 treatment when grown in the presence of fulvestrant, as withdrawal of fulvestrant restored signaling through the estrogen receptor alpha (ERalpha), partly overcoming the growth inhibitory effects of CI-1033. Thus, the resistant cells could switch between ERalpha and ErbB signaling for growth promotion. Although parental MCF-7 cell growth primarily depends on ERalpha signaling, a heregulin-1beta induced switch to ErbB signaling rescued MCF-7 cells from the growth inhibition exerted by fulvestrant-mediated blockade of ERalpha signaling. This interplay between ERalpha and ErbB signaling could be abrogated by combined therapy targeting both receptor systems. Thus, t
he present study indicates that upon development of antiestrogen resistance, antiestrogen treatment should be continued in combination with signal transduction inhibitors. Further, upfront combination of endocrine therapy with pan-ErbB inhibition may postpone or even prevent development of treatment resistance.
- PMID:
- 19697122
- [PubMed - indexed for MEDLINE]
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