Small molecule inhibitor shows promise in trastuzumab-resistant metastatic breast can

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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

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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

Abstract

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/m² 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/m² vinorelbine, so the dose was escalated to 240 mg neratinib- 25 mg/m² 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/m² 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.