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HER2 Found in Non-Breast Cancers, But So What?

Carlson, Robert H.

doi: 10.1097/01.COT.0000359124.46222.94
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ORLANDO, FL—Despite the excitement of finding HER2 amplification in non-breast cancers, suggesting that trastuzumab might be used to treat them, one expert still cautions that targeting HER2 will not necessarily affect growth in those tumors.

Jaap Verweij, MD, PhD, Professor of Experimental Chemotherapy and Pharmacology at the Daniel den Hoed Kliniek, Rotterdam Cancer Institute, and Head of the Department of Medical Oncology at Erasmus University Medical Center Rotterdam, talked about HER2 amplification in non-breast tumors during a poster-discussion session here at the ASCO Annual Meeting: “Amplification of HER2 doesn't tell you there is functionality,” he said.

Dr. Verweij was discussing a US Oncology Phase II study of lapatinib in patients with a variety of non-breast metastatic solid tumors that overexpressed HER2. The trial was novel in that it selected patients based on the molecular pathogenesis of their tumors rather than tumor histology.

Amplification of HER2 without functionality may have been the case with some tumors in this study, as only one of 32 patients achieved a complete response (in esophageal cancer) at 12 weeks and 10 had stable disease. The study was closed early due to the low response rate coupled with slow screening and enrollment, the authors said.

Dr. Verweij said amplification of HER2 is functional in breast cancer, of course, but said there is no preclinical or clinical data showing that is the case in other malignancies where it is amplified.

“So you can target overexpression or amplification as long as you want, but you're not going to get any effect if it doesn't function in tumor growth,” he said.

The possibility that HER2 overexpression has a function in non-breast solid tumors cannot be excluded based on data from this trial because there were too few patients, Dr. Verweij said, “but there is no really intriguing activity yet.”

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Unique Trial Design

On the other hand, Dr. Verweij said he was impressed with the target-specific, histology-independent, randomized-discontinuation study design. Patients were selected by a target in the tumor and not by the tumor histology.

Dr. Verweij recalled only one other study that used this approach, a Novartis study of imatinib in patients with tumors expressing the KIT receptor.

“[Those researchers] found out after the study that wild type KIT is not very sensitive to the agent; it's the mutated KIT receptor that is sensitive,” he said. “Activity was minimal because most patients were expressing wild type KIT in their tumors—you could say they were chasing the wrong target.

“So the message is, really know your target well before you design a study like this.”

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Random Discontinuation

A second novel feature of this trial's design was random selection of patients with stable disease at 12 weeks to continued lapatinib or to placebo.

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This allowed an assessment of whether the disease stabilized due to treatment or to the natural history of the disease, said first author Matthew D. Galsky, MD, a member of the US Oncology Translational Oncology Program and Director of the Phase I Clinical Trials Program at Comprehensive Cancer Centers of Nevada.

In an interview after the meeting, Dr. Galsky credited Daniel D. Von Hoff, MD, Physician-in-Chief at Translational Genomics Research Institute and Chief Scientific Officer at US Oncology, with developing the histology-independent, specific-target trial design. (The design was described in a recent article by Drs. Galsky and Von Hoff and colleagues, now available online in Investigational New Drugs.)

This double-blind, randomized discontinuation trial was sponsored by GlaxoSmithKline and designed to evaluate the activity of a drug selected by molecular pathogenesis rather than tumor histology.

Patients with HER2-amplified, treatment-refractory, metastatic gastroesophageal, bladder, ovarian, or uterine tumors were treated with lapatinib, an oral tyrosine kinase inhibitor of HER2. Primary objectives were response rates at 12 weeks and the percentage of patients who remained disease progression free at 24 weeks.

Dr. Galsky said the four tumor types were selected based on their reported frequencies of HER2 amplification.

After 12 weeks patients were restaged, and those with disease progression were removed from study. Patients achieving an objective response continued treatment.

Unique to this study, patients with stable disease were randomly selected to continue lapatinib or to initiate treatment with placebo.

Among the 32 patients, there was one complete response at 12 weeks, 10 with stable disease, 19 with progressive disease, and two whose status remained unknown.

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The median time to progression during open-label lapatinib was 78 days. Only seven patients with stable disease underwent randomization. Two patients with esophageal cancer remain on the study, and the single patient with a complete response remains so at Week 60 and the other remains with stable disease at Week 36.

“With the lack of response, it's not likely that lapatinib has a future in treating tumors that overexpress HER2,” Dr. Galsky said.

A drug may be a viable treatment for a tumor if it inhibits an entire pathway, he said, but not if it inhibits only the tip of the pathway.

© 2009 Lippincott Williams & Wilkins, Inc.
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