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Charles Geyer of Allegheny Hospital on Tykerb and the Complexities of Targeted Therapies


Name: Charles Geyer

Position: Director of breast cancer medical oncology at Allegheny General Hospital in Pittsburgh; director of medical affairs for the National Surgical Adjuvant Breast and Bowel Project

Education: MD, Texas Tech University School of Medicine

Charles Geyer was the principal investigator on the Tykerb clinical trial that was halted in April when it hit its primary endpoint of progression-free survival early, and he presented the study's results at the American Society of Clinical Oncologists meeting June 3 in Atlanta.

The drug was shown to be efficacious in women whose tumors were Her2-positive and who had ceased responding to Herceptin, and as a result, the drug will probably be indicated for Her2-positive patients, assuming the US Food and Drug Administration approves it.

But drug makers may not be content to allow their therapies to be relegated forever to a specialty population. ImClone, for example, broadened the patient population for its drug Erbitux after it had initially been indicated for EGFR-overexpressing colorectal cancer.

Pharmacogenomics Reporter spoke to Geyer last week to learn more about the newly developed targeted therapy and its future.

Does it look like Tykerb will remain a personalized therapy?

Tykerb certainly appears to be an effective way of blocking the function of Her2, and so we have a second drug to block an important target in Her2-positive breast cancer. You're going to see a lot of research done in looking at Tykerb [in] earlier stages of Her2-positive disease, not just the advanced patient population that's the focus of this particular study. But I think that's where the initial labeling will come from, because that's where the data are.

But is there a possibility Tykerb will become a therapy that's not just aimed at Her2 overexpressors, but at a broad population? Like Erbitux, which was originally indicated for patients with EGFR-overexpressing tumors?

That's the typical way that drugs are developed — in order to get an initial approval or indication, you have to identify a patient population — it helps to have an unmet need — a situation where the options for that patient population are, unfortunately, limited. And if you can show that use of a new drug improves things for them, then that gets it established, but once you've got a drug effective in more advanced settings, the obvious question, then, is, 'Can we broaden this and do better across more types of tumor or earlier stages of disease?'

So that's the natural progression of clinical research.

But I would expect that for some targeted therapies, it will be necessary to be able to identify responders for the life of the drug.

Yeah, but even by and large, with a targeted drug, generally these targets are not unique to one specific kind of cancer. The whole thing about targeted therapy is that you focus on the target, and you conduct a study in certain tumor types, but if you've got a target that's important in several cancers — angiogenesis inhibition is a good example of that with bevicizumab (Genentech's Avastin) — and the drug targets VEGF, and they look at it in metastatic colon cancer and it helps, and they look at it in lung cancer and it helps, and they look at it in breast cancer and it helps — [the drug's indications naturally broaden].

So hitting the target across different tumor types can be effective for improving therapy. It depends on the nature of the target, but broadly speaking, most of the targets that are being identified are not found in just one tumor type — they tend to be seen across different tumor types.

Sure, but does it seem that it will always be necessary to check for overexpression of Her2, as it is now with Tykerb?

If the overexpression is critical to the behavior of the cancer, like it appears to be with Her2 — that's one way of targeting it. It gets more complex if you've got situations where the targets may not be overexpressed. There's a lot of complexity to it that people are just now trying to unravel.

Is there any reason to think that a targeted drug like Pfizer's Sutent, which is indicated in renal cancer regardless of whether or not its targets, VEGF and PDGF, are overexpressed, will ever become a pharmacogenomic therapy?

Broadly speaking, the idealistic goal is to be able to understand the tumor, the host, and how they interact and pick the best agents that block the pathways to work the best against that tumor in that individual, and that could be due to a lot of different factors.

But Sutent blocks a number of different targets — one of the VEGF isoforms is its target. Now, there is a question there about how you identify which patient is likely to benefit from that. We know that groups of patients with renal cell cancer clearly do benefit, but you're asking an individualization question. [There] is a hope that certainly medical oncologists have that we will get to that point where we can not only diagnose the tumor with our biopsies, but figure out which program of drug would give the best results.

The way you get there is through these large trials that incorporate [a] collection of tissue specimens, like with breast cancer studies. Now you do large studies — you collect the blocks from primary tumors so you can study the tumors and see if you can correlate things in the tumor with outcome — there are things we can find that predict for really nice prolonged responses, things that can predict for resistance — you learn that and move forward.

That's how we do it in breast cancer, and it's similar in other tumor types as well.

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