Novartis-Schering drug vatalanib produces interesting early results

By Jerry Call

Interesting early results of a phase II trial for GIST were presented at the 2006 American Society of Clinical Oncology (ASCO) meeting. The drug, PTK787/ZK22584 (vatalanib), is being tested for GIST patients that are resistant to Glivec (Gleevec). Only 15 patients have been in the trial long enough to be assessed for response; therefore, the results of this small trial must be viewed with extreme caution.

Two of the 15 patients (13 percent) had a partial response (PR) to the drug and 8 patients (53 percent) had stable disease for more than 3 months. Overall this represents a 67 percent benefit rate for Glivec-resistant patients. The median time to progression (TTP) was 8.9 months. All of these numbers are very similar to the response rate of Sutent, the drug that is currently approved in the United States and Canada for Glivecresistant GIST.

The PTK787/ZK22584 project is a joint collaboration between Novartis and Schering AG. It is a multi-tyrosine kinase inhibitor and inhibits all three VEGF receptors as well as KIT and PDGFR.

The investigators for the phase II GIST trial are Heikki Joensuu, M.D., from Helsinki, Finland; Paolo G. Casali, M.D., from Milan, Italy; and Filippo DeBraud, M.D., Milan, Italy. Joensuu was the first doctor to ever treat a GIST patient with Glivec and was one of four investigators in the original phase II trials testing Glivec in GIST.

At the sarcoma poster session at ASCO, Dr. Joensuu hypothesized to me on why PTK787/ZK22584 might have a low toxicity profile. Joensuu showed a dendrogram showing the activity profile of Glivec, Sutent and PTK787. Each dot on the dendrogram indicated a kinase that is inhibited by the drug. The larger the dot, the more potently it is inhibited. Glivec is somewhat of a “cleaner” drug (in that it hits a single target), but it still has about 5 medium to large dots and about 11 smaller dots. Sutent (SU11248) is a relatively “dirty” drug (in that it hits multiple targets) and has some affinity for 74 different kinases. PTK787 was one of the “cleanest” drugs tested in this study by Milea Fabian et al., which was published in Nature Biotechnology.

Being a “dirty” drug is not necessarily a bad thing. Just how dirty a drug should be was the topic of an editorial in the October 13 issue of Nature. Dr. Michael Heinrich, M.D., a noted GIST expert, was featured in the article. “The trick is that most cancers have more than one target. They might have five or six targets and you have to knock out three to stop the cancer,” Heinrich said. “This is where dirty drugs come into play. You might be able to develop one dirty drug with three targets instead of three clean drugs with one target each.” Glivec was thought to be a clean drug. “CML has just one target. At first, Gleevec seemed to be a very specific drug that affected the single mechanism of action behind CML. We thought Gleevec was a clean drug, but it turned out to be dirty.” Heinrich said. “Gleevec for CML was not an accident. Druker (Dr. Brian Druker) understood both the drug and the target. And because we knew how Gleevec worked, we made the step to GIST,” Heinrich said. “In the case of GIST, we are using a side effect of Gleevec to treat cancer.”

It is an interesting question whether or not a relatively clean drug like PTK787 that hits a few vital targets will be as effective as a dirty drug that strongly inhibits those vital targets and may or may not inhibit other important targets.

As presented by Dr. George Demetri, M.D., at a previous ASCO meeting, the ability of Sutent to overcome secondary resistance to Gleevec probably comes from two factors; its inhibition of additional kinases that may be important to GIST (perhaps especially VEGFRs) and its ability to inhibit the secondary mutations that can occur in exons 13 and 14 of the c-kit gene. Dr. Michael Heinrich updated the activity profile of Sutent at the 2006 ASCO conference and confirmed that Sutent has activity against the secondary mutations that occur in exons 13 and 14, but not against the exon 17 and exon 18 secondary mutations that were tested.

If the early impressive results of PTK787 continue to hold up with larger numbers of patients, it will be interesting to see the activity profile against the secondary mutations that are the primary cause of resistance to Glivec.

Note: At a more recent meeting, Norman Scherzer spoke to another investigator connected to the vatalanib trial who reported some concerns with side effects, although not necessarily toxic in nature. This is a very early trial and we need a lot more data to draw any reliable conclusions.