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October 2009

It’s time to consider mutational status for resistant GIST patients: PDGFRA Mutations

This is the second article in a series discussing mutational status and resistant GIST. In the last article we began with a brief overview and wild-type GIST. In this article we focus on PDGFRA mutations with an emphasis on the imatinibresistant D842V mutation.

Mutations in the KIT and PDGFRA gene are the most frequent genetic event that drives the biology of GIST tumors. Targeting these defects remains the primary drug therapy for GIST. While KIT mutations are much more common, PDGFRA mutations still represent a significant percentage of GISTs. Approximately two-thirds of PDGFRA mutations are insensitive to Gleevec. This makes the management of patients with PDGFRA mutations more complex than those with KIT mutations.

In 2005, Drs. Christopher Corless, Michael Heinrich and colleagues reported on the PDGFRA mutational status of 1,105 GIST tumors. In this group, 80 tumors (7.2%) were found to have a PDGFRA mutation. The most common PDGFRA mutation was one that occurs in exon 18, a D842V mutation. D842V mutations are insensitive to Gleevec and Sutent, the two currently approved drugs for GIST.

Patients that are resistant to both Gleevec and Sutent may elect to participate in clinical trials. Many patients (at least in the United States) will try offlabel treatment with drugs that are approved for other cancers but not for GIST. The two approved KIT inhibitors (other than Gleevec and Sutent) that are the most advanced in trials for GIST are nilotinib (Tasigna) and sorafenib (Nexavar) and patients will often try one of these two drugs after failing Gleevec and Sutent. Both nilotinib and sorafenib, however, have shown limited effectiveness against the D842V mutation in the laboratory.

In 2008, Dr. Maria Debiec-Rychter of the Catholic University of Leuven, Belgium and her colleagues identified two drugs that inhibit the PDGFRA D842V mutation and represent possible treatments for patients with this mutation. Barbara Dewaele was the first author of the paper which was published in Clinical Cancer Research.

The Leuven team found that dasatinib and IPI-504 were both effective inhibitors of PDGFRAD842V mutations in laboratory experiments. These experiments included tests against Ba/F3 cells (cells engineered to test specific mutations) and actual tumor cells taken from a patient with the PDGFRAD842V mutation.

Dasatinib has been extremely effective for Gleevec-resistant chronic myelogenous leukemia (CML) and it is approved for that purpose in the United States and some other countries. Dasatinib is manufactured by Bristol-Myers Squibb and the trade name in America is Sprycel; while in trials, it is/was called BMS- 354825.

After a slow start in phase I trials that included 18 GIST patients, there is some renewed interest in dasatinib for GIST, at least in some unexplored populations, such as the open phase II trial in Switzerland for GIST patients that have never had Gleevec (first-line treatment or “Gleevec-naïve”). Gleevec-resistant GIST patients are also eligible for a phase II trial of dasatinib in advanced sarcomas in the United States.

IPI-504 also effectively inhibited the PDGFRAD842V mutation in the lab by a different mechanism than dasatinib. While dasatinib blocks the PDGFRA signal without damaging the PDGFRA protein, IPI-504 treatment results in the destruction of the PDGFRA protein. IPI- 504 is an HSP90 inhibitor that was in phase III trials for GIST. This trial was terminated in April of 2009 because of a higher than anticipated mortality rate for patients receiving IPI-504. It remains to be seen whether other HSP90 inhibitors in trials will be effective in GIST in general or the D842V mutation in particular.

Several other drugs have also shown some activity in the lab against the D842V mutation or the closely related D816V mutation in KIT. Given the similarity between these two mutations one could speculate that a drug that inhibits one mutation would have a good chance of inhibiting the other. In fact, this has been demonstrated with dasatinib which was shown to inhibit the KIT D816V mutation in 2006 (Shah et al) and PDGFRA D842V in 2008 (Dewaele et al).

Some other drugs that have shown in -vitro activity against the D842V or the KIT D816V mutation and are still in clinical trials are:

• MP470 (in phase I trials) – active against D842V
• PKC412 (in phase II trials) – active against D842V
• MLN518 (in phase II trials) – has shown activity against D816V mutation.

Drugs that have shown in-vitro activity against the D816V or D842V mutation but appear to have been withdrawn from development include:

• AP23464
• AP23848
• XL820 (Trials terminated in GIST)

The last few paragraphs illustrate both the promise and the perils of in-vitro testing. It is important to note that only twenty percent of drugs that enter into clinical trials will be approved. They may have unacceptable toxicity, limited effectiveness, or they may be directed against a target that turns out to be less important than it was thought to be.

However, for patients with a D842V mutation entering a clinical trial, in-vitro testing may prove to be the best available determining factor in choosing a drug treatment.

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