GIST and Gleevec: 5 years of progress

GIST has been around since 1983, but therapy didn’t arrive till 1999

By Jerry Call

While the term “GIST” was first used in 1983, the interesting parts of the GIST story begin in 1998. That was the year that a Japanese pathologist, Dr. Seiichi Hirota, found that GISTs often contain mutations in a gene called “c-kit”. The c-kit gene contains a “blueprint” for assembling a protein known as “KIT.”  This protein is a receptor which transmits survival and proliferation signals to cells. Hirota also found that in most GISTs, the KIT protein was “constitutively activated”, meaning it was always “stuck” in the on position, continuously signaling GIST tumors to survive and grow.

The second major part of the GIST story starts in the early 1990s, but does not start to become clear until 2000. Novartis scientists including Nicholas Lydon, Alex Matter, Elizabeth Buchdunger, Juerg Zimmermann and others had developed a new kind of drug called a “tyrosine kinase inhibitor.” They had developed this drug to inhibit a receptor known as PDGFR. This drug was to prove to be amazingly successful.

Meanwhile, Dr. Brian Druker of Oregon Health Science University (OHSU) had been doing research on a type of leukemia known as chronic myelogenous leukemia (CML). He knew that CML seemed to be caused by a defective protein called bcr/abl. Druker approached Lydon and asked if he had any inhibitors that he could test against the bcr/abl protein. Lydon responded by supplying several inhibitors including one called STI571. This drug proved to work extremely well against the bcr/abl protein. Several years later, clinical trials for CML started. Of course, the drug proved to be a major step forward for CML, but the STI571 story was not over yet.

The idea that STI571 might be used to inhibit KIT in GISTs was substantiated in 1999 in essentially simultaneous experiments at OHSU (Dr. Michael Heinrich) and the Brigham & Women’s Hospital  in Boston (Dr. Jonathan Fletcher). Heinrich showed that STI571 could block the activity of mutant forms of KIT in the test tube, while Fletcher found that STI571 shut down the growth of GIST cells grown in a petri dish.

In March 2000, STI571 was tried in a single GIST patient and seemed to halt progression of his/her disease. Phase I and phase II GIST trials were started in July of 2000.

The phase II GIST/Gleevec trial proved to be so successful that it was quickly expanded to include a total of 147 patients at three trial sites. Doctors and nurses were clearly excited about the results they were seeing in early patients, and omitted their typical cautious statements given during clinical trials.

Word quickly spread via the internet and among the sarcoma community that there was a new drug in trials for GIST and that, contrary to previous therapies, it seemed to be working very well. Patients with abdominal leiomyosarcoma were urged to have their pathology slides tested for c-kit, as a positive c-kit test in these patients probably meant they actually had GIST instead of leiomyosarcoma. This knowledge did not spread to the general oncology world until Dr. Charles Blanke presented early results of the phase II trial at a plenary session of the American Society of Clinical Oncology (ASCO) meeting in May of 2001. This marked the beginning of a period of time when many GIST patients were often better informed about treatment options than their local oncologists.

Within a few months of starting the phase II trials for GIST, sarcoma specialists and GIST patients both knew that something special was happening. In the United States and Canada, phase III trials were quickly organized by Dr. George Demetri and started in the record time of five weeks! A European phase III trial was also quickly organized and began accruing patients by February of 2001.

With no effective therapy prior to STI571, there was a large backlog of metastatic GIST patients in need of effective therapy. Since STI571 was not yet approved, the only way to get it was in the phase III trials. This introduced the GIST patient community to the world of clinical trials in an unprecedented way. Like most cancer patients, few GIST patients had ever participated in a clinical trial before. Now they were dependent on clinical trials for their survival. The extremely high participation rate for GIST patients in clinical trials continues to this day with several thousand patients having participated in one or more clinical trials.

In May 2001, STI571 was approved in the United States for CML patients and, in February 2002, for GIST patients with inoperable or metastatic disease. Approval in other countries soon followed. It received a few new names, Gleevec in the U.S. and Glivec internationally. GIST had gone from a cancer that was notorious for its resistance to chemotherapy, to a cancer where taking a few pills every day provided substantial benefit to about 85 percent of patients. These responses were longer lasting than most responses to standard types of cancer therapy.

During his 2001 ASCO presentation, Blanke presented information about the response rate of GIST tumors to Gleevec. He noted that GIST tumors having mutations in different parts of the gene (called exons) responded differently to Gleevec, with KIT exon 11 mutations responding the best, KIT exon 9 mutations having an intermediate response and GISTs with no KIT mutations (wild-type for KIT) responding the worst. The identification of exon mutations, called genotyping, was developed to a high degree of accuracy in the OHSU labs of Heinrich and Dr. Christopher Corless. This process moved from the lab to the clinic in early 2003.

By early 2003, Heinrich and Corless, along with Fletcher, had put together another piece of the GIST puzzle. They had found that some of the tumors that did not have c-kit mutations did have mutations in a closely related gene, PDGFRA. Almost simultaneously, this observation was confirmed by Hirota, who first discovered KIT mutations in GIST.

While Gleevec inhibits some of these mutations, the most common PDGFRA mutation, D842V, is resistant to Gleevec. The current estimates are that from 5 percent to 7 percent of GISTs have PDGFRA mutations. There are some data to suggest that these tumors are less aggressive than other GISTs, but this remains controversial.

Unfortunately, as with most types of chemotherapy, resistance to Gleevec eventually becomes a problem for most GIST patients. By two years after starting Gleevec, only about half of the patients are still responding to it.

Fletcher provided the first reports (that we are aware of) of why GIST tumors might become resistant to Gleevec at the 2003 ASCO meeting. These mechanisms of resistance were:

1. The acquisition of a new KIT or PDGFRA point mutation, superimposed on the baseline mutation in that gene.

2. Resistance by overexpression of the target protein (KIT).

3. Activation of an alternate receptor tyrosine kinase protein.

4. Functional resistance by KIT or PDGFRA activation, in the absence of a secondary genomic mutation, and with baseline KIT or PDGFRA mutations being outside the juxtamembrane hotspot regions.

There is a great deal of ongoing research to try to understand and overcome these mechanisms of resistance. Similar mechanisms of resistance have been reported in CML patients and in non small-cell lung cancer (NSCLC) patients taking a drug, Iressa, which is similar to Gleevec. This is one example of how GIST and CML are models for molecularly targeted therapy. Primary mutations were found in the target gene (EGFR) of Iressa sensitive tumors in NSCLC patients and secondary mutations caused resistance to Iressa—both were lessons learned from GIST and Gleevec.

By 2002, phase I trials had started for a new drug that would eventually prove to be effective for about 60 percent of GIST patients that became resistant to Gleevec. This new drug was called SU11248 and was developed by Sugen, one of the early leaders in the signal transduction field. To many patients this drug became known simply as “Sugen.” Sugen was purchased by Pharmacia which was then purchased by Pfizer. It was Pfizer that brought the drug to clinical trial. SU11248 is now known as “Sutent.”

In addition to being a powerful KIT and PDGFR inhibitor, Sutent also inhibits the VEGF receptors. These receptors are important for the growth of new blood vessels (angiogenesis) which are required for tumors to grow.

Sutent also appears to interact differently with the area where tyrosine kinase inhibitors like Gleevec and Sutent bind to the target protein. Mutations in different parts of the c-kit gene produce slightly different conformations of the KIT protein. A small difference in shape can make the difference between a drug being able to bind to the protein and not being able to bind to the protein. Sutent appears to be able to inhibit some types of mutations that Gleevec cannot inhibit.

The activity profile of Sutent appears to be somewhat different than Gleevec. Gleevec-resistant patients that go on to take Sutent and have KIT exon 9 mutations have the best chance of responding (in the Gleevec-resistant setting, most responses are stabilization of disease), while patients with exon 11 mutations have a significantly lower chance of responding. Patients that are wild-type for KIT and PDGFRA have an intermediate response rate.

After showing clear activity in Gleevec-resistant patients in the phase I trial, the Sutent trials expanded to include phase II and phase III trials. The phase III trials were controversial because of the use of a placebo.

By early 2005, the data monitoring board for the phase III Sutent trial had concluded that the drug had met its efficacy endpoints and that the trial could stop seven months early. In August of 2005, Pfizer submitted Sutent for governmental approval in the United States.

Sutent was not the only drug to be tested in resistant GIST. Early “targeted therapies” such as Herceptin for breast cancer proved to have moderate success. But it was the astonishing success of Gleevec in CML and GIST that really moved the field of molecularly targeted therapies into high gear. Buoyed by success, a new wave of enthusiasm swept through the world of oncology. This enthusiasm extended to the drug manufacturers who were eager to try their drugs using this new way of fighting cancer.

GIST represented a number of opportunities for testing new drugs. Most importantly perhaps, the primary target, KIT, was extremely well validated. Stop KIT signaling and you have an excellent chance of controlling GIST. This was true with new patients and most patients that were resistant to Gleevec.

Pfizer and Amgen were the first two drug companies to try their KIT inhibitors in Gleevec-resistant GISTs. The Amgen drug, AMG706, is in many ways similar to Sutent. They both inhibit KIT, PDGFR, and the VEGF receptors. One difference is that Sutent is given in a four week on, two week off schedule, while AMG706 is given continuously. A phase II trial is underway to see if patients can tolerate a lower dose of Sutent given continuously.

Amgen concentrated their initial phase II trial in Gleevec-resistant GIST. While we have anecdotal reports of some efficacy, we understand that formal results will not be presented until the 2006 ASCO meeting. We also understand that Amgen is planning a phase III trial to compare AMG706 to Gleevec as front-line therapy for GIST. This is expected to be a European trial.

One of the important innovations that Amgen used was to make the drug more widely available by having more trial sites. It is likely that this contributed to the rapid accrual of patients in their trial.

Combining Gleevec with other drugs represented another method to attack GIST tumors. Novartis, the maker of Gleevec, took the lead in this area. Their first two combinations included Gleevec + PKC412 and Gleevec + RAD001. PKC412 and RAD001 are also made by Novartis.

 PKC412 inhibits a number of targets including KIT, PDGFR, VEGF, FLT3, and several forms of protein kinase C (PKC). PKC412 has interesting in-vitro activity in a number of Gleevec-resistant mutations. Drug interactions between PKC412 and Gleevec have slowed this trial.

RAD001 is an mTOR inhibitor. Early reports from this trial indicate moderate success in Gleevec-resistant GIST. Some drug interaction issues have been resolved and it remains to be seen which type(s) of resistant patients this combination could help.

Another trial that combines Gleevec and Perifosine has recently started at M.D. Anderson Cancer Center in Houston, Texas. Perifosine inhibits AKT (and other targets), an important protein downstream from KIT. M.D. Anderson has been planning another combination trial with Gleevec and Genasense (a Bcl-2 inhibitor) but this trial has just gotten off the ground.

One method of overcoming Gleevec resistance is to design a Gleevec-like drug with a different shape so that it fits better into the binding pocket of the target protein. Two new drugs used this strategy for CML patients. BMS-354825 (Bristol-Myers Squibb) and AMN107 (Novartis) both proved to be very effective in Gleevec-resistant CML patients with response rates approaching 90 percent. These drugs were able to overcome almost all of the known secondary mutations that account for the majority of Gleevec-resistance in CML. The exception was one specific mutation, T315I. Other drugs are being tested against this mutation. BMS-354825 and AMN107 not only were active against secondary mutations, they also were many times more potent than Gleevec at inhibiting the bcr/abl protein.

BMS-354825 and AMN107 both inhibit bcr/abl, the protein responsible for CML, but they also inhibit KIT and PDGFRA, the proteins responsible for GIST, although neither drug appears to be as potent at inhibiting KIT as they are at inhibiting bcr/abl. Both of these drugs are in early trials for GIST: BMS-354825 as a single agent and AMN107 in combination with Gleevec. With the AMN107 + Gleevec combination, it is hoped that the two drugs will have a broad spectrum of activity against secondary mutations.

The latest drug to enter clinical trials for GIST is BAY 43-9006 or Nexavar. This drug has some similarities to Sutent and AMG706, but it adds another downstream target, RAF. It is in phase II trials at the University of Chicago and several other sites. There are a few anecdotal reports of responses in Gleevec-resistant GIST from previous sarcoma and solid-tumor trials. This drug won U.S. approval for treatment of renal cell cancer on December 21.

One of the newest strategies to treat resistant GIST is to try to bypass the problem of drug fit into multiple different types of mutations; in other words, to block KIT signaling by inhibiting a different protein that KIT is dependent on. This protein is HSP90, a protein that is required to stabilize KIT. Blocking HSP90 causes the mutated KIT protein to degrade and be destroyed by the cell. A new phase I trial testing IPI-504 should start very soon at Dana-Farber Cancer Institute in Boston. IPI-504 is a HSP90 inhibitor made by Infinity Pharmaceuticals.

In the summer of 2005, armed with a generous $2 million dollar start-up grant from Novartis, the Life Raft Group began strategic planning into GIST resistance research. This planning began with a core group of the most respected GIST researchers. The core group created an initial outline of projects and identified personnel that would form a larger research group.

The group recommended that the project be divided into two phases. In the first phase the research would be directed at high-priority research projects. The second phase would incorporate a more traditional research approach and be directed at developmental research projects. The second phase has not been funded at this time.

With the help of the entire GIST resistance research group, eight priority research areas were identified for adult GIST, with pediatric GIST forming the last priority area. In these priority areas there was an expectation that the research would quickly translate to the clinic.

The priority areas identified (in no particular order) included:

1. Oncogenic signaling mechanisms as novel therapeutic targets

2. KIT/PDGFRA wild-type GISTs

3. Primary resistance

4. Stable disease

5. Secondary resistance

6. KIT degradation

7. Murine (mouse) models

8. Resource development

9. Pediatric GIST

Six developmental research groups were identified. These areas were felt to have the same ultimate importance as the “priority” groups, but clinical translation might take longer. They were:

1. Pharmacology

2. KIT/PDGFRA antagonists

3. Genetic progression mechanisms

4. ICC/stem-cell biology

5. KIT synthesis

6. Maximizing therapeutic response

This new GIST resistance research project has researchers and patients working more closely together than ever before. It also requires the participating researchers to work very closely together and share their findings with each other on an ongoing basis.

It will be up to the GIST patient community to find a way to continue to fund the priority areas (the current funding is for two years) as well as to begin funding the developmental research areas that are currently not funded.