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BMS Gleevec Successor Shines at AACR; PGx Role Not Fully Clear, Yet Promising


WASHINGTON, DC — Bristol-Myers Squibb's dasatinib seems to be moving to succeed the pharmacogenomic drug Gleevec for two kinds of leukemia, according to data presented at the American Association for Cancer Research meeting, held here this week.

"Now for the first time, we have genotype datasets on a large number of patients" enrolled in a phase-II dasatinib trial, Charles Sawyers, an investigator at the Howard Hughes Medical Institute and a professor of medicine in the University of California, Los Angeles' department of hematology and oncology, said during his presentation on dasatinib data.

Genotyping data from the trial might be able to demonstrate how molecular diagnostics can guide treatment. Dasatinib, also known as BMS-354825, previously showed promising phase-I and -II results in Gleevec-resistant and -intolerant patients with chronic myelogenous leukemia and Philadelphia-chromosome positive amyotrophic lateral leukemia. Both drugs are protein kinase inhibitors.

There is currently no drug to take Gleevec's place for resistant patients, who are generally put on hormonal therapy.

A primary mutation that fuses the genes Bcr and Abl, called a Philadelphia chromosome, is the cause of CML and certain types of ALL and other leukemias. Gleevec and dasatinib attack the fusion protein to halt uncontrolled white blood-cell proliferation.

"Up to now, we have been treating mutations blindly with inhibitors … what we have to do from now on is to genotype these tumors and try to decide who gets what."

However, both compounds can be rendered useless by certain tumor-cell mutations, and last month, the US Food and Drug Administration granted dasatinib priority review for use in CML patients who are either refractory or sensitive to prior therapy with Gleevec. The FDA has until June 28 to take action on the compound.

Dasatinib is one of a few compounds designed to circumvent the mutations that can render CML cells resistant to Gleevec. Research on dasatinib may continue to reveal new mutations associated with resistance or intolerance to both dasatinib and Gleevec.UCLA owns the patents associated with the approximately 35 amino acid substitutions in the gene Bcr/Abl that can cause CML cells to become resistant to Gleevec. One of these mutations, known as T315I, can also cause resistance to dasatinib.

Of the 481 Gleevec-resistant or -sensitive patients that have been followed for about six months in the phase-II dasatinib study, 437 have been analyzed for mutation status, said Sawyers. Of those, 211 had developed mutations known to be responsible for resistance to Gleevec, and in that group, 19 had developed the T315I mutation, he said.

But other previously unknown genetic and cellular factors can also affect response to these compounds. "Even in patients who have genotypes that we predict would respond, there are some caveats-advanced stage patients don't always respond," Sawyers said during a press briefing. "I think what we'll do is incorporate genotyping into managing these patients."

Genzyme Genetics and Quest Diagnostics are laying claim to many of the diagnostic possibilities related to CML so far. In February, Genzyme launched a Bcr/Abl secondary-mutation diagnostic-which it offers at its CLIA laboratory-aimed at identifying patients whose CML cells had developed resistance to Gleevec. Meantime, Quest launched a similar assay last week as part of its Leumeta family of diagnostics.

UCLA awarded Genzyme an exclusive license for the mutations linked to Gleevec resistance, including T315I, and the firm has not sublicensed that property, according to a Genzyme spokesperson.

Quest did not respond to requests for information about its secondary mutation test in time for this publication.

Like many other laboratories, Genzyme and Quest also offer a test for the primary Bcr/Abl Philadelphia chromosome mutation. For example, Genzyme performs "thousands" of monitoring tests every year, marketing director Celeste Chenet-Monte told Pharmacogenomics Reporter in February. Quest almost certainly performs more.

"An issue that is of increasing importance is the possibility of combining several agents," said José Beselga, chief of medical oncology service and professor of medicine at the Vall d'Hebron University Hospital in Barcelona, Spain, during the AACR press briefing. Data shows that combining two or more protein kinase inhibitors results in fewer mutations and lower cell variety in cell-culture experiments, and thus less chance of drug resistance, he said.

Combination therapy with Gleevec and dasatinib, for example, might decrease somewhat the importance of secondary mutations that render tumor cells resistant to Gleevec. "I would predict that you would need to do only T315I [testing], but what came out of this analysis … is that by having 400-plus patients, is that there is another mutation, G250E," which confers sensitivity to dasatinib in cell culture, but confers resistance to dasatinib in CML patients in blast crisis, Sawyers told Pharmacogenomics Reporter. "There were only 10 patients who had that mutation in blast crisis, but that's a lot more than any other study has ever seen, and only one [of these] has responded" to dasatinib, he said.

Sawyers speculated that other genetic factors may be responsible for G250E-related dasatinib resistance. "It's not because dasatinib doesn't inhibit the Bcr/Abl enzyme, because it looks like it does — it's more that there's some other genetic region that modifies how the cell lives or dies based on Bcr/Abl inhibition," he said. "But it's a solvable problem."

A clinical trial of Gleevec-dasatinib combination therapy is now getting under way, said Sawyers.

As additional protein-kinase inhibitors are developed, they will probably each have specific strengths and weaknesses. "There is [a] need to develop kinase inhibitors that deal with T315I, [which confers resistance] to all drugs currently known, Beselga said. The compound BIRB-796, developed by Boehringer Ingelheim, appears to inhibit that mutation's effects, he said.

The next most-promising compound targeted at Bcr/Abl is Novartis' AMN-107, and several others are under development. "In every single disease type that we have these new solutions, the issue of genotyping becomes extremely important," said Beselga. "Up to now, we have been treating mutations blindly with inhibitors … what we have to do from now on is to genotype these tumors and try to decide who gets what."

— Chris Womack ([email protected])

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