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Regorafenib Appears to Work on All Common Resistance Mutations in GIST

Tuma, Rabiya S. PhD

doi: 10.1097/01.COT.0000430981.08056.a6


WASHINGTON—The U.S. Food and Drug Administration approved the use of regorafenib in February for the treatment of patients with gastrointestinal stromal tumors (GIST) that have progressed on imatinib and sunitinib. Regulatory approval was based on data from the Phase III GRID study which showed a 73 percent reduction in risk of progression in patients receiving regorafenib compared with placebo.

Now, results of a preplanned biomarker analysis indicate that regorafenib is active against all resistance mutations identified, researchers reported here at the American Association for Cancer Research Annual Meeting (Abstract LB-295 ).



“We couldn't find a group of patients who didn't respond to this drug,” said George D. Demetri, MD, Director of the Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School.

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New Technology Uses Circulating Tumor DNA

Although the tyrosine kinase inhibitors imatinib and sunitinib have greatly changed the prognosis for patients with metastatic GIST, most tumors eventually develop new mutations that allow them to escape the drugs. The secondary resistance mutations usually occur in the original driver gene, KIT or PDGFR.



While clinicians and researchers can use tumor biopsies to identify the resistance mutation, the technique is not ideal. Not only is it invasive, but it may also miss mutations due to heterogeneity within the tumor itself. Therefore, as Demetri explained, he and his colleagues wanted to test whether circulating tumor DNA could be used to identify resistance mutations.

The team used “BEAMing” (Beads, Emulsification, Amplification, and Magnetics) technology to isolate and characterize the DNA, mixing patient serum with magnetic beads coated with polymerase chain reaction primers designed to pick up specific known mutations. The samples are amplified, labeled with a fluorescent probe, and then analyzed using magnetic flow through a detector. Prior studies indicate that the technology can identify one mutant allele in 10,000 normal alleles.

Looking first at archival tumor samples to analyze the primary mutation in patient tumors, the researchers identified primary KIT mutations (exon 9 or 11) in 61 percent of the 102 samples available. By contrast, BEAMing technology identified mutations in only 17 percent of the 163 samples available.

Demetri notes that this low success rate highlights a key aspect of the BEAMing technology: It is very good at finding things when the primers are optimized, but if the primers are not optimized (as in the case of the primary mutations), then the technology is not nearly as powerful.

However, when the team looked for secondary resistance mutations (for which the primers were optimized), the serum samples proved to be more useful. The BEAMing technology uncovered secondary mutations in 47 percent of the samples, compared with 12 percent found in the tumor tissue.

Where the team could compare the results of the two approaches, there was 84 percent concordance in primary mutations.

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No Resistance Groups Found for Regorafenib

More important for clinicians, though, is the observation that all groups of patients appeared to benefit from regorafenib, regardless of the resistance mutations in their tumor. “Virtually all of the mutational [groups] show essentially the same benefit with this new drug regorafenib,” Demetri said at an AACR news conference. “So we can say with some degree of confidence that there is no big resistance group based on mutation subset.

“There is no group of patients who shouldn't at least try this drug,” he reiterated.

The moderator of the news conference, Giuseppe Giaccone, MD, PhD, Associate Director for Clinical Research at Georgetown Lombardi Comprehensive Cancer Center, said, “I think that the BEAMing technology is something that probably is going to be applied more and more to study patients who are developing resistance in a relatively simple way.

“One thing we will have to be careful about, though, is that heterogeneity in these tumors is a reality,” he continued. “So what you pick up in the blood may not tell you everything that is happening in the tumor. We will have to do multiple studies, serial studies, and potentially also take biopsies from these patients to understand what is happening in the blood and in the tumor.”

For his part, Demetri added another caution: “Our patients had kilograms of tumor. One of the questions is, how sensitive is this [technology] in a patient who has subclinical micrometastatic disease? We don't know. But that is why we do research. We are very excited about this type of technology in general.”

The GRID research team will present more detailed information on the mutation analysis and outcomes data at the ASCO Annual Meeting, Demetri told OT. But already the data look promising for patients. “Ultimately what we learned from this is that regorafenib is a much better, much different drug than we expected it to be.”

© 2013 Lippincott Williams & Wilkins, Inc.
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