GIST Response to Targeted Gleevec or Sutent: Role of Genes

CHICAGO, Sept. 15 -- Gastrointestinal stromal tumor (GIST) can be a moving target, and genetic differences may predict whether the malignancy will respond to Gleevec (imatinib) or Sutent (sunitinib).

So reported an Oregon researcher, who found that response of GIST mutations to Sutent is the opposite of that seen when the tumor is treated with Gleevec, the first-line agent.

The finding opens up the possibility of treating GIST patients differently on the basis of the genetic make-up of their tumors, reported Michael Heinrich, M.D., of the Oregon Health and Science University at a meeting here on molecular diagnostics in cancer therapeutic development, organized by the American Association for Cancer Research.

"The theme here is personalized medicine," Dr. Heinrich said before his presentation. "By understanding rationally what's wrong with a tumor one could make predictions about response to therapy."

Dr. Heinrich said it's well-known that a mutation in exon 11 of the c-kit gene of a GIST - found in about two-thirds of patients at the time of diagnosis and initial surgery -- predicts a high response and a long duration of response.

Indeed, for patients in Gleevec clinical trials with such mutations, "at five years we still haven't hit the median time to progression," he said.

At the same time, a mutation in exon nine of the gene predicts a less favorable response, while the response to the wild-type gene is less favorable still, he said.

Dr. Heinrich reported here that Sutent shows the opposite response. "There's a very strong correlation for progression-free survival and overall survival, but it was inverted from what you would expect with Gleevec." he said.

In a study of 97 patients who had developed resistance to Gleevec, Dr. Heinrich reported:

• 36% of patients who had an exon 11c-kit mutation at the time of diagnosis but later developed resistance had a clinical benefit (defined as partial response or stable disease for more than six months) when they were treated with Sutent.
• 63% of patients with an initial exon nine mutation had a clinical benefit.
• 56% of those with wild-type c-kit at the time of diagnosis showed a clinical benefit.

The partial response rate for tumors with exon nine mutations was 37% versus 5% for exon 11 mutations, a difference that was significant at P=0.003.

Also, progression-free survival and overall survival were significantly longer for patients with either an exon nine mutation or wild-type c-kit, compared to those with an exon 11 mutation, Dr. Heinrich reported.

Clinically, the finding opens up the possibility of tailoring treatment to the individual patients, Dr. Heinrich said.

Currently, doctors treating patients with either an exon nine mutation or wild-type c-kit would tend to respond to Gleevec treatment failure by escalating the dose of the drug and eventually switch to Sutent.

But based on this new information, he said, "I would be more inclined to switch earlier."

On the other hand, he said, if the c-kit mutation was on exon 11, "I would be more inclined to hold on to imatinib longer."

One difficulty in using this genetic information, Dr. Heinrich said, is that genotyping of GIST at the time of diagnosis is not routine. "I think it will increasingly come standard," Dr. Heinrich said.

Sutent is produced by Pfizer. Two of the investigators in this study were employees of Pfizer Global Research and Development.