Surviving GIST: Connecting the Dots

1. Surviving GIST:Connecting the Dots Life Fest 2006 Norman Scherzer & Jerry Call

2. Disclaimer! Jerry Call and Norman Scherzer are not physicians This presentation, and the opinions given, are intended to help patients discuss their care with their physicians. Nothing we present is intended to be a substitute for discussion with your physician.

3. Connecting the DotsSurvival Decision Making Consensus Medicine: What do the experts agree upon? Consensus vs. Excellence Waiting for the data: We are still waiting for the U.S. and European Phase lll GIST data to be combined. Survival Decision Making: Connecting the Dots To Survive In the Interim

4. Genotype The genotype is the specific genetic makeup of an individual, in the form of DNA. Typically, one refers to an individual's genotype with regard to a particular gene of interest. In GIST, it is typically used to describe the common mutations that occur in the KIT and PDGFRA genes-usually to the level of the affected exon, e.g., KIT exon 11.

5. Know your Mutation Mutational data can be used to: Determine Gleevec dose levels Predict response to Gleevec Predict response to Sutent Generate hypotheses about adjuvant treatment with Gleevec Help evaluate new drugs

6. PFS = Progression Free Survival We will be using the term PFS to help understand the effectiveness of treatments. PFS means Progression Free Survival, the length of time a patient remains alive and free of disease or stable-i.e...., minimal growth of existent tumors and no new tumors. When comparing groups, the term median PFS is often used. Example: A median PFS of 12 months means that half of the patients had a PFS of over 12 months and half had less than 12 months PFS.

7. Exon 11 Best response to Gleevec Appears to be a 4 to 5 month PFS advantage at high doses of Gleevec The PFS advantage of high-dose Gleevec may equal that of Sutent (about 5 months) About 1/3 of exon 11 patients respond to Sutent (with at least 6 months stability) High rate of secondary mutations upon resistance (62%)

8. Exon 9 Low-dose Gleevec = 4 months median PFS High-dose Gleevec = 19.5 months PFS Should any exon 9 patient be on low-dose Gleevec? Avoid low-dose for adjuvant? Excellent response to Sutent = 19.5 months PFS after progression on Gleevec; 63% to 80% benefit rate Lower rate of secondary mutations upon resistance (16%)

9. PDGFRA Exon 18, D842V mutation Insensitive to Gleevec and Sutent Poor candidate for adjuvant therapy? Other exon 18 mutations are less frequent and their response to drugs is unknown Exon 12 Sensitive to Gleevec; little other data Similar to exon 11 KIT mutations?

11. EORTC phase III trial Strong points Randomized trial Mutational data Large trial Weak points Fails to account for improvement in side effects over time. 60% of high-dose pts had a dose reduction, but are counted in the high-dose arm. The effect is a dilution of the data to show the minimum likely benefit of the high dose arm.