Surviving GIST:Surviving GIST:Connecting the DotsConnecting the Dots
Life Fest 2006Life Fest 2006
Norman Scherzer & Jerry CallNorman Scherzer & Jerry Call
Disclaimer!Disclaimer!
Jerry Call and Norman Scherzer are not Jerry Call and Norman Scherzer are not physiciansphysicians
This presentation, and the opinions given, This presentation, and the opinions given, are intended to help patients discuss their are intended to help patients discuss their care with their physicians.care with their physicians.
Nothing we present is intended to be a Nothing we present is intended to be a substitute for discussion with your substitute for discussion with your physician.physician.
Connecting the DotsConnecting the DotsSurvival Decision MakingSurvival Decision Making
Consensus Medicine: What do the experts Consensus Medicine: What do the experts agree upon? Consensus vs. Excellenceagree upon? Consensus vs. Excellence
Waiting for the data: We are still waiting for the Waiting for the data: We are still waiting for the U.S. and European Phase lll GIST data to be U.S. and European Phase lll GIST data to be combined. combined.
Survival Decision Making: Connecting the Dots Survival Decision Making: Connecting the Dots To Survive In the InterimTo Survive In the Interim
GenotypeGenotype
The genotype is the specific genetic makeup of The genotype is the specific genetic makeup of an individual, in the form of DNA. Typically, one an individual, in the form of DNA. Typically, one refers to an individual's genotype with regard to refers to an individual's genotype with regard to a particular gene of interest.a particular gene of interest.
In GIST, it is typically used to describe the In GIST, it is typically used to describe the common mutations that occur in the KIT and common mutations that occur in the KIT and PDGFRA genes-usually to the level of the PDGFRA genes-usually to the level of the affected exon, e.g., KIT exon 11.affected exon, e.g., KIT exon 11.
Know your MutationKnow your Mutation
Mutational data can be used to:Mutational data can be used to:
Determine Gleevec dose levelsDetermine Gleevec dose levels Predict response to GleevecPredict response to Gleevec Predict response to SutentPredict response to Sutent Generate hypotheses about adjuvant Generate hypotheses about adjuvant
treatment with Gleevectreatment with Gleevec Help evaluate new drugsHelp evaluate new drugs
PFS = Progression Free SurvivalPFS = Progression Free Survival
We will be using the term PFS to help We will be using the term PFS to help understand the effectiveness of treatments.understand the effectiveness of treatments.
PFS means Progression Free Survival, the length of PFS means Progression Free Survival, the length of time a patient remains alive and free of disease time a patient remains alive and free of disease oror stable-i.e...., minimal growth of existent tumors and no stable-i.e...., minimal growth of existent tumors and no new tumors.new tumors.
When comparing groups, the term median PFS When comparing groups, the term median PFS is often used. is often used. Example: A median PFS of 12 months means that Example: A median PFS of 12 months means that
half of the patients had a PFS of over 12 months and half of the patients had a PFS of over 12 months and half had less than 12 months PFS. half had less than 12 months PFS.
Exon 11Exon 11
Best response to GleevecBest response to Gleevec Appears to be a 4 to 5 month PFS Appears to be a 4 to 5 month PFS
advantage at high doses of Gleevecadvantage at high doses of Gleevec The PFS advantage of high-dose Gleevec The PFS advantage of high-dose Gleevec
may equal that of Sutent (about 5 months)may equal that of Sutent (about 5 months) About 1/3 of exon 11 patients respond to About 1/3 of exon 11 patients respond to
Sutent (with at least 6 months stability)Sutent (with at least 6 months stability) High rate of secondary mutations upon High rate of secondary mutations upon
resistance (62%)resistance (62%)
Exon 9Exon 9
Low-dose Gleevec = 4 months median PFSLow-dose Gleevec = 4 months median PFS High-dose Gleevec = 19.5 months PFSHigh-dose Gleevec = 19.5 months PFS Should any exon 9 patient be on low-dose Should any exon 9 patient be on low-dose
Gleevec? Avoid low-dose for adjuvant?Gleevec? Avoid low-dose for adjuvant? Excellent response to Sutent = 19.5 months PFS Excellent response to Sutent = 19.5 months PFS
after progression on Gleevec; 63% to 80% after progression on Gleevec; 63% to 80% benefit ratebenefit rate
Lower rate of secondary mutations upon Lower rate of secondary mutations upon resistance (16%)resistance (16%)
PDGFRAPDGFRA
Exon 18, D842V mutationExon 18, D842V mutation Insensitive to Gleevec and SutentInsensitive to Gleevec and Sutent Poor candidate for adjuvant therapy?Poor candidate for adjuvant therapy? Other exon 18 mutations are less frequent Other exon 18 mutations are less frequent
and their response to drugs is unknownand their response to drugs is unknown Exon 12Exon 12
Sensitive to Gleevec; little other dataSensitive to Gleevec; little other data Similar to exon 11 KIT mutations?Similar to exon 11 KIT mutations?
PFS Differs by Genotype and DosePFS Differs by Genotype and Dose
400 mg400 mg 800 mg800 mg
All phase III patientsAll phase III patients 21 months21 months 25 months25 months
All types (377 pts)All types (377 pts) 21.5 months21.5 months 24 months24 months
Exon 11 (248 pts)Exon 11 (248 pts) 25 months25 months 29 months29 months
Exon 9 (58 pts)Exon 9 (58 pts) 4 months4 months 19.5 months19.5 months
Wild-type (52 pts)Wild-type (52 pts) 19 months19 months 15.5 months15.5 months
Median PFS times were estimated by J. Call from Kaplan-Meier curves (EORTC data). Estimates are Median PFS times were estimated by J. Call from Kaplan-Meier curves (EORTC data). Estimates are rounded to 1/2 month.rounded to 1/2 month.
NOTE: This type of analysis is not as accurate as examining the numbers.NOTE: This type of analysis is not as accurate as examining the numbers.
EORTC phase III trialEORTC phase III trial
Strong pointsStrong points Randomized trialRandomized trial Mutational dataMutational data Large trialLarge trial
Weak pointsWeak points Fails to account for improvement in side effects over time.Fails to account for improvement in side effects over time. 60% of high-dose pts had a dose reduction, but are counted 60% of high-dose pts had a dose reduction, but are counted
in the high-dose arm.in the high-dose arm. The effect is a dilution of the data to show the The effect is a dilution of the data to show the
minimumminimum likely benefit of the high dose arm. likely benefit of the high dose arm.
0%
5%
10%
15%
20%
25%
12--18 18--24 24--30 30--36 36--42
Time periods
Perc
en
t p
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res
sin
g in
ea
ch
6 m
on
th p
eri
od
Higher Dosage ≥ 600
Lower Dosage< 600
Progression rates were relatively consistent in five six month time periods starting with month 12, although the fifth period (36 – 42 months) numbers are small. This brings us 42 months out from day one.On average, the progression rate in 6 month periods was almost twice as high in the lower dose group (19%), compared to the higher dose group (10%).
LRG Data-Progression rates over 6 month time LRG Data-Progression rates over 6 month time periods-analysis by actual doseperiods-analysis by actual dose
LRG DataLRG Data
Strong pointsStrong points Looked at actual dose as well as intent-to-treat Looked at actual dose as well as intent-to-treat
dosedose Weak pointsWeak points
Non-randomized; may introduce biasNon-randomized; may introduce bias Subjective progression criteria with no Subjective progression criteria with no
independent review (patient reported data)independent review (patient reported data) The effect is that this study may show the The effect is that this study may show the
maximummaximum possible benefit for high doses. possible benefit for high doses.
Drug Levels Fall over TimeDrug Levels Fall over Time
Gleevec levels may drop 30% to 40% Gleevec levels may drop 30% to 40% within one yearwithin one year
At least 3 different explanationsAt least 3 different explanations Increased drug clearanceIncreased drug clearance Decreased drug transport across the intestinal Decreased drug transport across the intestinal
barrierbarrier Decreased patient adherenceDecreased patient adherence
Side effects managementSide effects management Dose escalation strategiesDose escalation strategies
Implications of Falling Drug LevelsImplications of Falling Drug Levels
Patients on lower doses Patients on lower doses maymay be more at be more at risk for progressionrisk for progression
Starting at a lower dose and increasing the Starting at a lower dose and increasing the dose over time dose over time maymay restore drug levels restore drug levels
If we had routine drug-level testing dosage If we had routine drug-level testing dosage could be adjusted (whatever the cause)could be adjusted (whatever the cause) Better at following a patient over timeBetter at following a patient over time Requires expertise to evaluate a single test Requires expertise to evaluate a single test
resultresult
Higher Gleevec Dosage Level?Higher Gleevec Dosage Level?
Exon 11Maybe
Higher than 400 mg?
Wild-typeNo
Exon 9Yes!
Wait until progression occurs?
Wait for Progression to Cross-over?Wait for Progression to Cross-over?
Exon 11No???
Wait for progression to
cross-over?
Wild-typeYes??
Exon 9No!
Managing Higher Gleevec DosageManaging Higher Gleevec Dosage
Side effects are
worse at higher dosage
Side effects get
better over time
Start at 400 mg and
phase up to higher dose
Primary DiseasePrimary Disease
Know your riskOf recurrence
SurgeryPreferred treatment
Neoadjuvant Gleevec Adjuvant Gleevec•If it will make surgery easier
•Monitor closely for nonresponders
•Unknown benefit•Some hypotheses can be generated•Questionable for low-risk tumors•Know your genotype•Low-dose Gleevec unlikely to benefit exon 9 patients; could it promote resistance?
•Size•Mitotic rate•Other factors
•Clear margins at surgery•Tumor rupture
Adjuvant Treatment?Adjuvant Treatment?
Pros & Cons
Consider Adjuvant Treatment
If anxiety level is
high
Is mutational status known?
If risk of recurrence is high?
Pros & Cons of Adjuvant TreatmentPros & Cons of Adjuvant Treatment
Does It Prevent Does It Prevent Recurrence?Recurrence?
We Do Not KnowWe Do Not Know
Outstanding Clinical Trials: Limited to Outstanding Clinical Trials: Limited to evaluating 400mg of Gleevec for one year and evaluating 400mg of Gleevec for one year and three years but not higher dosage..three years but not higher dosage..
Does It Produce Resistance?Does It Produce Resistance?
We Do Not KnowWe Do Not Know More of a concern for Exon 9 More of a concern for Exon 9
patients treated with low-patients treated with low-dose Gleevec?dose Gleevec?
Know your Risk of RecurrenceKnow your Risk of Recurrence
Other FactorsOther Factors Clear marginsClear margins Tumor ruptureTumor rupture Small bowel Small bowel
may be more may be more aggressiveaggressive
Defining RiskDefining Risk
RiskRisk SizeSize Mitotic CountMitotic Count
Very lowVery low <2cm<2cm <5/50 HPF<5/50 HPF
Low Low 2-5cm2-5cm >5/50 HPF>5/50 HPF
IntermediateIntermediate >5cm>5cm 6-10/50 HPF6-10/50 HPF
5-10cm5-10cm <5/50 HPF<5/50 HPF
HighHigh >5cm>5cm >5/50 HPF>5/50 HPF
>10cm>10cm Any rateAny rate
Any sizeAny size >10/50 HPF>10/50 HPF
Caution: See the LRG website for additional explanatory material that goes with this table.
Recent papers by Miettinen provide better risk assessment, especially for gastric GISTs
Suggested Guidelines for Assessing the Malignant Potential Suggested Guidelines for Assessing the Malignant Potential of of Gastric GISTsGastric GISTs of Different Sizes and Mitotic Activity* of Different Sizes and Mitotic Activity*
Benign Benign (no tumor-related mortality detected)
Group 1 (no larger than 2 cm, no more than 5 mitoses/50 HPF)
Probably benignProbably benign (very low malignant potential, <3% PD)
Group 2 (>2 ≤5 cm, no more than 5 mitoses/50 HPF)Group 3a (>5 ≤10 cm, no more than 5 mitoses/50 HPF)
Uncertain or low malignant potentialUncertain or low malignant potential (no PDs but too few cases to reliably
determine prognosis)
Group 4 (no larger than 2 cm, >5 mitoses/50 HPF)
Low to moderate malignant potential Low to moderate malignant potential (12–15% tumor-related mortality)
Group 3b (>10 cm, no more than 5 mitoses/50 HPF)Group 5 (>2 ≤5 cm, >5 mitoses/50 HPF)
High malignant potential High malignant potential (49%–86% tumor-related mortality)
Group 6a (>5 cm ≤10 cm, >5 mitoses/50 HPF)
Group 6b (>10 cm, >5 mitoses/50 HPF)
*Miettinen et al, *Miettinen et al, Gastrointestinal Stromal Tumors of the Stomach. A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 1765 Cases With Long-term Follow-up
Can we Predict Adjuvant Gleevec Can we Predict Adjuvant Gleevec Benefit?Benefit?
Most likely to benefitMost likely to benefit High-risk patients withHigh-risk patients with
Exon 11 mutationsExon 11 mutations Exon 9 patientsExon 9 patients
• On high-dose GleevecOn high-dose GleevecOROR
• On Sutent ?On Sutent ?
Least likely to benefitLeast likely to benefit Low-risk patientsLow-risk patients High-risk patients withHigh-risk patients with
Exon 9 mutations while Exon 9 mutations while taking low-dose Gleevectaking low-dose Gleevec
Non-responsive mutationsNon-responsive mutations• PDGFRA D842APDGFRA D842A• Distal exon 11?Distal exon 11?
Wild-type GIST?Wild-type GIST?
No, but we can generate some hypotheses:No, but we can generate some hypotheses:
Metastatic DiseaseMetastatic Disease
Surgery for mets?Surgery for mets?
Responding patients(Stable)
Widespread progression
Local progression
Maybe
Yes! Perhaps followed by
a dose increase
Probably Not
Exon 11-MetastaticExon 11-Metastatic
Best responseto Gleevec
Dose-benefitFrom high-dose
controversial Low-dosePts w/
•Side-effect issues•Good adherence•Accept more risk
High-dosePts w/
•Less side effects•Accept less risk
Side effects
Wider therapeutic
range
PFS
Exon 9-MetastaticExon 9-Metastatic
Intermediate initialResponse to Gleevec
Large benefit fromHigh-dose Gleevec
Low-dose•Low response rate
•4 months median PFS
High-dose•8 times more likely to
have a response•20 months median PFS•Quick dose escalation?
Sutent63% to 80%Benefit after
IM progression
Should exon 9 patients take low-dose Gleevec?
Choosing a Clinical TrialChoosing a Clinical Trial
What Is Available?What Is Available? At this institutionAt this institution LocallyLocally NationallyNationally InternationallyInternationally
What Do We Know Now About Each What Do We Know Now About Each Drug?Drug?
Navigating a Phase l Clinical Trial-Timing Navigating a Phase l Clinical Trial-Timing Can Be EverythingCan Be Everything
Predicting drug response
Adjuvanttreatment
Drug selectionat resistance
Trialselection
Initial drugselection
Dose selection
Mutationaltesting
The Case for Mutational TestingThe Case for Mutational Testing