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

Surviving GIST: Connecting the Dots

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Surviving GIST: Connecting the Dots. Life Fest 2006 Norman Scherzer & Jerry Call. 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. - PowerPoint PPT Presentation

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Page 1: Surviving GIST: Connecting the Dots

Surviving GIST:Surviving GIST:Connecting the DotsConnecting the Dots

Life Fest 2006Life Fest 2006

Norman Scherzer & Jerry CallNorman Scherzer & Jerry Call

Page 2: Surviving GIST: Connecting the Dots

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.

Page 3: Surviving GIST: Connecting the Dots

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

Page 4: Surviving GIST: Connecting the Dots

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.

Page 5: Surviving GIST: Connecting the Dots

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

Page 6: Surviving GIST: Connecting the Dots

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.

Page 7: Surviving GIST: Connecting the Dots

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%)

Page 8: Surviving GIST: Connecting the Dots

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%)

Page 9: Surviving GIST: Connecting the Dots

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?

Page 10: Surviving GIST: Connecting the Dots

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.

Page 11: Surviving GIST: Connecting the Dots

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.

Page 12: Surviving GIST: Connecting the Dots

0%

5%

10%

15%

20%

25%

12--18 18--24 24--30 30--36 36--42

Time periods

Perc

en

t p

rog

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

Page 13: Surviving GIST: Connecting the Dots

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.

Page 14: Surviving GIST: Connecting the Dots

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

Page 15: Surviving GIST: Connecting the Dots

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

Page 16: Surviving GIST: Connecting the Dots

Higher Gleevec Dosage Level?Higher Gleevec Dosage Level?

Exon 11Maybe

Higher than 400 mg?

Wild-typeNo

Exon 9Yes!

Wait until progression occurs?

Page 17: Surviving GIST: Connecting the Dots

Wait for Progression to Cross-over?Wait for Progression to Cross-over?

Exon 11No???

Wait for progression to

cross-over?

Wild-typeYes??

Exon 9No!

Page 18: Surviving GIST: Connecting the Dots

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

Page 19: Surviving GIST: Connecting the Dots

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

Page 20: Surviving GIST: Connecting the Dots

Adjuvant Treatment?Adjuvant Treatment?

Pros & Cons

Consider Adjuvant Treatment

If anxiety level is

high

Is mutational status known?

If risk of recurrence is high?

Page 21: Surviving GIST: Connecting the Dots

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?

Page 22: Surviving GIST: Connecting the Dots

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

Page 23: Surviving GIST: Connecting the Dots

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

Page 24: Surviving GIST: Connecting the Dots

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:

Page 25: Surviving GIST: Connecting the Dots

Metastatic DiseaseMetastatic Disease

Page 26: Surviving GIST: Connecting the Dots

Surgery for mets?Surgery for mets?

Responding patients(Stable)

Widespread progression

Local progression

Maybe

Yes! Perhaps followed by

a dose increase

Probably Not

Page 27: Surviving GIST: Connecting the Dots

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

Page 28: Surviving GIST: Connecting the Dots

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?

Page 29: Surviving GIST: Connecting the Dots

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

Page 30: Surviving GIST: Connecting the Dots

Predicting drug response

Adjuvanttreatment

Drug selectionat resistance

Trialselection

Initial drugselection

Dose selection

Mutationaltesting

The Case for Mutational TestingThe Case for Mutational Testing