Steady-State Plasma Imatinib Levels in 142 GIST Patients

Distribution, Dose, Dose Escalation, and Response

Steady-State Plasma Imatinib Levels in 142 GIST Patients

Distribution, Dose, Dose Escalation, and Response

Laura K Nolden1, Linyee Shum2, Amaury Dumont1, Shreyaskumar Patel1, Dejka M Araujo1, Joseph A Ludwig1, Vinod Ravi1, Suzanne George3, Saroj Vadhan-Raj1, Robert S Benjamin1, Jonathan C Trent1

1UT-MD Anderson Cancer Center, Department of Sarcoma Medical Oncology and the Sarcoma Research Center; Houston, Texas, United States; 2Avantix Laboratories, Inc., New Castle, Delaware, United States; 3Dana-Farber Cancer Institute, Center for Sarcoma and Bone Oncology, Boston, Massachusetts, United States

Laura K Nolden1, Linyee Shum2, Amaury Dumont1, Shreyaskumar Patel1, Dejka M Araujo1, Joseph A Ludwig1, Vinod Ravi1, Suzanne George3, Saroj Vadhan-Raj1, Robert S Benjamin1, Jonathan C Trent1

1UT-MD Anderson Cancer Center, Department of Sarcoma Medical Oncology and the Sarcoma Research Center; Houston, Texas, United States; 2Avantix Laboratories, Inc., New Castle, Delaware, United States; 3Dana-Farber Cancer Institute, Center for Sarcoma and Bone Oncology, Boston, Massachusetts, United States

BackgroundBackground

Several studies from patients with GIST and CML suggest a correlation between imatinib steady-state plasma trough levels and patient outcomes

Several studies from patients with GIST and CML suggest a correlation between imatinib steady-state plasma trough levels and patient outcomes

Demetri, G et al. J Clin Oncol; 2009Demetri, G et al. J Clin Oncol; 2009

Larson, RA et al. Blood; 2008Larson, RA et al. Blood; 2008

Picard, S et al. Blood; 2007Picard, S et al. Blood; 2007

RationaleRationale

Variability in imatinib plasma levels could occur for several reasons:• Gastrectomy

• Unadjusted dosing (weight, BSA)

• Race, gender, age

• Duration of therapy

• Concomitant medications

Variability in imatinib plasma levels could occur for several reasons:• Gastrectomy

• Unadjusted dosing (weight, BSA)

• Race, gender, age

• Duration of therapy

• Concomitant medications

Blanke CD et al. J Clin Oncol, 2008Blanke CD et al. J Clin Oncol, 2008

Judson I et al. Cancer Chemother Pharmacol. 2005Judson I et al. Cancer Chemother Pharmacol. 2005

ObjectivesObjectives

• To determine the distribution of plasma imatinib levels in patients with GIST

• To determine factors that correlate with plasma imatinib level

• To determine the incremental effects of imatinib dose escalation

• To explore the median plasma levels and outcomes of patients with KIT exon 9 mutation

• To determine the distribution of plasma imatinib levels in patients with GIST

• To determine factors that correlate with plasma imatinib level

• To determine the incremental effects of imatinib dose escalation

• To explore the median plasma levels and outcomes of patients with KIT exon 9 mutation

Patient Response AssessmentPatient Response Assessment• Response was assessed within the first 4 months of

imatinib exposure

• Response was classified according to Choi criteria:

– CR, no radiographic evidence of GIST

– PR, > 10% decrease in GIST size or > 15% decrease in GIST radiodensity

– SD, less than 10% decrease or increase in GIST size and does not meet criteria of PR by radiodensity

– PD, > 10% increase in GIST size

– ND, patient underwent resection and no response could be assessed

• Response was assessed within the first 4 months of imatinib exposure

• Response was classified according to Choi criteria:

– CR, no radiographic evidence of GIST

– PR, > 10% decrease in GIST size or > 15% decrease in GIST radiodensity

– SD, less than 10% decrease or increase in GIST size and does not meet criteria of PR by radiodensity

– PD, > 10% increase in GIST size

– ND, patient underwent resection and no response could be assessed

Plasma Imatinib Level DeterminationPlasma Imatinib Level Determination

• 5/2008 - 9/2009, observational, retrospective study

• 142 GIST patients underwent therapeutic drug monitoring at M.D. Anderson Cancer Center

• Plasma imatinib levels were determined using a validated liquid chromatography-tandem mass spectrometry assay by Avantix Laboratories, Newark, DE.

• The steady-state level of imatinib was calculated:

Adj-Cmin = Cmeasured*exp (0.041 Δt)

• 5/2008 - 9/2009, observational, retrospective study

• 142 GIST patients underwent therapeutic drug monitoring at M.D. Anderson Cancer Center

• Plasma imatinib levels were determined using a validated liquid chromatography-tandem mass spectrometry assay by Avantix Laboratories, Newark, DE.

• The steady-state level of imatinib was calculated:

Adj-Cmin = Cmeasured*exp (0.041 Δt)Wang Y et al. Ther Drug Monit; Oct 2009

Patient CharacteristicsPatient Characteristics

CharacteristicCharacteristic nn ( % )( % )

FemaleFemale 6565 ( 45.8 )( 45.8 )

MaleMale 7777 ( 54.2 )( 54.2 )

CaucasianCaucasian 118118 ( 83.1 )( 83.1 )

African AmericanAfrican American 1212 ( 8.5 )( 8.5 )

HispanicHispanic 77 ( 4.9 )( 4.9 )

AsianAsian 55 ( 3.5 )( 3.5 )

Mean (stdev)Mean (stdev) Median (range)Median (range)

Age at Diagnosis (yrs)Age at Diagnosis (yrs) 54.8 (12.5)54.8 (12.5) 55 (19, 87)55 (19, 87)

Mean BSAMean BSA 2.0 (0.3)2.0 (0.3) 2.0 (1.3, 2.8)2.0 (1.3, 2.8)

Tumor CharacteristicsTumor Characteristics

Treatment CharacteristicsTreatment CharacteristicsGastrectomy nn ( % )( % )

Total gastrecomy 4 ( 2.8 )

Gastrectomy, partial, proximal 29 ( 20.4 )

Gastrectomy, partial, distal 16 ( 11.3 )

none 93 ( 65.5 )

Dose nn ( % )( % )

< 400 mg 5 ( 3.5 )

400 mg 91 ( 64.1 )

600 mg 18 ( 12.7 )

800 mg 27 ( 19.0 )

1200 mg 1 ( 0.7 )

Plasma Level DistributionPlasma Level Distribution

Plasma Level Distribution Imatinib Dose

Plasma Level Distribution Imatinib Dose

Imatinib Plasma LevelCorrelative Characteristics

Imatinib Plasma LevelCorrelative Characteristics

Significant factors• Age p = 0.0002• Gender p = 0.0004• Imatinib dose p = < 0.0001

Non-significant factors• BSA• Gastrectomy

Significant factors• Age p = 0.0002• Gender p = 0.0004• Imatinib dose p = < 0.0001

Non-significant factors• BSA• Gastrectomy

• Duration of imatinib• Race

• Duration of imatinib• Race

Plasma Level Distribution Choi Response (4 months)

Plasma Level Distribution Choi Response (4 months)

p = 0.009

Imatinib Plasma LevelIndividual Dose Escalation

Imatinib Plasma LevelIndividual Dose Escalation

p = 0.00047

mean 867 ng/mL

mean 1762 ng/mL

100 mg imatinib

296 ng/mL plasma level

KIT Mutations Predict Overall Survival(on imatinib; independent of dose)

KIT Mutations Predict Overall Survival(on imatinib; independent of dose)

KIT exon 9 (n=22)KIT exon 9 (n=22)

No kinase mutation (n=9)No kinase mutation (n=9)

KIT exon 11 (n=85)KIT exon 11 (n=85)

00 250250 500500 750750 10001000 12501250 1500150000

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

P-value=0.0004P-value=0.0004

DaysDays

Ov

era

ll S

urv

iva

l (%

)O

ve

rall

Su

rviv

al (

%)

Heinrich et al, J Clin Oncol 2007Heinrich et al, J Clin Oncol 2007

Progression-Free SurvivalKIT Genotype

Progression-Free SurvivalKIT Genotype

p = 0.08

p = 0.32

Imatinib Plasma LevelsKit Genotype

Imatinib Plasma LevelsKit Genotype

Genotype

Median Imatinib

Dose(mg)

Range (mg)

Average Imatinib

Plasma Level (ng/mL)

Range (ng/mL)

Exon 9800

400 - 1200 1741 446 - 4285

Exon 11 400 200 - 800 1470 256 - 4582

Wild-type 400 400 - 800 1497 673 - 2793

Other 400 400 - 800 1441 386 - 2904

SummarySummary• Imatinib plasma levels in our patients ranged from

256 – 4582 with a first quartile cutoff of 851ng/mL, lower than the published literature.

• Imatinib plasma levels correlated with age, gender, imatinib dose and Choi response

• Dose escalation of imatinib by 100 mg resulted in an average 296 ng/mL plasma level increase.

• Patients with KIT exon 9 mutation were treated with higher dose of imatinib, had higher plasma levels, and had a PFS similar to that of patients with exon 11 mutation

• Imatinib plasma levels in our patients ranged from 256 – 4582 with a first quartile cutoff of 851ng/mL, lower than the published literature.

• Imatinib plasma levels correlated with age, gender, imatinib dose and Choi response

• Dose escalation of imatinib by 100 mg resulted in an average 296 ng/mL plasma level increase.

• Patients with KIT exon 9 mutation were treated with higher dose of imatinib, had higher plasma levels, and had a PFS similar to that of patients with exon 11 mutation

Randomized Study of Imatinib Plasma SARC-019

Randomized Study of Imatinib Plasma SARC-019

Advanced GIST on Imatinib 400mg/day (N=400)

Measure Imatinib Plasma Level

<1100 ng/mL (N=100) >1100 ng/mL (N=300)

Randomize

Arm AImatinib 400mg/day

Plasma Level TestingNo Dose Adjustment

Arm BImatinib 600mg/day

Plasma Level TestingAdjust Dose

Arm CImatinib 400mg/day

Plasma Level TestingNo Dose Adjustment

Arm D (Exon 9)Imatinib 4-800mg/dayPlasma Level TestingNo Dose Adjustment

Control Cohort (N=50)

KIT Genotype

PIs Suzanne George and Jon Trent

AcknowledgementsAcknowledgements

Robert Benjamin

Shreyaskumar Patel

Dejka Araujo

Joseph Ludwig

Vinod Ravi

Alex Lazar

Robert Benjamin

Shreyaskumar Patel

Dejka Araujo

Joseph Ludwig

Vinod Ravi

Alex Lazar

Supported by a grant from the Institute for Personalized Cancer Therapy at M. D. Anderson Cancer Center

Suzanne George

Linyee Shum

Saroj Vadhan-Raj

Wei Qiao

Jon Trent

Billy Wang

Suzanne George

Linyee Shum

Saroj Vadhan-Raj

Wei Qiao

Jon Trent

Billy Wang

Concomitant MedicationsConcomitant Medications• Cyp3A4 inhibitors may increase TKIs

– ketoconazole, itraconazole, erythromycin, and clarithromycin, grapefruit, star fruit

• CYP3A4 inducer may decrease TKIs– dexamethasone, phenytoin, carbamazepine,

rifampin (80%), phenobarbital or St. John's Wort

• CYP3A4, CYP2C8, CYP2C9, CYP2D6 are competitively inhibited by TKIs– Warfarin, midazolam, macrolides, caffeine

• Cyp3A4 inhibitors may increase TKIs– ketoconazole, itraconazole, erythromycin, and

clarithromycin, grapefruit, star fruit

• CYP3A4 inducer may decrease TKIs– dexamethasone, phenytoin, carbamazepine,

rifampin (80%), phenobarbital or St. John's Wort

• CYP3A4, CYP2C8, CYP2C9, CYP2D6 are competitively inhibited by TKIs– Warfarin, midazolam, macrolides, caffeine