Imatinib � GIST

Imatinib – In GIST ……. : 

Imatinib – In GIST ……. J. Jebasingh Dept. of Medical Oncology Madurai Medical College

Why Imatinib? : 

Why Imatinib? GIST is resistant to conventional chemotherapy  P-gp  MRP-1 Radiotherapy not effective Diffuse involvement in abdomen limits dose of RT Surgery not effective in metastatic disease Multifocal liver / peritoneal involvement

Chemotherapy TrialsAdvanced GIST : 

Chemotherapy TrialsAdvanced GIST Number of Partial Response Regimen Patients n (%) DOX + DTIC 43 3 (7%) DOX + DTIC +/– IF 60 10 (15%) IF + VP-16 10 0 (0%) Paclitaxel 15 1 (7%) Gemcitabine 17 0 (0%) Liposomal DOX 15 0 (0%) DOX 12 0 (0%) DOX or docetaxel 9 0 (0%) High-dose IF 26 0 (0%) EPI + IF 13 0 (0%) Various 40 4 (10%) DTIC/MMC/DOX/ CDDP/GM–CSF 21 1 (5%) Temozolamide 19 0 (0%) TOTAL 280 19 (6.8%)

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Result of such extensive disease Death within 2 years

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What changed the dismal prognosis ?

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Imatinib mesylate Tyrosine kinase inhibitor C-kit Bcr-abl PDGFR

What led to discovery of Imatinib : 

What led to discovery of Imatinib Ciba-Geigy in a bid to develop a drug to reduce coronary stent re-stenosis Tried 2-phenylaminopyrimidine This was found to Inhibit bcr-abl Signal Transduction Hence called, STI 571 (Imatinib) Later found to inhibit KIT receptor also by culture testing

First patient to be treated with Imatinib : 

First patient to be treated with Imatinib 54 year old female with heavily pretreated metastatic GIST Imatinib 400 mg once daily was started in March 2000 Rapid response sustained for 3 years N. Engl. J. Med., 344: 1052-1056, 2001

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Pretreatment One month of therapy H&E (at diagnosis) H&E Ki 67 CD117 Joensuu H et al. N Engl J Med. 2001;344:1052-1056. The First GIST Patient: Histology

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Jun 27, 2000 Oct 4, 2000 CT Scan Results Before Imatinib After Imatinib

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ATP = imatinib contact point Proliferation Survival Adhesion Invasion Metastasis Angiogenesis Imatinib Kit Receptor

Kit Mutation in GISTResponse to Imatinib (n=332) : 

Kit Mutation in GISTResponse to Imatinib (n=332)

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Overall Survival by Genotype Exon 11 Exon 9 No Mutation

Questions : 

Questions What is the right dosage? Will neoadjuvant therapy improve outcome? Will adjuvant therapy improve outcome? What are the mechanisms of Imatinib resistance? What are the treatment options for patients who progressed on Imatinib?

Right dose : 

Right dose A multicenter phase II trial of STI571 was initiated in July 2000 Patients with un-resectable or metastatic GIST were randomized to receive 400 or 600 mg of STI571 per day 147 patients were enrolled There were no significant differences in response 88 percent were alive one year after the initiation of treatment with Imatinib NEJM Volume 347:472-480 August 15, 2002

EORTC Phase III Imatinib for Advanced GISTSurvival Benefit : 

Verweij, et al 2004 EORTC Phase III Imatinib for Advanced GISTSurvival Benefit

EORTC Phase III Imatinib for Advanced GISTProgression-free Survival Benefit : 

EORTC Phase III Imatinib for Advanced GISTProgression-free Survival Benefit Verweij, et al 2004

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Answer 400 mg/day to start with is adequate Higher dose No increased survival Only higher toxicity In exon 9 mut Imatinib 800 mg/d has higher RFS

Will neo-adjuvant therapy improve outcome? : 

Will neo-adjuvant therapy improve outcome? Yes In unresectable / borderline resectable GIST Start Imatinib 400 mg/ day 4- 6 months later Definitive surgery to be planned

Will adjuvant therapy improve results? : 

Will adjuvant therapy improve results? Yes Better RFS with Imatinib for 1 year NCI trial Resected GIST with tumors > 3 cm Recurrence at 15 months 3 % with Imatinib 17 % with placebo

Why is adjuvant therapy required? : 

Why is adjuvant therapy required? MSKCC trial of 200 patients with completely resected GIST (80 of them) RFS of 54 % (46 % relapsed) without Imatinib MD Anderson in 191 patients Only 10 % were disease free on long-term follow up

But how long and cons? : 

But how long and cons? Longer duration may be required Under trial in Scandinavia for 2 / 3 years vs 1 year High cost of treatment Genotype study may dictate future adjuvant therapy

Prognostic factors of GIST : 

Prognostic factors of GIST

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Other factors Cell type Spindle (70%) – Good Epitheloid (30%) – Poor Genotype Exon 11 – Good Exon 9 – Poor No mutation (WT) – worse

What is Imatinib resistance? : 

What is Imatinib resistance? Not without difficulty Primary resistance (< 20 %) Secondary resistance (Majority) During the course of treatment Due to clonal evolution

Type of Progression : 

Type of Progression Stable disease Limited progression Widespread progression Nodular progression

Therapy by Type of Progression : 

Therapy by Type of Progression Limited or Nodular Progression Hepatic Artery Embolization Hepatic Radio-frequency Catheter Ablation Surgical Resection Widespread progression Increase Imatinib to 800 mg daily Sunitinib Clinical Trial

Side effects of Imatinib : 

Side effects of Imatinib Edema Reduces with time Low salt diet Diuretics Nausea Taken with food Muscle cramps Increased fluid intake

Role of PET scan : 

Role of PET scan High uptake of FDG-PET by GIST Glucose transport protein linked to KIT receptor Response to Imatinib seen in PET scan within 24 hours

PET scan 4 weeks later : 

PET scan 4 weeks later

Modified RECIST for GISTCT Size + Density (Choi) : 

Modified RECIST for GISTCT Size + Density (Choi) Tumor size decrease of >10% or tumor density decrease of >15% were highly correlated with decrease in SUV by >70% to a value <2.5 on PET. RECIST criteria substantially underestimate, at least initially, the value of therapy with imatinib for GIST.

Is GIST familial? : 

Is GIST familial? Rarely yes Hyperpigmentation Urticaria pigmentosa Overactive KIT on melanocytes

Other diseases with KIT expression : 

Other diseases with KIT expression Sarcomas SCLC Seminomas Melanomas Desmoid tumors Ovarian carcinomas Neuroblastomas Lymphoma (some types) AML

CML : 

CML Clonal disorder of stem cell Bcr-abl fusion protein Enhanced TK activity Increased proliferation & reduced differentiation Stem cell transplant once the cure, now replaced by – “ Imatinib” Dramatically increased survival

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Major Cytogenetic Responses with Imatinib Mesylate Were Rapid Imatinib mesylate IFN- + ara-C Months Since Randomization % Responding 83% 20% 0 10 20 30 40 50 60 70 80 90 100 0 3 6 9 12 15 18 21

Complete Hematologic Responses Were Rapid With Imatinib Mesylate : 

Complete Hematologic Responses Were Rapid With Imatinib Mesylate 96% 67% 0 10 20 30 40 50 60 70 80 90 100 0 3 6 9 12 15 18 21 % Responding Months Since Randomization Imatinib mesylate IFN- + ara-C

CML : 

CML Results of treatment

Approved indications of Imatinib : 

Approved indications of Imatinib CML – All phases including pediatric GIST – Adjuvant , Metastatic Ph + ALL – Relapse DFSP – Unresectable / Metastatic MDS / MPD – With PDGFR mutation HES – PDGFR mutation

Other diseases where Imatinib is promising : 

Other diseases where Imatinib is promising Hepatic fibrosis Systemic sclerosis & AI disorders Acute hepatitis Glioblastoma multiforme

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Thank you