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All About Gleevec (Glivec)

Response Rate

Phase II results-responses to Gleevec in 147 patients with advanced GIST. Poster PDF 71 KB ¹
(based on a median follow-up of 52 months through May 13, 2005).

NOTE: The phase II trial is not the largest GIST trial, but it does have the most "mature" data. This data was recently updated at the 2006 ASCO GI conference in January, 2006. This trial information is useful for determining “response rates”, but it was not adequately powered to determine the effectiveness of different dose levels.
View a discussion about Gleevec dose levels

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Patients often want to know how fast Gleevec "works". PET scans can give an early indication of how well a patient is likely to respond to Gleevec. PET scans have indicated that GISTs can start responding "metabolically" as soon as 24 hours after a single dose of Gleevec as shown by decreased glucose uptake into tumors. Tumor shrinkage usually lags behind the "metabolic" response (see table 2 below).

F18-FDG-PET Provides Early Evidence of Biological Response to STI571 in Patients with Malignant Gastrointestinal Stromal Tumors (GIST) Poster PDF 238 KB

Treatment with Gleevec can have Several Different Results

Understanding the different ways that tumors can respond is necessary to understand "response":

1) Most of the tumors cells die; but VERY, VERY IMPORTANTLY, in almost every case some GIST tumors cells do not die and are waiting to reemerge if you stop Gleevec. In this case, a biopsy might show very weak staining for c-kit (KIT) and most of the "material" recovered from the biopsy can just be degraded cellular contents (proteins, etc) that remain after the tumor cells die.

2) Tumor cells might just stop proliferating, but not die; again waiting to start growing as soon as you stop Gleevec. It is important to understand that patients with "stable disease" tend to do just as well as patients with enough shrinkage to qualify as a "partial response". See Figure 4 (from the phase II poster) below (Figures 1 thru 3 from the phase II poster are not shown here; see the phase II poster for these figures).

3) You can have a mixed response, with some tumors shrinking and some stable, or even growing.

4) Some tumors that are dying can actually swell and appear larger on a CT scan. This is not progression, but tumors that are responding to treatment. These tumors will usually have a change in density and appear darker on a CT scan and the border may become better defined. A PET scan of this type tumor will typically show decreased glucose uptake.

5) Some tumors that have a density very close to the surrounding liver may not show up on an initial CT scan. Treatment with Gleevec can cause these tumors to become less dense and they will then show up on later CT scans. This can be very misleading as they APPEAR LIKE NEW TUMORS!²

6) About 15% of patients fail to respond to initial treatment with Gleevec.

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"Standard PET (scans) proved to be a sensitive, rapid, and reliable indicator of response or resistance to Gleevec. In all patients with a response, the [18F] fluoro-2-deoxy-D-glucose uptake in the tumor had decreased markedly from base line as early as 24 hours after a single dose of Gleevec. Increases in tumor-related glycolytic activity, activity at new sites, or both were seen in all patients with disease progression. PET results correlated with subsequent evidence of a response or progression on CT or MRI scans.³

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• 5 patients in the 400 mg per day group and 8 patients in the 600 mg-group were withdrawn from the study.
• The estimated one year survival for all patients was 88 percent.
• Median survival (the time point when half of patients had died) for all patients was 58 months. Median survival has not been reached for patients with exon 11 mutations (as of May 13, 2005).
• 81.6% of patients remained on study at a follow-up of (more than) 9 months.
• About one third of patients remain on study (study start date was July, 2000) as of the 2006 ASCO GI conference (January 2006).

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Intent to treat dose. Note that clinical trials use the dose that patient was randomized to receive as the reported dose. That means the doses reported here may not reflect the dose the patient was receiving. For example, a patient that had unacceptable side effects at 600mg may have had their dose reduced to 400mg (or in a few cases, less than 400mg). This patient could have received 400mg for the majority of the time they were in the trial, but they would still be counted in the 600mg arm if that is where they started.

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Phase I Study results ⁴

Note: Although this was a phase I study, we note that it was done subsequent to the phase II study. It is our feeling that the data from the two studies are comparative.

An objective response was achieved in 25 of 36 (69%) GIST patients, 19 (53%) of whom had a confirmed partial response. The remaining 6 patients with an objective response had either an unconfirmed partial response or a 20% to 29% tumor regression. Of GIST patients who did not achieve an objective response, 7 (19%) were stable and only 4 (11%) had progressive disease. Responses were generally rapid, occurring within 8 days of treatment initiation, as revealed by 18FDG-PET scans. Tumor-related symptoms were relieved in 24 of 27 (89%) patients treated with Gleevec, often within a week after beginning therapy. Updated data indicate that with a minimum follow-up of 11 months (range 11 to 15 months), 29 patients were still on treatment; 18/36 (50%) have PR and 11/36 (30%) have SD, resulting in clinical benefit in 80% of patients. A sustained response was not seen in any non-GIST patient (ie, with c-Kit–negative STS), which is consistent with the postulated role of c-Kit in the GIST disease process and the mechanism of action of Glivec.

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Exon Mutations Affect Response Rate

The PowerPoint presentation by Dr. Christopher Corless and Dr. Michael Heinrich which was given at the London GIST conference gives an excellent overview of this topic.

KIT Mutational Status Predicts Clinical Response to Glivec in Patients With Metastatic GIST

Correlation of target kinase genotype with clinical activity of imatinib mesylate (IM) in patients with metastatic GI stromal tumors (GISTs) expressing KIT (KIT+)

KIT & PDGFRA mutations in GIST: A to Z by Dr. Michael Heinrich

Looking for kinase mutations in GISTs: how, when and why? by Dr. Christopher Corless

KIT exon mutations in GIST

Mutations in the KIT receptor

The information in genes is divided into different sections called exons and introns. Exons contain coding information and introns do not. Mutations in different exons in the gene cause changes in shape in different parts of the KIT receptor. Mutations in the following exons of the c-kit gene are known to occur in GIST.

Exon 11-This is the most commonly mutated exon in GIST. In phase II trials, exon 11 mutations were found in 68% of cases. Mutations in exon 11 generally respond to treatment with Gleevec better than mutations in other exons.

Exon 9-Exon 9 mutations are the second most common mutation. In phase II trials, exon 9 mutations were found in 16% of cases. They are only known to occur when the primary tumor originates in the small bowel and colon. GISTs with exon 9 mutations have a lower response rate to Gleevec therapy when compared to exon 11 mutations.

Exon 13 and exon 17 mutations are rare in GIST.

Some GIST tumor cells do not contain c-kit mutations. This is called "wild-type" c-kit. GIST with wild-type tumors do not respond as well as other types, but since some signaling may still occur through the KIT receptor and since there is about a 35% chance that PDFGR-Alpha mutations may be involved, and since Gleevec is known to inhibit PDGFR-Alpha and KIT, treatment with Gleevec is beneficial in many cases.

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Note: The Life Raft Group is posting this information as provided to us by Oregon Health Sciences University (OHSU). This is not an endorsement and other labs or hospitals might provide this service in the future.

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KIT & PDGFRA Gene Mutation Screening

Background Data and Interpretation

Testing for mutations in the KIT and PDGFRA genes is available through the Molecular Diagnostics Laboratory of Oregon Health & Science University (OHSU). This testing can provide physicians and their patients information on the likelihood of response to therapy with imatinib mesylate (STI571; Gleevec^TM), as detailed below. Regardless of the test results, however, all patients eligible for treatment should undergo a therapeutic trial with the drug. Even among patients with tumors lacking a detectable KIT or PDGFRA gene mutation, the response to imatinib mesylate is higher than the response to traditional chemotherapy (<5%).

Approximately 80-85% of gastrointestinal stromal tumors (GISTs) have an oncogenic mutation in the gene encoding KIT tyrosine kinase.^5,6 Another 5-7% of GISTs have a mutation in the gene encoding the related kinase PDGFRA (platelet-derived growth factor receptor alpha).⁷ KIT and PDGFRA mutations are mutually exclusive in GISTs. In both genes, the observed mutations result in expression of a mutant form of kinase that is constitutively “turned on” and helps drive the growth of the tumor. Approximately 7-12% of GISTs have no detectable KIT or PDGFRA gene mutation. What supports the growth of this subset of GISTs remains unclear.

Based on an interim analysis of the CSTI-B2222 phase II trial of imatinib mesylate in the treatment of non-operable malignant GI stromal tumor, there is a relationship between the kinase mutation status of a GIST and the likelihood of drug response, as summarized in the table below.⁸

In addition to having a higher rate of response to therapy, patients with GISTs harboring an exon 11 mutation have more durable responses and better overall survival than those with exon 9 mutations or those with no mutation detected in either kinase gene.⁸

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Methods

Testing is performed in two stages. KIT exons 9 and 11 are screened first, as approximately 80% of GISTs will have a mutation in one of these two exons. KIT exons 13 and 17, and PDGFRA exons 12 and 18 are screened in the second stage. If no mutations are found in these exons, the tumor is presumed to be “wildtype”, although there remains a small (less than 1%) possibility that a mutation was missed elsewhere in either gene.

DNA is extracted and purified from paraffin-embedded tumor tissue. The indicated exons of the KIT and PDGFRA genes are amplified by PCR, and the products are screened for mutations by denaturing HPLC (WAVE system, Transgenomic, Inc.). Based on analysis of over 400 GIST samples, the sensitivity and specificity of this combined HPLC plus sequencing approach are >98%.

How to Order the Test

Requests for KIT and PDGFRA mutation screening must originate from a pathologist or treating physician. One paraffin block of the tumor (either biopsy or surgical specimen) or 15 unstained sections of the tumor should be sent to address listed below. A copy of the original pathology report as well as the patient’s insurance information must be included.

KIT/PDGRRA Mutation Screening Service (Heinrich/Corless lab website)

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1. C. D. Blanke, H. Joensuu, G. D. Demetri, M. C. Heinrich, B. Eisenberg, J. Fletcher, C. L. Corless, E. Wehrle, K. B. Sandau, M. von Mehren. Outcome of Advanced Gastrointestinal Stromal Tumor (GIST) Patients Treated With Imatinib Mesylate:Four-Year Follow-Up of a Phase II Randomized Trial Poster PDF 71KB ASCO 2006 Presentation
NOTE: *The submitted abstract mistakenly stated that 63% of patients have died of Progressive Disease. The correct value is 40%.
2. K. M. Linton, M. B. Taylor, J. A. Radford. Response Evaluation in GIST treated with Imatinib-misdiagnosis of disease progression on CT due to cystic change in liver metastases. 2005 ASCO Abstract 9047
3.  George D. Demetri, M.d., Margaret Von Mehren, M.D., Charles D. Blanke, M.D., Annick D. Van Den Abbeele, M.D., Burton Eisenberg, M.D., Peter J. Roberts, M.D., Michael C. Heinrich, M.D., David A. Tuveson, M.D., Ph.D., Samuel Singer, M.D., Milos Janicek, M.D., Ph.D., Jonathan A. Fletcher, M.D., Stuart G. Silverman, M.D., Sandra L. Silberman, M.D., Ph.D., Renaud Capdeville, M.D., Beate Kiese, M.Sc., Bin Peng, M.D., Sasa Dimitrijevic, Ph.D., Brian J. Druker, M.D., Christopher Corless, M.D., Christopher D. M. Fletcher, M.D., and Heikki Joensuu, M.D. Effect of the Tyrosine Kinase Inhibitor STI571 in a Patient with a Metastatic Gastrointestinal Stromal Tumor
4.  Lancet. 2001;358:1421-1423. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. This information is furnished by Novartis in their "GIST Clinical Monograph" which is intended for international Medical Professionals.
5. Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res61:8118-8121, 2001.
6. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Human Pathology 33:484-495, 2002
7. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen C-J, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri G, Fletcher CDM, Fletcher JA. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708-710, 2003.
8. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen C-J, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CDM, Silberman S, Dimitrijevic S, Fletcher JA.  Kinase mutations and imatinib mesylate response in patients with metastatic gastrointestinal stromal tumor. J Clin Onc 21:4342-4349, 2003.
9. Annick D. Van den Abbeele, R.D. Badawi1, M. Janicek, C. Blanke, H. Joensuu, P. Roberts, S. Silberman, S. Dimitrijevic, G.D. Demetri for the GIST Collaborative PET Study Group. F18-FDG-PET Provides Early Evidence of Biological Response to STI571 in Patients with malignant Gastrointestinal Stromal Tumors (GIST) Poster PDF 238 KB