FDA Approves Use of Imatinib (Gleevec) for Adjuvant Therapy of Resected GIST

On December 19, 2008, the FDA approved use of imatinib (Gleevec) for adjuvant therapy of resected adult GIST (GI Stromal Tumor). 

GISTs are tumors of the bowel wall that originate in the interstitial cells of Cajal, part of the autonomic cell network that control movement of food and fluids through the bowel.  GIST occurs in 5000-6000 patients per year in the US.  The tumors have an appearance often confused with other bowel wall smooth muscle tumors, known as leiomyomas or sarcomas.  GISTs have mutations of cell surface proteins that activate cell proliferation, primarily in the cellular gene c-kit, but also in PDGFRA (platelet derived growth factor receptor-A).  Common mutations are in exon 11 and exon 9 of the c-kit gene.  Imatinib was found to inhibit the activation of c-kit in patients (those with imatinib-sensitive mutations), and it was approved in 2001 by the FDA for treatment of metastatic GIST, after clinically-meaningful responses (overall approximately 40% of patients have radiographic responses by CT scan, compared to historical responses seen in only 0-5% of chemotherapy-treated GIST)  and disease control was demonstrated in early studies.  Further investigation has shown that imatinib improves progression-free survival (PFS).  The PFS has ranged between 17-24 months in metastatic GIST, depending on the dose of imatinib.  Significant differences in response and PFS with imatinib therapy have been established for differing mutations in c-kit (and PDGFRA). 

The use of imatinib for adjuvant therapy (post-resection treatment) after complete resection of GIST tumors (when patients have no other apparent disease) was studied in the ACSOG Z9001 study.  This was a randomized, double-blind study of imatinib for patients with GIST at high risk for recurrence after resection.  The study enrolled 644 patients, and it was stopped in 2007, after a significant improvement in PFS was determined for patients receiving adjuvant imatinib therapy (400 mg/d x 12 months).  After 18 months of median follow-up, PFS was 97% in the imatinib group versus 83% in the placebo group.  The improvement in PFS was seen across a broad range of tumor size. 

Therefore, patients who have had surgery for GIST should now receive at least one year of adjuvant imatinib therapy.  The duration of imatinib therapy continues to be studied in other ongoing investigations.   It is very important for patients with GIST tumors to be correctly identified when resection occurs, so the benefit of adjuvant therapy is not potentially missed.  The CD117 stain may help to differentiate GIST from other soft tissue tumors of the bowel.  However, there have been reports of CD117-negative GISTs.  PDGFRA staining may also prove helpful.  Molecular genetic analysis of c-kit and PDGFRA may not only help to  identify patients with GIST, but because certain mutations in these genes is associated with imatinib resistance, testing may serve to help assess the potential benefit of therapy, as other drugs have been developed that have activity in imatinib-resistant forms of GIST.  These specialized tests may be obtained by consultation and specimen referral to specialized pathology labs.  Such testing can be done on archival tumor tissue.   For example, tumor tissue may be sent for analysis at MD Anderson Pathology Lab.  A requistion form and instruction is here in the attachment:

MD Anderson Pathology Requisition

Other labs that have experience in testing GISTs:

• ARUP Laboratory, Salt Lake City (http://www.aruplab.com/)
• MD Anderson Cancer Center, Houston, TX (http://www.mdanderson.org/labs/mdl/)
• Oregon Health & Science University, Portland, OR (http://www.heinrich-corless.net/services.html)

A review of expanding information about GIST therapy is beyond the scope of this brief post.  Additional information is available through GIST support groups (www.liferaftgroup.org, www.gistsupport.org, www.gistinfo.org). Patients who are interesting on medical oncology consultation at CORT may call 972-566-5588.  Information about CORT is available at our website: www.CORTPA.com.