Imatinib mesylate after surgery dramatically reduces risk of cancer returning in patients with gastrointestinal stromal tumors

The U.S. Food and Drug Administration, in late December 2008, approved imatinib mesylate (Glivec®, Novartis AG, Lichtstrasse 35, 4056 Basel, Switzerland and Gleevec®, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, NJ) for the post-surgery treatment of adult patients following complete surgical removal of KIT (CD117)-positive gastrointestinal stromal tumors (GIST).

The tyrosine kinase inhibitor imatinib mesylate is now the only post-surgery treatment indicated to delay the return of this highly aggressive cancer, filling a major need for GIST patients in the United States. The filing received FDA priority review status in August 2008, with regulatory reviews currently underway in other regions, including the European Union (EMEA) and Switzerland.

Soft Tissue Sarcoma
While most cancers are carcinomas, gastrointestinal stromal tumors (GIST) belong to a group of cancers known as soft tissue sarcomas. These cancers grow from cells of the body’s connective or supportive tissues such as bone, cartilage, tendons, nerves, fat, muscle, synovial tissue, or blood vessels.

A life-threatening disease
GIST is a life-threatening cancer of the GI tract affecting the digestive tract or nearby structures within the abdomen. It is the most common mesenchymal tumor of the gastrointestinal tract originating from cells found in the stomach and small intestine, Interstitial Cells of Cajal (ICCs) or from less differentiated stem cells or precursor cells, known as mesenchymal precurser cells, in the gut wall, which can develop into ICCs.

These Interstitial Cells of Cajal or ICCs are part of the autonomic nervous system , and generally found in the myenteric plexus and nearby areas between the circular and longitudinal layers of the gastrointestinal tract. Their function is to regulate gastrointestinal motility, or peristalsis, which is the autonomic movement of the GI tract to propel food and liquid through the digestive tract through the stomach and intestines.

Incidence
Data concerning the worldwide prevalence of GIST is lacking. But some population based studies estimate the annual incidence to be 4,500 - 6,000 new cases per year in the United Sates (15-20 cases per million population), of which more than 90% are KIT-positive.

Genetics
KIT - also known as CD117 - is a protein that, when mutated, has been identified as one of the major causes of GIST. These mutations result in spontaneous activation of tyrosine kinase domains, providing a constant growth stimulus to the tumor cells.

Many GIST contain mutations in exon 11 and, to a lesser degree, in exons 9, 13 or 16, of the c-kit (KIT) protooncogene coding for C-KIT (CD117). Imatinib mesylate inhibits the activity of several proteins such as KIT.

Some GISTs have a mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene. Furthermore, a snall number of GISTs, aproximately 5-15%, have no detectable KIT or gene mutation. This includes most pediatric GISTs and GISTs arising in patients with an inactivation of the neurofibromatosis gene (NF1).

Like most cancers, GIST affects older people. The average age at presentation is 50 to 60 years of age. Children are rarely affected, while familial GIST develops in younger or middle-aged adults.

Difficult to diagnose
Most patients, especially those with smaller tumors, are asymptomatic. Asymptomatic GISTs can be discovered incidentally during endoscopy or laparoscopy as well as during computed tomography (CT). Biopsy and endoscopic ultrasound are generally used for staging. However, because tumors are slow growing and symptoms of GIST are generally not different than other GI complaints such as nausea, vomiting, bleeding, dyspepsia and obstruction, earely detection of the cancer is rather dificult.

Approximately 60% of these tumors occur in the muscular wall of the stomach. However tumors may also develop in the small intestine, colon, rectum, esophagus and other intra-abdominal locations. The likelihood of malignant behavior is dependent on the size of the tumor and its rate of growth. Metastases usually occur within the abdominal cavity and/or the liver.

Treatment options
Early gastrointestinal stromal tumors, or GIST that has not yet metastasized, is often treated initially with surgery to remove the cancer. Unfortunately, the risk of recurrence is high, and GIST remains relatively resistant to chemotherapy and/or radiation therapy. Targeted drugs that inhibit the KIT, such as imatinib mesylate, offer an important approach to treating these cancers. These drug are intended to be given to patients following surgery to help prevent recurrence.

However, in some cases patients with gastrointestinal stromal tumors (GIST) whose disease has progressed or who are unable to tolerate treatment with imatinib mesylate require alternative treatment. Researchers found that sunitinib malate (Sutent®, Pfizer Oncology, Pfizer Inc, 235 East 42nd Street, New York, NY 10017), an orally-available small-molecule multiple receptor tyrosine kinase inhibitor, delayed the time it takes for tumors or new lesions to grow in patients with this tare type of cancer. Specifically, the median time-to-tumor progression (TTP) for patients treated with sunitinib malate was 27 weeks compared to 6 weeks for patients who were not treated.

Established efficacy
The efficacy of imatinib mesylate was established in a clinical trial in which patients received either imatinib mesylate or a placebo for one year after surgical removal of the tumor. The optimal treatment duration is not known.

There were significantly fewer recurrences of GIST in patients receiving imatinib mesylate than in patients who did not. The most frequently reported adverse reactions were diarrhea, fatigue, nausea, swelling of the feet, decreased red blood cell counts, rash, vomiting and abdominal pain.

Recurrence
After initial removal, GIST tumors can return in as many as one of two patients. Recurrent GISTs are often more aggressive than primary tumors, with relapses associated with lower survival rates.

'After surgery, my doctor told me there was a high likelihood that my gastrointestinal tumors would come back. I immediately searched for a possible solution and found the Glivec clinical trial, which aimed to help patients like me,' said Roslyn Fuller, a GIST patient. 'This FDA approval is good news for me and other GIST patients who will now have the option to start treatment with Glivec earlier to help prevent recurrence.'

Phase II study
The approval for this new indication is based on data from an international Phase III trial sponsored by the National Cancer Institute. The study showed a dramatic reduction in the return of GIST after surgery in patients treated for about one year with imatinib mesylate versus placebo.

The FDA regulatory filing for the adjuvant GIST indication was based on data from a Phase III, double-blind, randomized, multicenter, international study of more than 700 GIST patients who had undergone surgery to remove their tumors. The efficacy endpoint of the study was recurrence-free survival (RFS), defined as the time from the date of randomization to the date of recurrence or death from any cause. Participants were randomized to receive either imatinib mesylate 400 mg/day or a matching placebo for one year.

Based on a 14-month median follow up, 91.6% of patients receiving imatinib mesylate remained cancer-free compared with 80.2% of those taking placebo. (30 RFS events out of 359 patients in the imatinib mesylate arm (8.4%) compared to 70 RFS events out of 354 patients in the placebo arm (19.8%) (hazard ratio=0.398 [95% CI: 0.259, 0.610], p<0.0001).'Approval of Gleevec offers health care professionals and patients an important new therapeutic option for patients with this uncommon gastrointestinal disease,' said Richard Pazdur, M.D., director, Office of Oncology Drug Products, Center for Drug Evaluation and Research, FDA. 'It illustrates how the continued study of a once novel drug throughout its product lifecycle can yield new and important uses.'

Revolution in the making
Imatinib mesylate was first approved by the FDA in 2001. It is one of the first drugs in a class of agents that block cellular communications that result in tumor growth. Soon after the introduction of effective molecularly targeted therapies such as imatinib mesylate and sunitinib malate the standard of practice for GIST rapidly changed.

'When Glivec was first approved for the treatment of inoperable and/or metastasized KIT-positive GIST six years ago, it revolutionized the treatment of this life-threatening cancer,' said David Epstein, President and CEO, Novartis Oncology. 'This atest FDA approval means patients can benefit from Glivec earlier in the course of their disease.'

Multiple indications
The drug is now approved for nine indications, including the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML), Kit (CD117)-positive gastrointestinal stromal tumors which cannot be surgically removed and/or have already spread to other parts of the body (metastasized) and five other rare diseases.

Mode of Action
The effectiveness of imatinib mesylate is based on overall hematological and cytogenetic response rates and progression-free survival in CML, on hematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on hematological response rates in SM, HES/CEL, on objective response rates and progression-free survival in unresectable and/or metastatic GIST, on recurrence free survival in adjuvant GIST, and on objective response rates in DFSP. Increased survival in controlled trials has been demonstrated only in newly diagnosed chronic phase CML and GIST.

For more information, visit:

• Gleevec Official site
• GSI (GIST Support International) site
• Novartis corporate site.
• Novartis Oncology Medical Services site

Also read PubMed abstracts:

• Mazzola P, Spitale A, Banfi S, et al. Epidemiology and molecular biology of gastrointestinal stromal tumors (GISTs): a population-based study in the South of Switzerland, 1999-2005. Histol Histopathol. 2008 Nov;23(11):1379-86.
• Yan BM, Kaplan GG, Urbanski S, et al. Epidemiology of gastrointestinal stromal tumors in a defined Canadian Health Region: a population-based study. Int J Surg Pathol. 2008 Jul;16(3):241-50.
• Mucciarini C, Rossi G, Bertolini F, et al. Incidence and clinicopathologic features of gastrointestinal stromal tumors. A population-based study. BMC Cancer. 2007 Dec 20;7:230.
• Tryggvason G, Kristmundsson T, Orvar K, et al. Clinical study on gastrointestinal stromal tumors (GIST) in Iceland, 1990-2003. Dig Dis Sci. 2007 Sep;52(9):2249-53.
• Demetri GD, Benjamin RS, Blanke CD, et al. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw. 2007 Jul;5 Suppl 2:S1-29; quiz S30.
• Rubió J, Marcos-Gragera R, Ortiz MR, et al. Population-based incidence and survival of gastrointestinal stromal tumours (GIST) in Girona, Spain. Eur J Cancer. 2007 Jan;43(1):144-8.
• Steigen SE, Eide TJ. Trends in incidence and survival of mesenchymal neoplasm of the digestive tract within a defined population of northern Norway. APMIS. 2006 Mar;114(3):192-200.
• Goettsch WG, Bos SD, Breekveldt-Postma N, et al. Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer. 2005 Dec;41(18):2868-72.
• Tryggvason G, Gislason HG, Magnusson MK, et al. Gastrointestinal stromal tumors in Iceland, 1990-2003: the Icelandic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer. 2005 Nov 1;117(2):289-93.
• Irving JA, Lerwill MF, Young RH. Gastrointestinal stromal tumors metastatic to the ovary: a report of five cases. Am J Surg Pathol. 2005 Jul;29(7):920-6.
• Wingen CB, Pauwels PA, Debiec-Rychter M, et al. Uterine gastrointestinal stromal tumour (GIST). Gynecol Oncol. 2005 Jun;97(3):970-2.
  Nilsson B, Bümming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden. Cancer. 2005 Feb 15;103(4):821-9.
• Tran T, Davila JA, El-Serag HB. The epidemiology of malignant gastrointestinal stromal tumors: an analysis of 1,458 cases from 1992 to 2000. Am J Gastroenterol. 2005 Jan;100(1):162-8.
• Heinrich MC, Corless CL, Demetri GD et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1;21(23):4342-9.
• Belics Z, Csapo Z, Szabo I, et al. Large gastrointestinal stromal tumor presenting as an ovarian tumor. A case report. J Reprod Med. 2003 Aug;48(8):655-8.
• Borden EC, Baker LH, Bell RS, et al. Soft tissue sarcomas of adults: state of the translational science. Clin Cancer Res. 2003 Jun;9(6):1941-56.
• Igwilo OC, Byrne MP, Nguyen KD, et al. Malignant gastric stromal tumor: unusual metastatic patterns. South Med J. 2003 May;96(5):512-5.
• Reith JD, Goldblum JR, Lyles RH, et al. Extragastrointestinal (soft tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome. Mod Pathol. 2000 May;13(5):577-85.

Visit:

• Update in the Management of Gastrointestinal Stromal Tumors (GIST): A Report from ASCO 2007.
• Life Raft Group. Managing Initial Recurrence. Accessed January 2009.
• Z9001: A Phase III Randomized Double-blind Study of Adjuvant STI571 (Glivec®) Versus Placebo in Patients Following the Resection of Primary Gastrointestinal Stromal Tumor (GIST). Accessed January 2009.
• American Cancer Society. Cancer Reference Information. Detailed Guide for Gastrointestinal Stromal Tumors. Key Statistics. Accessed January 2009.
• US Department of Health and Human Services. Agency for Healthcare Research and Quality (AHRQ). Technology Assessment: Report on the Relative Efficacy of Oral Cancer Therapy for Medicare Beneficiaries Versus Currently Covered Therapy, Part 2. Imatinib for Gastrointestinal Stromal Tumors (GISTs) Accessed January 2009.

Also see:

• Full prescribing information for imatinib mesylate.
• CenterWatch drug information for imatinib mesylate.
• Full prescribing information for sunitinib mesylate.
• Highlight of prescribing information for sunitinib mesylate.
• CenterWatch drug information for sunitinib malate.

Order the book:

• Magic Cancer Bullet: How a Tiny Orange Pill May Rewrite Medical History.