FDA approves Novartis drug Gleevec® label recommending extending treatment to three years for certain GIST patients after surgery

EAST HANOVER, N.J., Feb. 1, 2012 /PRNewswire/ -- Novartis announced today that following a priority review, the US Food and Drug Administration (FDA) has approved an update to the Gleevec^® (imatinib mesylate)[*] tablets label to recommend 36 months of treatment after surgery for adult patients with KIT (CD117)-positive gastrointestinal stromal tumors (GIST) who met the risk of recurrence inclusion criteria of the pivotal trial. This treatment regimen has been shown to improve recurrence-free survival (RFS) and overall survival (OS) for KIT+ GIST patients compared to 12 months of treatment(3).

The US approval was based on data from an international, multicenter, open-label, Phase III clinical trial. Results of the study showed that 36 months of Gleevec treatment significantly prolonged RFS compared to 12 months of Gleevec treatment, which was a 54% reduction in the risk of recurrence (p<0.0001). In addition, 36 months of Gleevec treatment resulted in a 55% reduction in the risk of death compared to one year of treatment (p=0.0187). The median time of follow-up was 42 months for RFS and 48 months for OS(3).

"This approval represents another important step in the progress of KIT+ GIST treatment that began a decade ago when Gleevec was first approved to treat metastatic KIT+ GIST," said Herve Hoppenot, President, Novartis Oncology. "With the significant survival benefit resulting from three years of adjuvant treatment, GIST patients now have a more effective regimen to help manage their disease."

Gastrointestinal stromal tumors are a rare, life-threatening cancer of the gastrointestinal tract. The major cause of GIST is an abnormal form of the protein KIT which causes cells to grow uncontrollably and become cancerous(4). Patients with GIST are at risk of recurrence following complete resection of primary GIST(2).

In August 2011, the US National Comprehensive Cancer Network (NCCN) updated its clinical practice guidelines to recommend consideration of at least three years of adjuvant therapy with Gleevec for patients with high-risk GIST(2).

In addition to extending the Gleevec label to three-year treatment duration in patients with KIT+ GIST after surgery, the FDA has agreed that all accelerated post-approval commitments for this indication have been met, confirming the clinical benefit of adjuvant treatment with Gleevec.

Study details
The SSG XVIII clinical trial was conducted by the Scandinavian Sarcoma Group (SSG) and the Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie (AIO). This trial was a multicenter, prospective, randomized study for the evaluation of adjuvant treatment with Gleevec of histologically confirmed KIT+ GIST(5).

The primary endpoint of the study was to compare, within the first five years, recurrence-free survival in patients with a greater than 50% estimated risk of GIST disease recurrence, following diagnosis and treatment with adjuvant Gleevec for either 12 or 36 months. The secondary endpoints included overall survival and treatment safety(1).

Three hundred ninety-seven patients entered the study. Inclusion criteria for risk of recurrence was defined as tumor diameter >5.0 cm and mitotic count >5/50 high power fields (HPFs); or tumor diameter >10.0 cm, any mitotic count; or tumor of any size with a mitotic count >10/50 HPFs; or tumors ruptured into the peritoneal cavity.

Recurrence-free survival was longer in the 36-month group compared to the 12-month group (HR 0.46, 95% CI 0.32-0.65; p<0.0001). Patients assigned to 36 months of Gleevec after surgery had longer overall survival (HR 0.45, 95% CI 0.22-0.89; p=0.0187). Almost all patients experienced side effects while taking Gleevec. Gleevec was generally well tolerated. The proportion of patients who discontinued Gleevec during the assigned treatment period for reasons other than GIST recurrence was 26% over the full three year treatment period in the 36-month group and 13% in the 12-month group(1).

Novartis provided the study drug and supported the study financially. Additional funding was received from the Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation and Helsinki University Research Funds.

About Gleevec
Gleevec^® (imatinib mesylate) tablets are indicated for the treatment of patients with KIT (CD117)-positive gastrointestinal stromal tumors (GIST) that are cancerous, cannot be surgically removed, and/or have spread to other parts of the body. Gleevec is also approved for use after surgery in patients that have had their KIT (CD117)-positive GIST completely removed.

Gleevec Important Safety Information
Gleevec can cause fetal harm when administered to a pregnant woman. Women taking Gleevec should not become pregnant, and should be advised of the potential risk to the unborn child.

Gleevec is often associated with edema (swelling) and serious fluid retention. Studies have shown that edema (swelling) tended to occur more often among patients who are 65 and older or those taking higher doses of Gleevec.

Cytopenias (reduction or lack of certain cell elements in blood circulation), such as anemia, have occurred. If the cytopenia is severe, your doctor may reduce your dose or temporarily stop your treatment with Gleevec.

Severe congestive heart failure and left ventricle dysfunction have been reported, particularly in patients with other health issues and risk factors. Patients with heart disease or risk factors or history of renal failure will be monitored and treated for the condition.

Severe liver problems (hepatotoxicity) may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Gleevec.

Bleeding may occur. Severe gastrointestinal (GI) bleeding has been reported in patients with KIT+ GIST. GI tumor sites may be the cause of this bleeding; therefore, GI symptoms should be monitored at the start of treatment.

In patients with hypereosinophilic syndrome (a condition with increased eosinophils, which are a type of white blood cell) and heart involvement, cases of heart disease (cardiogenic shock/left ventricular dysfunction) have been associated with the initiation of Gleevec therapy.

Skin reactions, such as fluid-filled blisters, have been reported with the use of Gleevec. Clinical cases of hypothyroidism (reduction in thyroid hormones) have been reported in patients taking levothyroxine replacement with Gleevec.

Long-term use may result in potential liver, kidney, and/or heart toxicities; immune system suppression may also result from long-term use.

GI perforation (small holes or tears in the walls of the stomach or intestine), in some cases fatal, has been reported.

Growth retardation has been reported in children taking Gleevec. The long-term effects of extended treatment with Gleevec on growth in children are unknown.

Cases of tumor lysis syndrome (TLS), which refers to a metabolic and electrolyte disturbance caused by the breakdown of tumor cells, have been reported and can be life-threatening in some cases. Correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of Gleevec.

Reports of motor vehicle accidents have been received in patients receiving Gleevec; patients are cautioned about driving a car or operating machinery.

Almost all patients with KIT+ GIST treated with Gleevec experience side effects at some time. Some common side effects you may experience are fluid retention, muscle cramps or pain and bone pain, abdominal pain, loss of appetite, vomiting, diarrhea, decreased hemoglobin, abnormal bleeding, nausea, fatigue and rash.

Gleevec is sometimes associated with stomach or intestinal irritation. Gleevec should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including deaths, of stomach or intestinal perforation (a small hole or tear).

If you are experiencing any of the mentioned side effects, please be sure to speak with your doctor immediately.

Do not take any other medications without talking to your doctor or pharmacist first, including Tylenol^® (acetaminophen); herbal products (St. John's wort, Hypericum perforatum); Coumadin^® (warfarin sodium); rifampin; erythromycin; metoprolol; ketoconazole; and Dilantin^® (phenytoin). Taking these with Gleevec may affect how they work, or affect how Gleevec works. 

You should also tell your doctor if you are taking or plan to take iron supplements. Patients should also avoid grapefruit juice and other foods that may affect how Gleevec works.

Please see full Prescribing Information.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by terminology such as "recommending," "to recommend," or similar expressions, or by express or implied discussions regarding potential future revenues from Glivec. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Glivec to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Glivec will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Glivec could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; unexpected manufacturing issues; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2011, the Group's continuing operations achieved net sales of USD 58.6 billion, while approximately USD 9.6 billion (USD 9.2 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 124,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

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References
(1)  Joensuu H, et al. Twelve vs. 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO). 47th Annual Meeting of the American Society of Clinical Oncology. Abstract No. LBA1. June 5, 2011.
(2)  National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology: Soft Tissue. Version 2, 2011.
(3)  Gleevec^® (imatinib mesylate) tablets prescribing information. East Hanover, New Jersey: Novartis Pharma.
(4)  American Cancer Society. Cancer Reference Information. Detailed Guide for Gastrointestinal Stromal Tumors. http://www.cancer.org/acs/groups/cid/documents/webcontent/003103-pdf.pdf. Accessed on January 23, 2012.
(5)  Study Comparing 12 Months Versus 36 Months of Imatinib in the Treatment of Gastrointestinal Stromal Tumor (GIST). Available at: http://clinicaltrials.gov/show/NCT00116935. Accessed on January 9, 2012.

[*] Known as Glivec^® (imatinib) tablets outside the US, Canada and Israel.

Novartis Media Relations

Julie Masow
Novartis Corporation
+1 212 830 2465 (direct)
+1 862 579 8456 (mobile)
[email protected]

Sabrina Oei
Novartis Oncology
+1 862 778 6387 (direct)
+1 862 210 0993 (mobile)
[email protected]

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