- Estimated one-year, recurrence-free survival was 98% for Kit-positive GIST patients taking Gleevec vs. 83% for patients taking placebo(1)
- Historically, one in two patients experienced recurrence of GIST(2) within a median of two years after surgery(3)
- Gleevec is the only treatment in the US and Switzerland indicated to reduce risk of recurrence of GIST after surgery; regulatory review is underway in the EU(4)
EAST HANOVER, N.J., March 18, 2009 /PRNewswire/ -- Data published today online and in an upcoming print issue of The Lancet show that Gleevec(R) (imatinib mesylate) tablets*, when taken after surgery, substantially reduces the rate of recurrence of Kit-positive gastrointestinal stromal tumors (GIST) compared with placebo.
The Phase III study published today was led by the American College of Surgeons Oncology Group (ACOSOG) and examined post-surgery, or adjuvant, treatment of more than 700 GIST patients. Researchers found that 98% of patients receiving 400 mg of Gleevec daily remained tumor-free one year after surgery. The study also found Gleevec to be safe and well-tolerated, with a low rate of serious adverse events(1).
GIST is a life-threatening cancer of the gastrointestinal tract. After initial surgery to remove the tumor, GIST can return in one of two patients(2) within a median of two years(3).
"The standard of care after surgical removal of primary GIST has been clinical and radiologic observation, since standard chemotherapeutic agents have been ineffective in this disease. This frequently resulted in tumor recurrence," said Ronald DeMatteo, MD, Memorial Sloan Kettering Cancer Center, New York, NY. "Now, as The Lancet reports, by treating patients with Gleevec after removal of their initial tumor, we can proactively impact the course of this disease by delaying, and in some patients possibly preventing, the return of the cancer."
Gleevec was recently approved in the US, Switzerland and several other countries for the treatment of Kit-positive GIST in the adjuvant setting(4), based on the ACOSOG data. Further follow up is necessary to understand the continued impact on prevention of recurrent disease and overall survival. This approval represented the tenth indication for Gleevec in the US.
The double-blind, randomized, multicenter study was conducted throughout the US and Canada. It included 713 GIST patients whose tumors had been surgically removed. The study compared the recurrence-free survival (RFS) of patients taking either Gleevec 400 mg daily or placebo immediately following surgery. The results showed that 98% of those receiving Gleevec remained recurrence-free one year following surgery compared with approximately 83% of those receiving placebo (P<0.0001)(1).
The investigators reported that Gleevec therapy was well tolerated by most patients, with side effects similar to those observed in previous clinical trials with Gleevec. These include nausea, diarrhea and swelling (edema)(1).
*Known as Glivec(R) (imatinib) outside the US, Canada and Israel.
About gastrointestinal stromal tumors (GIST)
Gastrointestinal stromal tumors (GIST) belong to a group of cancers known as soft tissue sarcomas(3). The most common sarcomas, they can be found most often in the stomach and small bowel(3). The incidence of GIST is estimated to be up to 6,000 new cases per year in the US(5), of which approximately 95% are Kit-positive(3). Median time to recurrence is approximately two years(3). Kit (also known as CD117) is the protein that, when mutated, has been identified as one of the major causes of GIST. Gleevec inhibits the activity of several proteins, including Kit(3).
Gleevec tablets are indicated for the adjuvant treatment of adult patients following complete surgical removal of Kit (CD117)-positive GIST. Gleevec is also indicated for the treatment of patients with Kit (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST).
Important safety information(4)
In Phase III unresectable or metastatic GIST trials (400 mg/day; 800 mg/day), severe (NCI Grades 3/4/5) lab abnormalities - including neutropenia (3%; 4%) and anemia (5%; 6%) - and severe adverse reactions (NCI Grades 3/4/5), including severe fluid retention (9% to 13%) and edema (9%; 13%), fatigue (12%; 12%), abdominal pain (14%; 12%), nausea (9%; 8%), diarrhea (8%; 9%), rash (8%; 9%), vomiting (9%; 8%) and myalgia (6%; 4%) were reported among patients receiving Gleevec.
In the adjuvant treatment of GIST trials (Gleevec; placebo), severe (NCI Grades 3 and above) lab abnormalities - decrease in hemoglobin (1%; 0%), and increase in liver enzymes (ALT) (3%; 0%) - and severe adverse reactions (NCI Grades 3 and above), including fatigue (2% to 1%), periorbital edema (1%; 0%), abdominal pain (3%; 1%), nausea (2%; 1%), diarrhea (3%; 1%), rash (3%; 0%) and vomiting (2%; 1%) were reported among patients receiving adjuvant treatment with Gleevec.
Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.
Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse reactions or hematologic adverse reactions. Therapy with Gleevec was discontinued for adverse reactions in 5% of patients at both dose levels studied. Complete blood counts should be performed weekly for the first month, biweekly for the second month and periodically thereafter as clinically indicated (for example, every 2-3 months).
A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment. Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended. Imatinib should be used with caution in patients with severe renal impairment.
In the Phase III unresectable or metastatic GIST studies, 13% of patients reported (NCI Grades 3/4) hemorrhage at any site. In the Phase II unresectable or metastatic GIST study, 5% of patients were reported to have severe gastrointestinal (GI) bleeds and/or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds.
Patients should be weighed and monitored regularly for signs and symptoms of edema, which can be serious or life-threatening. There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure and GI perforation.
Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of Gleevec at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction.
Consider potential toxicities - specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use.
Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking Gleevec tablets and to avoid breast-feeding while taking Gleevec tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking Gleevec should use adequate contraception. If the patient does become pregnant while taking Gleevec, the patient should be advised of the potential hazard to the fetus.
Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6 and CYP2C9. Dosage of Gleevec should increase by at least 50%, and clinical response should be carefully monitored, in patients receiving Gleevec with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with Gleevec include ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions). For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron.
Common side effects of Gleevec tablets
The majority of patients who received Gleevec in the Phase III unresectable or metastatic GIST study experienced adverse reactions at some time. The most frequently reported adverse reactions (400 mg/day; 800 mg/day) (all Grades) were edema (77%; 86%), nausea (58%; 65%), muscle cramps (32%; 30%), diarrhea (56%; 58%), fatigue (69%; 75%), abdominal pain (57%; 55%), rash and related terms (56%; 70%) and vomiting (37%; 41%)*.
The majority of both Gleevec and placebo-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include (Gleevec; Placebo) (all Grades) diarrhea (60%; 29%), fatigue (57%; 41%), nausea (53%; 29%), peripheral edema (27%; 15%), abdominal pain (21%; 22%), rash (26%; 13%), and vomiting (26%; 14%)*.
Supportive care may help management of some mild-to-moderate adverse reactions so that the prescribed dose can be maintained whenever possible. However, in some cases, either a dose reduction or interruption of treatment with Gleevec may be necessary.
Gleevec tablets should be taken with food and a large glass of water to minimize GI irritation. Gleevec tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4.
Patients should be informed to take Gleevec exactly as prescribed, not to change their dose or stop taking Gleevec unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose.
*For more detailed study information please see full Prescribing Information.
The foregoing release contains forward-looking statements that can be identified by terminology such as "estimated," "probably" or similar expressions, or by express or implied discussions regarding potential new indications or labeling for Gleevec, regarding the long-term impact of a patient's use of Gleevec, or regarding potential future revenues from Gleevec. 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 Gleevec to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Gleevec will be approved for any additional indications or labeling in any market. Neither can there be any guarantee regarding the long-term impact of a patient's use of Gleevec. Nor can there be any guarantee that Gleevec will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Gleevec 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; 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.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG which provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals and consumer health products. Novartis is the only company with leading positions in these areas. In 2008, the Group's continuing operations achieved net sales of USD 41.5 billion and net income of USD 8.2 billion. Approximately USD 7.2 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 96,700 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.us.novartis.com.
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