Six-year pivotal study data reinforce the superiority of Tasigna® over Gleevec® in newly-diagnosed patients with Ph+ CML
- Fewer patients on Tasigna vs. Gleevec had their leukemia progress to advanced stage, a key goal of treatment in CML and important clinical benefit (1)
- Patients on Tasigna had higher rates of early, deep and sustained molecular response, including MR4.5 (1), a very low level of the protein that causes Ph+ CML
- ENESTnd six-year data confirm the favorable risk/benefit profile of Tasigna vs. Gleevec in newly-diagnosed CML patients
EAST HANOVER, N.J., Dec. 8, 2014 /PRNewswire/ -- Six-year results from the randomized Phase III ENESTnd study continue to demonstrate the superiority of Tasigna® (nilotinib) compared to Gleevec® (imatinib mesylate)[*] at achieving higher rates of early, deep and sustained molecular responses in newly-diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) patients1. The six-year update from the ENESTnd trial was presented at the 56th annual meeting of the American Society of Hematology (ASH) in San Francisco.
"At the ENESTnd six-year follow up, we still see consistent evidence of deeper molecular response and fewer progressions to advanced disease in patients taking Tasigna compared to those on Gleevec," said Giuseppe Saglio, MD, ENEST studies investigator, Professor of Internal Medicine and Haematology and Director of the Department of Molecular Medicine and Targeted Therapy, San Luigi University Hospital at the University of Turin, Orbassano, Italy. "These data provide further evidence of the consistent clinical profile of Tasigna as a leading treatment in newly-diagnosed patients."
The six-year data demonstrated higher rates of early and deeper sustained molecular response with Tasigna, including MR4.5, and a reduced risk of progression compared to Gleevec1. The difference in the rates of MR4.5 showed continued improvement for both Tasigna 300 mg and 400 mg twice-daily arms compared to Gleevec (MR4.5: 6-10% difference by one year, 22-23% difference by six years)1. MR4.5 represents an extremely low level of detectable BCR-ABL protein, the cause of Ph+ CML (measured in the blood at 0.0032% or less on a standardized International Scale). A higher proportion of patients in the Tasigna arms versus the Gleevec arm achieved BCR-ABLIS </= 10% at 3 months1.
Further, there were fewer progressions to accelerated phase/blast crisis (AP/BC) with Tasigna versus Gleevec1. Sixteen patients treated with Gleevec had CML-related deaths, compared to 6 and 4 patients on the Tasigna 300 mg and 400 mg twice-daily arms, respectively1. The safety profile of Tasigna remained consistent with previous reports. The most common adverse events were rash, headache, ALT increase and nausea, and the cardiovascular events rates were higher in the Tasigna arms compared to Gleevec1.
"Fifteen years ago at ASH, our first pivotal CML data were presented, representing the start of a revolutionary shift in the treatment of patients with this disease. Through our ongoing research, we better understand today the role that early, deep and sustained molecular responses have on the outcomes of patients with CML," said Bruno Strigini, President, Novartis Oncology. "We are now taking this knowledge a step further by exploring deeper molecular response like MR4.5 and the impact it may have on how we treat CML in the future."
Novartis Commitment to CML
Over the past several decades, Novartis research in Ph+ CML has helped transform the disease from a fatal leukemia to a chronic condition and today, the company continues its long-standing commitment to the global CML community. Two of the ENEST treatment-free remission (TFR) studies ENESTfreedom and ENESTop, which will evaluate the feasibility of stopping treatment, and achieving successful TFR and deep molecular response on Tasigna in patients with CML in the chronic phase, have completed enrollment.
Stopping treatment is not a clinical recommendation and should only be attempted in the context of a well-controlled clinical study2. A very important part of these TFR studies is the inclusion of regular molecular monitoring with International Scale Real-Time Quantitative Polymerase Chain Reaction (IS RT-Q-PCR) testing. Once treatment is stopped, molecular monitoring is used to identify if a patient's level of disease remains in deep molecular response or if the reintroduction of treatment is needed3.
ENESTnd study details1
ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients) is a Phase III, randomized, open-label, multicenter trial comparing the efficacy and safety of Tasigna versus Gleevec in adult patients with newly diagnosed Ph+ CML in chronic phase. It is the largest global randomized comparison of two oral therapies ever conducted in newly-diagnosed Ph+ CML patients.
The study is being conducted at 217 global sites with 846 patients enrolled. Patients were randomized to receive Tasigna 300 mg twice daily (n=282), Tasigna 400 mg twice daily (n=281) or Gleevec 400 mg once daily (n=283). The primary endpoint was major molecular response (MMR) at 12 months; the key secondary endpoint was durable MMR at 24 months (patients having MMR when evaluated at both 12 and 24 months). MMR was defined in this study as 0.1% or less of BCR-ABL as measured by IS RT-Q-PCR. Patients on the Tasigna 300 mg twice-daily arm or on the Gleevec treatment arm who had suboptimal response or treatment failure were allowed to escalate dose and/or switch to Tasigna 400 mg twice daily in a separate extension study. These data, presented at ASH, were the six-year (defined as 72 cycles of 28 days) follow up.
The six-year ENESTnd update found that higher rates of MMR and MR4.5 by six years were achieved in Tasigna versus Gleevec-treated patients. The difference in the rates of MMR and MR4.5 continued to be higher for both Tasigna 300 mg and 400 mg twice-daily arms compared to Gleevec (MMR: 24-28% difference by one year, 16-18% difference by six years; MR4.5: 6-10% difference by one year, 22-23% difference by six years). Fewer patients progressed to AP/BC on Tasigna versus Gleevec. The estimated rates of patients whose disease did not progress to AP/BC on study at 72 months in the Gleevec, Tasigna 300 mg and Tasigna 400 mg twice-daily arms were 92.2%, 95.8% and 97.8%, respectively. The estimated rates of patients on study who are alive (OS) at 72 months in the Gleevec, Tasigna 300 mg and Tasigna 400 mg twice-daily arms were 91.4%, 91.6% and 95.8%, respectively. The estimated rates of freedom from death due to a CML-related cause at 72 months in the Gleevec, Tasigna 300 mg and Tasigna 400 mg twice-daily arms were 93.9%, 97.7% and 98.5%, respectively. More patients in the Tasigna arms (n=234 and 232 for 300mg and 400 mg arms respectively) versus the Gleevec arm (n=176) achieved BCR-ABLIS </= 10% at 3 months. The safety profile of Tasigna remained consistent with previous reports. The most common adverse events were rash, headache, ALT increase and nausea. Although cardiovascular events rates were higher in the Tasigna arms compared to Gleevec, fewer progressions to AP/BC, or death from CML were reported in the Tasigna arms compared to Gleevec.
About Tasigna
TASIGNA® (nilotinib) is approved for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA for this indication is based on major molecular response and cytogenetic response rates at 12 months. The study is ongoing and further data will be required to determine long-term outcome.
TASIGNA is also approved in more than 90 countries for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant or intolerant to at least one prior therapy, including Gleevec. The effectiveness of TASIGNA for this indication is based on hematologic and cytogenetic response rates.
IMPORTANT SAFETY INFORMATION for TASIGNA® (nilotinib) Capsules
WARNING: QT PROLONGATION AND SUDDEN DEATHS
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- Myelosuppression: Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter
- Cardiac and Vascular Events: Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported
- Pancreatitis and Elevated Serum Lipase: TASIGNA can cause increases in serum lipase. Caution is recommended in patients with a history of pancreatitis
- Hepatotoxicity: The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase
- Electrolyte Abnormalities: TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia
- Drug Interactions: The concomitant use of strong CYP3A4 inhibitors or anti -arrhythmic drugs and other drugs that may prolong the QT interval should be avoided. Grapefruit products should also be avoided
- The concomitant use of strong CYP3A4 inducers should be avoided. The concomitant use of proton pump inhibitors with TASIGNA is not recommended
- When the concurrent use of a H2 blocker is necessary, administer approximately 10 hours before and approximately 2 hours after the TASIGNA dose. If necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the TASIGNA dose
- Food Effects: TASIGNA must be taken on an empty stomach. No food should be consumed for at least 2 hours before the dose and for at least 1 hour after the dose is taken
- Hepatic Impairment: TASIGNA exposure is increased in patients with impaired hepatic function
- Tumor Lysis Syndrome: Cases of tumor lysis syndrome have been reported in TASIGNA-treated patients who were resistant or intolerant to prior CML therapy. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA
- Total Gastrectomy: The exposure of TASIGNA is reduced in patients with total gastrectomy
- Lactose: Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption
- Monitoring Laboratory Tests: Chemistry panels, including electrolytes, calcium, magnesium, lipid profile, and glucose should be checked prior to therapy and periodically
- Embryo-Fetal Toxicity: Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do
- ADVERSE REACTIONS: The most commonly reported non-hematologic adverse reactions (≥20% in patients) were nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats. Hematologic adverse drug reactions include myelosuppression: thrombocytopenia, neutropenia and anemia
- DOSE ADJUSTMENTS OR MODIFICATIONS: TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematologic toxicities that are not related to underlying leukem ia, clinically significant moderate or severe non hematologic toxicities, laboratory abnormalities or concomitant use of strong CYP3A4 inhibitors
Please see full Prescribing Information including Boxed WARNING.
About Gleevec
Gleevec® (imatinib mesylate) tablets are indicated for newly diagnosed adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase (CP). Gleevec is also indicated for the treatment of patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in CP after failure of interferon-alpha therapy.
GLEEVEC Important Safety Information
GLEEVEC can cause fetal harm when administered to a pregnant woman. Women 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. Caution patients about driving a car or operating machinery.
Almost all patients 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 words such as "goal," "ongoing," "exploring," "may," "commitment," "continues," "will," "being conducted," or similar terms, or by express or implied discussions regarding potential new indications or labeling for Tasigna or Gleevec, or regarding potential future revenues from Tasigna and Gleevec. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Tasigna or Gleevec will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that Tasigna and Gleevec will be commercially successful in the future. In particular, management's expectations regarding Tasigna and Gleevec could be affected by, among other things, the uncertainties inherent in research and development, including unexpected clinical trial results and additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing pressures; unexpected manufacturing issues, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. 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, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2013, the Group achieved net sales of USD 57.9 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 133,000 full-time-equivalent associates and sell products in more than 150 countries around the world. For more information, please visit http://www.novartis.com.
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References
- Larson, R, et al. Efficacy and Safety of Nilotinib (NIL) vs Imatinib (IM) in Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Long-Term Follow-Up (f/u) of ENESTnd. Poster Presentation. Abstract #4541. 54th Annual Meeting of the American Society of Hematology. 2014. San Francisco, Calif.
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia, V1.2014. Available at: http://www.nccn.org/patients/guidelines/cml
- Kim, D. Recent advances in the path toward the cure for chronic myeloid leukemia. The Korean Journal of Hematology. 2011; 46(3), 169-174.
[*]Known as Glivec® (imatinib) outside the US, Canada and Israel.
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