Novartis long-term Phase III data show Ph+ CML patients on Tasigna® achieved significantly deeper molecular response versus Gleevec®

EAST HANOVER, N.J., Dec. 10, 2012 /PRNewswire/ -- The latest results from two Phase III clinical trials further establish the benefits of Tasigna^® (nilotinib) compared to Gleevec^® (imatinib mesylate) tablets* in the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in newly diagnosed patients and in those with residual disease who switched to Tasigna after long-term treatment with Gleevec.

Findings from both studies were presented in oral sessions at the 54^th annual meeting of the American Society of Hematology (ASH) in Atlanta.

Two-year results from ENESTcmr showed that switching to Tasigna led to deeper molecular responses** in patients who still had evidence of residual disease after long-term therapy with Gleevec¹. More than twice as many patients treated with Tasigna continued to achieve undetectable BCR-ABL versus Gleevec. The difference between groups by 24 months was statistically significant (22.1% vs. 8.7%; p=0.0087) and that difference has doubled since the 12-month analysis. Significantly more patients treated with Tasigna achieved MR4.5 or undetectable BCR-ABL versus Gleevec regardless of the BCR-ABL transcript level at baseline¹. In studies published to date, no patients achieving and maintaining MR4.5 have progressed to advanced stages of CML^2,3,4,5,6.

"Tasigna should be considered as a leading option for frontline therapy because it allows many patients to achieve deeper responses earlier, which we have associated with improved long-term outcomes," said Timothy P. Hughes, MD, ENEST study investigator, Head of the Department of Haematology at Royal Adelaide Hospital and Clinical Professor at the University of Adelaide, Australia.

Also presented at ASH are the results of a four-year landmark analysis from ENESTnd which showed that more than three times as many patients achieved early molecular response (reduction in BCR-ABL transcript levels to less than or equal to 10% at months three and six) with Tasigna as frontline therapy instead of Gleevec⁷. The investigators correlated early molecular response with future major molecular response (MMR) and MR4.5, as well as an increased probability of progression-free survival and overall survival⁷.

In a separate four-year analysis of efficacy and safety data from ENESTnd also presented at ASH, the difference in the rates of both MR4 and MR4.5 continued to be significantly higher for Tasigna, with the difference in favor of Tasigna increasing over time (MR4: 9-14% difference by one year, 17-24% difference by four years; MR4.5: 6-10% difference by one year, 14-17% difference by four years)⁷. Overall survival remained similar in all groups at four years, but fewer CML-related deaths occurred in both the Tasigna 300 mg twice daily (n=5) and 400 mg twice daily (n=4) arms versus Gleevec (n=13)⁷.

"We are encouraged by the continued strong findings from newly-presented CML data at ASH," said Herve Hoppenot, President, Novartis Oncology. "Our dedication to ongoing research in CML over the past decades has helped to transform the disease from a fatal diagnosis to a chronic condition. We are now starting the next chapter in our commitment to helping patients with this disease by exploring in Tasigna clinical trials the idea that some patients may be able to safely stop therapy after achieving sustained and deep molecular response."

Novartis Commitment to CML
Novartis Oncology helped pioneer the transformation of Ph+ CML to a treatable, chronic condition. As an industry leader in CML, Novartis is committed to furthering the understanding of this disease and to redefining once again what is possible for the future of Ph+ CML. The company plans to initiate in early 2013 a robust clinical trial program evaluating the possibility of treatment-free remission in CML, which means sustaining deep molecular response after stopping therapy. Nine treatment-free studies are planned to be conducted in study centers across more than 50 countries.

Worldwide, CML is responsible for a little over 10% of all adult cases of leukemia, with an incidence of one to two cases per 100,000 people per year^8,9.

ENESTcmr study details
ENESTcmr (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Complete Molecular Response) is an open-label, randomized, prospective, multi-center Phase III study of Tasigna 400 mg twice daily versus standard-dose Gleevec (400 mg or 600 mg once daily) comparing kinetics of molecular response for patients with Ph+ CML in chronic phase who had achieved complete cytogenetic response (CCyR) but were still BCR-ABL positive (i.e., had evidence of residual leukemia) after at least two years of treatment with Gleevec. The study enrolled 207 patients. The patients were randomized into one of two treatment arms: Tasigna 400 mg twice daily versus continuing Gleevec 400 mg or 600 mg once daily (same dose as at study entry)¹.

The primary endpoint was the rate of confirmed best complete molecular response by 12 months of study therapy with Tasigna or Gleevec. Secondary objectives included the kinetics of molecular response, duration of molecular response, progression-free survival and overall survival in both arms. These data, presented at ASH, were the 24-month follow-up¹.

More than twice as many patients treated with Tasigna continued to achieve undetectable BCR-ABL versus Gleevec.  The difference between groups by 24 months was statistically significant (22.1% vs. 8.7%; p=0.0087). Compared to the 12-month analysis, the difference between the treatment arms doubled over time from 6.7% to 13.4%. Among patients without documented MR4.5 at baseline, cumulative incidence of MR4.5 was over twice as high in Tasigna-treated patients versus those who stayed on Gleevec (42.9% vs. 20.8%; p=0.0006) and the difference increased over time from 12 to 24 months. Significantly more patients treated with Tasigna achieved MR4.5 versus Gleevec regardless of the BCR-ABL transcript level at baseline. In patients without documented MMR, MR4 and MR4.5 at baseline, the differences were superior in all subsets (29.2% vs. 3.6%; p=0.016; 31.1% vs. 11.5%; p=0.003 and 42.9% vs. 20.8%; p=0.0006, respectively)¹.

ENESTnd study details
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^7,10,11.

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 RQ-PCR. Planned follow-up is for five years. Patients on the Gleevec treatment arm who had suboptimal response or treatment failure were allowed to escalate dose and/or switch to Tasigna in a separate extension study. These data, presented at ASH, were the 48-month minimum follow-up^7,10,11.

The ENESTnd landmark analysis was based on BCR-ABL transcript levels at three and six months using data with a minimum follow-up of four years. The Tasigna 300 mg BID (n=282) and Gleevec 400 mg QD (n=283) treatment arms were used for the analysis. Rates of MMR, MR4.5, progression-free survival and overall survival were evaluated among patients grouped according to their BCR-ABL transcript levels of less than or equal to 1%, >1% to less than or equal to 10%, and >10% at three and six months. Among evaluable patients at three months, 9% of patients (n=24) in the Tasigna arm versus 33% (n=88) in the Gleevec arm had BCR-ABL transcript levels of >10%. Patients with a BCR-ABL transcript level of >10% had a significantly lower probability of future MMR or MR4.5 as well as poorer progression-free survival and overall survival compared with patients who had BCR-ABL transcript levels less than or equal to 10% at three months. Fewer patients in the Tasigna arm versus the Gleevec arm had BCR-ABL transcript levels >10% at three and six months. Early molecular response at three and six months correlated with future MMR and MR4.5 as well as an increased probability of progression-free survival and overall survival⁷.

The four-year ENESTnd update found continued significantly higher rates of MMR, MR4 and MR4.5 by three years were achieved in Tasigna versus Gleevec-treated patients. The difference in the rates of both MR4 and MR4.5 continued to be significantly higher for Tasigna, with the difference in favor of Tasigna increasing from year one to year four (MR4: 9-14% difference by one year, 17-24% difference by four years; MR4.5: 6-10% difference by one year, 14-17% difference by four years). Among patients who achieved MMR, more patients achieved MR4 or MR4.5 on Tasigna 300 mg twice daily (68%) and Tasigna 400 mg twice daily (62%) compared with Gleevec (49%). No patient in any arm progressed after achieving MR4.5. Significantly fewer patients progressed to accelerated phase/blast crisis on Tasigna versus Gleevec. Nearly twice as many patients had emergent mutations on Gleevec (n=21) versus either Tasigna arm (n=11 in each arm), with five patients overall developing mutations between two and three years. Overall survival remained similar in all groups at three years, but fewer CML-related deaths occurred in both the Tasigna 300 mg twice daily (n=5) and 400 mg twice daily (n=4) arms versus Gleevec (n=14). Both drugs were well tolerated. Few new adverse events (AEs) and laboratory abnormalities were observed between two and three years. Rates of discontinuation due to AEs were 10%, 14%, and 11% in the Tasigna 300 mg BID, Tasigna 400 mg BID, and Gleevec arms, respectively¹¹.

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.

BOXED WARNING and Important Safety Information for TASIGNA (nilotinib):

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.

Caution is recommended in patients with a history of pancreatitis.

The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase.

TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia (see Boxed WARNING).

The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. Grapefruit products should also be avoided. 

The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's wort).

TASIGNA must not be taken with food.

TASIGNA exposure is increased in patients with impaired hepatic function.

Cases of tumor lysis syndrome have been reported in TASIGNA treated patients with resistant or intolerant CML. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA.

The exposure of TASIGNA is reduced in patients with total gastrectomy.

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.

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. The safety and effectiveness of TASIGNA in pediatric patients have not been established.

In newly diagnosed Ph+ CML-chronic phase, the most commonly reported nonhematologic adverse drug reactions (>10%) were rash, pruritus, headache, nausea, fatigue, and myalgia.

In resistant or intolerant Ph+ CML-chronic phase, the most commonly reported nonhematologic adverse drug reactions (greater than or equal to 10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting, and myalgia.

In resistant or intolerant Ph+ CML-accelerated phase, the most commonly reported nonhematologic adverse drug reactions (greater than or equal to 10%) were rash, pruritus, and fatigue.

TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic 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 terminology such as "planned," "expected," "will," "potential," "can," "may," "would," "recommend," "expected," or similar expressions, or by express or implied discussions regarding potential new business opportunities. 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 to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that any such business opportunities will develop in the manner, scale or time frame anticipated. In particular, management's expectations 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; competition in general; government, industry and general public pricing pressures, and unexpected reimbursement decisions; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; 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 127,000 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. Hughes TP, Lipton JH, Spector N et al. Switching to Nilotinib Associated with Continued Deeper Molecular Responses in CML-CP Patients with Minimal Residual Disease After > to 2 Years on Imatinib: ENESTcmr 2-Year Follow-Up Results. ASH abstract #694, 2012.
2. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12(9):841-851.
3. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119(5):1123-1129.
4. Discontinuation study of imatinib in adult CP CML patients who have a complete molecular response to imatinib. Trial identifier NCT01564836. http://www.clinicaltrials.gov. Updated March 27, 2012. Accessed September 25, 2012.
5. Multicenter trial estimating the persistence of molecular remission in chronic myeloid leukemia in long term after stopping imatinib (STIM2). Trial identifier NCTO1343173. http://www.clinicaltrials.gov. Updated June 13, 2012. Accessed September 25, 2012.
6. Shami PJ, Deininger M. Evolving treatment strategies for patiensnewly diagnosed with chronic myeloid leukemia: the role of second-generation BCR-ABL inhibitors as first-line therapy. Leukemia. 2012;26(2):214-224.
7. Hochhaus A, Hughes TP, Saglio G et al. Outcome of Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Based on Early Molecular Response and Factors Associated with Early Response: 4-Year Follow-up Data from ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Newly Diagnosed Patients). ASH abstract #167, 2012.
8. American Cancer Society. Detailed Guide: CML. What are the key statistics about CML? (09/07/2012  Revision) Available at: http://www.cancer.org/Cancer/Leukemia-ChronicMyeloidCML/DetailedGuide/leukemia-chronic-myeloid-myelogenous-key-statistics. Accessed October 2012.
9. Central European Leukemia Study Group. About CML. Available at: http://www.cml-info.com/de/healthcare-professionals/about-cml.html. Accessed October 2012.
10. A Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) (ENESTnd). Trial identifier NCT00471497.  http://www.clinicaltrials.gov. Updated July, 18, 2012. Accessed November 20, 2012.
11. Kantarjian HM, Kim DW, Issaragrilsil S et al. ENESTnd 4-Year (y) Update: Continued Superiority of Nilotinib vs Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome–Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP). ASH abstract #1676, 2012.

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

**In ENESTcmr, molecular response (reduction of BCR-ABL transcripts in the blood of patients) is measured at four levels, based on an international standard:

• MMR (less than or equal to 0.1% BCR-ABL)
• MR4 (less than or equal to 0.01% BCR-ABL)
• MR4.5 (less than or equal to 0.0032% BCR-ABL)
• Undetectable BCR-ABL (no detectable BCR-ABL transcript level with sample sensitivity of at least 4.5 log)

SOURCE Novartis