Novartis, a global healthcare leader, announced results from the phase 3b ENEST1st study in over 1,000 patients with newly-diagnosed, BCR-ABL positive chronic myeloid leukaemia (CML), confirming the benefits of first-line Tasigna treatment seen in earlier trials.

The final results of this large study, conducted in 26 European countries, were presented at the 20th Congress of the European Hematology Association (EHA) in Vienna.

"These results show patients with BCR-ABL positive CML in chronic phase receiving first-line treatment with Tasigna achieved rapid and high rates of molecular response and had a very low rate of progression to advanced disease," said Dr. Andreas Hochhaus, head of the department of haematology and medical oncology, Jena University Hospital, Germany.

"These findings from 26 countries, which are a collaboration of 307 trial sites and 14 standardized laboratories monitoring the incidence of MR4.0 as primary endpoint, confirm and complement data from the pivotal ENESTnd trial."

The primary endpoint in ENEST1st was the rate of Molecular Response 4 (MR4.0) at 18 months. MR4.0, which is a 4 log reduction in BCR-ABL, represents a very low level of detectable BCR-ABL, the cause of Ph+ CML (measured as BCR-ABL <=0.01 per cent on the International Scale [BCR-ABLIS] or undetectable BCR-ABL in cDNA with >=10,000 ABL transcripts).

At 18 months, 38.4 per cent of Tasigna-treated patients (n=1,052) reached MR4.0. These data demonstrate high rates of early and deep molecular response with Tasigna. The rate of disease progression in the study was low, with six patients, or 0.6 per cent, advancing to the accelerated phase/blast crisis stage of the disease. Despite the higher median age of patients in ENEST1st than in previous Tasigna studies, the safety results were consistent with the known safety profile of Tasigna. The most common adverse events (AE) were rash, itch and headache. Grade 3/4 AEs related to hepatotoxicity and pancreatitis occurred in 0.4 per cent and 0.6 per cent of patients, respectively. Grade 3/4 thrombocytopenia (low blood platelet count) and neutropenia (low white blood cell count) occurred in 6.0 per cent and 4.8 per cent of patients, respectively.

"Our commitment to CML remains strong and is exemplified by this trial, as well as further study of deep molecular response with Tasigna and the possibility for some patients with Ph+ CML to stop their treatment and achieve sustained treatment-free remission," said Bruno Strigini, president, Novartis Oncology. "In addition, we are developing new compounds with different mechanisms of action, which could help address the resistance to existing medications that some patients experience.

ENEST1st (Evaluating Nilotinib Efficacy and Safety Trial as First-Line Treatment) is a phase 3b, open-label study that evaluated the efficacy and safety of Tasigna 300 mg twice daily (BID) in a large population of adult patients with newly diagnosed CML-chronic phase (CP) using a network of 14 European Treatment and Outcome Study (EUTOS) standardized laboratories to monitor MR.

The study was conducted in 26 European countries with 1,089 patients treated. Specifically, 90.3 per cent of patients were Philadelphia chromosome positive (Ph+) and 97.0 per cent had typical BCR-ABL transcripts. Sokal risk scores were low, intermediate and high in 34.6 per cent, 37.5 per cent and 18.1 per cent of patients, respectively (9.8 per cent missing). EUTOS scores were low in 82.6 per cent and high in 8.6 per cent of patients (8.7 per cent missing). A total of 80.9 per cent of patients completed 24 months of treatment; 19.1 per cent discontinued early, most frequently due to AEs (10.7 per cent). The AEs seen in this study were consistent with the known safety profile of Tasigna. Thirteen patients (1.2 per cent) died by 24 months; of those 13 deaths, one was attributed to CML progression (16 months after study drug discontinuation).

The primary endpoint was the rate of MR4.0 (BCR-ABL <=0.01 per cent on the International Scale [BCR-ABLIS] or undetectable BCR-ABL in cDNA with >=10,000 ABL transcripts) at 18 months. The MR4.0 rate in all treated patients with <=3 months of prior Glivec treatment (n=1,052) was 38.4 per cent at 18 months and 40.4 per cent at 24 months. As assessed with multicenter molecular monitoring, MR rates in this study provided prospective confirmation of the centrally reviewed MR rates in the pivotal ENESTnd study. In ENESTnd, Tasigna demonstrated higher rates of early and deeper sustained molecular response, including MR4.5, and a reduced risk of progression compared to Glivec.

Consistent with prior studies, ENEST1st demonstrated the importance of early molecular response to frontline treatment. Molecular testing can vary in countries around the world, thus reinforcing the importance of these consistent findings. Patients with BCR-ABL1IS <= 1 per cent at 3 months achieved the highest rates of MMR, MR4.0, and MR4.5 at later time points, while no patient with BCR-ABL1IS > 10 per cent at 3 months achieved MR4.0 by 24 months.

Within the study duration of two years, the most common AEs of any cause were rash (21.4 per cent), itch (16.5 per cent), and headache (15.2 per cent). Study investigators conclude relatively low rates of these AEs may reflect improvements in the management of Tasigna-treated patients. Peripheral artery disease (PAD) occurred in 1.9 per cent of patients, ischemic heart disease (IHD) in 3.4 per cent, and ischemic cerebrovascular conditions (ICVE) in 0.8 per cent; 0.6 per cent of patients had excess fluid around the lung. These findings are consistent with what was seen in ENESTnd at the same duration of therapy. The most frequently observed grade 3/4 biochemical abnormalities were decreased phosphate (14.3 per cent) and increased lipase (7.2 per cent); glucose and lipid monitoring was not mandated in the study protocol.

Tasigna (nilotinib) is approved in more than 110 countries for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML) in adult patients resistant or intolerant to at least one prior therapy, including Glivec (imatinib), and in more than 85 countries for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase.