Novartis presents finding from the ENEST (Evaluating Nilotinib Efficacy and Safety in clinical Trials) clinical research programme at the 53rd Annual Meeting of the American Society of Haematology (ASH) in San Diego.

The phase III clinical trial data which contributes to the growing evidence that adult patients with Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in chronic phase who are treated with Tasigna (nilotinib) have deeper levels of response compared to those treated with Glivec (imatinib).

Tasigna (nilotinib) is 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 Glivec, and for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase. Tasigna should be taken twice daily 12 hours apart. Tasigna should not be taken with food and no food should be consumed for two hours after dosing. Patients taking Tasigna should avoid grapefruit juice and CYP3A4 inhibitors.

ENESTcmr is the first exploratory randomized trial to investigate the impact of switching adult patients with residual disease after a minimum of two years of treatment with Glivec to Tasigna to determine if a deeper level of response could be achieved.

The study showed that twice as many patients switched to Tasigna 400 mg twice a day achieved undetectable Bcr-Abl levels by 12 months compared to Glivec (23% taking Tasigna 400 mg twice daily and 11% taking Glivec 400 mg or 600 mg once daily; p= 0.0202). The primary endpoint, which is more stringent than conventional measures, is undetectable Bcr-Abl level in two consecutive samples. Samples with any detectable level were not considered to be in complete molecular response (CMR). The lowest detected Bcr-Abl value was 0.00073%. This endpoint showed a two-fold difference in confirmed undetectable CMR for 13% of patients on Tasigna versus 6% of patients on Glivec, although statistical significance was not achieved (p=0.108). The study has a planned follow-up of four years.

After 36 months of follow-up, data from the phase III ENESTnd clinical trial in adult patients with newly diagnosed Ph+ CML in chronic phase continued to show significantly more patients achieved CMR, defined in this study as at least a 4.5 log reduction from baseline or a trace amount of 0.0032% or less of Bcr-Abl compared to Glivec (32% taking Tasigna 300 mg twice daily and 15% taking Glivec 400 mg once daily). The ENESTnd study also continued to show that first-line treatment with Tasigna resulted in significantly fewer patients progressing to advanced phase and blast crisis (AP/BC) stages of disease compared to Glivec, leading to a significantly lower number of CML-related deaths in patients taking Tasigna versus Glivec (p=0.0356).

“Data from both ENESTnd and ENESTcmr reinforce that patients taking Tasigna have a greater chance of achieving CMR, the deepest level of response measurable today, compared to those taking Glivec,” said Timothy P Hughes, MD, ENEST study investigator and Clinical Professor at the University of Adelaide, Australia. “We are encouraged by what we saw in ENESTcmr and further follow-up on both trials should help to determine if more patients can reach undetectable levels of CML over time, which could have important implications for determining criteria for future studies on discontinuation of therapy.”

CML is a disease in which the body produces cancerous white blood cells. Almost all patients with CML have an abnormality known as the Philadelphia chromosome, which is comprised of a protein called Bcr-Abl that causes malignant white blood cells to proliferate. The success of treatment for CML can be measured by a test called real-time quantitative polymerase chain reaction (RQ-PCR). A molecular response means RQ-PCR shows a reduction in Bcr-Abl in the blood; a CMR means no Bcr-Abl is detected. In recent investigator-initiated studies, select patients who achieved durable CMR have been able to cease therapy without relapse for trial periods lasting from six months to a year.

“Data from the ENESTnd 36-month update and the ENESTcmr trial at ASH continue to reinforce the benefits of Tasigna over Glivec, and support the use of Tasigna for adult patients with chronic-phase Ph+ CML,” said Hervé Hoppenot, president, Novartis Oncology. “We look forward to even more progress in the future as we observe the impact of achieving deep and sustained molecular response with Tasigna for people living with this cancer.”

ENESTcmr is an open-label, randomized, prospective, multi-centre phase III study of Tasigna 400 mg twice daily versus standard-dose Glivec (400 mg or 600 mg once daily) comparing kinetics of CMR 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 leukaemia) after at least two years of treatment with Glivec. The study enrolled 207 patients. The patients were randomized into one of two treatment arms: Tasigna 400 mg twice daily versus continuing Glivec 400 mg or 600 mg once daily (same dose as at study entry).

The primary endpoint was the rate of confirmed best cumulative CMR by 12 months of study therapy with Tasigna or Glivec. Samples with any detectable level were considered not to be in CMR. The lowest detected Bcr-Abl value was 0.00073%. Secondary objectives included the kinetics of CMR, duration of CMR, progression-free survival and overall survival in both arms. CMR was defined at three levels: CMR (CMR =4.5-log, undetectable Bcr-Abl by RQ-PCR at a sensitivity of less than 0.0032%), CMR4 (CMR =4-log, undetectable Bcr-Abl by RQ-PCR at a sensitivity of 0.01% or less) and CMR4.5 (CMR =4.5-log, undetectable Bcr-Abl by RQ-PCR at a sensitivity of 0.0032% or less).

These data showed that 23% of patients taking Tasigna achieved undetectable disease (24 patients) by 12 months compared to 11% (11 patients) taking Glivec.

A majority of patients in both treatment arms received prior Glivec treatment for at least three years before entering the trial. Patients randomized to receive Tasigna were given a new treatment while the others continued to receive a therapy that they had been taking for a minimum of two years.

During this study, discontinuation due to adverse events occurred in 8.9% and 1% for Tasigna- and Glivec-treated patients, respectively. The majority of these were asymptomatic laboratory adverse events. The adverse events seen in ENESTcmr were similar to other studies for patients switched from chronic Glivec therapy to Tasigna.

ENESTnd is a phase III randomized, open-label, multi-centre trial comparing the efficacy and safety of Tasigna versus Glivec 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 Glivec 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 Glivec 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 36-month minimum follow-up.

Results showed that fewer patients in the core treatment group progressed to accelerated phase or blast crisis while on treatment with Tasigna at 300 mg twice daily (n=2) and 400 mg twice daily (n=3) versus Glivec at 400 mg once daily (n=12) with 36 months of minimum follow-up. Analysis of the broader study group, including patients followed after discontinuation of the study, showed 9 patients on Tasigna 300 mg twice daily, 6 patients on Tasigna 400 mg twice daily and 19 patients on Glivec progressed.

Over the past three years a total of 38 patients (5%) died during the ENESTnd study (17 patients taking Glivec, 13 taking Tasigna 300 mg twice daily and 8 taking Tasigna 400 mg twice daily). Tasigna treatment was also associated with significantly lower rates of CML-related deaths (5 patients taking Tasigna 300 mg twice daily, 4 patients taking Tasigna 400 mg twice daily and 14 patients taking Glivec) consistent with the significant improvement observed with progression to AP/BC. Since the last data cut-off there were a total of five CML related deaths (4 with Glivec 400 mg once daily and 1 with Tasigna 400 mg twice daily).

The median follow-up for this study was 36 months. Overall, 90% and 88% of patients remained in the study on Tasigna 300 mg twice daily and Glivec 400 mg once daily, respectively.

Rates of discontinuation due to adverse events or laboratory abnormalities continued to be lowest for Tasigna 300 mg twice daily (10%) compared to Tasigna 400 mg twice daily (14%) and Glivec 400 mg once daily (11%).