Date: 2014-12-08
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition, being held December 6-9 in San Francisco, CA
Company: Novartis (Switzerland)
Product: Tasigna® (nilotinib)
Action
mechanism: Tasigna® (nilotinib) is an orally available signal transduction inhibitor of the Bcr-Abl kinase, c-kit and Platelet Derived Growth Factor (PDGF), all of which play a role in cell proliferation, cell migration, and angiogenesis.
Disease: Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase
Therapeutic area: Cancer - Oncology
Country:
Trial
details: ENESTcmr is an open-label, randomized, prospective, multi-center 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 leukemia) 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 greater than or equal to 4.5-log, undetectable Bcr-Abl by RQ-PCR at a sensitivity of less than 0.0032%), CMR4 (CMR greater than or equal to 4-log, undetectable Bcr-Abl by RQ-PCR at a sensitivity of 0.01% or less) and CMR4.5 (CMR greater than or equal to 4.5-log, undetectable Bcr-Abl by RQ-PCR at a sensitivity of 0.0032% or less).
ENESTnd is a Phase III randomized, open-label, multicenter 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
Latest
news: * On December 8, 2014, Novartis announced that six-year results from the randomized Phase III ENESTnd study continue to demonstrate the superiority of Tasigna® (nilotinib) compared to Glivec® (imatinib) at achieving higher rates of early, deep and sustained molecular responses in newly-diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) patients. 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. 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 Glivec® The difference in the rates of MR4.5 showed continued improvement for both Tasigna 300 mg and 400 mg twice-daily arms compared to Glivec (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 Glivec arm achieved BCR-ABLIS <= 10% at 3 months. Further, there were fewer progressions to accelerated phase/blast crisis (AP/BC) with Tasigna versus Glivec®. Sixteen patients treated with Glivec® had CML-related deaths, compared to 6 and 4 patients on the Tasigna 300 mg and 400 mg twice-daily arms, respectively. 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 Glivec®. The six-year ENESTnd update found that higher rates of MMR and MR4.5 by six years were achieved in Tasigna® versus Glivec®-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 Glivec® (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 Glivec®. The estimated rates of patients whose disease did not progress to AP/BC on study at 72 months in the Glivec®, 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 Glivec®, 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 Glivec®, 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 Glivec® 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 Glivec®, fewer progressions to AP/BC, or death from CML were reported in the Tasigna® arms compared to Glivec®. * On December 12, 2011, Novartis announced that the findings from the ENEST (Evaluating Nilotinib Efficacy and Safety in clinical Trials) clinical research program were presented at the 53rd Annual Meeting of the American Society of Hematology (ASH) in San Diego. 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).
