The latest results from two Phase III clinical trials establish the benefits of nilotinib (Tasigna?, Novartis) compared to imatinib mesylate tablets (Gleevec?, Novartis) 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 nilotinib after long-term treatment with Gleevec.

Findings from both studies were presented in oral sessions at the 54th annual meeting of the American Society of Hematology (ASH) in Atlanta GA, December 8 – 11, 2012.

ENESTcmr trial
Two-year results from ENESTcmr trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials ? Complete Molecular Response; NCT00760877) showed that switching to nilotinib led to deeper molecular responses in patients who still had evidence of residual disease after long-term therapy with imatinib mesylate [1]. More than twice as many patients treated with Tasigna continued to achieve undetectable BCR-ABL versus Gleevec.

Undetectable BCR-ABL
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 nilotinib achieved MR4.5 or undetectable BCR-ABL versus imatinib mesylate 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] “Nilotinib 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.

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Landmark analysis
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 nilotinib as frontline therapy instead of imatinib mesylate [7]. 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 survival [7].

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Efficacy and safety of ENESTnd
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 nilotinib, with the difference in favor of nilotinib 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].

Commitment
“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.”

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 design
ENESTcmr is an open-label, randomized, prospective, multi-center Phase III study of Tasigna 400 mg twice daily versus standard-dose imatinib mesylate (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: nilotinib 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 nilotinib or imatinib mesylate. 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-up [1].

ENESTnd study design
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 nilotinib versus imatinib mesylate 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 nilotinib 300 mg twice daily (n=282), nilotinib 400 mg twice daily (n=281) or imatinib mesylate 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 nilotinib in a separate extension study. These data, presented at ASH, were the 48-month minimum follow-up [7,10,11]

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 nilotinib 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.

References
[1] 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. Updated March 27, 2012. Last accessed September 25, 2012.
[5] Multicenter trial estimating the persistence of molecular remission in chronic myeloid leu
kemia in long term after stopping imatinib (STIM2). Trial identifier NCTO1343173. Updated June 13, 2012. Last 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) Last accessed October 2012.
[9] Central European Leukemia Study Group. About CML. Last 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. Updated July, 18, 2012. Last 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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