The European Commission has approved nilotinib (Tasigna?, Novartis) as a treatment for adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

Nilotinib is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in the chronic phase. The new agent has also been approved in over 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 imatinib (Glivec?; known as Gleevec? in the USA, Canada and Israel)[8]. The effectiveness of nilotinib for this indication is based on confirmed hematologic and unconfirmed cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

The approval from the European Commission followed a positive opinion from the Committee for Medicinal Products for Human Use (CHMP). It is based on findings from a pivotal Phase III trial demonstrating superiority to the standard of care imatinib in achieving molecular and cytogenetic response and delaying cancer progression. These data were first published in the June 17 issue of The New England Journal of Medicine [1] and were confirmed by 18-month median follow-up data presented at the 46th American Society of Clinical Oncology (ASCO) annual meeting held in June 2010 [2].

The US Food and Drug Administration (FDA), Swissmedic and Japan’s Ministry of Health, Labour and Welfare have also approved nilotinib in this first-line indication. Regulatory submissions are under review in other countries worldwide.

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“We are pleased that Tasigna is now approved for newly diagnosed Ph+ CML patients in chronic phase in the member states of the European Union,” said Herv? Hoppenot, President, Novartis Oncology. “With this expanded indication, newly diagnosed patients can benefit from a Bcr-Abl tyrosine kinase inhibitor that, according to pivotal data, surpassed the standard of care Glivec, in key measures of efficacy, including delaying disease progression at 12 months.”

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In laboratory studies, nilotinib has been shown to be a potent and selective inhibitor of the Bcr-Abl protein that causes production of cancer cells in Ph+ CML,[3]. It has also been shown to be active against a broad spectrum of Bcr-Abl mutations associated with resistance to imatinib [4].

In its pivotal head-to-head trial, nilotinib surpassed imatinib in key measures of treatment efficacy, as has been reported. nilotinib eliminated Bcr-Abl faster and more deeply than imatinib and resulted in lower rates of cancer progression after 12 months of therapy[1]. Major molecular response (MMR), a measure of deep reduction in Bcr-Abl, is considered to be a critical therapeutic milestone associated with good long-term outcomes for patients with Ph+ CML in chronic phase[5]-[7]. Treatment with nilotinib led to higher rates of both MMR and complete cytogenetic response (CCyR) (undetectable levels of the Philadelphia chromosome that is the hallmark of this cancer) compared with imatinib [1].

After a median of 18 months of follow-up treatment, two patients on the nilotinib 300 mg twice daily arm progressed to either accelerated phase or blast crisis while 17 patients on the imatinib arm progressed to either accelerated phase or blast crisis. In the study, nilotinib and imatinib were generally well tolerated. Fewer patients discontinued due to adverse events from the nilotinib 300 mg twice daily arm of the study compared to the imatinib 400 mg once daily arm.

The randomized, open-label, multicenter trial, called ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients), compared the efficacy and safety of nilotinib versus imatinib in adult patients with newly diagnosed Ph+ CML in chronic phase[1]. It is the largest global randomized comparison of two oral therapies ever conducted in newly diagnosed Ph+ CML patients in chronic phase.

This year, Novartis also began collaboration with molecular diagnostics company Cepheid to develop a new FDA cleared/approved Bcr-Abl test, which adheres to the International Scale. The goal of the collaboration is to help doctors more reliably monitor Ph+ CML patients. Cepheid and Novartis also will develop a next generation test, which is expected to enable even more sensitive testing, indicating the depth of a patient’s response to tyrosine kinase inhibitors, including nilotinib and imatinib. Currently, there are no FDA cleared/approved tests to monitor for Bcr-Abl.

Earlier this month nilotinib was also approved by Japan’s Ministry of Health, Labour and Welfare to offer as a treatment for adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

References:
[1] Saglio G, Kim D-W, Surapol Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9.
[2] Larson R, Philipp le Coutre, Reiffers J, Hughes T. et al. Nilotinib is Superior to Imatinib in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd Beyond One Year. Abstract # CRA6501. American Society of Clinical Oncology 2010 Annual Meeting
[3] le Coutre P, Ottmann OG, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or-intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008 Feb 15;111(4):1834-9.
[4] Swords R, Mahalingam D, Padmanabhan S, et al. Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib. Drug Des Devel Ther. 2009 Sep 21;3:89-101
[5] Hochhaus A, O’Brien SG, Guilhot F,et al. IRIS Investigators. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009 Jun;23(6):1054-61.
[6] M?ller MC, Hanfstein B, Erben P, et al. Molecular response to first line imatinib therapy is predictive for long term event free survival in patients with chronic phase chronic myelogenous leukemia – an interim analysis of the randomized German CML Study IV. Blood (ASH Annual Meeting Abstracts) 2008, 112: Abstract 333.
[7] Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009 Dec 10;27(35):6041-51.
[8] Glivec? (imatinib) prescribing information. Basel, Switzerland: Novartis International AG; March 2009

For more information:
[9] Summary of Product Characteristics (Nilotinib, Tasigna?)
[10] EPAR Summary for the Public.

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