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Nilotinib Vs Imatinib in Patients with Newly Diagnosed

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Nilotinib Vs Imatinib in Patients with Newly Diagnosed Leukemia (2012) 26, 2197–2203 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu ORIGINAL ARTICLE Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue RA Larson1, A Hochhaus2, TP Hughes3, RE Clark4, G Etienne5, D-W Kim6, IW Flinn7, M Kurokawa8, B Moiraghi9,RYu10, RE Blakesley10, NJ Gallagher11, G Saglio12 and HM Kantarjian13 Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients compares nilotinib and imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). With a minimum follow-up of 3 years, major molecular response, molecular response of BCR-ABLp0.01% expressed on the international scale (BCR-ABLIS;MR4) and BCR-ABLISp0.0032% (MR4.5) rates were significantly higher with nilotinib compared with imatinib, and differences in the depth of molecular response between nilotinib and imatinib have increased over time. No new progressions occurred on treatment since the 2-year analysis. Nilotinib was associated with a significantly lower probability of progression to accelerated phase/blast crisis vs imatinib (two (0.7%) progressions on nilotinib 300 mg twice daily, three (1.1%) on nilotinib 400 mg twice daily and 12 (4.2%) on imatinib). When considering progressions occurring after study treatment discontinuation, the advantage of nilotinib over imatinib in preventing progression remained significant (nine (3.2%) progressions on nilotinib 300 mg twice daily, six (2.1%) on nilotinib 400 mg twice daily and 19 (6.7%) on imatinib). Both nilotinib and imatinib were well tolerated, with minimal changes in safety over time. Nilotinib continues to demonstrate superior efficacy in all key response and outcome parameters compared with imatinib for the treatment of patients with newly diagnosed CML-CP. Leukemia (2012) 26, 2197–2203; doi:10.1038/leu.2012.134 Keywords: chronic myeloid leukemia; ENESTnd; nilotinib; imatinib; progression; newly diagnosed INTRODUCTION occurred within the first 3 years of treatment, indicating that this 5 Nilotinib (Tasigna; Novartis Pharmaceuticals Corporation, East represents an important milestone. This report presents the Hanover, NJ, USA) is a selective inhibitor of BCR-ABL and a more updated results of the ENESTnd trial for patients within this potent inhibitor than imatinib in vitro.1 Based on data from the important 3-year time frame. Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients (ENESTnd) phase 3 trial in which nilotinib MATERIALS AND METHODS demonstrated superiority over imatinib, nilotinib has been widely approved throughout the world for the treatment of patients Patients, study design and treatments 3,4 with newly diagnosed Philadelphia chromosome-positive (Ph þ ) Study criteria for eligibility have been extensively described previously. chronic myeloid leukemia in chronic phase (CML-CP).2 Written informed consent was obtained from each patient, and the study ENESTnd is an international, open-label, randomized study was conducted according to the ethical principles of the Declaration of Helsinki. As described previously, patients X18 years of age were eligible comparing the efficacy and safety of nilotinib 300 and 400 mg for this study if they had newly diagnosed Ph þ CML-CP within the twice daily and imatinib 400 mg once daily in patients with newly previous 6 months. A total of 846 patientsX18 years of age, with newly 3 diagnosed Ph þ CML-CP. In previous reports after 1 and 2 years diagnosed Ph þ CML-CP within the previous 6 months, were randomized of treatment, nilotinib demonstrated superior efficacy to imatinib to nilotinib 300 mg twice daily (n ¼ 282), nilotinib 400 mg twice daily with significantly faster and higher rates of complete cytogene- (n ¼ 281) or imatinib 400 mg once daily (n ¼ 283).3,4 Randomization was tic response (CCyR), major molecular response (MMR), deeper stratified according to Sokal risk score at the time of diagnosis.3,4 The study was registered at ClinicalTrials.gov (NCT00471497). molecular response of BCR-ABLp0.01% expressed on the inter- 3,4 national scale (BCR-ABLIS;MR4) and BCR-ABLIS 0.0032% (MR4.5).3,4 As described previously, patients in the imatinib arm could be dose- p escalated to 400 mg twice daily if they had a suboptimal response per Moreover, there were significantly lower rates of progression to investigator assessment and could receive nilotinib as part of a separate accelerated phase/blast crisis (AP/BC) and fewer CML-related extension study in the case of treatment failure.6 In contrast, nilotinib- deaths in the nilotinib arms when compared with imatinib. treated patients could not dose-escalate, although patients in the nilotinib The International Randomized Study of Interferon vs STI571 300 mg twice-daily arm could discontinue the study and also enter the trial showed that most disease progression events on imatinib extension study to receive nilotinib 400 mg twice daily for cases of 1University of Chicago, Chicago, IL, USA; 2Abteilung Ha¨matologie/Onkologie, Universita¨tsklinikum Jena, Jena, Germany; 3Royal Adelaide Hospital, SA Pathology, Adelaide, Australia; 4Royal Liverpool University Hospital, Liverpool, UK; 5Institut Bergonie´, Bordeaux, France; 6Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea; 7Sarah Cannon Research Institute, Nashville, TN, USA; 8University of Tokyo, Tokyo, Japan; 9Hospital Jose Maria Ramos Mejia, Buenos Aires, Argentina; 10Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 11Novartis Pharma AG, Basel, Switzerland; 12University of Turin, Orbassano, Italy and 13MD Anderson Cancer Center, The University of Texas, Houston, TX, USA. Correspondence: RA Larson, University of Chicago, 5841S Maryland Avenue, MC2115, Chicago, IL 60637, USA. E-mail: [email protected] Received 1 May 2012; accepted 3 May 2012; accepted article preview online 18 May 2012; advance online publication, 15 June 2012 ENESTnd 3-year results RA Larson et al 2198 suboptimal response or treatment failure, and patients in the nilotinib on nilotinib 300 mg twice daily, 36.6 (range, 0.2–46.0) months on 400 mg twice-daily arm could only enter the extension study to receive nilotinib 400 mg twice daily and 35.5 (range, 0.0–46.5) months on imatinib 400 mg twice daily for treatment failure. imatinib. The median time on study (from randomization to last Using a central laboratory in Portland, OR, USA (MolecularMD), molecular available date on study, including follow-up after discontinuation response was assessed by real-time quantitative PCR at baseline, monthly of treatment) was B37.6 months across all three arms. The (1 month ¼ 28 days) for 3 months and every 3 months thereafter. At baseline and at 6, 12, 18 and 24 months, conventional bone marrow median (25th–75th percentile) dose intensity was 594 (548–600) cytogenetic analyses were performed on core treatment. After 24 months mg/day in the nilotinib 300 mg twice-daily arm and 778 (594–799) on core treatment, only patients without MMR or with any clinical indica- mg/day in the nilotinib 400 mg twice-daily arm. In the imatinib tion of progressive disease (that is, additional chromosomal abnormalities arm, the median dose intensity was 400 (395–470) mg/day. on previous bone marrow assessments, increase in BCR-ABL transcripts of By the time of data cutoff, B95% of patients in each treatment at least fivefold) had a cytogenetic assessment. Progression to AP/BC while arm were still in active follow-up (that is, either remained on patients were on treatment was assessed based on hematological and treatment or remained in follow-up after discontinuation of study cytogenetic data. Progression events were also reported solely based on treatment) or completed follow-up (that is, died on treatment the investigators’ assessments every 3 months after discontinuation of or during follow-up after discontinuation of treatment). Overall, treatment up to 10 years from randomization and were not censored at the time at which patients received subsequent therapy after disconti- 29.1%, 26.3% and 38.2% of patients in the nilotinib 300 mg twice- nuation of treatment in the ENESTnd study. Also, overall survival (OS) daily, nilotinib 400 mg twice-daily and imatinib arms, respectively, information was collected every 3 months up to 10 years from discontinued core treatment by the time of data cutoff (Table 1). randomization, including follow-up after treatment discontinuation. Only Discontinuations due to adverse events or laboratory abnormali- about 5% of patients in each arm were unavailable for these long-term ties were observed in 9.9%, 14.2% and 11.0% of patients in the assessments after discontinuation. nilotinib 300 mg twice-daily, nilotinib 400 mg twice-daily and imatinib arms, respectively. More patients in the imatinib arm Endpoints (20.1%) discontinued treatment due to disease progression, As reported, the MMR rate at 1 year was the primary efficacy endpoint.3,4 treatment failure or suboptimal response compared with the MMR was defined as BCR-ABLISp0.1% by real-time quantitative-PCR in nilotinib 300 mg twice-daily arm (9.9%) or the nilotinib 400 mg peripheral blood. MMR was assessed conservatively based on evaluation of twice-daily arm (5.3%). b3a2 and b2a2 BCR-ABL transcripts. Patients with atypical transcripts or unavailable or missing samples were considered as nonresponders. Other Efficacy endpoints included the rate of MMR, MR4 and MR4.5 by 3 years; time to progression to AP/BC (defined as progression to AP/BC or death due Consistent with the results at 1 and 2 years of follow-up, the MMR to CML, whichever occurred first), including events on treatment and rate by 3 years (Figure 1) was significantly higher for nilotinib events after discontinuation of study treatment; progression-free survival 300 mg twice daily (73%, Po0.0001) and nilotinib 400 mg twice (progression defined as progression to AP/BC or death due to any cause daily (70%, Po0.0001) compared with imatinib (53%).
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