Study Design and Endpoints

Transcription

1 Complete Molecular Response (CMR) Rate With Nilotinib in Patients With CML-CP Without CMR After 2 Years on Imatinib: Preliminary Results From the Randomized ENESTcmr Trial Timothy P. Hughes, Jeffrey H. Lipton, Brian Leber, Nelson Spector, Francisco Cervantes, Ricardo Pasquini, Nelma Cristina D. Clementino, Anthony P. Schwarer, Francois-Xavier Mahon, Delphine Réa, David T. Yeung, Suzanne Kamel-Reid, Israel Bendit, John Reynolds, Lisa Williams, Tomasz Szczudlo, Susan Branford

2 Introduction 40% of imatinib-treated patients with CML-CP who achieved durable CMR were able to cease therapy without recurrence 1,2 The majority (55%) of patients with CML do not achieve CMR on imatinib even with long-term therapy (> 6 years) 3 In ENESTnd, significantly more patients treated with nilotinib achieved MMR, MR 4 and MR 4.5 compared with imatinib 4 The current report of ENESTcmr includes a minimum of 12 months follow-up on all patients 1. Mahon F, et al. Lancet Oncol. 2010;11: Ross DM, et al. Leukemia. 2010;10: Branford S, et al. Clin Cancer Res. 2007;13: Kantarjian H, et al. Lancet Oncol. 2011;12:

3 Eligibility Ph+ CML-CP previously treated with imatinib (400 mg or 600 mg daily) for 2 years Documented CCyR by standard cytogenetics or peripheral blood BCR-ABL IS < 1% Persistent disease as demonstrated by 2 positive BCR-ABL transcript levels by RQ-PCR performed in the last 9 months Age 18 years ECOG performance 0-2 QTcF < 450 ms Adequate organ function

4 Study Design and Endpoints R A N D O M I Z E END POINTS Primary Nilotinib 400 mg BID N = 207 1:1 randomization stratified by: Prior imatinib ( 36 mos, > 36 mos) AND Prior interferon (None, 12 mos, > 12 mos) Imatinib continue same dose 4-year study Confirmed CMR (undetectable BCR-ABL) by 12 months Secondary Kinetics of molecular response (undetectable BCR-ABL levels, MR 4 and MR 4.5 over time RQ-PCR for primary and secondary endpoints was performed every 3 months and assessed at a central laboratory in Adelaide, Australia Safety profile RQ-PCR, real-time quantitative polymerase chain reaction; CCyR, complete cytogenetic response

5 Definitions of Molecular Endpoints 100 Absolute values Baseline BCR-ABL% IS MMR 0.1% -1 log -2 log -3 log -4 log CMR = Undetectable by PCR with sensitivity 4.5 logs -5 log

6 Definitions of Molecular Endpoints 100 Absolute values Baseline BCR-ABL% IS MMR 0.1% -1 log -2 log -3 log -4 log MR 4.5 = Detectable OR undetectable by PCR -5 log

7 Definitions of Molecular Endpoints 100 Absolute values Baseline BCR-ABL% IS MMR 0.1% -1 log -2 log -3 log -4 log MR 4 = Detectable OR undetectable by PCR -5 log

8 Baseline Demographics (N = 207) Nilotinib 400 mg BID n = 104 Imatinib mg QD n = 103 Median age, years (range) 46 (23 82) 52 (19 76) Prior duration of imatinib > 36 months, % Prior duration of interferon, % None months > 12 months Responses at baseline, % Missing 1 1 BCR-ABL IS > 0.1% BCR-ABL IS > % BCR-ABL IS 0.01% CMR (Undetectable BCR-ABL)* 2 2 *With a sample sensitivity of 4.5 logs. 12 month follow-up

9 Patient Disposition (N = 207) Nilotinib 400 mg BID n = 104 Imatinib mg QD n = 103 Still on treatment, % Discontinued, % 16 4 Adverse event(s) 9 1 Withdrawal of consent 4 1 Death 1* 0 Other 3 2 *59 year-old male with medical history of diabetes, hyperlipidemia, hypertension, and obesity died due to suspected acute myocardial infarction. Includes pregnancy, protocol violation, and transient loss of MMR. 12 month follow-up

10 Treatment Duration and Median Dose Median time on treatment, months Median dose intensity, mg/day Nilotinib 400 mg BID n = 101 Prior Imatinib 400 mg QD n = 60 Imatinib n = 103 Prior Imatinib 600 mg QD n = month follow-up

11 % with CMR CMR (Undetectable BCR-ABL*) by 12 Months (ITT) P =.02 P = CMR Confirmed CMR (Primary endpoint) Of patients on study at 12 months, 14.9% on nilotinib vs 6.1% on imatinib achieved confirmed CMR (P =.04) *With 4.5-log assay sensitivity. Intention-to-treat analyses included all patients randomized to the study, whether or not they received study drug (n = 3 pts on nilotinib did not) or had CMR at baseline (n = 2 on nilotinib; n = 2 on imatinib). 12 month follow-up

12 Cumulative Incidence of MR 4 (in patients without MR 4 at baseline) Nilotinib Imatinib n = 74 n = 78 % with MR Hazard ratio (95%CI) = 2.1 (1.2, 3.7) Months Since Randomization 48.6% P = % 12 month follow-up

13 Cumulative Incidence of MR 4.5 (in patients without MR 4.5 at baseline) Nilotinib Imatinib n = 94 n = 91 % with MR Hazard ratio (95%CI) = 2.3 (1.2, 4.2) Months Since Randomization 33.0% P = % 12 month follow-up

14 % with CMR Cumulative Incidence of CMR (in patients without CMR at baseline) Nilotinib Imatinib n = 101 n = Hazard ratio (95%CI) = 2.2 (1.05, 4.7) Months Since Randomization 20.8% 10.0% P = month follow-up

15 % Patients Molecular Response Rates by 12 Months (in patients without indicated response at baseline) P =.006 P =.008 P = MR 4 MR 4.5 CMR (Undetectable BCR-ABL)* *With 4.5-log assay sensitivity. 12 month follow-up

16 BCR ABL Ratio (%) BCR-ABL Ratio (%) Over Time Nilotinib Imatinib Undetectable levels Baseline Months Since Randomization Joined median values, white lines extending to 25th-75th percentiles. 12 month follow-up

17 BCR-ABL Ratio (%) Over Time Sample timepoint Median BCR-ABL ratio (%) Nilotinib 400 mg BID n = 104 Imatinib mg QD n = 103 Baseline month follow-up

18 % with MMR MMR by 12 months (in patients without MMR at baseline) P = patients had a confirmed loss of MMR (1 on each arm)

19 Drug-Related Adverse Events Drug-related adverse events (AEs), % Nilotinib 400 mg BID n = 104 Imatinib mg QD n = 103 Any AE Grade 3/4 AEs 29 2 AEs leading to discontinuation 9 0 Serious AEs 4 0 Patients experienced AEs early on nilotinib after switch from long-term imatinib therapy. These changes were expected and consistent with the safety profile of nilotinib observed in other studies

20 Drug-Related Adverse Events Nilotinib 400 mg BID n = 101 AEs ( 10%), % Grade 1 Grade 2 Grade 3 Grade 4 Headache Pruritis Rash Nausea Fatigue Myalgia Laboratory abnormalities ( 5%), % Increased liver enzymes Increased lipase Increase bilirubin Hypophosphatemia Increased amylase month follow-up

21 Summary By 12 months, 12.5% vs 5.8% of patients achieved confirmed CMR on nilotinib vs imatinib (P =.108) Twice as many patients achieved MR 4, MR 4.5 and CMR on nilotinib Patients remaining on imatinib had minimal evidence of improvement in molecular response Patients switched to nilotinib had a median 0.5-log reduction in BCR-ABL Nilotinib safety profile was consistent with prior studies

22 Conclusions For patients with ongoing BCR-ABL positivity on imatinib, switching to nilotinib leads to faster, deeper molecular responses Deeper molecular responses on nilotinib may increase patient eligibility for future TKI discontinuation studies Ultimate success of this strategy will be assessed in the discontinuation study ENESTop

23 ENESTcmr Contributing Investigators Argentina B Moiraghi Australia C Arthur S Durrant J Szer M Hertzberg T Hughes D Joske A Schwarer K Taylor T Mills Brazil PE Dorlhiac Llacer N Clementino N Spector R Pasquini C Souza Canada J Lipton D Forrest B Leber R Delage L Busque France A Guerci-Bresler F Nicolini M Tulliez G Etienne D Rea Spain JL Steegmann S Osorio S del Castillo F Cervantes E Olavarria-Lopez Central Molecular Monitoring Susan Branford Jodi Prime