2 nd Generation TKI Frontline Therapy in CML

Transcription

1 2 nd Generation TKI Frontline Therapy in CML Elias Jabbour, M.D. April 212 New York Frontline Therapy of CML in imatinib 4 mg daily - nilotinib 3 mg BID - dasatinib 1 mg daily Second / third line - nilotinib, dasatinib, bosutiinib, ponatinib - allogeneic SCT Other - omacetaxine, decitabine, peginterferon alfa-2a - hydrea, cytarabine, combos of TKIs and with TKIs - investigational: hedgehog inhibitors, JAK2 inhibitors, IL3-DT 1

2 Results with Imatinib in Early CP CML The IRIS Trial at 8-Years 34 (55%) patients on imatinib on study Projected results at 8 years: -CCyR 83% - 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP - Event-free survival 81% - Transformation-free survival 92% - If MMR at 12 mo: 1% - Survival 85% (93% CML-related) Annual rate of transformation: 1.5%, 2.8%, 1.8%,.9%,.5%, %, %, &.4% Deininger. Blood 114: abst 1126, 29 Probability Long-Term Outcome With Imatinib in ECP CML (ITT) Survival PFS CHR EFS Loss of MCyR 63% (88% per IRIS definition) Time From Start of Imatinib Therapy (months) EFS: death, progression to AP/BP, loss of CHR, loss of MCyR, or WBC, failure to achieve MCyR, intolerance de Lavallade. J Clin Oncol. 26: 3358; 28 2

3 Frontline Rx with Dasatinib or Nilotinib at MDACC Parallel studies with nilotinib (4 mg BID) or dasatinib (1 mg QD or 5 mg BID) Nilotinib ib Dasatinib ib % Response N=1 N=93 CGCR by 12 mos MMR by 12 mos yr Survival yr TFS yr EFS yr FFS 78 8 Rx discontinuation 11 9 Quintas-Cardama. Blood 118: abst 454, 211. Pemmaraju. Blood 118; abst 17; 211 Event-Free Survival by Treatment in ECP CML 1. Prob bability Event-Free Im atinib 4 m g Im atinib 8 mg Dasatinib Nilotinib Total Events p = Cortes. Blood 29; abst 338 & 341; Updated October 21 3

4 Nilotinib vs. Imatinib in CML (ENEST-nd). Study Design N = centers 35 countries Nilotinib 3 mg BID (n = 282) R A N D O M Nilotinib 4 mg BID (n = 281) I Z E D * Imatinib 4 mg QD (n = 283) *Stratification by Sokal risk score Follow-up 5 years Saglio. Blood 118: abst 452, 211 Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML 846 pts randomized to nilotinib 3 mg BID (n=282), nilotinib 4 mg BID (n=281), or imatinib 4 mg QD (n=283) Minimum follow-up 36 mo Outcome Nil 3 Nil 4 IM 4 % CCyR* % MMR** % BCR-ABL.32%** % Discontinued treatment % Entered extension study % Survival at 36 months * by 24 months, ** by 36 months Saglio et al. ASH 211; Abstract #452 4

5 Nilotinib vs. Imatinib in CML (ENEST-nd). Cumulative Incidence of MMR % With MMR Nilotinib 3 mg BID Nilotinib 4 mg BID Imatinib 4 mg QD n By 1 Year 55%, P <.1 51%, P <.1 24%-28% By 3 Years 73%, P <.1 7%, P <.1 17%-2% 53% % Since Randomization Saglio. Blood 118; abst 452, 211 % With MMR Nilotinib vs. Imatinib in CML (ENEST-nd). MMR by 3 Years According to Sokal Risk P =.264 P =.2 P = n = Low Intermediate High Nilotinib 3 mg BID Imatinib 4 mg QD Saglio. Blood 118; abst 452, 211 5

6 Nilotinib vs. Imatinib in CML (ENEST-nd). Cumulative Incidence of MR 4.5 % With MR Nilotinib 3 mg BID Nilotinib 4 mg BID Imatinib 4 mg QD n By 1 Year 11%, P <.1 7%, P <.1 6%-1% By 3 Years 32%, P <.1 28%, P =.3 13%-17% 15% 1% Since Randomization 36 Saglio. Blood 118; abst 452, 211 Nilotinib vs. Imatinib in CML (ENEST-nd). MR 4.5 by 3 Years According to Sokal Risk % With MR P = P = P =.99 n = Low Intermediate High Nilotinib 3 mg BID Imatinib 4 mg QD 24 9 Saglio. Blood 118; abst 452, 211 6

7 Nilotinib vs. Imatinib in CML (ENEST-nd). Progression to AP/BP on Core Rx P =.3 Number of Patients s, n P =.59 P = P = % 1.1% 4.2%.7% 1.8% 6.% Including Clonal Evolution Nilotinib 3 mg BID Nilotinib 4 mg BID Imatinib 4 mg QD No new progressions on core Rx since 2-year analysis Saglio. Blood 118; abst 452, 211 Nilotinib vs. Imatinib in CML (ENEST-nd). Survival After Progression to AP/BP % Alive Median survival 1.5 months Progressed = 34 Died = 23 Alive = Since Progression Saglio. Blood 118; abst 452, 211 7

8 Nilotinib vs. Imatinib in CML-CP. Adverse Events and Grade 3/4 Myelosuppression Any grade Grade 3/4 Fluid retention Diarrhea Headache Muscle cramps Nausea Pruritus Rash Vomiting Anemia Neutropenia Thrombocytopenia -.5 Rate difference (imatinib - nilotinib) with 95% CI -.4 Favors imatinib Hochhaus. Haematologica. 21;95(s2):459 [abst 1113] Favors nilotinib (3 mg BID) Dasatinib Versus Imatinib Study In Treatmentnaïve CML (DASISION). Trial Design N= centers 26 countries Dasatinib 1 mg QD (n=259) Randomized* Imatinib 4 mg QD (n=26) *Stratified by Hasford risk score Follow-up 5 years Primary endpoint: Confirmed CCyR by 12 months Secondary/other endpoints: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival Kantarjian. JCO. 29:abst 651; 211 8

9 Dasatinib vs Imatinib in Newly Diagnosed Chronic Phase CML 519 pts randomized to dasatinib 1 mg QD (n=259) or imatinib 4 mg QD (n=26) Median follow-up 28 mo Outcome Das 1 IM 4 % CCyR % MMR % BCR-ABL.32% 17 8 % discontinued therapy New mutations (No.) 1 1 * by 24 months Kantarjian. JCO. 29:abst 651; 211 DASISION. Cumulative Incidence of CCyR 1 By 12 months 85% By 24 months 86% 8 82% % 6 73% Dasatinib 1 mg QD 4 Imatinib 4 mg QD cccyr rate by 24 months for dasatinib vs imatinib was 8% vs 74% Kantarjian. JCO. 29:abst 651; 211 9

10 DASISION. Cumulative Incidence of MMR 1 Dasatinib 1 mg QD % Imatinib 4 mg QD By 12 months 46% By 24 months 64% 46% P< % Median time to MMR in all patients calculated by competing risk analysis was 15 months for dasatinib and 36 months for imatinib Kantarjian. JCO. 29:abst 651; 211 DASISION. Cumulative Incidence of BCR-ABL.32% (MR4.5; 4.5-log reduction)* 1 8 Dasatinib 1 mg QD Imatinib 4 mg QD % By 24 months 17% 9% Hochhaus. ASH 211 1

11 DASISION: Transformation To AP/BP CML (ITT) 1 Dasatinib 1 mg QD Imatinib 4 mg QD % n/n 6/259 13/26 9/259 15/26 On study Including follow-up beyond discontinuation Kantarjian. JCO. 29:abst 651; 211 DASISION. Forest Plot Comparing Differences in AE Rates for Dasatinib and Imatinib Any grade Grade 3/4 Fluid retention Superficial edema Pleural effusion Myalgia Nausea Vomiting Diarrhea Fatigue Headache Rash Neutropenia Thrombocytopenia Anemia Kantarjian. JCO. 29:abst 651; Rate Difference (dasatinib-imatinib) with 95% CI Favors dasatinib Favors imatinib 11

12 DASISION: Outcome by Response at pts randomized to dasatinib 1 mg QD vs imatinib 4 mg QD PCR in central lab by IS at 3, 6, 12, 18 and 24 months 3 month Percentage transcripts CCyR MMR AP/BP Dasatinib >1-1% % Imatinib >1-1% % * By 24 months Hochhaus et al. ASH 211; Abstract #2767 DASISION: BCR-ABL Levels at 3 * 1 % of Patients % Dasatinib 1 mg QD Imatinib 4 mg QD 64% >1-1% 36% >1-1% 1% 16% 1% n/n 198/ /239 37/235 85/239 1% >1% BCR-ABL Level at 3 *Calculated from total number of evaluable patients with PCR assessments at 3 months Hochhaus et al. ASH 211; Abstract #

13 Probability of CMR at 12 by Response at 3 and By Therapy 3-mo Transcript Level Percentage IM 4 IM 8 Dasatinib Nilotinib >1 * > * Only one patient evaluable in cohort Naqvi et al. ASH 211; Abstract #3784 Kaplan-Meier Plots of PFS According To BCR-ABL Level at 3 months Dasatinib 1 mg QD Imatinib 4 mg QD not progressed % BCR-ABL level at 3 months BCR-ABL level at 3 months 4 1% 1% >1 1% >1 1% >1% 2 >1% not progressed % For 1% vs >1% comparison: P< For 1% vs >1% comparison: P=.4 Hochhaus et al. ASH 211; Abstract #

14 Kaplan-Meier Plots of OS According To BCR-ABL level at 3-month Dasatinib 1 mg QD Imatinib 4 mg QD % alive BCR-ABL Level at 3 months 1% >1 1% >1% % alive BCR-ABL Level at 3 months 1% >1 1% >1% For 1% vs >1% comparison: P=.137 For 1% vs >1% comparison: P=.81 Hochhaus et al. ASH 211; Abstract #2767 Bosutinib Efficacy and Safely in Newly Diagnosed CML (BELA): Study Design R Bosutinib A 5 mg/day N n = 25 D N = 52 O 139 sites M 31 countries I Imatinib Phase 3 open-label trial in newly diagnosed CP CML Randomization is stratified based on Sokal risk score and geographical regions. Z E 4 mg/day n = year follow-up 8-year follow-up 1-year analysis Key eligibility criteria: cytogenetic diagnosis of Philadelphia chromosome positive (Ph+) CP CML 6 mo prior, no prior therapy other than hydroxyurea or anagrelide Primary endpoint: complete cytogenetic response (CCyR) at 12 months Key secondary and exploratory endpoints: MMR at 12 months, time to and duration of CCyR and MMR, time to transformation to AP/BP CML, event-free survival (EFS), and overall survival (OS) Safety and tolerability Cortes et al. ASH 211; abstract #455 14

15 Bosutinib vs Imatinib in Newly Diagnosed Chronic Phase CML 52 pts randomized to bosutinib 5 mg QD (n=25) or imatinib 4 mg QD (n=252) Minimum follow-up 24 mo % Outcome Bos 5 IM 4 CCyR* 79 8 MMR* 61 5 CMR* Failure 4 13 AP/BP 2 5 Death 3 5 * by 24months Cortes et al. ASH 211; abstract #455 CML Frontline Rx. Toxicities of TKIs Bothersome chronic side-effects less frequent with nilotinib than with imatinib: nausea, cramps, aches, weight gain, fluid retention, periorbital edema Rashes, headaches more frequent q with nilotinib Pleural effusions; cytopenias more frequent with dasatinib 15

16 Suboptimal Response to Imatinib 4 mg/d in CP CML: GIMEMA CML WP Analysis of 423 Consecutive Patients 98% 98% 55% 63% p<.1 p<.1 79% 33% p<.1 85% 51% p<.1 Castagnetti. Hematologica 29;94 abstract 528 EFS by Response to IM at 6 and 12 Mos 281 pts; imatinib frontline (4mg in 73, 8mg in 28) Suboptimal response at 6-12 months: 12-17% with 4mg, 1-4% with 8mg (p=.2) month response.6 12 month response No. Events (%) Failure 9 6 (67).1 Suboptimal 1 5 (5) p<.1 Optimal (6) No. Evaluable (%) Failure 14 8 (57).1 Suboptimal 19 3 (16) p<.1 Optimal (4) Alvarado. Cancer. 29;115:

17 Outcome by 12-Month Response in CML CP 848 pts randomized to IM 4mg, IM 8mg, or IM 4 + IFN Median FU: 4 months 12-month BCR-ABL/ABL (IS) N Percentage PFS OS <.1% CCyR 11%.1-1% >1% P value Outcome independent of treatment arm Hehlman et al. JCO 211;29: MDACC Retrospective Analysis: MCyR at 6 Associated With OS 1. Landmark analysis at 6 mos Proportion alive Cytogenetic response at 6 mos Total Dead P-value Complete Partial Minor Others a Patients with MCyR have better OS than patients that do not Kantarjian H. Cancer. 28;112:

18 MDACC Retrospective Analysis: CCyR at 12 Associated With PFS 1. Landmark analysis at 12 mos.8 Proportion PFS Cytogenetic response at 12 mos Total Failure P-value Complete Partial Minor 5 2 Others Patients with CCyR have better PFS than patients that do not. Similar results were observed in patients achieving CCyR at 18 and 24 mos. Kantarjian H. Cancer. 28;112: Hammersmith Experience. CCyR at 12 Associated With PFS Landmark analysis at 12 mos bability of PFS a Pro CCyR at 12 mos (n = 121) No CCyR at 12 mos (n = 72) de Lavallade. J Clin Oncol. 28;26(2): % P =.7 74% 18

19 Survival After Imatinib Therapy by Molecular Response Achieved at 3 Optimal PCR value determined by Receiver operating characteristic (ROC) curve Prob bability of survival BCR-ABL/ABL<9.8% OS= 93.3% BCR-ABL/ABL>9.8% OS= 54% p<.1 Time from onset of imatinib therapy (years) Marin et al, JCO 211; [Epub ahead of print] CML IV: Long-Term Impact of Response at pts randomized to imatinib 4, imatinib + IFN, imatinib + ara-c, imatinib 8 33 month analysis: PCR in 692 pts, cytogenetics ti in 46 3 mo transcript levels predictive of achievement of CCyR and MMR Cytogenetics Molecular % 5-year (% Ph+) [BCR-ABL/ABL (IS)] outcome 35% >35% 1% >1% PFS OS Hanfstein et al. ASH 211; Abstract #783 19

20 TKI Frontline Therapy in CML CCyR AT Time Periods (ITT) 465 patients with CML frontline therapy Imatinib 4 mg (n=71), imatinib 8 mg (n=21), nilotinib (n=1), and dasatinib (n=93) onse Rate (%) Resp IM4 IM8 NILOT DASAT Alattar. Blood 118; abst 745, 211 Response Rate (%) 9 8 TKI Frontline Therapy in CML Response AT Time Periods (ITT) 1 CMR MMR IM4 IM8 NILOT DASAT Alattar. Blood 118; abst 745, 211 2

21 TKI Frontline Therapy in CML Long-Term Outcome By Response Time Event-Free Survival Transformation-Free Survival p<.1 Alattar. Blood 118; abst 745, 211 EFS and Survival by 12-month Response- CCyR vs Others with TKI Frontline Rx Jabbour E et al. Blood

22 Optimal Response To 2 nd TKIs-Frontline. Response (N=167) on therapy Response Total (%) 3 (N=16) 6 (N=155) 12 (N=129) Optimal 16 (1) Sub-optimal Failure Optimal 152 (98) Sub-optimal 3 (2) Failure Optimal 128 (99) Sub-optimal 1 (1) Failure Optimal 99 (84) 18 (n=119) Sub-optimal 14 (12) Failure 5 (4) Median follow-up 33 months (range, 3 to 66 months) Jabbour E et al. JCO Optimal Response To 2 nd TKIs-Frontline. Event-free by 3 mo Response Jabbour E et al. JCO

23 Optimal Response To 2 nd TKIs-Frontline. Event-free by 6 mo Response Jabbour E et al. JCO TKI Frontline Therapy in CML Earlier Responses with dasatinib or nilotinib compared to imatinib 4 mg Superior outcome with newer agent Improved long-term outcome due to higher rate of early responses 23

24 CML 212. New Proposed Algorithm Second generation Check CG at 3 and 6 mos: At 3 mo - CCyR Home free -PCyR Recheck at 6 mo - Less than MCyR Careful monitoring;? third generation TKIs At 6 mo - CCyR Home free - Less than CCyR Careful monitoring;? third generation TKIs Jabbour. J Clin Oncol. 211;29: My Desk On A Good Day! JC 48 24

25 Leukemia Questions? Pager Elias Jabbour, M.D. 25