New Horizons 2011 Newly diagnosed CML moving 2nd generation TKIs to first line therapy Gianantonio Rosti Dept. Of Hematology and Oncology St. Orsola-Malpighi University Hospital Bologna (Italy) GIMEMA CML Working Party
Imatinib: 12-months CCyR and MMR rates Across CML Frontline Trial Baccarani et al, Blood 2010: abs n. 668)
559 Pts, Imatinib FL, 2003-2007 Estimated OS, PFS, FFS, EFS Events Failures Progressions Deaths N 169 132 67 54 GIMEMA, 2011 (data on file, unpublished) GIMEMA CML WP
Higher MMR Leads to Lower Progression to Advanced Disease for Nilotinib Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD P<0.00010001 60 P<0.0001 20 P=0.0095 % MMR 50 44 43 40 MMR = AP/BC 30 22 20 10 2 Num mber of patients with event 15 10 5 P=0.0037 1 11 0 MMR - Month 12 0 Progression to AP/BC No patient who progressed to AP/BC achieved MMR on study
DASISION: First-Line Dasatinib vs Imatinib in CML-CP Confirmed CCyR Rate By Month Of Treatment onfirme ed CCy yr, % C 100 80 60 40 20 0 P=0.0086 P=0.0366 77 78 67 70 Mo 12 Mo 18 Dasatinib 100 mg QD Imatinib 400 mg QD Confirmed CCyR (CCyR detected in 2 consecutive assessments) by 12 mos = primary endpoint Shah et al, ASH 2010
DASISION: First-Line Dasatinib vs Imatinib in CML-CP Transformation To Advanced Phase CML 100 6 Progresse ed to AP/ /BP, % 100 4 2 0 Dasatinib 100 mg QD Imatinib 400 mg QD 2,3 5 patients who achieved a CCyR progressed to AP/BP CML (2 dasatinib, 3 imatinib) 3,5 n/n 6/259 9/260 No patient who achieved a MMR progressed to AP/BP CML to date P ti t f ll d f t f ti f t 60 d ft th l t d f Patients were followed for transformation for up to 60 days after the last dose of study drug. Clonal evolution without additional criteria for AP CML was not counted as transformation Shah et al, ASH 2010
Overall Survival* ENESTnd: Nilotinib vs Imatinib in CML-CP Nilotinib 300 mg BID n = 282 Nilotinib 400 mg BID n = 281 Imatinib 400 mg gqd n = 283 Total number of deaths 9 6 11 Estimated 24-month rate of OS 97.4% 97.8% 96.3% P-value (OS) 0.6485 0.2125 CML-unrelated 4 3 1 CML-related 5 3 10 Estimated 24-month rate of OS considering only CML deaths 98.9% 98.9% 96.7% P-value (CML deaths) 0.1930 0.04850485 *ITT population Including deaths after discontinuation of treatment 7 Data cut-off: 20Aug2010
DASISION: First-Line Dasatinib vs Imatinib in CML-CP Patient Disposition And Treatment Discontinuations Number (%) of treated patients Dasatinib 100 mg QD N = 258 Imatinib 400 mg QD N = 258 Still on treatment 210 (81) 206 (80) Discontinued 48 (19) 52 (20) Progression* 9 (3) 13 (5) Treatment Failure 6 (2) 11 (4) Adverse event (AE) 16 (6) 11 (4) Non-hematologic 9 (3) 8 (3) Hematologic 7 (3) 3 (1) Unrelated AE 5 (2) 1 (<1) Death 4(2) 1(<1) Other 8 (3) 15(6) *Increasing WBC count; loss of CHR; loss of MCyR including 30% rise in Ph+ metaphases and additional chromosomal abnormalities; or progression to AP/BP PFS rates at 18 mos were 94.9% for dasatinib and 93.7% for imatinib Overall, there have been 11 deaths in the dasatinib arm, including 1 newly reported death due to bladder cancer; and 6 deaths in the imatinib arm. At this early time point, OS rates at 18 mos were 96.0% for dasatinib and 97.9% for imatinib Includes consent withdrawal, loss to follow-up, pregnancy, patient request and poor/non compliance
ENESTnd: Nilotinib vs Imatinib in CML-CP Study Drug-Related Adverse Events and Grade 3/4 Myelosuppression Fluid retention Diarrhea Headache Muscle Spasm Any grade Grade 3/4 Nausea Pruritis Rash Vomiting Anemia Neutropenia Thrombocytopenia -0.5-0.4-0.3-0.2-0.1 Favors imatinib 9 0 0.1 0.2 0.3 0.4 0.5 Rate difference (imatinib - nilotinib) with 95% CI Favors nilotinib (300 mg BID) Data cut-off: 20Aug2010
DASISION: First-Line Dasatinib vs Imatinib in CML-CP Forest Plots Comparing Differences In AE Rates Fluid retention 60 Superficial edema 25 Pleural effusion 31 Myalgia 56 Nausea 23 Any grade Vomiting 12 Diarrhea 47 Fatigue 21 Headache 32 Rash 29 Neutropenia 57 Grade 3/4 Thrombocytopenia 49 Anemia 29 No. of patients Dasatinib -0.4-0.2 0.0 0.2 0.4 Rate Difference (dasatinib-imatinib) with Exact 95% CI Imatinib 111 92 0 99 55 27 50 28 27 44 52 27 18 Favors dasatinib Favors imatinib
The Optimal Frontline Strategy for CML CONDITIONS Imatinib 1. Same long-term leukemia free CML Early CP survival 2 nd Generation TKI 2 nd Generation TKI 2. Same rate of progression to AP/BP 3. Same QOL EFS EFS
New Horizons 2011 Moving ALL NEWLY DIAGNOSED PATIENTS TO 2nd gen. TKIs AS first line therapy Costs Brief-term safety Long-term safety..
European LeukemiaNet recommendations Optimal Response Suboptimal Response Failure Warnings Baseline NA NA NA High risk 3 Months CHR and at least minor CyR (Ph+ 65%) 6 Months At least PCyR (Ph+ 35%) (Ph+ > 35%) No CyR (Ph+ > 95%) Less than CHR NA Less than PCyR 12 Months CCyR PCyR (Ph+ 1-35%) No CyR Less than PCyR 18 Months MMR b Less than MMR b Less than CCyR NA CCA/Ph+ a NA Less than MMR b Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051.
Treating CML after Resistance to Imatinib With second generation TKIs The 80% of 40% Rule Nilotinib & Dasatinib > CCyR rate 40% 80% CCyR are stable at 24 months 80% of 40% Rule: 30% rescued properly Kantarjian HM, et al. Haematologica. 2009; and and Shah et al. Hematologica 2010
European LeukemiaNet recommendations Optimal Response Suboptimal Response Failure Warnings Baseline NA NA NA High risk 3 Months CHR and at least minor CyR (Ph+ 65%) 6 Months At least PCyR No CyR (Ph+ > 95%) Less than PCyR Less than CHR No CyR (Ph+ 35%) (Ph+ > 35%) (Ph+ > 95%) 12 Months CCyR PCyR (Ph+ 1-35%) Less than PCyR (Ph+ >35%) 18 Months MMR b Less than MMR b Less than CCyR CCA/Ph+ a NA NA Less than MMR b NA Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051.
Higher MMR Leads to Lower Progression to Advanced Disease for Nilotinib Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD 60 P<0.00010001 RELEVANT PROBLEM P<0.0001 20 P=0.0095 % MMR 50 40 44 43 A DECISION POINT TO IMPLEMENT 15 P=0.0037 2 nd GENERATION TKIs EARLY ON, ABOLISHING 11 THE MMR = AP/BC RISK OF PROGRESSION 10 IS NOT (YET) 22 AVAILABLE 30 20 10 2 0 0 MMR - Month 12 Progression to AP/BC Num mber of patients with event 5 1 No patient who progressed to AP/BC achieved MMR on study
% respo onding IRIS: Estimated CCyR to First-line Imatinib by Sokal Group 100 90 80 70 60 95% CI 91% (87-96) 84% (76-92) 69% (58-81) 81) 50 p< 0.001 40 30 n=201 20 10 0 Low risk Intermediate risk High risk n=111 n=71 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Months since randomization Druker et al. NEJM 2006; 355: 2408-17
% MM MR 80 70 60 50 40 30 20 10 0 ENESTnd: Nilotinib vs Imatinib in CML-CP MMR Rates by 24 Months According to Sokal Risk* P =.003 P =.002 P<.0001 73 74 74 53 67 P =.0008 44 65 P <.0001 56 P =.002 n = 103 103 104 101 100 101 78 78 78 Low Intermediate High 32 Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD *ITT population; P values are provided for descriptive purposes only and are not adjusted for multiple comparisons 19 Data cut-off: 20Aug2010
New Horizons 2011 Newly diagnosed CML moving 2nd generation TKIs to first line therapy Gianantonio Rosti Dept. Of Hematology and Oncology St. Orsola-Malpighi University Hospital Bologna (Italy) GIMEMA CML Working Party