2nd generation TKIs to first line therapy

Transcription

1 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

2 Imatinib: 12-months CCyR and MMR rates Across CML Frontline Trial Baccarani et al, Blood 2010: abs n. 668)

3 559 Pts, Imatinib FL, Estimated OS, PFS, FFS, EFS Events Failures Progressions Deaths N GIMEMA, 2011 (data on file, unpublished) GIMEMA CML WP

4 Higher MMR Leads to Lower Progression to Advanced Disease for Nilotinib Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD P< P< P= % MMR MMR = AP/BC Num mber of patients with event P= MMR - Month 12 0 Progression to AP/BC No patient who progressed to AP/BC achieved MMR on study

5 DASISION: First-Line Dasatinib vs Imatinib in CML-CP Confirmed CCyR Rate By Month Of Treatment onfirme ed CCy yr, % C P= P= 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

6 DASISION: First-Line Dasatinib vs Imatinib in CML-CP Transformation To Advanced Phase CML Progresse ed to AP/ /BP, % 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

7 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 Estimated 24-month rate of OS 97.4% 97.8% 96.3% P-value (OS) CML-unrelated CML-related Estimated 24-month rate of OS considering only CML deaths 98.9% 98.9% 96.7% P-value (CML deaths) *ITT population Including deaths after discontinuation of treatment 7 Data cut-off: 20Aug2010

8 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

9 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 Favors imatinib Rate difference (imatinib - nilotinib) with 95% CI Favors nilotinib (300 mg BID) Data cut-off: 20Aug2010

10 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 Rate Difference (dasatinib-imatinib) with Exact 95% CI Imatinib Favors dasatinib Favors imatinib

11 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

12 New Horizons 2011 Moving ALL NEWLY DIAGNOSED PATIENTS TO 2nd gen. TKIs AS first line therapy Costs Brief-term safety Long-term safety..

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14 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:

15 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

16 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:

17 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< RELEVANT PROBLEM P< P= % MMR A DECISION POINT TO IMPLEMENT 15 P= nd GENERATION TKIs EARLY ON, ABOLISHING 11 THE MMR = AP/BC RISK OF PROGRESSION 10 IS NOT (YET) 22 AVAILABLE 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

18 % respo onding IRIS: Estimated CCyR to First-line Imatinib by Sokal Group % CI 91% (87-96) 84% (76-92) 69% (58-81) 81) 50 p< n= Low risk Intermediate risk High risk n=111 n= Months since randomization Druker et al. NEJM 2006; 355:

19 % MM MR ENESTnd: Nilotinib vs Imatinib in CML-CP MMR Rates by 24 Months According to Sokal Risk* P =.003 P =.002 P< P = P < P =.002 n = 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

20 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