Dasatinib: il vantaggio dal multitarget 25 maggio 2013 Drssa Patrizia Pregno S.C. Ematologia Kinase selectivity profiles of nilotinib and dasatinib Imatinib 4 targets AMN107 4 targets 50 X Dasatinib 15 targets 325 X IMA 16 X NILO IC50 < 10 nM 10-50 nM 50-250 nM 250-1000 nM After Fabian et al. Nature Biotech. 2005;23:329 Dasatinib inhibits growth of imatinib-resistant BCR-ABL-expressing Ba/F3 cell lines in vitro 1.2 Parental Ba/F3 cells BCR-ABL E255K 1 Relative growth after 48 hours of drug exposure Ba/F3 T315I T315I M351T 0.8 M244V G250E 0.6 Q252H E255K 0.4 Q252R “wt” BCR-ABL 0.2 Y253F Y253H M351T E255V 0 0 1 5 10 50 100 Concentration of Dasatinib (nM) attivo su > 100 mutazioni incluse quelle della regione del p-loop poco attivo anche su V299L F317L/V e T315 I F317L E355G F359V H396R F486S Shah et al., Science, 2004 Inibitori delle tirosin‐chinasi: diversa selettività Imatinib Nilotinib ABL ARG BCR-ABL KIT PDGFR DDR1 NQO2 ABL ARG BCR-ABL KIT PDGFR DDR1 NQO2 7 7 targets targets Weisberg E, et al. Br. J. Cancer. 2006; 94:1765-1769. Weisberg E, et al. Br. J. Cancer. 2006; 94:1765-1769. Dasatinib ABL ARG BCR-ABL KIT PDGFR SRC YES FYN LYN HCK LCK FGR BLK FRK CSK BTK TEC BMX TXK DDR1 DDR2 ACK ACTR2B ACVR2 BRAF EGFR/ERBB1 EPHA2 EPHA3 EPHA4 EPHA5 targets FAK GAK GCK HH498/TNNI3K 55 ILK LIMK1 LIMK2 MYT1 NLK PTK6/Brk QIK QSK RAF1 RET RIPK2 SLK SLK36/ULK SYK TAO3 TESK2 TYK2 ZAK Attività di Dasatinib E’ in grado di inibire: * BCR-ABL1 nella conformazione inattiva/attiva del domain chinasico ABL * c-KIT, PDGF-R ed EPHA2 * Src chinasi come Lyn, Yes e Src E’ in grado di bloccare i «signaling pathways» intracellulari attivati da BCR-ABL1 in vitro inclusi i segnali di trasduzione e di attivazione di trascrizione di Stat-5 Non è substrato di MDR protein-1 Non è substrato di OCT-1 e la sua attività non è influenzata da una iper-espressione di OCT-1 Attività di Dasatinib sui progenitori L’ espressione di Src chinasi è aumentata nelle cellule staminali CD34+ e nella frazione CD34+CD38- in tutte le fasi di LMC. E’ più attivo di Imatinib sul compartimento delle cellule staminali, ma le cellule primitive quiescenti sono resistenti al farmaco. E’ in grado di inibire la P mitogen-activated protein kinase MAPK9, Akt e STAT5 nei progenitori di LMC, ma non è in grado di alterare il livello delle proteine che regolano l’apoptosi nelle cellule CD34+. Copland m et al, Blood 2006, 107 (11, 4532-9 DASISION (CA180-056): Study Design Treatmentnaïve CML-CP patients (N=519) Dasatinib 100 mg QD (N=259) Long-term Randomizeda 108 Centers follow-up Imatinib 400 mg QD (N=260) 26 Countries aStratified Primary endpoint by EURO (Hasford) risk score Confirmed CCyR (cCCyR) by 1 year DASISION (CA180-056):NCT00481247; CCyR = complete cytogenetic response PFS was defined as doubling of WBC ; loss of CHR; increase in Ph-positive metaphases to >35%; transformation; or death from any cause Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106]. DASISION 3-Year Update Patient Disposition and Discontinuation Treated patients, n (%) Dasatinib 100 mg QD N=258 Imatinib 400 mg QD N=258 183 (71) 179 (70) 75 (30) 79 (31) 17 (7) 18 (7) 8 (3) 12 (5) 27 (11) 16 (6) 20 (8) 12 (5) 7 (3) 4 (2) Unrelated AE 6 (2) 2 (<1) Deathb 4 (2) 1 (<1) Poor /nonadherence 0 (0) 4 (2) 13 (5) 26 (10) Still on treatment Discontinued Progressiona Treatment failure Adverse event (AE) Nonhematologic Hematologic Otherc aIncreasing WBC count; loss of CHR; loss of MCyR, including 30% rise in Ph+ metaphases and additional chromosomal abnormalities; or progression to AP/BP due to death, which represents a subset of total deaths: 17 deaths overall in dasatinib arm, 20 deaths in imatinib arm CIncludes consent withdrawal, loss to follow-up, pregnancy, patient request, and poor/nonadherence bnDiscontinuation Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106]. DASISION 3-Year Update Adverse Events of Clinical Interest (any Grade) Overall, most AEs occurred within the first year with minimal increases between 1-2 years and 2-3 years One patient in each arm experienced a QTc interval prolongation ≤1 month from the start of treatment; no patients between 3 months and 3 years developed a QTc prolongation Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106]. DASISION 3-Year Update 3-Year Rates of Grade 3/4 Lab Abnormalities Dasatinib 100 mg QD Imatinib 400 mg QD AST ↑ Neutropenia Creatinine ↑ Total bilirubin ↑ ALT ↑ Thrombocytopenia Potassium ↓ Calcium ↓ Anemia Phosphorus ↓ % % The majority of Grade 3/4 lab abnormalities occurred within the first year Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106]. DASISION 3-Year Update Transformation To AP/BP CML by 3 Years Number of Patients, n Dasatinib 100 mg QD Imatinib 400 mg QD p=ns 16 p=ns 13 11 8 N ns= non-significant 259 260 On study 259 260 Including follow-up beyond discontinuation (ITT)a aYearly evaluations after discontinuation are currently stipulated per protocol; additional information on patient status may be provided by investigators at other times Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106]. DASISION 3-Year Update Overall Survival (OS) and Progression Free Survival (PFS) Dasatinib 100 mg QD N=259 Imatinib 400 mg QD N=260 Hazard ratio 17 20 - Estimated 3-year OS, % 93.7 (90.6-96.7) 93.2 (90.1-96.4) HR=0.86 (0.45-1.65) Estimated 3-year PFS, % 91.0 (87.4-94.7) 90.9 (87.1-94.6) HR=1.00 (0.55-1.80) Total number of deaths,a n aOn study treatment and in follow-up after discontinuation of randomized treatment PFS was defined as doubling of WBC ; loss of CHR; increase in Ph-positive metaphases to >35%; transformation; or death from any cause Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106]. DASISION: European Subpopulation Analyses Table 6. Deaths on treatment or after discontinuation Treated patients, n (%) European subpopulation Global population Dasatinib 100 mg QD N=74 Imatinib 400 mg QD N=96 Dasatinib 100 mg QD N=258 Imatinib 400 mg QD N=258 3 (4) 8 (8) 17 (7) 20 (8) CML progression 0 5 (5) 9 (3) 14 (5) Cardiovascular disease 0 1 (1) 2 (1) 1 (<1) Infectiona 2 (3) 0 5 (2) 1 (<1) Bleeding 0 0 0 1 (<1) 1 (1) 0 1 (<1) 0 0 2 (2) 0 3 (1) Total deaths Other neoplasm Other aFor the Global population, deaths due to infection in the dasatinib arm included sepsis/infection (no organism identified), meningoencephalitis (Klebsiella), and pneumonia; in the European population the two deaths due to infection included sepsis/infection (no organism identified) and meningoencephalitis (Klebsiella). EHA 2012 16 BMS Confidential - Not for Further Copying or Distribution DASISION 3-Year Update Cumulative Incidence of MMR (BCR-ABL ≤0.1%) Dasatinib 100 mg QD % With MMR 100 Imatinib 400 mg QD P<0.0001 1.6-Fold higher likelihood of achieving MMR with dasatinib; HR=1.62 (1.30-2.02) 80 By 3 years 68% By 2 years 64% By 1 year 46% 60 55% 40 46% 20 23% 0 0 12 24 36 Months Hasford Risk Score MMR 3-y cumulative rates Low Intermediate High Dasatinib Imatinib 83% 65% 65% 57% 61% 43% Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106]. DASISION 3-Year Update Cumulative Incidence of MR4 and MR4.5 Dasatinib 100 mg QD 40 40 35% 28% P=0.00635 P=0.00069 30 12% 20 18% 22% 10 5% 0 0 12 % with MR4.5 30 % with MR4 Imatinib 400 mg QD 22% 17% 20 3% 10 12% 9% 0 24 Months 36 2% 0 12 24 36 Months MR4 = BCR-ABL ≤0.01% MR4.5 = BCR-ABL ≤0.0032% Hochhaus A, et al. J Clin Oncol 30, 2012 [abstract 6504]. Kaplan-Meier Analyses Progression-free survival* (no AP/BP or loss of response) 100 80 % without failure % not progressed 100 60 24 months Dasatinib: 93.7% Imatinib: 92.1% 40 20 Failure-free survival* (ELN 2006 criteria) 80 60 24 months Dasatinib: 91.2% Imatinib: 87.8% 40 20 0 0 0 10 20 Months 30 40 0 10 20 Months 30 40 Overall survival† 100 % alive 80 60 * Patients who discontinued for other reasons were censored at last hematologic or cytogenetic evaluation 24 months Dasatinib: 95.3% Imatinib: 95.2% 40 20 † Surviving 0 0 10 20 Months 30 40 patients were followed after discontinuation and were censored on the last date known to be alive An exploratory analysis from 3 year DASISION followup examining the impact on patient outcomes of early complete cytogenetic responses at 3 months and major molecular responses at 12 months Elias Jabbour,1 Neil Shah,2 Charles Chuah,3 Carolina Pavlovsky,4 Jiri Mayer,5 M Brigid Bradley-Garelik,6 David Dejardin,7 Hesham Mohamed,8 Andreas Hochhaus,9 Guiseppe Saglio10 1 MD Anderson Cancer Center University of Texas, Houston, Texas, 2 Helen Diller Family Comprehensive Cancer Center, UCSF School of Medicine, San Francisco, CA, 3Singapore General Hospital,Singapore, 4 FUNDALEU,Centro de Internación e Investigación Clínica Angélica Ocampo, Buenos Aires, Argentina, 5 University Hospital Brno, Brno Czech Republic, 6 Bristol-Myers Squibb, Wallingford, CT, USA, 7 BristolMyers Squibb, Braine l’Alleud, Belgium, 8 Bristol-Myers Squibb, Plainsboro, NJ, USA 9Universitätsklinikum Jena, Jena, Germany, 10 University of Torino, Ospedale San Luigi Gonzaga, Orbassano-Torino, Italy Molecular and Cytogenetic Response at 3 Months P<0.0001 P<0.0001 100 Dasatinib 100 mg QD 84% 81% % of patients 80 >1-10% 64% PCyR Imatinib 400 mg QD 67% 60 PCyR >1-10% 40 CCyR ≤1% 20 CCyR ≤1% 0 n//N 198/235 154/239 ≤10% BCR-ABL at 3 Months 171/210 148/221 PCyR/CCyR at 3 Months BCR-ABL of <10% and ≤1% are not fully concordant with ≥PCyR and CCyR, respectively 96% and 83% of dasatinib and imatinib pts with ≥PCyR had <10% BCR-ABL, respectively 68% and 26% of dasatinib and imatinib pts with CCyR had ≤1% BCR-ABL, respectively MR4.5 According to BCR-ABL Level at 3 Months Dasatinib 100 mg QD Imatinib 400 mg QD 84% of patients had ≤10% BCR-ABL 48% of patients had ≤1% BCR-ABL 64% of patients had ≤10% BCR-ABL 13% of patients had ≤1% BCR-ABL BCR-ABL level at 3 months ≤1% >1-10% >10% ≤10% vs >10% ≤1% vs >1% Patients with MR4.5 (%) 100 80 60 40 MR4.5 3-Year 37.5% } P<.0001 14.0% } P=.0380 2.7% P=.0004 P<.0001 80 60 40 20 20 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Months BCR-ABL level at 3 months ≤1% >1-10% >10% ≤10% vs >10% ≤1% vs >1% 100 0 3 6 3-Year MR4.5 43.8% } P<.0001 11.5% } P=.0204 2.4% P=.0008 P<.0001 9 12 15 18 21 24 27 30 33 36 39 42 Months Saglio G, et al., Blood 2012;120:[abstract 1675]. Patients not progressed (%) PFS According to BCR-ABL Level at 3 Months Dasatinib 100 mg QD Imatinib 400 mg QD 84% had ≤10% BCR-ABL 64% had ≤10% BCR-ABL 100 100 80 80 60 BCR-ABL level at 3 months ≤1% >1-10% >10% ≤10% vs >10% 40 20 60 3-Year PFS 92.3% } P=.9639 94.0% } P=.0135 68.2% P=.0003 BCR-ABL level at 3 months ≤1% >1-10% >10% ≤10% vs >10% 40 20 3-Year PFS 100% } P=.3459 94.9% } P=.0002 75.2% P<.0001 0 0 0 6 12 18 24 30 36 42 0 6 12 98 81 22 93 79 19 24 30 36 42 20 76 37 7 25 13 Months Months Subjects at risk ≤1% 112 112 105 >1-10% 85 83 81 >10% 36 33 28 18 89 75 16 60 52 11 24 21 6 Subjects at risk ≤1% 32 31 30 >1-10% 121 119 116 >10% 84 81 71 30 112 59 29 108 55 28 106 51 Saglio G, et al., Blood 2012;120:[abstract 1675]. OS According to BCR-ABL Level at 3 Months Dasatinib 100 mg QD Imatinib 400 mg QD 84% had ≤10% BCR-ABL 100 Patients alive (%) 64% had ≤10% BCR-ABL 100 80 80 60 BCR-ABL level at 3 months ≤1% >1-10% >10% ≤10% vs >10% 40 20 0 0 6 12 18 60 3-Year OS 95.5% } P=.7342 96.5% } P=.0525 85.9% P=.0348 24 30 36 40 20 0 42 0 BCR-ABL level at 3 months ≤1% >1-10% >10% ≤10% vs >10% 3-Year OS 100% } P=.3453 95.0% } P=.0110 87.8% P=.0036 6 24 12 Months Subjects at risk 112 112 110 ≤1% 85 84 >1-10% 86 37 37 35 >10% 109 83 34 106 83 33 18 30 36 42 30 116 70 28 96 55 11 33 20 Months 104 79 27 85 66 22 29 25 9 Subjects at risk 32 32 32 ≤1% 121 120 >1-10% 122 85 85 82 >10% 32 118 80 31 118 76 Saglio G, et al., Blood 2012;120:[abstract 1675]. PFS According To Cytogenetic Response at 3 Months Dasatinib 100 mg QD Imatinib 400 mg QD 81% of patients had PCyR/CCyR 67% of patients had PCyR/CCyR 100 % Not Progressed 100 P<0.0001 80 P<0.0026 80 60 60 PCyR 40 CCyR P=0.2185 CCyR, N=139 20 PCyR 40 CCyR CCyR, N=79 20 PCyR, N=68 PCyR, N=31 <PCyR, N=39 0 0 6 12 < PCyR, N=73 0 24 Months For ≥PCyR vs <PCyR at 3 months 3-year PFS rates were 93.9% vs 71.3% 36 42 P=0.8062 0 6 12 24 Months For ≥PCyR vs <PCyR at 3 months 3-year PFS rates were 93.7% vs 77.3% 36 42 OS According To Cytogenetic Response at 3 Months Dasatinib 100 mg QD Imatinib 400 mg QD 81% of patients had PCyR/CCyR 67% of patients had PCyR/CCyR 100 80 80 60 60 % Alive 100 PCyR/CCyR <PCyR 40 P=0.0115 CCyR, N=140 20 <PCyR, N=39 0 6 12 <PCyR 40 PCyR, N=68 < PCyR, N=73 0 24 Months For ≥PCyR vs < PCyR at 3 months 3-year OS rates were 96.4% vs 84.2% 36 42 P=0.3681 CCyR, N=80 20 PCyR, N=31 0 PCyR/CCyR 0 6 12 24 Months For ≥PCyR vs < PCyR at 3 months 3-year OS rates were 93.9% vs 93.1% 36 42 PFS According To Response at 12 Months % Not Progressed Dasatinib 100 mg QD Imatinib 400 mg QD 100 100 80 80 60 MMR and/or CCyR <CCyR 40 60 MMR and/or CCyR P<0.0001 <CCyR 40 MMR, N=95 20 P<0.0001 MMR, N=64 20 CCyR (no MMR), N=85 CCyR (no MMR), N=87 <CCyR, N=26 <CCyR, N=50 0 0 0 6 12 24 Months 36 42 0 6 12 24 Months 36 42 OS According To Response at 12 Months Dasatinib 100 mg QD 100 100 80 80 60 % Alive Imatinib 400 mg QD MMR and/or CCyR <CCyR 40 60 MMR and/or CCyR P=0.0503 <CCyR 40 MMR, N=64 MMR, N=95 20 20 CCyR (no MMR), N=86 <CCyR, N=28 0 0 6 12 Months P=0.0041 CCyR (no MMR), N=89 < CCyR, N=52 0 24 36 42 0 6 12 24 Months 36 42 DASISION: European Subpopulation Analyses Table 8. Mutations identified during treatment: 2-year follow-up European subpopulation Global population Dasatinib 100 mg QD N=74 Imatinib 400 mg QD N=96 Dasatinib 100 mg QD N=259 Imatinib 400 mg QD N=260 47 (64) 75 (78) 181 (70) 206 (79) Samples analyzed for mutations, n 25 43 93 128 Patients with newly detected mutations on treatment, n 3 2 14 14 2 – – – 1 1 1 – – – 6 2 2 3 1 9 3 1 1 – Patients with eventsa triggering mutation analyses, n (%) No CCyR at 1 year No CCyR at 1 year and 5-fold increase in BCR-ABL No MMR at 1 year No MMR at 1 year and 5-fold increase in BCR-ABL levels Loss of CCyR and 5-fold increase in BCR-ABL levels Mutations F317L (2) V299L (1) T315I (1) detectedb M244V (1) E355G (1) F317L (1) F317I (1) V299L (3) T315I (9) G250E (1) M244V (1) L248V (1) G250E (1) E255K/V (3) D276G (1) M351T (3) E355G (2) F359C/V (4) L387M (1) H396P (1) E450G (1) Mutations were detected by direct sequencing aNo CCyR or MMR within 1 year, loss of CCyR, 5-fold increase in BCR-ABL, off-treatment due to progression, treatment failure, or other event, including AEs unrelated to study drug, study drug toxicity, consent withdrawal, loss to follow-up, pregnancy,patient request, and poor/nonadherence b1 patient in the dasatinib arm and 5 in the imatinib arm had more than one mutation EHA 2012 30 BMS Confidential - Not for Further Copying or Distribution Conclusions 3-year follow-up from DASISION continues to support dasatinib 100 mg QD as first-line treatment for newly diagnosed CML-CP – Deeper cytogenetic and molecular responses with dasatinib vs imatinib : • at 3 mo, ≤10% BCR-ABL (84% vs 64%) & MCyR (81% vs 67%) • at 12 mo, MMR (46% vs 23%) & CCyR (83% vs 72%) – Fewer transformations to AP/BP 3-month <10% BCR-ABL and MCyR and 12-month CCyR associated with: – Higher probability of PFS and OS at 36 months Management of patients with lack of 3-month <10% BCR-ABL or less than MCyR and 12-month less than CCyR remains to be determined Safety profile continues to be well tolerated with minimal changes from 2 to 3 years OPTIM study : dose adapted to PK Patients > 18 years old in untreated CP Dasatinib initiated at 100 mg QD PK evaluation (Cmin and Cmax measurements) performed after 7 ‐ 10 days of therapy Cmin < 3nM continue dasatinib 100 mg QD Cmin > 3nM RANDOM Continue dasa 100 mg daily “adaptation” arm: dose adjusted to Cmin less than 3 nM Rousselot P et al, ASH 2010 Six-year FU of pts with imatinib-resistant or intolerant CML-CP receiving dasatinib (CA180-034) Study design 670 Randomized 662 Treated 100 mg QD (n=165) 100 mg CP-CML with • Resistance • Intolerance to imatinib • Suboptimal response 50 mg BID (n=167) 140 mg QD (n=163) 140 mg 70 mg BID (n=167) BID, twice daily. Shah N et al, ASCO 2012, abs 6506 Abstract 6506: Shah et al 6-year follow-up of CA180-034 Patient disposition Treated patients, % 100 mg QD (n=165) 140 mg QD (n=163) 50 mg BID (n=167) 70 mg BID (n=167) 31 24 30 28 Progressiona 21 26 16 16 Study drug toxicity 21 26 24 29 Request 14 14 12 11 Otherb 6 6 6 8 AE unrelated to drug 4 2 5 4 No responsec 2 2 5 3 Death unrelated to drug <1 0 0 1 On treatment Reason for discontinuation aProgression (as reported by investigator) was defined as increasing white blood cell count, loss of CHR or MCyR, ≥30% increase in Ph+ metaphases, confirmed AP/BP disease, or death; bcommercial supply and/or travel requirements, transplant, noncompliance or to avoid toxicity, unknown reason, developed mutation, pregnancy, other malignancy; cas reported by the investigator. AE, adverse event; CHR, complete hematologic response; MCyR, major cytogenetic response. 34 Abstract 6506: Shah et al 6-year follow-up of CA180-034 Response rates (dasatinib 100 mg QD) Best overall response within 2 years CHR: 92% MCyR: 63% CCyR: 50% 100 % With MMR 80 60 35% 41% 42% 42% 40 20 0 0 12 24 36 48 60 72 Months CCyR, complete cytogenetic response; MMR, major molecular response. 35 Abstract 6506: Shah et al 6-year follow-up of CA180-034 PFS and OS in imatinib-resistant and -intolerant patients 100 mg QD (n=165) 140 mg QD (n=163) 50 mg BID (n=167) 70 mg BID (n=167) Imatinib-resistant, n 124 124 123 126 Rate of PFS, % 46 32 50 45 Rate of OS, % 69 73 72 67 43 44 44 42 Rate of PFS, % 58 66 53 55 Rate of OS, % 78 87 79 81 Imatinib-intolerant, n 36 Abstract 6506: Shah et al 6-year follow-up of CA180-034 Exploratory analysis: PFS by time to BCR-ABL ≤10% Analysis restricted to imatinib-resistant patients with >10% transcript level at baseline % Not progressed 100 80 60 40 0-3 Months 6 Months 12 Months >12 Months 20 0 0 12 24 36 48 60 72 Months Earlier achievement (≤3 months) of BCR-ABL ≤10% is a significantly (P<.002) better predictor of prolonged PFS than later achievement 37 Abstract 6506: Shah et al 6-year follow-up of CA180-034 % Not progressed Exploratory analysis: PFS by BCR-ABL level at 3 months Overall population 100 64% 80 60 40 20 0 P<.0001 ≤10% >10% 0 3 Patients at risk ≤10% 325 >10% 228 12 24 36 289 173 241 109 202 76 Months 48 60 72 172 58 146 36 40 6 ≤10% >10% Imatinib-resistant, n 222 202 Rate of PFS, % 62 25 Imatinib-intolerant, n 103 26 Rate of PFS, % 68 30 38 26% Abstract 6506: Shah et al 6-year follow-up of CA180-034 Exploratory analysis: effect of baseline factors on survival by BCR-ABL level at 3 months PFS OS 100 64% 80 60 P<.0001 40 20 0 ≤10% >10% 03 12 Patients at risk ≤10% 225 201 >10% 194 147 36 48 60 59% 40 0 72 P<.0001 60 20 26% 24 83% 80 % Alive % Not progressed 100 ≤10% >10% 0 3 12 24 Months 167 95 138 67 36 48 60 72 177 121 160 104 54 33 Months 119 50 100 31 26 5 226 199 218 182 202 164 189 139 Patients who achieved BCR-ABL ≤10% at 3 months had a significantly higher rate of PFS, regardless of the presence or absence of the following baseline factors: – Mutationsa – PCyRa – CHRa aData not shown. PCyR, partial cytogenetic response. 39 Abstract 6506: Shah et al 6-year follow-up of CA180-034 Exploratory analysis: survival by BCR-ABL ≤10% versus CHR at 3 months Analysis excludes patients with CHR and BCR-ABL ≤10% at baseline PFS OS CHR + ≤10% vs CHR + >10% comparison P<.0001 CHR + ≤10% vs CHR + >10% comparison P<.0001 100 64% 80 60 21% 40 20 0 CHR+≤10% CHR+>10% No CHR 03 Patients at risk CHR+≤10% 124 CHR+>10% 105 No CHR 29 55% 60 40 20 14% 80% 80 % Alive % Not progressed 100 0 36% CHR+≤10% CHR+>10% No CHR 12 24 36 48 Months 60 72 0 3 12 24 36 48 Months 60 72 112 81 14 94 52 6 76 37 2 59 18 2 18 1 1 124 106 32 121 96 26 112 89 20 105 73 17 88 55 10 32 17 3 69 27 2 40 97 64 13 Abstract 6506: Shah et al 6-year follow-up of CA180-034 Nonhematologic AEs (dasatinib 100 mg QD, n=165) 47.3 Headache Headache 0.6 Musculoskeletal Pain Musculoskeletal Pain 48.5 3.0 46.7 Infection Infection 6.1 41.3 Diarrhea Diarrhea 4.3 37.0 Fatigue Fatigue 4.3 32.8 Rash Rash 2.4 31.1 Arthralgia Arthralgia 33.2 Dyspnea Dyspnoea 2 Years 2.4 23.6 Hemorrhage Hemorrhage 3.0 Nausea Nausea 0.6 2 Years 23.7 Abdominal Pain Abdominal Pain 5 Years 6 Years Grade 3/4 25.5 Superficial Edema 4 Years 22.4 0.6 Superficial Edema 4 Years 5 Years 6 Years 2.5 17.0 Myalgia Myalgia 0.0 Pleural Effusion Pleural Effusion 5.3 25.3 5.3 0 All grades 1.8 10 20 30 40 50 60 70 80 90 Percent Two cases with the term pulmonary arterial hypertension were reported. Neither case was confirmed with a diagnostic right heart catheterization and both were considered to be unrelated to dasatinib by the investigators 41 100 Abstract 6506: Shah et al 6-year follow-up of CA180-034 Grade 3/4 AEs (dasatinib 100 mg QD, n=165) Cumulative incidence of hematologic AEs Two-year chemistry abnormalities 9,9 Phosphorus ↓ 36.4 Neutropenia Thrombocytopenia AST ↑ 0,6 Total bilirubin ↑ 0,6 Potassium ↓ 0,6 Calcium ↓ 0,6 2 Years 23.6 4 Years 5 Years Anemia ALT ↑ 6 Years 12.7 0 Creatinine ↑ 0 0 20 40 60 80 100 0 Percent 20 40 60 Percent 42 80 100 Abstract 6506: Shah et al 6-year follow-up of CA180-034 Transformation to AP/BP on study (dasatinib 100 mg QD) % Transformation 12 100 10 8 6 4 n=2 n=2 n=4 n=1 n=0 n=1 1 2 3 4 5 6 2 0 Years Transformation to AP/BP on study by 6 years – All patients: 10/166 (6%) – Imatinib-resistant patients: 9/124 (7%) – Imatinib-intolerant patients: 1/43 (2%) 43 Abstract 6506: Shah et al 6-year follow-up of CA180-034 Conclusions In the longest reported follow-up of patients treated with a second-generation BCRABL inhibitor, dasatinib was generally well-tolerated – No new safety signals identified With six years of follow-up of dasatinib in the second-line setting: – – – – – 31% of patients randomized to 100 mg daily remain on study The cumulative CCyR rate is 50% The cumulative MMR rate is 42% Six percent of patients have experienced transformation to AP/BP on study in the 100 mg once daily treatment arm The estimated overall survival rate is 71% for 100 mg daily ● 12.5% of patients have died due to CML Exploratory analyses reveal – A reduction in BCR-ABL/ABL of ≤ 10% at three months is highly predictive of superior longer term PFS and OS irrespective of: ● ● ● Resistance or intolerance to imatinib Presence or absence of mutations at time of switch Baseline response level 44 DASISION: Analysis of Lymphocytosis and Response Retrospective analysis of lymphocytosis (> 3.6 x 109/L on ≥ 2 occasions) in patients from DASISION (N = 516) Cumulative incidence of lymphocytosis higher on dasatinib: Dasatinib, 68/258 (26%) Imatinib, 15/258 (6%); P < .0001 Cumulative responses higher in dasatinib-treated patients with lymphocytosis at any time, no relationship in imatinib-treated patients Lymphocytosis CCyR cCCyR MMR Dasatinib (n=258) Yes 93% 85% 68% No 85% 76% 54% Imatinib (n=258) Yes 53% 53% 27% No 83% 72% 42% Schiffer C, et al. Blood. 2010;116(21): [abstract 358]. Dasatinib and Pleural Effusion Risk factors Quintas-Cardama A, JCO 2007 in multivariate analysis Arterial hypertension History of cardiac disorders Twice vs once daily dosage AP/BP only in univariate analysis Shah NP, JCO 2008 • 140 vs 100 mg dosage De Lavallade et al, BJH 2008 Single Center; 62 pts in I or II line; 27% CML advanced phase Hypertension Cardiac disorders Hypercholesterolemia Skin rash under imatinib History of autoimmune disorders Dasatinib and PE: a role for age Risk factors evaluated: age,, duration of CML, sex, prior SCT, lymphocytosis Lymphocytosis was associated with a 1.7 increased risk of PE PORKKA K. et al, Cancer Jan 2010 Role of comorbidities in predicting PE Breccia M. et al, Hematologica 2011 Valent P et al, Haematologica 2011 Dasatinib and Pulmonary Hypertension Mattei D et al 51 Dasatinib and Pulmonary Hypertension Montani, Circulation 2012 • Evaluation of incident cases of dasatinib‐associated PH reported in the French PH registry • From November 2006 to September 2010 identified 9 incident cases treated by dasatinib at the time of PH diagnosis • At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. • Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient • Only one of these 9 patients had risk factors for cardiac or pulmonary diseaeses or comorbidities: hypertension and coronary artery disease 52 Dasatinib and Pleural Effusion Mechanism unknown Management immune-mediated pathogenesis combined inhibition of Src (affecting vascular permeability) and PDGFR (affecting interstitial fluid pressure and vascular permeability) allergen-induced histamine secretion in basophils Resolution is rapid after dasatinib discontinuation, accelerated by adding diuretics or steroids. Transient discontinuations of dasatinib have been reported to be for a median duration of 27 days, (although this duration was contributed to by some patients remaining off therapy post pleural effusion resolution ,due to simultaneous occurrence of other grade 3/4 events). Conclusions Dasatinib is a multitarget TKI , able to inhibit BCR-ABL , c-KIT, PDGFR, EPHA-2 and Src kinase family (Lyn, Yes e Src) It is more active than imatinib on the stem cell compartment, but the primitive quiescent cells are resistant to the drug. Well tolerated safety profile of Dasatinib. The onset of pleural effusion is favored by known risk factors. Its treatment is usually manageable and does not affect the outcome 3-year follow-up from DASISION continues to support dasatinib 100 mg QD as first-line treatment for newly diagnosed CML-CP Deeper cytogenetic and molecular responses with dasatinib vs imatinib : • at 3 mo, ≤10% BCR-ABL (84% vs 64%) & MCyR (81% vs 67%) • at 12 mo, MMR (46% vs 23%) & CCyR (83% vs 72%) Fewer transformations to AP/BP 3-month <10% BCR-ABL and MCyR and 12-month CCyR associated with higher probability of PFS and OS at 36 months Conclusions With six years of follow-up of dasatinib in the second-line setting: 31% of patients randomized to 100 mg daily remain on study The cumulative CCyR rate is 50% and the cumulative MMR rate is 42% Six percent of patients have experienced transformation to AP/BP on study in the 100 mg once daily treatment arm The estimated overall survival rate is 71% for 100 mg daily with 12.5% of patients died due to CML Exploratory analyses reveal a reduction in BCR-ABL/ABL of ≤ 10% at 3 months is highly predictive of superior long-term PFS and OS irrespective of: Resistance or intolerance to imatinib Presence or absence of mutations at time of switch Baseline response level Grazie! Drssa Patrizia Pregno S.C. Ematologia 2° generation TKIs in first line therapy of CP‐CML Results of trials Reduced rate of progression to AP/BC Increased and earlier CCyR rate Increased and earlier MMR and CMR rate No major safety issues Data at 36/48 months Survival? Longstanding CMR? Open questions Dasatinib / Nilotinib to be used as first line treatment in all patients? In selected patients? Young population High/intermediate Sokal risk Evaluating comorbidities As early shift in patients with suboptimal response? Novel TKIs and Immunity (2) DASATINIB • The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib • Dasatinib inhibits T-cell activation and proliferation • Dasatinib inhibits the proliferation and function of CD4+CD25+ regulatory T cells • Dasatinib inhibits recombinant viral antigen-specific murine CD4+ and CD8+ T-cell responses and NK-cell cytolytic activity in vitro and in vivo • Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy Hantschel. PNAS 2007; Schade, Blood 2004; Fei, BJH 2008; Fraser, Exp Hematol 2009; Mustjoki, Leukemia 2009 Altered bone metabolism Dasatinib • c‐FMS inhibition and downstream signaling inhibition (Erk e Akt) • PDGFR and c‐KIT inhibition • Inhibition of tumour‐associated macrophages and osteoclasts • Abnormalities in bone metabolism may be a general class effect of TKIs. Brownlow et al, Leukemia 2008 Clinical implications of differential TK profiles Dasatinib/Nilotinib Cautions QTc prolongation: Both – Baseline EKG, close K+ and Mg++ monitoring, drug I/A Pancreatitis, uncontrolled diabetes, severe liver disease: Nilotinib Hypertension, COPD, CCF, chest wall injury, asthma, pneumonia, GI bleeding, autoimmune disorders, aspirin: Dasatinib Modified from Giles et al. Leukemia 2009. Conclusions…. 2nd generation TKIs reduce the rate of progression in all studies Possible Explanations • Higher potency in inhibiting BCR‐ABL1 TK • Lower dependence of intra/extracellular mechanisms of drug influx/efflux • Higher capability in suppressing “permissive environment” for the development of resistance – Mutations of BCR‐ABL1 – Activation of alternative TK activities Considerations • …even if patients respond well to therapy, until the achievement of very low levels of residual disease (at least MMR?) patients may still have some risk of losing response and also of progression. • …it is important also to have a fast response , as for those patients who are late in reducing the leukemic burden the risk of non responding and of progression is higher. 2° generation TKIs in first line therapy of CP‐CML Results of trials Open questions • Reduced rate of progression • Dasatinib / Nilotinib to be to AP/BC used as first line treatment in all patients? • Increased and earlier CCyR rate • In selected patients? • Increased and earlier MMR – Young population and CMR rate – High/intermediate Sokal risk • No major safety issues – Evaluating comorbidities • Data at 36/48 months • As early shift in patients • Survival? with suboptimal response? • Longstanding CMR?
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