Chi sono i candidati agli inibitori di JAK2

Transcription

1 Chi sono i candidati agli inibitori di JAK2 Francesco Passamon, Hematology, University Hospital Varese, Italy

2 Ruxoli8nib (US approved in MF; EAP study and compassionate use in Italy) SAR (phase 3 ongoing) CEP701 (phase 1,2) SB1518 (phase 1,2) CYT387 (phase 1,2) AZD1480 (phase 1,2) NS018 (phase1,2) LY (phase 1,2) JAK2 inhibitors Passamon8 et al., Curr Opin Hematol Mar;19(2):

3 Are JAK2 inhibitors only for MF pa6ents carrying JAK2 muta6on?

4 JAK2 V617F Muta6on in MPNs Binding to receptors Chaperoning Stabilising at membrane Catalytically inactive, inhibits basal activity Signaling through P transfer Wild type JAK2 Chr 9 Heterozygous V167F V617F V617F V617F Point Mito6c muta6on recombina6on Homozygous V167F UPD at 9p24 FERM SH2 PseudoKinase Kinase JH5 JH3 JH7 JH6 JH4 JH2 JH1 V617F James et al. Nature 2005; 434: ; Baxter et al. Lancet 2005; 365: ; Levine et al. Cancer Cell 2005; 7:387 97; Kralovics et al. NEJM. 2005: 352: ; Ungureanu et al. Nat Struc Mol Biol 2011; 18:971 6

5 JAK2 in MPNs MPN JAK2+ PV: 98% ET: 50 60% MF: 50 60% Passamonti et al. Blood 2006

6 Why JAK2 V617F muta6on is unlikely to be the primary muta6onal event in MPNs? MPN may arise also in the absence of JAK2 muta8on Familial MPN may have a mixed phenotype in the absence of germinal transmission of JAK2 or MPL muta8ons ET and PV may be clonal (X inac8va8on assays) with V617F present only in a minority of cells AML post V617F pos MPN may be V617F neg sugges8ng the existence of a pre JAK2 clone, on the background of which 2 independent gene8c events occurred, one V617F pos leading MPN, another unknown mut pos leading AML

7 High Throughput Molecular Technologies Iden6fy Muta6ons Affec6ng Mul6ple Func6ons Muta6ons affec6ng the JAK STAT signaling JAK2 MPL LNK c CBL SOCS1 3 NF1 Muta6ons affec6ng the epigene6c regula6on TET2 EZH2 ASXL1 IDH1/2 DNMT3A PRC2 JAK2V617F Muta6ons associated with leukemic transforma6on IDH1/2 IKZF1 TP53 NF1 RUNX1 NRAS KRAS DNMT3A

8 JAK2 inhibitors reduce phosphorila6on of JAK & STAT independently of the underlying muta6ons JAK2 Immune response Gain of func6on MPL CBL STAT3/5 ac8va8on Inflamma6on Angiogenesis (VEGF) Loss of func6on LNK NF1 Prolifera6on (CCND1) Resistance to apoptosis (BCL2L1, MCL1, BIRC5) Passamon8 et al, Oncotarget Jun;2(6):

9 Inhibi6on of JAK2 signaling and cell prolifera6on in JAK2 (V617F) driven mouse models Quintas Cardama et al Blood 2010 Ruxoli,nib inhibits pstat5 independently from the underlying ac,va,ng muta,on Quintás Cardama A, et al. Blood. 2010;115:

10 Ruxoli6nib in COMFORT II: Reduc6on of spleen size by JAK2V617F Muta6on Status At Week 48 a Change From Baseline, % Ruxoli6nib JAK2V617F posi8ve (n = 75) JAK2V617F nega8ve (n = 22) Unknown muta8on status (n = 1) BAT Primary endpoint JAK2V617F posi8ve (n = 24) JAK2V617F nega8ve (n = 8) Unknown muta8on status (n = 2) At week 48, the vast majority of pa8ents receiving ruxoli8nib experienced spleen volume reduc8ons, including JAK2V617F posi8ve (88% [66/75]) and JAK2V617F nega8ve (91% [20/22]) pa8ents a For patients with spleen volume assessments by MRI/CT at both baseline and week 48. Harrison C, et al. N Engl J Med Mar 1;366(9):

11 Are JAK2 inhibitors only for PMF or also for post PV, post ET MF?

12 COMFORT I Study Design and Demographics COMFORT I is a randomized, blinded, mul8center phase 3 trial with ruxoli6nib Pa8ents with PMF, PPV MF, or PET MF with 2 IWG risk factors, with PLT > 100 x10 9 /L N = 309 Randomize 1:1 Ruxoli6nib 15 or 20 mg orally BID n = 155 Placebo n = 154 Ruxoli6nib crossover and extension phase COMFORT I Primary Endpoint Number of subjects achieving 35% reduc6on in spleen volume from baseline to week 24 Verstovsek S, et al. NEJM (9):

13 COMFORT II Study Design and Demographics COMFORT II is a randomized, open label, mul8center phase 3 trial with ruxoli6nib Pa8ents with PMF, PPV MF, or PET MF with 2 IWG risk factors, with PLT > 100 x10 9 /L N = 219 Randomize 2:1 Ruxoli6nib (INC424) 15 or 20 mg orally BID n = 146 Best available therapy (BAT) n = 73 Pa8ents with progressive splenomegaly eligible for extension phase Ruxoli8nib (n = 146) BAT (n = 73) Ruxoli6nib crossover and extension phase Age, median yrs MF type, % PMF PPV/PET MF 53 33/14% 39 (53) 27/19% HR/IR 2 IPSS risk 60% / 40% 59% / 40% COMFORT II Primary Endpoint Number of subjects achieving 35% reduc6on in spleen volume from baseline to week 48 Spleen length, cm Harrison C, et al. NEJM (9):

14 Predictors of response: efficacy by subgroups Propor8on of pa8ents in each subgroup with 35% reduc8on in spleen volume from baseline at Week 48 Mul8variate analysis suggests a higher response rate among pa8ents with PET MF (vs PMF); trends for star8ng dose, palpable spleen length and JAK2V617F muta8on status Harrison et al ASH 2011

15 Are pa6ents with low hemoglobin or lowplatelet not candidate to JAK2 inhibitors?

16 COMFORT II: anemia and thrombocytopenia Hemoglobin Grade 1 n (%) Grade 2 n (%) Grade 3 n (%) Grade 4 n (%) Ruxoli8nib (n = 146) 24 (16) 55 (38) 50 (34) 12 (8) BAT (n = 70) 16 (23) 28 (40) 15 (21) 7 (10) Platelet count Ruxoli8nib (n = 146) 46 (32) 41 (28) 9 (6) 3 (2) BAT (n = 69) 11 (16) 4 (6) 3 (4) 2 (3) Percentage is based on baseline total n. Pts receiving 1 PRBC transfusion while on treatment, n (%) Ruxoli8nib (n = 146) BAT (n = 73) 75 (51%) 28 (38%) Units transfused/month, mean

17 PMF, male 68 years DIPSS int 2 Ruxoli6nib 15 mg BID Ematologia Varese, 2012

18 JAKARTA Study Design JAKARTA is a randomized, blinded, mul8center phase 3 trial with SAR Pa8ents with PMF, PPV MF, or PET MF with 2 IWG risk factors with PLT > 50 x10 9 /L N = 225 Randomize 1:1:1 SAR mg orally per day SAR mg orally per day Placebo SAR crossover and extension phase JAKARTA Primary Endpoint Number of subject achieving 35% reduc8on in spleen volume from baseline to cycle 6, and confirmed 4 weeks thereaqer

19 POST PV MF, female 65 years, DIPSS int 2 SAR Ematologia Varese, 2012

20 Which prognos6c models in MF?

21 Current Risk Stra6fica6on in PMF IPSS DIPSS Age > 65 years Hb < 10 g/dl WBC > 25 x109/l Blasts 1% Cons8tu8onal symptoms Low risk No factor (IPSS/DIPSS) Intermediate 1 risk score 1 (IPSS) score 1 2 (DIPSS) Intermediate 2 risk score 2 (IPSS) score 3 4 (DIPSS) High risk score 3 (IPSS) score 5 (DIPSS) Passamon8 et al, Blood 2010; 115: Cervantes et al, Blood 2009; 113:

22 The IPSS at Diagnosis of PMF Probability Years 95 % CI 95 % CI 95 % CI Low Intermediate 1 Intermediate % CI High 135 months 22% 95 months 29% 48 months 28% 27 months 21% Risk group Low 0 Int 1 1 Int 2 2 High 3 Cervantes et al, Blood 2009; 113:

23 DIPSS model to predict survival of PMF Risk Factors Age > 65 yrs WBC >25 x10 9 /L Hb < 10 g/dl PB blasts 1% Const. symptoms Score value 1 2 x x x x x Risk Score Low 0 Intermediate 1 Intermediate 2 High 1 to 2 3 to 4 5 to 6 Passamon8 et al, Blood 2010; 115:

24 Which strategy in MF with JAK2 inhibitors?

25 Strategy 1: To treat splenomegaly independently from IPSS Spleen reduc8on is the main effect of JAK2 inhibitors with a high rate of clinical improvements Ruxoli8nib (> 300 pts): 40%/30% at 6/12 months SAR (39 pts): 40%/45%at 6/12 months Splenomegaly is present in 80% of LR and Int 1 Low risk pa8ents have a 80% survival at 20 years with standard therapies No data in LR and Int 1 pa8ents Need of inves8ga8ve trial in LR and Int 1

26 Strategy 2: To treat higher risk IPSS Most knowledge is on Int 2 and HR pa8ents Survival of Int 2 pa8ents is 4 years Survival of HR pa8ents is 2 years HSCT is the only alterna8ve Medical need Survival advantage has been demonstrated in COMFORT 1 and in a retrospec8ve historical matched control study

27 COMFORT I update on Survival (ITT) HR=0.50 ( ) P=0.04 Number of Patients at Risk Ruxolitinib Number of Patients at Risk Placebo Aqer a median follow up of 51 weeks, 13 (8.4%) deaths in ruxoli8nib group and 24 (15.7%) deaths in placebo group Verstovsek et al. N Engl J Med Mar 1;366(9):

28 No survival improvement with Ruxoli6nib: Ruxoli6nib treated group at Mayo Clinic (n=51) vs. historical Mayo control group (n=410; unmatched) Tefferi et al, NEJM 2011

29 Survival improvement with Ruxoli6nib: MDACC (n=107) vs. historical matched control group (n=310; HR+Int 2 IPSS, PLT >100 x10 9 /L) Ruxolitinib N=107 Hazard ratio= % CI: p-value=0.022 Control N=310 Number of Patients at Risk MDACC Study Number of Patients at Risk Historical Control Verstovsek S, et al. ASH a

30 Conclusions Are JAK2 inhibitors only for MF pa6ents carrying JAK2 muta6on? Are JAK2 inhibitors only for PMF or also for post PV, post ET MF? Are pa6ents with low hemoglobin or low platelet not candidate to JAK2 inhibitors? Which prognos6c models in MF? Which strategy in MF with JAK2 inhibitors? NO NO NO for Hb YES for PLT IPSS/DIPSS To treat Int 2, HR pts To inves6gate Int 1, LR