Il tra'amento delle sindromi mieloprolifera1ve croniche: stato dell arte e scenari futuri A.M. Vannucchi CRIMM, Centro Ricerca e Innovazione delle

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1 Il tra'amento delle sindromi mieloprolifera1ve croniche: stato dell arte e scenari futuri A.M. Vannucchi CRIMM, Centro Ricerca e Innovazione delle mala9e mieloprolifera<ve AOU Careggi, Università degli Studi, Firenze Neoplasie di origine mieloide: uno scenario in evoluzione Firenze novembre 2016

2 **Hydroxyurea for symptoma<c splenomegaly in countries where ruxoli<nib is not approved for low- risk pa<ents. *** For pa<ents with symptoma<c splenomegaly and/or cons<tu<onal symptoms if allowed by the label A. M. Vannucchi et al. Ann Oncol 2015;26:v85- v99

3 Dura1on of Spleen Response Loss of response: no longer a 35% reduc1on that is also a > 25% increase over nadir Events Censored Ruxoli<nib a n = (43.6%) 44 (56.4%) BAT a n = (100%) Median dura1on of response: 3.2 y The KM es1mated probability of maintaining response 3 years, 0.51 (95% CI, ) 5 years, 0.48 (95% CI, ) Ruxolitinib, n = BAT, n = At 5 years, 88% of pa<ents (45/51) who remained on treatment had improvements from baseline in spleen volume, and 67% (34/51) achieved 35% reduc<ons a For pa<ents who achieved a 35% reduc<on at any <me during randomized treatment; crossover pa<ents are not summarized. Harrison CN, et al. Blood (23):59

4 Recommendations: Ruxolitinib is recommended for improving splenomegaly in: Patients with intermediate-2 or high risk disease and either symptomatic or severe splenomegaly (strong recommendation) Patients with intermediate-1 risk disease and either symptomatic or severe splenomegaly not responsive or intolerant to HU or interferon (weak recommendation) Patients with intermediate-1 risk disease and both symptomatic and severe splenomegaly not previously treated with any cytoreductive agent (weak recommendation) Severe splenomegaly refers to splenomegaly palpable 15 cm below the costal margin. Symptomatic splenomegaly refers to the concurrent presence of a splenomegaly and local symptoms not attributable to other causes, such as pain in the left upper quadrant of the abdomen, or impairment of food intake due to early satiety.

5 Mean Change From Baseline Mean Change From Baseline COMFORT- I Improvements in EORTC QLQ- C30 Over Time Global Health Status/QoL Mean Change From Baseline 10 Fatigue Weeks RUX PBO Weeks Arrows indicate improvement Role Functioning Weeks Mean Change From Baseline Physical Functioning Weeks Verstovsek S, et al. Blood. 2013;122:abstract 396.

6 Recommendations. Accurate assessment by the tools such as MPN10 should be performed before any clinical decision regarding the use of ruxolitinib for improving disease-associated symptoms. Ruxolitinib is recommended for improving disease-related symptoms in patients with a MPN10 score higher than 44 or refractory severe itching (score >6) or unintended weight loss (>10% in the last 6 months) not attributable to other causes or unexplained fever (Strong recommendation).

7 Rank Preserving Structural Failure Time (RPSFT) Analysis of Survival in COMFORTs Ruxoli<nib vs control (ITT): HR = 0.65; 95% CI, ; P =.01. Ruxoli<nib vs control (RPSFT- corrected for crossover) HR = 0.29; 95% CI, ; P =.01. Vannucchi AM, et al. Haematologica 2015; 100:

8 Overall Survival 5.0y Update of COMFORT- II Median Overall Survival Ruxolitinib (ITT) = not reached BAT (ITT) = 4.1 years BAT (RPSFT) = 2.7 years Probability Ruxolitinib BAT (ITT) BAT (RPSFT) n = Time, years Median OS was not yet reached in the ruxoli<nib arm (ie, > 5 years) ITT: HR, 0.67 (95% CI, ); P =.06 RPSFT: HR, 0.44 (95% CI, ) in favor of ruxoli<nib vs BAT HR, hazard ra<o; ITT, intent- to- treat; RPSFT, Rank- Preserving Structural Failure Time. Harrison CN, et al. Blood (23):59

9 Recommendations. The evidence supports a survival benefit associated with ruxolitinib but its quality according to GRADE was judged to be very low. Therefore, ruxolitinib should not be recommended uniquely for improving survival (weak recommendation).

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11 The panel listed the most relevant issues to be considered in assessing infec<on risk and deemed that ruxoli<nib could not be contraindicated in any specific subset of high- infec<ve risk pa<ents but that cau<on, specific monitoring or prophylac<c measures are recommended in pa<ents with at least one risk factor.

12 Clinical Benefits of Ruxoli1nib in Myelofibrosis Cytopenias (eg. Anemia & thrombocytopenia) Infec1ons MF

13 ReTHINK Trial Design ReTHINK is a phase III randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of ruxolitinib in early MF Pts and HMR mutations Screening (Day 40 to Day 1) Treatment Phase Period 1 Period 2 MF Patients Spleen 5 cm below LCM HMR+ (ASXL1, EZH2, SRSF2 or IDHI1/2) N = 320 1:1 Ruxolitinib 10 mg bid Placebo PFS- 1 a Ruxolitinib 5/15/20 mg bid Ruxolitinib 5/15/20 mg bid PFS- 2 Survival Follow up 13 End of study definition: ~1 year after 90 PFS-1 events on blinded study treatment have been confirmed and the primary analysis reported (estimated duration of 5.5 to 6 years) If there is a need for long-term follow up, the study may continue for up to 5 years after LPFV if the primary objective is met a If progression is achieved by spleen or symptoms

14 High Molecular Risk Prognostic Category harboring 1 mutation in any one of ASXL1, EZH2, SRSF2, IDH1/2 Overall Survival Blast Transformation A HMR status is associated with reduced OS and increased risk of blast transforma<on in PMF pa<ents independent of IPSS/DIPPS- plus Vannucchi AM, et al. Leukemia. 2013;27:1861-9

15 ReTHINK Trial Design ReTHINK is a phase III randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of ruxolitinib in early MF Pts and HMR mutations Screening (Day 40 to Day 1) Treatment Phase Period 1 Period 2 MF Patients Spleen 5 cm below LCM HMR+ (ASXL1, EZH2, SRSF2 or IDHI1/2) N = 320 1:1 Ruxolitinib 10 mg bid Placebo PFS- 1 a Ruxolitinib 5/15/20 mg bid Ruxolitinib 5/15/20 mg bid PFS- 2 Survival Follow up 15 End of study definition: ~1 year after 90 PFS-1 events on blinded study treatment have been confirmed and the primary analysis reported (estimated duration of 5.5 to 6 years) If there is a need for long-term follow up, the study may continue for up to 5 years after LPFV if the primary objective is met a If progression is achieved by spleen or symptoms

16 ESMO Clinical Prac1cal Guidelines for PV Vannucchi AM et al, Ann Oncol 2015; 26:v85- v99

17 Interferon alpha in Polycythemia Vera IFN- α has shown evidence of: Molecular responses in pa<ents with early stages of PV Relieving pruritus in some pa<ents Inducing complete hematologic responses Based upon phase 2 studies in a limited number of pa<ents IFN- α affects rates of thrombosis, the evolu<on to AML or secondary MF, and the development of bone marrow fibrosis Data from phase 3 trials (MPD- RC112, PROUD- PV) are awaited However, 15-25% of the pa<ents have to discon<nue treatment with pegylated IFN because of toxici1es 1. Mascarenhas J, et al. Haematologica. 2014;99: Barbui T, et al. Blood Rev. 2012;26: Kiladjian JJ et al. Blood 2008; 112;

18 DRAFT Oral Presentation EHA 2016 RESPONSE-2 Study Design Resistance to or intolerance of HU (modified ELN criteria) Phlebotomy requirement Nonpalpable spleen ECOG PS 2 Prerandomization (day 35) Hct, 40%-45% RESPONSE: Spleen >5 cm Randomized (1:1) Ruxolitinib 10 mg bid n = 74 BAT n = 75 Week 28 (primary analysis) Crossover to ruxolitinib Extended treatment phase Week 260 Week 80 RESPONSE: Week 32 Week 260 Final analysis Ruxolitinib-randomized patients had their doses individually titrated for efficacy and safety (to a maximum of 25 mg bid) Investigator-selected BAT as monotherapy included HU (at a tolerated dose if the patient were likely to receive benefit), interferon (IFN)/peg-IFN, anagrelide, pipobroman, immunomodulatory drugs, or observation All patients received low-dose aspirin unless medically contraindicated bid, twice daily; Passamon< F, Lancet Oncol, 2016

19 DRAFT Oral Presentation EHA 2016 Primary Response: Hct Control at Week 28 P <.0001 OR, 7.28 (95% CI, ) OR, odds ratio. 19

20 DRAFT Oral Presentation EHA 2016 Primary Response: Hct Control at Week 28 P <.0001 OR, 7.28 (95% CI, ) Response trial (w32) At randomization, BAT monotherapy included HU (49.3% of patients), IFN/peg-IFN (13.3%), pipobroman (6.7%), lenalidomide (1.3%), no medication (28.0%), and other (1.3%) RESPONSE: BAT included HU (59%), IFN/pegylated IFN (12%), anagrelide (7%), pipobroman (2%), IMIDs (5%), and observation (15%) OR, odds ratio. 20

21 Durability of Combined Primary Response and Hct Control With Ruxoli1nib At the planned 80-week analysis Ruxoli1nib (n=110) BAT* (n=112) Ruxoli1nib Crossover (n=98) Ongoing treatment, n (%) 91 (82.7) 0 81 (82.7) Median treatment exposure, wk The probability of maintaining the primary response in the ruxoli<nib arm for >80 weeks from <me of response was 92% The probability of maintaining Hct control in the ruxoli<nib arm for at >80 weeks from <me of response was 89% Srdan Verstovsek et al. Haematologica 2016;101:

22 DRAFT Oral Presentation EHA 2016 Complete Hematologic Remission at Week 28 CHR defined as Hct control without phlebotomy, PLT count /L, and WBC count /L. P =.0019 OR, 5.58 (95% CI, ) 22

23 DRAFT Oral Presentation EHA 2016 Complete Hematologic Remission at Week 28 CHR defined as Hct control without phlebotomy, PLT count /L, and WBC count /L. P =.0019 OR, 5.58 (95% CI, ) Response trial (w32) 23

24 Con1nuing Control of Blood Cell Counts in Pa1ents Receiving Ruxoli1nib Changes in WBC Counts and Platelet Counts in Ruxoli1nib Arm N Week 32 % Pa1ents Week 80 % Pa1ents WBC 10 x 10 9 /L in pa<ents with baseline WBC >10 x 10 9 /L WBC 10 x 10 9 /L in pa<ents with baseline WBC >15 x 10 9 /L Platelets 400 x 10 9 /L in pa<ents with baseline platelet count >400 x 10 9 /L The probability of maintaining CHR for 80 weeks from 1me of response was 69% Percentage of pa<ents with normalized WBC and platelet counts improved over 1me with ruxoli1nib treatment Srdan Verstovsek et al. Haematologica 2016;101:

25 Changes in disease- related symptoms in pa1ents with PV receiving ruxoli1nib or standard therapy Vannucchi AM et al, NEJM 2015; 372: Mesa R et al, EJH 2016, online

26 Impact of Ruxoli1nib on Pruritus by the PSIS* Scale at Week 32 Mean Change From Baseline at Week How severe was PV-related itching during the past 7 days? 2.2,00 How bothered by PV-related itching during the past 7 days? 2.0,00 Rux How much PV-related itching interfered with daily life during the past 7 days? 1.5,300 BAT How bothered by PV-related itching during the past 24 hours? How much PV-related itching interfered with daily life during the past 24 hours? 1.4 Improvement,300 Pruritus severity and its interference on daily life improved with ruxolitinib and was unchanged/worsened with BAT *Pa1ents responded to each ques1on on a scale of 0 (not at all) to 10 (worst imaginable) Vannucchi AM, et al. N Engl J Med. 2015;372:

27 Adverse Events Exposure, Patient-Years Ruxolitinib (n=110) n (exp adjusted rate) BAT (n=111*) 73.6 n (exp adjusted rate) All infections 67 (29.4) 43 (58.4) Grade 3 or 4 9 (4.0) 3 (4.1) Herpes zoster infection 12 (5.3) 0 Grade 3 or 4 2 (0.9) 0 Nonmelanoma skin cancer 10 (4.4) 2 (2.7) Patients with a history of NMSC 6 (24.2) 1 (22.3) Patients without a history of NMSC 4 (2.0) 1 (1.4) Disease progression Myelofibrosis 3 (1.3) 1 (1.4) AML 1 (0.4) 0 *1 pa<ent was randomized to BAT but did not receive study treatment There were 3 addi<onal events of NMSC aqer crossover, 1 in a pa<ent with a history of skin cancer or precancer Pa<ents with history of NMSC: n=12, 24.8 pt- yrs exposure in ruxoli<nib arm; n=7, 4.5 pt- yrs exposure in BAT arm Pa<ents without a history of NMSC: n=98, pt- yrs exposure in ruxoli<nib arm, n=104, 69.1 pt- yrs exposure in BAT arm There was 1 addi<onal report of myelofibrosis in the ruxoli<nib arm, but this was not confirmed with bone marrow biopsy; there were 3 cases of myelofibrosis in the BAT arm aqer crossover to ruxoli<nib; 1 of these pa<ents developed AML Good hematologic tolerability: Anemia G>3=0.9%, Thr penia G>3 2.6%, Neutropenia G>3 0.4%, Lymphopenia G>39.7% Kiladjian JJ et al, EHA 2015

28 Rate of Thromboembolic Events in RESPONSE Trial Treatment Group Ruxoli1nib (n = 110) BAT (n = 111 a ) Exposure, Pa<ent- Years Number of Pa1ents (Rate per 100 Pa<ent- Years of Exposure) All Grades Grade 3/4 All Grades Grade 3/4 All thromboembolic events 4 (1.8) 2 (0.9) 6 (8.2) b 2 (2.7) Preliminary evidence of the lower rate of thromboembolic events observed in the ruxoli1nib arm vs the BAT arm. Consistent with the observed effects of ruxoli<nib on hematocrit, WBC counts, and C- reac<ve protein levels, which are all associated with thromboembolic risk Kiladjian et al, EHA 20th Congress, Vienna 2015, abstract 5447 Samuelson BT al Blood Coagul Fibrinolysis Nov 13. [Epub ahead of print]

29 I Nuovi Agen1 Terapeu1ci Nuovi JAK2 inibitori Nuovi schemi terapeu1ci per Ruxoli1nib Nuovi target Cocktails

30 JAK2 Inhibitors: Molecules and Clinical Trials JAK inhibitor (Company) MF PV/ET Note CEP701 (Cephalon) STOPPED AZD1480 (AstraZeneca) XL019 (Exelixis) STOPPED STOPPED NS- 018 (NS Pharma) I, ongoing STOPPED BMS (BMS) I/II, ongoing STOPPED LY (Lilly) II, ongoing I finished STOPPED Momelo<nib (Gilead) III, ongoing ONGOING Pacri<nib (CTI) III, ongoing COMPLETED, on Hold Fedra<nib (Sanofi) III, completed I/II completed STOPPED Ruxoli<nib (Incyte/Novar<s) III, completed (2) II, ongoing (low plt) II, completed (ET,PV) III, completed (PV) MF, APPROVED

31 Pacri1nib: PERSIST- 1 Study Design Key Eligibility Criteria PMF, PET-MF, or PPV-MF Intermediate- or high-risk disease Palpable spleen 5 cm No exclusion for baseline platelet levels; stratified by platelet counts 100,000/µL, 50,000-<100,000/µL, and <50,000/µL No exclusion for baseline Hgb levels No prior treatment with JAK2 inhibitors R (2:1) N=327 Pacritinib 400 mg qd (n=220) Best Available Therapy (BAT) a excluding ruxolitinib (n=107) a Cross-over from BAT allowed after progression or after Week 24 assessment Stratification at randomization: platelet count category, risk category, and region Study endpoints Primary: proportion of patients achieving a 35% reduction in spleen volume (by MRI/CT) from baseline to Week 24 Secondary: proportion of patients with a 50% reduction in Total Symptom Score (TSS) from baseline to Week 24 on the Myeloproliferative Neoplasm Symptom Assessment Form v 2.0 Trial conducted in US, Europe, Russia, and Oceania CT, computed tomography; Hgb, hemoglobin; JAK, Janus kinase; MRI, magnetic resonance imaging; PET-MF, post-essential thrombocythemia myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis; R, randomized. Mesa RA, et al. ASCO Abstract LBA7006.

32 Spleen Volume Reduc<on 35% Primary Objec1ve: Spleen Volume Reduc1on At Week 24 as Assessed by MRI/CT ITT popula1on: 19.1% vs. 4.7%, PAC vs. BAT (p=0.0003) Evaluable popula1on a : 25.0% vs. 5.9%, PAC vs. BAT (p=0.0001) Change From Baseline, % PAC (n=168) Patients b BAT (n=85) 35% decrease a Evaluable population: patients had both baseline and Week 24 spleen assessment by MRI or CT; n=168 for PAC and n=85 for BAT. b As of last patient s 24 week visit. BAT, best available therapy; CT, computed tomography; ITT, intent to treat; MRI, magnetic resonance imaging; PAC, pacritinib. Mesa RA, et al. ASCO Abstract LBA7006.

33 Secondary Objec1ve: Symptom Improvement Pa<ents Achieving 50% Reduc<on in TSS At Week 24 (ITT PopulaAon) p< p= p= p= Patients ITT <50,000/μL <100,000/μL 100,000/μL Platelet Subgroup BAT, best available therapy; ITT, intent to treat; PAC, pacritinib; TSS, total symptom score.

34 Changes in Platelet Levels, Hemoglobin, and Hematological Toxicity RBC Transfusion Dependence Over Time Mean Platelets 10 9 /L (± SEM) Patients With Baseline Platelets <50,000/µL Mean Platelets 10 9 /L (± SEM) 1,a PAC BAT p= b p= b Mean Hgb (g/dl) (± SEM) PAC BAT Patients With Baseline Hgb <10 g/dl Mean Hgb (g/dl) (± SEM) 1,a 0 BL BL Weeks Weeks At baseline, 15.9% of PAC and 14.0% of BAT pa<ents were RBC transfusion dependent, per Gale criteria ( 6 units/90 days 2 ) Patients Patients Achieving RBC Transfusion Independence 1 p=0.043 a By central laboratory. b Based on linear regression using mixed model. BAT, best available therapy; BL, baseline; Hgb, hemoglobin; PAC, pacritinib; RBC, red blood cell. 1. Mesa RA, et al. ASCO Abstract LBA Gale RP, et al. Leuk Res. 2011;35:8-11.

35 Momelo1nib: Phase 3 Studies N = 420 1:1 randomization Momelotinib + placebo Ruxolitinib + placebo JAK inhibitor naïve Randomized, Double Blind Primary endpoint: Spleen Response by MRI at week 24 Day 1 Week 24 Year 5 N = 150 2:1 randomization Momelotinib N = 100 Best Available Therapy (ruxolitinib and no treatment allowed) N = 50 Previous JAK inhibitor exposure Randomized, Open Label Required ruxoli<nib dose adjustment to < 20mg BID and concurrent hematologic toxicity Primary endpoint: Spleen Response by MRI at week 24 Day 1 Week 24 Year mg Tablet QD

36

37 Inhibi1on of Telomerase Ac1vity in MPN Upregulated telomerase ac<vity favours prolifera<on and replica<on immortality of neoplas<c progenitor cells MPN cells have evidence of dysregulated telomerase ac<vity IMETELSTAT is the first telomerase inhibitor in clinical development Compe<<vely binds to RNA template of telomerase and inhibits is ac<vity IMETELSTAT inhibited growth of spontaneous CFU- MK from ET pts Tefferi A et al, NEJM 2015; 373: Ruella M et al, Exp Hematol Jul;41(7):627-34; Baerlocher GM, et al. Blood Nov 2012; 120: 179.

38 Complete/Par1al Responses Induced by Imetelstat Imetelstat induced complete or par1al responses in 21% of pa1ents with refractory myelofibrosis. In some pa<ents, reversal of marrow fibrosis was documented and the burden of mutant clones decreased. Myelosuppression was the key toxic effect. A phase-2 study in Ruxoresistant patients with 2 dose levels is ongoing Tefferi A et al, NEJM 2015; 373:

39 PRM- 151: Recombinant Analog of PTX- 2 Verstrovsek S, courtesy

40 Reduced PTX- 2 Levels in Pa1ents with MF Verstrovsek S, courtesy

41 PRM- 151: Results of a Phase 2 Study in MF A phase-2 study in Ruxo-resistant patients is ongoing Verstrovsek S, courtesy

42 Safety and Efficacy of Ruxoli1nib Combina1ons RUX- PAN RUX- LDE RUX- BKM naive RUX- BKM pretreat Spleen Response (at 24w) 56.5% 44.4% 45.5% 22.2% Mean spleen reduc1on at 24w 41.7% 30.8% 38.8% 26.5% Adverse events Diarrhea: 68%, 18% gradoe3/4 Astenia :50%, 12% grade 3/4 Fa<gue: 29%, 6% grade 3/4 Raised CK 37%, 18,5% grade 3/4 Myalgia:29,6%, 7,4% grade 3/4 Diarrhea: 25,9%, 3,7% grade 3/4 Fa<gue: 25,9%; 0 grade 3/4 Anxiety 15,9%, 4,8% grade 3-4 Depression: 14,3%, 3,2% grade 3/4 Iperglycemia: 12,7%; 3,2% grade 3/4 Kiladjian; et al, ASH 2014 Durrant; et al, ASH 2014 Gupta et al, ASH 2014

43 Combo Therapy Brault L, et al. Haematologica. 2010;95(6): Shapiro GI. J Clin Oncol. 2006;24(11): Pinzon- Or<z M, et al. EHA 2014 abst. S710

44 Ruxoli1nib + LGH447 + LEE011 Reduced Spleen Size and Allele Burden to a Greater Degree than Ruxoli1nib Alone Spleen Weight Allele Burden Spleen Weight, g Vehicle * RUX * RUX + LGH447 + LEE011 * p < 0.05 Wild Type (no Ba/F3) Rela1ve JAK2 V617F Allele Burden, % 100 Vehicle * RUX * * p < 0.05 RUX + LGH447 + LEE011 The triple combina<on resulted in greater reduc<ons in spleen size compared with ruxoli<nib alone, reducing spleen weight to levels at or below those in wt animals The triple combina<on solely resulted in a substan<al reduc<on in JAK2 V617F allele burden in Ba/F3- JAK2 V617F mice compared with ruxoli<nib monotherapy A phase-1b study in Ruxo-resistant patients is ongoing Pinzon- Or<z M, et al. EHA 2014 abst. S710

45 MPN Therapy There are new firm points for treatment in MPN pa<ents There are new drugs close to have completed their experimenta<on phases There remains a lot of s<ll clinically unmet medical needs Therefore, we s<ll need new molecules and new schemes Neoplasie di origine mieloide: uno scenario in evoluzione Firenze novembre