CCO_Viewpoints_in_MF_Downloadable_1.pptx

MF Cco

1. Expert Viewpoints in Myelofibrosis: Advancing Treatment Strategies With Next-Generation Therapeutics Provided by Clinical Care Options, LLC Supported by an educational grant AbbVie Inc.

2. Please feel free to use and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact [email protected] for details About These Slides Slide credit: clinicaloptions.com

3. Faculty Abdulraheem Yacoub, MD Professor of Medicine The University of Kansas Medical Center Kansas City, Kansas Abdulraheem Yacoub, MD : consultant/advisor/speaker: AbbVie, Acceleron, Apellis, CTI Pharma, Gilead, Incyte, Notable Labs, Novartis, Pfizer, PharmaEssentia, Servier.

4. Introduction to MF Arber. Blood. 2016;127:2391. Khoury. Leukemia. 2022;36:1703 CML Philadelphia Chromosome (-) Philadelphia Chromosome (+) Megakaryocyte proliferation (enlarged, mature morphology) JAK2 (~50% of patients), CALR, or MPL mutations Thrombocytosis (platelet count ≥ 450 x 10 9 /L) ET Bone marrow trilineage myeloproliferation JAK2 mutation (nearly all patients) Increased Hgb, Hct, or RCM Subnormal serum EPO PV Megakaryocyte proliferation (reticulin/collagen fibrosis) JAK2 (~50% of patients), CALR, or MPL mutations Anemia Leukocytosis Leukoerythroblastosis Splenomegaly Increased serum LDH MF

5. MF Management Goals Reduce splenomegaly Improve symptoms Improve survival Management goals may evolve over time and may vary based on risk

6. Treatment of MF Based on Risk and Symptoms/Signs NCCN. Clinical practice guidelines in oncology: myeloproliferative neoplasms. v.3.2023. nccn.org. Low Risk Intermediate-1 Intermediate-2 High Risk Asymptomatic  observation or clinical trial Symptomatic   clinical trial, observation, or  ruxolitinib Management of cytopenias Allo-HSCT (selected patients) Transplant eligible  a llo-HSCT Transplant ineligible   r uxolitinib  or  fedratinib (if platelets >50K) or pacritinib (especially if platelets <50K) or momelotinib or clinical trial Anemia, thrombocytopenia, symptom management Projected Median OS 5 Yr Lower Risk MIPSS-70: ≤3 MIPSS-70+ version 2.0: ≤3 DIPSS-Plus: ≤1 DIPSS: ≤2 MYSEC-PM: <14 Higher Risk MIPSS-70: ≥4 MIPSS-70+ version 2.0: ≥4 DIPSS-Plus: >1 DIPSS: >2 MYSEC-PM: ≥14

7. Ruxolitinib and Fedratinib for Patients With Higher-Risk MF COMFORT-I/-II: randomized phase III studies in which patients with i ntermediate 2–risk/high-risk MF received ruxolitinib (15 or 20 mg BID) vs placebo (COMFORT-I, N = 309) or best available therapy (COMFORT-II, N = 149) Outcome COMFORT-I, Wk 24 1 P Value COMFORT-II, Wk 48 2 P Value Ruxolitinib (n = 155) Placebo (n = 154) Ruxolitinib (n = 144) BAT (n = 73) Spleen volume reduction ≥35%, % 41.9 0.7 <.001 28 <.001 ≥50% reduction in MFSAF TSS, % 45.9 5.3 <.001 NR NR NR 1. Verstovsek. NEJM. 2012;366:799. 2. Harrison. NEJM. 2012;366:787. 3. Pardanani. JAMA Oncol. 2015;1:643. JAKARTA: randomized phase III study in which patients with i ntermediate 2–risk/high-risk MF received fedratinib vs placebo (N = 289) Outcome Fedratinib 400 mg (n = 96) Placebo (n = 96) P Value Spleen volume reduction ≥35% at Wk 24, % 36 1 <.001 ≥50% reduction in MFSAF TSS at Wk 24, % 36 7 <.001

8. PERSIST-1 and PERSIST-2: Phase III Trials of Pacritinib for MF Primary endpoint: SVR ≥35% at Wk 24 (assessed by MRI or CT) Primary endpoints: SVR ≥35% at Wk 24 and ≥50% reduction in TSS at Wk 24 PERSIST-1 1 PERSIST-2 2 Pacritinib 200 mg PO BID (n = 107) 1. Mesa. Lancet Haematol. 2017;4:e225. 2. Mascarenhas. JAMA Oncol. 2018;4:652. Adults with int-1, int-2, or high-risk MF; any platelet count ; JAK2 inhibitor naive (n = 327) Pacritinib 400 mg PO QD (n = 220) BAT (excluding JAKi) (n = 107) Pacritinib 400 mg PO QD (n = 104) BAT (including r uxolitinib) (n = 100) Adults with int-1, int-2, or high-risk MF; platelets ≤100 x 10 9 /L ; prior JAK2 inhibitors allowed (n = 311) Pacritinib : oral kinase inhibitor with JAK2, FLT3, and IRAK1 specificity

9. PERSIST-2: Spleen/Symptom Response SVR35 ≥50% Reduction in Modified TSS Patients With Platelets <50 x 10 9 /L, Wk 24 Mascarenhas. JAMA Oncol. 2018;4:652. 30 20 10 30 20 10

10. PERSIST-2: Hematologic Stability/Improvement Transfusion Burden in Patients Who Received ≥1 RBC Transfusion on Study Clinical Improvement in Hgb Levels in Patients With Baseline Anemia, Baseline to Wk 24* Pacritinib Reduced Transfusion Burden in Patients Not Transfusion Independent at Baseline, Baseline to Wk 24 Transfusion independence defined according to Gale criteria (0 units over course of 12 wk). *International Working Group response criteria: increase of ≥2.0 g/dL or RBC transfusion independence for ≥8 wk prior; anemia defined as Hgb <10 g/dL. Mascarenhas. JAMA Oncol. 2018;4:652. PAC 200 mg BID BAT 25% 12% PAC 200 mg BID BAT 22% 9% Baseline Wk 24 1.06 1.71 0.67 1.33 Median RBC Transfusion Units/Mo PAC 200 mg BID BAT PAC 200 mg BID BAT

11. Selected Novel Therapies in Trials for MF Chifotides. Clin Lymphoma Myeloma Leuk. 2022;22:210. Greenfield. J Hematol Oncol. 2021;14:103. Transcription CALR JAK JAK STAT Y STAT P Y STAT P Y STAT P Y STAT P Y Nucleus Telomerase inhibitor ( imetelstat ) BCL-2 BCL-2/BCL-xL inhibitor ( navitoclax ) HDM2 HDM2 inhibitor ( navtemadlin ) MUT Anti-CALR-mutant monoclonal antibody ( INCA033989 ) Nuclear export inhibitor ( selinexor ) CRM1/XPO1 JAK JAK CD123-targeted antibody ( tagraxofusp ) IL-3 BET BET inhibitor ( pelabresib )

12. International, randomized, double-blind phase III trial; median follow-up: 14.9 mo (range: 0.0-29.5) Navitoclax (ABT-263): oral inhibitor of anti-apoptotic proteins BCL-xL and BCL-2 TRANSFORM-1: Navitoclax + Ruxolitinib vs Placebo + Ruxolitinib in Previously Untreated MF Pemmaraju. ASH 2023. Abstr 620. NCT04472598. Primary endpoint: SVR35 at Wk 24 assessed for superiority by MRI/CT using IWG criteria Secondary endpoints: change in TSS from BL to Wk 24 using MFSAF v4.0, SVR35 at any time, duration of SVR35, anemia response using IWG criteria, safety Adults with JAKi-naive, intermediate-2 –risk /high-risk MF; measurable splenomegaly per DIPSS+; evidence of symptoms related to MF; ECOG PS 0-2 (N = 252) Stratified by risk (intermediate-2 vs high risk), PLT (≤ vs >200 x 10 9 /L) Navitoclax 100/200 mg PO QD* + Ruxolitinib 15/20 mg PO BID † (n = 125) Placebo PO QD + Ruxolitinib 15/20 mg PO BID † (n = 127) *PLT >150 x 10 9 /L: 200 mg QD; PLT ≤150 x 10 9 /L: 100 mg QD with escalation to 200 mg after ≥7 days if PLT ≥75 x 10 9 /L. † PLT >200 x 10 9 /L, 20 mg BID; PLT 100-200 x 10 9 /L, 15 mg BID.

13. TRANSFORM-1: SVR35 at Wk 24 Study met primary endpoint Pemmaraju. ASH 2023. Abstr 620. Improvement Worsening Change F rom Baseline at Wk 24 (%) 80 60 40 20 -20 -40 -60 -80 P <.0001 63.2% (n = 79) 31.5% (n = 40) NAV + RUX (n = 114) PBO + RUX (n = 106) -35%

14. TRANSFORM-1: TSS at Wk 24 TSS responses were not significantly different between groups; at Wk 24, mean change in TSS from baseline was -9.7 (95% CI: -11.8 to -7.6) with NAV + RUX vs -11.1 (95% CI: -13.2 to -9.1) with PBO + RUX ( P = .2852) Pemmaraju. ASH 2023. Abstr 620. Improvement Worsening Change in TSS From Baseline at Wk 24 30 20 10 -10 -20 -30 -40 -50 -60 -70 Change in TSS From Baseline at Wk 24 NAV + RUX (n = 107) PBO + RUX (n = 107) -10 NAV + RUX (n = 113) PBO + RUX (n = 117) Patients With Change (%) NAV + RUX (n = 113) PBO + RUX (n = 117) TSS Improvement ≥-10 TSS50 39.2% 41.7% 60 40 20 Patients With TSS Improvement ≥-10 or TSS50 From Baseline at Wk 24 n = 47 n = 54 n = 45 n = 50

15. TRANSFORM-1: Safety Most common AEs: thrombocytopenia, anemia, neutropenia, diarrhea Most common serious AEs were COVID-19 pneumonia and pneumonia, each observed in n = 3 with navitoclax + ruxolitinib and n = 2 with placebo + ruxolitinib Pemmaraju. ASH 2023. Abstr 620. AEs in >30% of Patients Receiving Navitoclax, n (%) Navitoclax + Ruxolitinib (n = 124) Placebo + Ruxolitinib (n = 125) Any Grade Grade ≥3 Any Grade Grade ≥3 Thrombocytopenia 112 (90) 63 (51) 62 (50) 19 (15) Anemia 74 (60) 57 (46) 61 (49) 49 (39) Neutropenia 56 (45) 47 (38) 7 (6) 5 (4) Diarrhea 42 (34) 6 (5) 17 (14) Bleeding/hemorrhagic events 30 (24) 2 (2) 27 (22) 7 (6) COVID-19 26 (21) 1 (1) 23 (18) 7 (6) Contusion 13 (10) 7 (6) Abdominal pain 11 (9) 1 (1) 8 (6) 1 (1) Abdominal pain upper 9 (7) 1 (1) 10 (8) 1 (1) Bone pain 9 (7) 6 (5)

16. MANIFEST-2: Pelabresib + Ruxolitinib vs Placebo + Ruxolitinib for JAK Inhibitor – Naive MF Randomized, double-blind, placebo-controlled phase III trial Pelabresib : novel oral BET inhibitor Primary endpoint: SVR35 at Wk 24 Key secondary endpoints: TSS change and TSS50 at Wk 24, safety Rampal. ASH 2023. Abstr 628. Adult patients with JAK inhibitor – naive MF (primary or post ET/PV) with TSS ≥10 (or ≥3 for 2 symptoms) using MFSAF v4.0; DIPSS score ≥ int-1; spleen volume ≥450 cm 3 ; ECOG PS 0-2 (N = 431) Pelabresib 125 mg PO QD* x 14 days + Ruxolitinib per label † (lowered by 5 mg BID at start) x 21 days (n = 214) Stratified by DIPSS risk (int-1 vs int-2 vs high), platelet count (100-200 vs >200 x 10 9 /L), and spleen volume (<1800 vs ≥1800 cm 3 ) Placebo PO QD x 14 days + Ruxolitinib per label † (lowered by 5 mg BID at start) BID x 21 days (n = 216) *125 mg start with protocol-defined dose modifications due to AEs and/or treatment response allowed (50-175 mg). † 10-15 mg BID starting dose based on platelet count with mandatory dosage increase of 5 mg after 1 cycle, with maximum dose of 25 mg.

17. MANIFEST-2: SVR35 at Wk 24 Rampal. ASH 2023. Abstr 628. Outcome Pelabresib + Ruxolitinib (n = 214) Placebo + Ruxolitinib (n = 216) P Value SVR35 at Wk 24, % 65.9 35.2 Difference (95% CI) 30.4 (21.6-39.3) <.001 Mean % change in spleen volume at Wk 24 -50.6 (n = 171) -30.6 (n = 183) 95% CI -53.2 to -48 -33.7 to -27.5 Pelabresib + ruxolitinib (n = 171) Placebo + ruxolitinib (n = 183) Change in Spleen Volume From Baseline (%) 50 -50 -100 35% reduction

18. MANIFEST-2: TSS at Wk 24 Rampal. ASH 2023. Abstr 628. Outcome Pelabresib + Ruxolitinib (n = 214) Placebo + Ruxolitinib (n = 216) P Value TSS50 at Wk 24, % 52.3 46.3 Difference (95% CI) 6.0 (-3.5 to 15.5) .216 Pelabresib + ruxolitinib (n = 184) Placebo + ruxolitinib (n = 193) Change in TSS From Baseline (%) 150 -50 -100 50 100 200 50% reduction

19. MANIFEST-2: Safety TEAEs in ≥10% of Patients, % Pelabresib + Ruxolitinib (n = 214) Placebo + Ruxolitinib (n = 216) TEAEs in ≥10% of patients Any Grade Grade ≥3 Any Grade Grade ≥3 Anemia 43.9 23.1 55.6 36.4 Thrombocytopenia 32.1 9.0 23.4 5.6 Decreased platelet count 20.8 4.2 15.9 0.9 Diarrhea 23.1 0.5 18.7 1.4 Dysgeusia 18.4 0.5 3.7 Constipation 18.4 24.3 Nausea 14.2 0.5 15.0 Cough 12.7 11.2 Asthenia 11.8 0.5 13.6 Fatigue 11.8 0.5 13.6 Dizziness 11.3 8.9 Headache 11.3 0.5 10.7 COVID-19 11.3 15.9 1.9 Dyspnea 9 0.5 13.1 0.9 Rampal. ASH 2023. Abstr 628.

20. Primary refractory to first-line JAK inhibitor Consider alternative JAK inhibitor Suboptimal response to JAK inhibitor Dose optimization; consider combination trials Progression after response on JAK inhibitor Alternative agents, clinical trials JAK Inhibitor Failure: Response-Adaptive Therapy

21. Response Criteria for MF Are Difficult to Apply in Daily Clinical Practice Designed for clinical trials Multiple parameters Some parameters, including histologic response and molecular response, are not routinely used in clinical practice Almost impossible to apply in daily clinical practice Response Categories Required Criteria (for all response categories, benefit must last ≥12 wk to qualify as a response) Spleen response Baseline splenomegaly that is palpable at 5-10 cm, below LCM, becomes not palpable  or Baseline splenomegaly that is palpable at >10 cm, below LCM, decreases by ≥50% Baseline splenomegaly that is palpable at <5 cm, below LCM, is not eligible for spleen response Spleen response requires confirmation by MRI or CT showing ≥35% spleen volume reduction Symptom response ≥50% reduction in MPN-SAF TSS Tefferi. Blood. 2013;122:1395.

22. Defining Ruxolitinib Failure in Clinical Practice Primary Resistance* Intolerance ‡ No change in spleen length by palpation No reduction in spleen-related symptoms No reduction in MPN-SAF score or considered to remain unacceptable to patient Loss of initial spleen response and return to baseline Loss of initial symptom response and return to baseline Secondary Resistance † Any unacceptable treatment-emergent toxicity Platelet count <35 x 10 9 /L Doubling of RBC transfusion rate after 3 mo and requiring 2 units at least every 8 wk Progression ‡ Increase in blast % in bone marrow or peripheral blood to ≥10% New palpable splenomegaly Leukemic transformation *Requires minimum of 12 wk receiving therapy at maximally tolerated dose or ≥20 mg/day. † Preferably captured by MPN-SAF; alternatively, responses no longer considered acceptable by patient. ‡ After any duration of therapy. Mascarenhas. Future Oncol. 2023;19:763. Ruxolitinib PI.

23. JAK Inhibitor Efficacy and Tolerability in MF: Systematic Review and Network Meta-analysis Analysis of randomized, controlled trials with JAK inhibitors vs ruxolitinib 7 trials; 1953 patients Pacritinib Momelotinib Fedratinib 1L: fedratinib efficacy comparable to ruxolitinib, less thrombocytopenia 1L: less effective for splenomegaly than ruxolitinib 2L: effective after ruxolitinib exposure 1L: momelotinib with comparable efficacy to ruxolitinib for splenomegaly; improvement of anemia This analysis suggests that choice of JAK inhibitor may depend on line of treatment and risk of onset of severe anemia and/or thrombocytopenia Sureau. Blood Cancer J. 2021;11:135

24. MOMENTUM: Momelotinib for Patients With MF, Anemia, and Previous JAK Inhibitor Therapy International, double-blind, randomized phase III trial Patients with DIPSS intermediate-1/2 –risk or high-risk PMF, post-ET MF, or post-PV MF and Hgb <10 g/dL; splenomegaly and TSS ≥10; previous JAK inhibitor (N = 195) Momelotinib 200 mg QD + Placebo (n = 130) Danazol 600 mg + Placebo (n = 65) Verstovsek. Lancet. 2023;401:269. Primary endpoint: TSS at Wk 24 Secondary endpoints: transfusion independence, splenic response rate at Wk 24 Wk 24 After Wk 24, patients could receive momelotinib 200 mg QD (open label/ crossover) 2:1

25. MOMENTUM: Efficacy Outcome, Wk 24 Test Order Criterion for Significance Momelotinib (n = 130) Danazol (n = 65) P Value TSS response rate (primary endpoint),* % 1 Superiority ( P ≤.05) 25 9 .0095 (superior) Transfusion independence rate, † % 2 Noninferiority 30 20 .0116 (noninferior) Splenic response rate (≥25% reduction), % 3 Superiority ( P ≤.05) 39 6 <.0001 (superior) TSS change from baseline 4 Superiority ( P ≤.05) -11.5 -3.9 .0014 (superior) Splenic response rate (≥35% reduction), % 5 Superiority ( P ≤.05) 22 3 .0011 (superior) No transfusion to Wk 24, % 6 Superiority ( P ≤.05) 35 17 .0012 (superior) 25 Verstovsek. Lancet. 2023;401:269. *≥50% reduction in mean TSS over 28 days prior to end of Wk 24 vs baseline. † Proportion of subjects with TI status defined as not requiring RBC transfusion for last 12 wk of 24-wk randomized period, with all Hgb levels ≥8 g/dL during 12-wk interval.

26. MOMENTUM: Transfusion Independence Rate at Wk 24 and Mean Hgb Over Time Transfusion Independence Rate (%) 35 30 25 20 15 10 5 Baseline Wk 24 Baseline Wk 24 Momelotinib (n = 130) Danazol (n = 65) 13 15 30 20 P = .0116 (noninferior) Mean Hgb Levels (g/dL) Wk Since Randomization 11 10 9 8 BL 4 8 12 16 20 24 28 32 36 40 44 48 Double-blind Randomization Period Open-label Period Momelotinib Danazol Momelotinib Danazol → momelotinib Patients at Risk, n 129 105 112 93 87 88 83 67 56 44 42 36 28 65 54 50 38 36 36 29 31 21 19 18 13 7 Momelotinib Danazol Verstovsek. Lancet. 2023;401:269.

27. Additional Agents and Combinations in Phase III Trials for Patients With JAK Inhibitor Failure Agent MoA Key Phase II Trial Active/Ongoing Phase III Trials Key Population Key Data Trial Population (1° EP) Navitoclax (+ ruxolitinib) BCL-xL/ BCL-2 inhibitor REFINE: MF with PD/suboptimal response to ruxolitinib SVR35, Wk 24: 27% TSS50, Wk 24: 30% TRANSFORM-2 (NCT04468984) MF R/R with ruxolitinib (SVR35) Imetelstat Telomerase inhibitor IMBark: MF R/R to JAKi Median OS: 28.1 mo SVR35/TSS50, Wk 24: 10%/32% IMpactMF (NCT04576156) MF R/R to JAKi (OS) Navtemadlin MDM2 inhibitor KRT-232-101: MF R/R to JAKi SVR35, Wk 24: 16% TSS50, Wk 24: 30% BOREAS (NCT03662126) MF R/R with JAKi (SVR35) Harrison. JCO. 2022;40:1671. Mascarenhas. JCO. 2023:JCO2201972. Mascarenhas. EHA 2020. Abstr EP1107. Verstovsek. Future Oncol. 2022;[Epub].

28. INDEPENDENCE: Luspatercept in Patients With MF and Anemia Receiving JAK Inhibitor Therapy International, double-blind, randomized phase III trial Patients with MF; receiving stable, continuous JAK2 inhibitor therapy; requiring RBC transfusions* (planned N = 309) Luspatercept Placebo NCT04717414. Primary endpoint: RBC-TI ≥12 wk at Wk 24 Secondary endpoints: additional RBC-TI parameters, reduction of transfusion burden, Hgb increase, change in serum ferritin, AEs * Transfusion frequency 4-12 RBC units/12 wk prior to randomization with no interval of >6 wk without a transfusion; transfusions scored in determining eligibility when given for treatment of symptomatic anemia with pretransfusion Hgb ≤9.5 g/dL or asymptomatic anemia with pretransfusion Hgb ≤7 g/dL.

29. Tagraxofusp (CD123 Inhibitor): Phase I/II Study in R/R MF After JAK Inhibitor 29/39 patients (74%) had baseline splenomegaly 54% had SVR by palpation; ≥50% reduction in 29% 15 patients evaluable for SVR by imaging 7/15 patients (47%) achieved ≥10% SVR; 2/7 patients achieved ≥35% SVR 14/39 patients had ≥50% improvement in TSS Change in TSS From Baseline 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 -100 -40 20 -80 -20 -60 TSS TSS and spleen 6 12 18 30 24 36 54 0.0 0.0 0.2 0.6 0.4 0.8 42 48 Mo Median OS: 26.6 mo (95% CI: 12.9-51.1) 39 30 22 14 8 12 7 5 3 All MF Proportion Alive Yacoub. ASH 2021. Abstr 140. Change in TSS From Baseline (%)

30. Go Online for More CCO Coverage of Myelofibrosis Downloadable slides with all the key data CME-certified text activity featuring expert perspectives on evidence informing optimal treatment of MF, with a focus on novel data and emerging strategies Podcast discussing key aspects of contemporary management of MF Interactive Treatment Decision Support Tool for MF where you can enter your own case scenarios to get management recommendations from experts clinicaloptions.com/oncology clinicaloptions.com/MFtool