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Future oncology 18(22), 2393-2402 (2022). doi:10.2217/fon-2022-0235, Published by Future Medicine Ltd, London

Contains fulltext : 220650.pdf (Publisher’s version ) (Open Access) Fedratinib is an oral, selective Janus kinase 2 (JAK2) inhibitor. The phase II JAKARTA2 study assessed fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) who were resistant or intolerant to prior ruxolitinib per investigator assessment. Patients received fedratinib 400 mg/day in 28-day cycles. The JAKARTA2 outcomes were initially reported using a last-observation-carried forward (LOCF) analysis in a "Per Protocol" population. This updated analysis of JAKARTA2 employs intention-to-treat analysis principles without LOCF for all treated patients (ITT Population; N = 97), and for a patient subgroup who met more stringent definitions of prior ruxolitinib failure (Stringent Criteria Cohort; n = 79). Median duration of prior ruxolitinib exposure was 10.7 months. The primary endpoint was spleen volume response rate (SVRR; >/=35% spleen volume decrease from baseline to end of cycle 6 [EOC6]). The SVRR was 31% in the ITT Population and 30% in the Stringent Criteria Cohort. Median duration of spleen volume response was not reached. Symptom response rate (>/=50% reduction from baseline to EOC6 in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF]) was 27%. Grade 3-4 anemia and thrombocytopenia rates were 38% and 22%, respectively. Patients with advanced MF substantially pretreated with ruxolitinib attained robust spleen responses and reduced symptom burden with fedratinib.

MF is a life-threatening myeloproliferative neoplasm. The JAKi ruxolitinib and fedratinib are the only FDA approved treatment options for MF. Despite benefits reported with ruxolitinib in the front-line setting, a high proportion of patients (pts) discontinue treatment (Abdelrahman 2015), and the median overall survival (OS) is 13-16 months (Kuykendall 2018; Newberry 2017; Schain 2019; Palandri 2019; Mcnamara 2019), highlighting a great unmet need for pts non-responsive to a JAKi treatment. Imetelstat, a first-in-class telomerase inhibitor, has shown meaningful clinical improvement in IMbark, a Phase 2 study in pts with Int-2 or high-risk MF who have relapsed after or are refractory to JAKi (Mascarenhas EHA 2020, ASH 2020). Treatment with imetelstat 9.4 mg/kg resulted in 32.2% symptom response (total symptom score [TSS] reduction ≥50%) at Week 24 and median OS of 28.1 months with overall study follow up of 42 months. Dose-dependent inhibition of telomerase with imetelstat resulted in on-target activity that correlated with clinical benefits; dose-dependent reduction in variant allele frequency of MF driver mutations indicated targeting of the underlying malignant clone. The Phase 2 results support continued study of imetelstat 9.4 mg/kg in a Phase 3 randomized controlled study. Study MYF3001 (IMpactMF; NCT04576156) is an open label, randomized (2:1), multicenter, Phase 3 study of imetelstat compared with BAT in ~320 pts with Int-2 or high-risk MF refractory to JAKi treatment. Pts will be randomized to receive imetelstat 9.4 mg/kg IV every 21 days or investigator selected BAT (including hydroxyurea, thalidomide, interferon, danazol, hypomethylating agents, chemotherapy, or other non-JAKi containing therapy as appropriate). Eligible pts will be stratified based on a) Int-2 or high-risk per Dynamic International Prognostic Scoring System; b) platelet count at entry (platelets ≥ 75 and < 150 x 10 9/L vs ≥ 150 x 10 9/L). Pts who meet progressive disease criteria and discontinue BAT may be eligible to crossover to imetelstat. The primary endpoint is OS, and one interim analysis is planned when >70% of death events have occurred. Secondary endpoints include symptom and spleen response rates at Week 24, progression-free survival, clinical response assessment per modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment criteria, time to and duration of response, reduction in degree of bone marrow fibrosis, safety, pharmacokinetics, and patient-reported outcomes. Biomarkers and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones. Approximately 180 sites are planned in North and South America, Europe, Middle East, Australia, and Asia. The study is open for enrollment. Disclosures Mascarenhas: Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude: Consultancy; Geron: Consultancy, Research Funding; Geron: Consultancy; Galecto: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forbius: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merus: Research Funding. Harrison: Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kiladjian: Taiho Oncology, Inc.: Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Komrokji: BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Geron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; AbbVie: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Koschmieder: Abbvie: Other: Travel support; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Shire: Honoraria, Other; CTI: Membership on an entity's Board of Directors or advisory committees, Other; Alexion: Other: Travel support; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Image Biosciences: Other: Travel support; Baxalta: Membership on an entity's Board of Directors or advisory committees, Other; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Karthos: Other: Travel support. Vannucchi: AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berry: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sherman: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Verstovsek: Incyte Corporation: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; Roche: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: Imetelstat, a first-in-class telomerase inhibitor, is undergoing clinical development but is not approved for treatment of MF

Introduction: Imetelstat is a first-in-class telomerase inhibitor that targets cells with high telomerase activity and human telomerase reverse transcriptase (hTERT) expression, characteristics observed in MDS patients (pts) across all disease stages. IMerge (MDS3001, NCT02598661) is a Phase 2/3 global study of imetelstat for red blood cell (RBC) transfusion dependent (TD) pts with non-del 5q LR-MDS ESA-R/R, who have limited treatment options. The results from the Phase 2 part indicated that imetelstat achieved durable transfusion independence (TI) with a manageable safety profile. Among 38 pts with median follow-up of 24 months, ≥8-week (w), ≥24-w, ≥1-year (y) TI rates were 42%, 32% and 29%, respectively (Steensma JCO 2020, Platzbecker ASH 2020). Aims: To assess the correlation between imetelstat's on-target activity with clinical benefits and safety data as of 10-May 2021 in the Phase 2 part of IMerge. Methods: Peripheral blood samples pre and after 1 and 2 cycles of imetelstat administration were collected to analyze hTERT level by Taqman RT-PCR assay. ≥50% hTERT reduction by imetelstat was considered optimal pharmacodynamic (PD) effect. Correlation analyses between the optimal PD and efficacy, including TI rates ≥8-w, ≥24-w, and ≥1-y, duration of the longest TI, and OS, as well as hematological and liver function lab parameters were performed. Results: hTERT analyses on 35/38 pts with matched pre- and post-1 to 2 cycles of treatment samples available demonstrated on-target activity/optimal PD effect of imetelstat in 54.3% (19/35) of pts. Pts who achieved optimal PD had significantly higher rates of TI compared to pts who did not achieve optimal PD: 63.2% (12/19) vs 25% (4/16) had ≥8-w TI (p=0.0411); 57.9% (11/19) vs 12.5% (2/16) had ≥24-w TI (p=0.0125); and 52.6% (10/19) vs 6.3% (1/16) had ≥1-y TI (p=0.0125) (Fig A). Pts who achieved optimal PD effect had a greater reduction in transfusions (both absolute change in transfusion units and % of change in transfusion burden) in the best 8-week interval compared to pts who did not. In addition, pts who achieved optimal PD had a significantly longer median TI duration (68.4 w, 95% CI 4.9, 92.4) compared to those who did not (5.5 w, 95% CI 2.3, 6.6) with a hazard ratio of 0.364 (95% CI 0.167, 0.794, log-rank p value=0.0087, Fig B). Furthermore, median OS was 57.0 months (95% CI 34.6, -) in pts who achieved optimal PD vs 40.7 months (95% CI 26.9, -) in pts who did not, and the 4-year OS rate was 58.4% vs 31.0%, respectively, although not statistically significant. Pts who achieved optimal PD also had lower rates of Grade 3+neutropenia (52.6%), thrombocytopenia (57.9%), or liver function elevations (5.3%) compared to pts who did not achieve optimal PD (68.8%, 68.8% and 18.8%, respectively), although the differences were not statistically significant. Conclusion: Optimal PD effect of imetelstat treatment was demonstrated by ≥50% hTERT reduction. A significant correlation was observed between optimal PD effect of imetelstat and durable TI and improved 4-year OS rate, effectively linking imetelstat activity to clinical efficacy. Additionally, pts who achieved an optimal PD effect by imetelstat treatment did not have higher rates of cytopenias or liver enzyme elevations compared to pts without optimal PD effect. Enrollment is ongoing for the Phase 3 part of IMerge, a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo. Figure 1 Figure 1. Disclosures Santini: Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux: JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Raza: Celgene Inc: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Genoptix: Speakers Bureau; Kura Oncology: Research Funding; Janssen R&D: Research Funding; Syros Pharmaceuticals: Research Funding; Onconova Therapeutics: Research Funding, Speakers Bureau. Germing: Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria. Font: CELGENE-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses; GILEAD: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Abbvie: Other: Travel, accomodations, expenses. Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Sherman: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Platzbecker: Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Celgene/BMS: Honoraria. OffLabel Disclosure: Imetelstat, a first-in-class telomerase inhibitor, is under clinical development but not approved for treatment of MDS

Background: Imetelstat is a first-in-class telomerase inhibitor currently in clinical development for hematologic myeloid malignancies. IMbark (MYF2001; NCT02426086) was a 2-dose (9.4 mg/kg or 4.7 mg/kg IV every 3 weeks), randomized Phase 2 study of imetelstat in intermediate-2/high-risk myelofibrosis (MF) relapsed or refractory to prior Janus kinase inhibitor treatment. Comparing the 9.4 mg/kg arm to the 4.7 mg/kg arm, the rate of symptom response (total symptom score [TSS] reduction ≥50%) at Week 24 was 32.2% and 6.3%, respectively (Mascarenhas et al, ASH 2018 #685), and median overall survival (OS) was 28.1 months (mos) (95% confidence interval [CI]: 22.8, 31.6) for the 9.4 mg/kg arm and 19.9 mos for the 4.7 mg/kg arm (95% CI: 17.1, 33.9) with an overall study follow up of 42 mos (Mascarenhas et al, EHA 2020, EP1107). Dose-dependent on-target pharmacodynamic (PD) activity of imetelstat was observed and it correlated with clinical responses and longer OS (Mascarenhas et al, EHA 2020 EP1098). Here we report the results of imetelstat exposure-response analyses from IMbark to further evaluate the benefit/risk profile and justify 9.4 mg/kg every 21 days as the optimal dosing regimen for the planned Phase 3 study of imetelstat in refractory MF. Methods: The average plasma concentration (Cavg) of imetelstat was used to define the exposure. The Cavg values of 107 patients (pts) were grouped into 4 quartiles (Q1-4) representing different levels of imetelstat exposure regardless of the protocol-specified dose arm assignment. Optimal PD effect of imetelstat was defined as ≥50% reduction in telomerase activity or human telomerase reverse transcriptase (hTERT) from baseline. The exposure-response relationships between exposure quartiles and PD effect, symptom response, OS, and laboratory safety parameters were assessed. Results: The association between the 4 exposure quartiles and dose levels showed that 89% of pts in Q1 (the lowest exposure quartile) were treated with 4.7 mg/kg, while 96% of pts in Q4 (the highest exposure quartile) were treated with 9.4 mg/kg. The pts in the 4.7 mg/kg arm who had higher exposure in Q3 and Q4 were mainly those with dose escalation to 9.4 mg/kg, and pts in the 9.4 mg/kg arm who had lower exposure in Q1-Q2 were mainly those with dose delay, reduction, or interruption. 51.9% of pts in Q1, 63% in Q2 (vs Q1, p=0.5826), 77.8% in Q3 (vs Q1, p=0.0861), and 80% in Q4 (vs Q1, p=0.0439) achieved the optimal PD effect, respectively, indicating exposure-dependent on-target activity of imetelstat. The symptom response rate for pts in exposure quartile Q1, Q2, Q3, and Q4 was 7.4%, 18.5% (vs Q1, p=0.4203), 18.5% (vs Q1, p=0.4203), and 38.5% (vs Q1, p=0.0091), respectively. Median OS was 18.9 mos in Q1, 23.6 mos in Q2 (hazard ratio [HR]=0.663; 95% CI: 0.350, 1.259; log-rank p=0.2097), 24.6 mos in Q3 (HR=0.656; 95% CI 0.348, 1.236; p=0.1920) and 30.6 mos in Q4 (HR=0.467; 95% CI: 0.236, 0.925; p=0.0260), respectively. The exposure-response analyses showed that pts in the highest exposure quartile were more likely to have better clinical outcome. The relationship between exposure quartiles and hematological and liver function safety parameters was assessed. There were no significant differences between each imetelstat exposure quartile group on the change from baseline in hemoglobin concentration, platelet count, and neutrophil counts; or in the rate of Grade 3+ neutropenia, thrombocytopenia, and elevations in alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, and bilirubin. Pts with higher imetelstat exposure had similar rates of Grade 3+ adverse events as pts with lower exposure, suggesting that the lower dose does not improve safety. Conclusions: In summary, the exposure-response analysis results indicated 9.4 mg/kg and 4.7 mg/kg covered the therapeutic window of imetelstat in MF pts. Imetelstat 9.4 mg/kg every 21 days treatment yielded higher exposure, leading to higher rate of pts achieving the optimal PD effect, consistently better clinical benefits, such as higher symptom response and significantly longer median OS, and had a similar safety profile as 4.7 mg/kg with regard to hematologic and liver function parameters. This exposure-response analysis of benefit/risk profile supports 9.4 mg/kg every 21 days as the optimal dosing regimen for the planned imetelstat Phase 3 study in refractory MF. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Komrokji:Acceleron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; Geron: Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Niederwieser:Amgen: Speakers Bureau; Novartis: Speakers Bureau; Daiichi: Research Funding; Cellectis: Membership on an entity's Board of Directors or advisory committees. Reiter:Gilead: Other: travel support ; Incyte: Consultancy, Other: travel support ; AOP: Consultancy, Other: travel support ; Celgene,: Consultancy, Other: travel support ; Abbvie: Consultancy, Other: travel support ; Deciphera: Consultancy, Other: travel support ; Blueprint: Consultancy, Other: travel support ; Novartis: Consultancy, Honoraria, Other: travel support , Research Funding. Scott:Agios, BMS: Honoraria; Alexion, Incyte, Novartis, Regeneron: Consultancy; BMS, Novartis: Research Funding. Baer:AbbVie: Other: Institutional research funding; Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding. Hoffman:Protagonist: Consultancy; Dompe: Research Funding; Forbius: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Odenike:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Other: Institutional research funding; Astra Zeneca: Research Funding; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company.

Background: Myelofibrosis (MF) is a life-threatening myeloproliferative neoplasm. Ruxolitinib, a Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor and fedratinib, a JAK2/FLT3 inhibitor, are the only approved treatment options for MF. Despite the benefits reported with ruxolitinib in the front-line setting, a high proportion of patients discontinue treatment, the 1-, 2-, and 3-year discontinuation rates are 49%, 71%, and 86%, respectively (Abdelrahman et al, 2015). For patients who discontinue treatment with ruxolitinib, the median overall survival (OS) is dismal and ranges from 13 to 16 months (Kuykendall et al, 2018; Newberry et al, 2017; Schain et al, 2019; Palandri et al, 2019; Mcnamara et al, 2019). There remains a great unmet need for patients who are non-responsive to and have discontinued treatment with a JAK inhibitor. Imetelstat, a first-in-class telomerase inhibitor, has shown meaningful clinical improvement in symptom response and improved OS in IMbark, a Phase 2 study in patients with intermediate-2 or high-risk MF who have relapsed after or are refractory to JAK inhibitors (Mascarenhas et al, ASH 2018 #685; Mascarenhas et al, EHA 2020 #EP1107). Nineteen (32.2%) patients in the 9.4 mg/kg arm and 3 (6.3%) patients in the 4.7 mg/kg arm achieved symptom response (total symptom score [TSS] reduction ≥50%) at Week 24. As of clinical cutoff (7 February 2020), with an overall study follow up of 42 months, median OS was 28.1 months for the 9.4 mg/kg arm (95% confidence interval [CI]: 22.8, 31.6) and 19.9 months for the 4.7 mg/kg arm (95% CI: 17.1, 33.9). The improvement in OS for patients treated with 9.4mg/kg imetelstat was further supported by analyses of IMbark patients with closely matched real world controls (Kuykendall et al, EHA 2019 #PS1456). Taken together, these findings support continued study of imetelstat 9.4 mg/kg dose in a well-designed Phase 3 randomized controlled study in patients with refractory MF. Methods: Study MYF3001 is an open label, randomized (2:1), multicenter, Phase 3 study of imetelstat compared with best available therapy (BAT) in approximately 320 patients with intermediate-2 or high-risk MF (primary MF, post-essential thrombocythemia-MF, or post-polycythemia vera-MF) who are refractory to JAK inhibitor treatment. Approximately 214 patients will be randomized to Arm A to receive imetelstat, and approximately 106 patients will be randomized to Arm B to receive BAT. Eligible patients will be stratified based on: a) intermediate-2 or high-risk per Dynamic International Prognostic Scoring System (DIPSS); and b) platelet count at study entry (platelets ≥75 x 109/L and The primary endpoint of the study is OS. Secondary endpoints include symptom response rate at week 24, progression-free survival, spleen response rate at week 24, clinical response assessment per modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG MRT) criteria, time to and duration of response, reduction in the degree of bone marrow fibrosis, safety, pharmacokinetics, and patient-reported outcomes. One interim analysis based on OS is planned. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with OS and clinical responses. Mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. The study will be conducted at approximately 150 centers in North and South America, Europe, Asia, and Middle East. Disclosures Mascarenhas: Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy. Harrison:Promedior: Honoraria; Celgene: Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Sierra Oncology: Honoraria; Shire: Honoraria, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; Roche: Honoraria; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau. Mesa:Promedior: Research Funding; Genentech: Research Funding; Samus Therapeutics: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy; CTI BioPharma: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Sierra Oncology: Consultancy. Komrokji:Incyte: Honoraria; BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Geron: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Agios: Honoraria, Speakers Bureau. Koschmieder:Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Geron Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte/Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; CTI Biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Promedior: Other. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Verstovsek:PharmaEssentia: Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; CTI Biopharma Corp: Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding.

Background: Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Both cytogenetic abnormalities and gene mutations in MF carry prognostic significance. Development of novel agents for treatment of MF to target the underlying malignant clones remains a significant area of unmet need. IMbark (MYF2001; NCT02426086) is a randomized Phase 2 study of imetelstat (9.4 mg/kg or 4.7 mg/kg) in intermediate-2/high-risk MF relapsed/refractory to prior Janus kinase inhibitor treatment. Comparing the 9.4 mg/kg arm to the 4.7 mg/kg arm, the rate of symptom response (total symptom score [TSS] reduction ≥50%) was 32.2% and 6.3%, respectively (Mascarenhas et al ASH 2018 #685), and median overall survival (OS) was 28.1 months (mos) (95% confidence interval [CI]: 22.8, 31.6) and 19.9 mos (95% CI: 17.1, 33.9) with an overall study follow up of 42 mos (Mascarenhas et al, EHA 2020, EP1107). Dose-dependent target inhibition as evaluated by reduction of telomerase activity and human telomerase reverse transcriptase level correlated with clinical responses and longer OS; also, reduction in variant allele frequency (VAF) of driver mutations by imetelstat was reported (Mascarenhas et al EHA 2020 #EP1098). Aims: To evaluate imetelstat activity on depletion of malignant cells (cytogenetically abnormal clones and mutation burden); to assess the relationships between baseline cytogenetic status and change in mutation VAF with clinical benefits such as spleen volume reduction, symptom response, bone marrow fibrosis improvement, and OS. Methods: Cytogenetic analyses were performed on bone marrow aspirates. Peripheral blood samples pre and post imetelstat administration were collected and granulocytes were isolated to analyze mutations and VAF by next-generation sequencing (NGS) using the Illumina TruSight Myeloid Sequencing Panel. Bone marrow fibrosis was assessed by a central pathologist. Results: 83 patients (pts) had baseline cytogenetic results available; 45 (54.2%) had an abnormal karyotype, including 32 (71.1%) with a sole abnormality, the most prevalent being deletions 13q- (24.4%) and 20q- (8.8%), and 5 (11.1%) with a complex karyotype. Spleen and symptom responses were observed in pts with or without abnormal karyotype. Of the 24 pts that had identified cytogenetic abnormalities at baseline and with matched post-treatment cytogenetic results available, 5 (20.8%) achieved ≥50% reduction in their cytogenetically abnormal clones, and interestingly they all had sole deletion 13q-. 49 pts had matched pre- and post-imetelstat treatment (3-14 mos) NGS data and had at least one mutation at baseline. 46.2% of pts (12/26) in the 9.4 mg/kg vs 17.4% (4/23) in the 4.7 mg/kg arm (p=0.0321) achieved ≥20% VAF reduction in any of the mutated genes present at baseline. In addition, pts who achieved ≥20% VAF reduction had higher rates of spleen response (12.5% vs 3%), symptom response (31.3% vs 24.2%) or bone marrow fibrosis improvement (54.4% vs 25%) compared to pts who did not have VAF reduction regardless of dose level (Fig. 1A). Furthermore, a prolonged median OS was seen (Fig. 1B) in pts who achieved ≥20% VAF reduction (31.6 mos, 95% CI: 21.5, NE) vs those with no VAF reduction (22.8 mos, 95% CI: 17.1, 31.6). The 3-year survival rate was 45.5% for pts who achieved ≥20% VAF reduction vs 14.9% for pts with no VAF reduction. Conclusions: Clinical responses to imetelstat treatment were observed regardless of baseline cytogenetic status, and a subset of pts achieved ≥50% reduction in cytogenetically abnormal clones. Significant dose-dependent reductions of mutation burden by imetelstat were noted and correlated with improved overall clinical benefits including higher rates of spleen and symptom responses, bone marrow fibrosis improvement, and prolonged OS. Together with the clinical data that suggest improvement in median OS in these pts, the data presented here further demonstrate that imetelstat has disease-modifying activity by targeting malignant cells, as evidenced by depletion of cytogenetically abnormal clones and reduction in mutation burden. These results will be confirmed in the planned Phase 3 study in refractory MF. Figure Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Komrokji:Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; Agios: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Acceleron: Honoraria; AbbVie: Honoraria; Geron: Honoraria; Incyte: Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Niederwieser:Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Daiichi: Research Funding. Reiter:Gilead: Other: travel support ; Incyte: Consultancy, Other: travel support ; AOP: Consultancy, Other: travel support ; Celgene,: Consultancy, Other: travel support ; Abbvie: Consultancy, Other: travel support ; Deciphera: Consultancy, Other: travel support ; Blueprint: Consultancy, Other: travel support ; Novartis: Consultancy, Honoraria, Other: travel support , Research Funding. Scott:Alexion, Incyte, Novartis, Regeneron: Consultancy; BMS, Novartis: Research Funding; Agios, BMS: Honoraria. Baer:Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding; AbbVie: Other: Institutional research funding. Hoffman:Protagonist: Consultancy; Forbius: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding. Odenike:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Other: Institutional research funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company.

TPS7056 Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients (pts) with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in MDS pts across all disease stages. IMerge (MDS3001) is a Phase 2/3 global study of imetelstat for TD pts with non-del(5q) LR MDS post ESA therapy. The results from Phase 2 part indicated that imetelstat achieved durable RBC transfusion independence (RBC-TI) and the most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias. Among 38 pts with median follow-up of 24 months, 8-week, 24-week and 1-year TI rates were 42%, 32% and 29%, respectively; these responses were seen across different LR MDS subtypes. Median TI duration was 20 months and the longest TI was 2.7 years. A high and durable hematologic improvement-erythroid (HI-E) rate of 68% for a median duration of 21 months were also achieved. Reduction of variant allele frequency of mutations by imetelstat treatment was observed in some pts and correlated with clinical benefits (Platzbecker et al EHA 2020; Steensma et al JCO 2020). These results support the Phase 3 part of the trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 3 part of the study is open for enrollment to adult pts with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs placebo that will enroll approximately 170 pts and will be conducted at approximately 120 centers in North America, Europe, Asia and Middle East. Imetelstat is administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics, and quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. The study is currently recruiting pts. Clinical trial information: NCT02598661.

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study (Tefferi et al, Blood Cancer J 2016) supported initiation of a study in TD LR MDS patients. The Phase 2 part of IMerge demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 32%, with median duration of TI being 88 weeks. The responses were seen across different subtypes of LR MDS (Platzbecker et al, EHA 2020, S183). No new safety signal was identified. These results support the Phase 3 part of the trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrolment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 130 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of hematologic improvement-erythroid (HI-E), the amount and relative change in RBC transfusions, rate of complete response or partial response, overall survival, progression of MDS, pharmacokinetics, and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Fenaux:Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Steensma:CRISPR: Current equity holder in publicly-traded company; Aprea Therapeutics: Research Funding; Takeda: Consultancy; BMS/Celgene: Consultancy; Onconova: Consultancy; Arena: Current equity holder in publicly-traded company; H3 Biosciences: Research Funding; Astex Pharmaceuticals, Otsuka: Consultancy; Arrowhead Pharmaceuticals: Current equity holder in publicly-traded company. Font:Abbvie: Other: Travel, accommodations, expenses; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Diez-Campelo:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Jang:Bristol Myers Squibb: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Santini:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria; Johnson & Johnson: Honoraria.

Introduction The phase II ABOUND.PS2 study (NCT02289456) assessed safety/tolerability of a first-line modified nab-paclitaxel/carboplatin regimen for patients with advanced non-small cell lung cancer (NSCLC) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2. Methods Chemotherapy-naive patients with stage IIIB/IV NSCLC and ECOG PS 2 received four cycles of nab-paclitaxel 100 mg/m2 days 1 and 8 plus carboplatin area under the curve 5 day 1 q3w (induction). Patients without progression received nab-paclitaxel monotherapy (100 mg/m2 days 1 and 8 q3w) until progression/unacceptable toxicity. Primary endpoint: percentage of patients discontinuing induction due to treatment-emergent adverse events (TEAEs). Results 11/40 treated patients (27.5%; 95% CI, 14.60–43.89) discontinued chemotherapy induction due to TEAEs; 16/40 (40.0%) continued nab-paclitaxel monotherapy. Median progression-free and overall survival were 4.4 (95% CI, 2.99–7.00) and 7.7 (95% CI, 4.93–13.17) months. Grade 3/4 TEAEs during induction included neutropenia (22.5%), anemia (17.5%), thrombocytopenia (5.0%), and peripheral neuropathy (2.5%). Conclusion This nab-paclitaxel–based regimen was tolerable in patients with advanced NSCLC and ECOG PS 2, with efficacy comparable to historical chemotherapy data.

Introduction: Cytopenias are a leading cause of ruxolitinib (RUX) discontinuation for patients (pts) with myelofibrosis (MF). Though RUX 5 mg BID is recommended for pts with platelet (PLT) counts of 50 to Methods: JAKARTA and JAKARTA2 enrolled adult pts with intermediate- or high-risk MF, PLT counts ≥50 × 109/L, and ECOG PS scores ≤2. These analyses include pts in both studies who received FEDR 400 mg QD (starting dose), and JAKARTA pts randomized to PBO. Outcomes are also assessed for a subgroup of JAKARTA2 pts who met new, more stringent criteria for RUX relapsed/refractory (R/R) or intolerant ("Stringent Criteria Cohort"). RUX R/R required ≥3 mo RUX Tx with an initial response followed by spleen regrowth or suboptimal response; RUX intolerance required ≥28 d of RUX Tx with development of RBC transfusion requirement or grade ≥3 cytopenias, hematoma, or hemorrhage. Endpoints of this analysis were spleen volume response rate (SVRR; the proportion of pts who achieved ≥35% spleen volume reductions) and symptom response rate (RR; ≥50% reduction in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF] from BL to end of cycle 6 [EOC6]). SVRR analyses were intention-to-treat (ITT); pts missing data at EOC6 were considered nonresponders. Results: In JAKARTA, the overall SVRR at EOC6 in the FEDR 400 mg and PBO arms was 47% and 1%, respectively (P In the BL PLT 99%. At EOC6, rates of grade 3-4 thrombocytopenia (preferred term) for all pts in the JAKARTA FEDR 400 mg and PBO arms were 5% and 6%, respectively; in the subgroup of pts with BL PLT counts In JAKARTA2, median prior RUX Tx duration for all pts (N=97) was 10.7 mo. SVRR overall was 31% (Figure) and symptom RR was 27%. Median duration of spleen volume response was not reached at study termination. Among pts with BL PLT counts Median duration of FEDR Tx in pts with BL PLT counts Conclusion: Pts with MF who entered JAKARTA or JAKARTA2 with PLT counts Disclosures Harrison: Celgene: Honoraria, Speakers Bureau; AOP: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; CTI: Speakers Bureau; Promedior: Honoraria; Janssen: Speakers Bureau; Sierra Oncology: Honoraria; Shire: Speakers Bureau; Roche: Honoraria; Incyte: Speakers Bureau; Gilead: Speakers Bureau. Schaap:Celgene: Consultancy; Novartis: Consultancy. Vannucchi:Celgene: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ITALFARMACO: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kiladjian:AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy. Passamonti:Roche: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zweegman:Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz:BMS: Consultancy; Stemline: Research Funding; Promedior: Research Funding; Celgene: Consultancy, Other: Travel; Incyte: Research Funding; Constellation: Research Funding; Asana: Research Funding; Gilead: Research Funding; CTI: Research Funding; NS Pharma: Research Funding; Samus: Research Funding; Novartis: Research Funding; Janssen: Research Funding. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Rose:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene: Employment, Equity Ownership. Berry:Celgene: Employment, Equity Ownership. Brownstein:Celgene: Employment, Equity Ownership. Mesa:AbbVie: Research Funding; NS Pharma: Research Funding; Incyte: Other: travel, accommodations, expenses, Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; CTI: Research Funding; Galena Biopharma: Consultancy; Shire: Honoraria; Genentech: Consultancy; LaJolla: Consultancy; PharmaEssentia: Research Funding; Genotech: Research Funding; Celgene Corporation: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; Baxalta: Consultancy; Promedior: Research Funding; Pfizer: Research Funding; Sierra Oncology: Consultancy; Gilead Sciences: Research Funding; Samus: Research Funding.

Background: Treatment (Tx) options for patients (pts) with MF are limited following RUX failure. Fedratinib (FEDR) is an oral, selective inhibitor of JAK2. The phase II JAKARTA2 study of FEDR in pts with MF previously treated with RUX was initiated shortly after RUX was approved, and at the time there were no well-established criteria for RUX failure. Pt eligibility for JAKARTA2 was determined per investigator assessment. JAKARTA2 findings were originally reported using a last-observation-carried-forward (LOCF) analysis method in the "Per Protocol" population (pts with a baseline [BL] and ≥1 post-BL spleen assessment) (Harrison, Lancet Haematol,2017). Since JAKARTA2 was conducted, clinical experience with RUX has better informed criteria for RUX failure. Objective: To evaluate FEDR safety and efficacy using intention-to-treat (ITT) analyses for all pts enrolled in JAKARTA2 (ITT Population), and for a subgroup of pts who met more stringent definitions for RUX relapsed, refractory, or intolerant ("Stringent Criteria Cohort") than used in the original analysis. Methods: Adult pts with intermediate- or high-risk primary, post-polycythemia vera, or post-essential thrombocythemia MF, platelet counts ≥50 × 109/L, and ECOG PS scores 0-2 were enrolled. Pts were assessed by investigators to be RUX-resistant after receiving ≥14 days of prior RUX therapy, or RUX-intolerant due to toxicity following any duration of RUX exposure. The Stringent Criteria Cohort comprised pts who met the following criteria for RUX relapsed, refractory or intolerant: relapsed/refractory required ≥3 mo of prior RUX Tx with an initial response followed by spleen regrowth or suboptimal response; RUX intolerance required ≥28 days of RUX Tx with development of RBC transfusion requirement or grade ≥3 cytopenias, hematoma, or hemorrhage. Initial FEDR dose was 400 mg/day in 28-day cycles. The primary endpoint was spleen volume response rate (SVRR); ie, the proportion of pts who achieved a ≥35% spleen volume reduction from BL to end of cycle 6 (EOC6). LOCF analysis was not used; pts missing an EOC6 spleen volume measure were deemed nonresponders. Results: In the ITT Population (N=97), median age was 67 yrs (range 38-83) and 55% of pts had primary MF. Outcomes of prior RUX therapy are shown in the Table. In the ITT Population, 64 pts (66%) were resistant and 32 (33%) were intolerant to RUX per investigators. Median BL spleen volume was 2894 mL (~14× normal). Median prior RUX exposure was 11.7 mo in RUX-resistant pts and 7.0 mo in RUX-intolerant pts. Median duration of FEDR Tx on-study was 24.4 weeks. SVRR at EOC6 in the ITT Population was 31% (95%CI 22, 41), with similar rates between RUX-resistant pts (33% [22, 46]) and RUX-intolerant pts (28% [14, 47]). All but 1 pt with EOC6 data (n=51) had some degree of spleen volume reduction (Figure). The Stringent Criteria Cohort included 79/97 pts (81%) who met stringent definitions of RUX relapsed (n=18, 23%), refractory (n=47, 60%), or intolerant (n=14, 18%) (Table), with median prior RUX exposures of 11.8, 11.4, and 8.7 mo, respectively. Median duration of FEDR Tx was 24.3 weeks. SVRR in the Stringent Criteria Cohort overall was 30% (95%CI 21, 42). SVRR in RUX relapsed, refractory, and intolerant pts was 28% (95%CI 10, 54), 32% (19, 47), and 29% (8, 58), respectively. All pts with available assessments (n=41) had spleen volume reductions from BL at EOC6 (Figure). In the Stringent Criteria Cohort, adverse events (AEs) were reported with generally similar frequency among RUX relapsed, refractory, and intolerant pts, with rates of grade 3-4 anemia of 44%, 49%, and 29%, respectively; and grade 3-4 thrombocytopenia of 28%, 19%, and 14%. Proportions of RUX relapsed, refractory, or intolerant pts who discontinued FEDR Tx due to an AE were 22%, 17%, and 29%, respectively. Conclusion: Tx with FEDR in JAKARTA2 pts, who had substantial prior exposure to RUX, was associated with a robust spleen response rate, similar to or higher than rates seen with other JAK inhibitors when used as front-line Tx for MF (Harrison, NEJM, 2012; Mesa, Lancet Haematol, 2017; Mesa, JCO, 2017). About one-third of pts in JAKARTA2 achieved a spleen volume response and most pts had some degree of spleen volume reduction during FEDR Tx, regardless of whether they were relapsed, refractory, or intolerant to RUX. Long-term FEDR Tx in pts previously exposed to RUX is currently under study in 2 ongoing phase III studies (NCT03755518, NCT03952039). Disclosures Harrison: Shire: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Promedior: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Speakers Bureau; AOP: Honoraria; Roche: Honoraria; Janssen: Speakers Bureau; Sierra Oncology: Honoraria; Gilead: Speakers Bureau; CTI: Speakers Bureau. Schaap:Novartis: Consultancy; Celgene: Consultancy. Vannucchi:ITALFARMACO: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Celgene: Consultancy; AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Jourdan:Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schouten:Novartis: Honoraria; Sanofi: Honoraria; Gilead: Honoraria; Alexion: Honoraria, Other: Travel expenses. Passamonti:Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz:Novartis: Research Funding; Samus: Research Funding; Janssen: Research Funding; CTI: Research Funding; Stemline: Research Funding; Gilead: Research Funding; Constellation: Research Funding; NS Pharma: Research Funding; Incyte: Research Funding; BMS: Consultancy; Celgene: Consultancy, Other: Travel; Asana: Research Funding; Promedior: Research Funding. Verstovsek:Incyte: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Rose:Celgene Corporation: Employment, Equity Ownership. Shen:Celgene: Employment, Equity Ownership. Berry:Celgene: Employment, Equity Ownership. Brownstein:Celgene: Employment, Equity Ownership. Mesa:Gilead Sciences: Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; CTI: Research Funding; AbbVie: Research Funding; Genotech: Research Funding; Incyte: Other: travel, accommodations, expenses, Research Funding; Galena Biopharma: Consultancy; NS Pharma: Research Funding; LaJolla: Consultancy; Samus: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; Shire: Honoraria; Baxalta: Consultancy; Sierra Oncology: Consultancy; Celgene Corporation: Research Funding; Promedior: Research Funding; Genentech: Consultancy; PharmaEssentia: Research Funding.

To examine the current extent of the obesity problem in 2 large pediatric clinical registries in the US and Europe and to examine the hypotheses that increased body mass index (BMI) z-scores (BMIz) are associated with greater hemoglobin A1c (HbA1c) and increased frequency of severe hypoglycemia in youth with type 1 diabetes (T1D).International (World Health Organization) and national (Centers for Disease Control and Prevention/German Health Interview and Examination Survey for Children and Adolescents) BMI references were used to calculate BMIz in participants (age 2-18 years and ≥ 1 year duration of T1D) enrolled in the T1D Exchange (n = 11,435) and the Diabetes Prospective Follow-up (n = 21,501). Associations between BMIz and HbA1c and severe hypoglycemia were assessed.Participants in both registries had median BMI values that were greater than international and their respective national reference values. BMIz was significantly greater in the T1D Exchange vs the Diabetes Prospective Follow-up (P.001). After stratification by age-group, no differences in BMI between registries existed for children 2-5 years, but differences were confirmed for 6- to 9-, 10- to 13-, and 14- to 17-year age groups (all P.001). Greater BMIz were significantly related to greater HbA1c levels and more frequent occurrence of severe hypoglycemia across the registries, although these associations may not be clinically relevant.Excessive weight is a common problem in children with T1D in Germany and Austria and, especially, in the US. Our data suggest that obesity contributes to the challenges in achieving optimal glycemic control in children and adolescents with T1D.