Rose, Shelonitda

Abstract The ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non–transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B were transfusion dependent (TD); and patients in cohort 3A/3B had stable ruxolitinib treatment before and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment was extended if clinical benefit was observed at day 169. The primary end point was anemia response rate (NTD, ≥1.5 g/dL hemoglobin increase from baseline; TD, transfusion-independence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary end point. In cohorts 1 and 3A (NTD), 27% and 50% of patients, respectively, had mean hemoglobin increase of ≥1.5 g/dL from baseline. Among TD patients, ∼50% had ≥50% reduction in transfusion burden. Reduction in total symptom score was observed in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had ≥1 adverse event (AE); 47% had ≥1 treatment-related AE (TRAE; 11% grade ≥3), most frequently hypertension (18%), managed with medical intervention. One patient had a serious TRAE leading to luspatercept discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients, ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept improved anemia and transfusion burden across cohorts; the safety profile was consistent with previous studies. This trial was registered at www.ClinicalTrials.gov as #NCT03194542.

Abstract Background: Splenomegaly is a marker of disease progression in MF; larger spleen size (SS) is correlated with poorer survival and debilitating MF symptoms. In a retrospective real-world study of 408 patients (pts) with MF treated with ruxolitinib (RUX), pts with SS ≥ 10 cm below the left costal margin (LCM) were significantly less likely to attain a spleen response than pts with SS < 10 cm (Palandri 2017); this finding has not been reported in clinical trials of RUX. FEDR is a JAK2-selective inhibitor approved in the US, EU, Canada, and elsewhere as first-line (1L) MF treatment (Tx) and in pts previously treated with RUX. FEDR was evaluated as 1L MF Tx in the phase 3, placebo (PBO)-controlled JAKARTA trial, and in the phase 2, single-arm JAKARTA2 trial in pts previously treated with RUX. Pts allocated to FEDR 400 mg/day (d) in these trials reported substantial reductions from baseline (BL) in spleen volume and MF symptom severity after 6 FEDR Tx cycles. It is important to determine whether spleen volume and symptom improvements during FEDR Tx are influenced by degree of pre-Tx splenomegaly. Objective: Investigate the clinical efficacy of FEDR 400 mg/d in pts in JAKARTA & JAKARTA2 with large spleens at BL. Methods: The JAKARTA trial assessed FEDR 400 mg/d, FEDR 500 mg/d, and placebo in pts with JAK-inhibitor-naïve MF, and the JAKARTA2 trial evaluated FEDR 400 mg/d (starting dose) in pts resistant/intolerant to prior RUX. Both studies enrolled pts with intermediate- or high-risk MF, SS > 5 cm from LCM by palpation, platelets ≥ 50 ×10 9/L, and ECOG PS ≤ 2. These analyses include pts in each trial allocated to receive FEDR 400 mg/d in continuous 28d Tx cycles. Too few pts had BL SS < 10 cm by palpation in JAKARTA (n = 21) and JAKARTA2 (n = 12) for meaningful comparison vs SS ≥ 10 cm. Thus, in these post hoc analyses we divided pts according to the median SS (mSS) at BL in each study , and assessed changes from BL in spleen volume and MFSAF total symptom score (TSS) at the end of cycle 6 (EOC6). Spleen volume was assessed by MRI/CT scan; MFSAF TSS was the sum of 6 MF symptom scores: night sweats, early satiety, pruritus, pain under ribs-left side, abdominal discomfort, and bone/muscle pain. Pts must have had spleen volume and/or TSS data at BL and EOC6. R esults: In JAKARTA, 96 pts were randomized to FEDR 400 mg/d; mSS at BL for all pts was 16 cm (range 5-40). Median (range) BL spleen volume was 1771 (316-3396) mL in the < mSS cohort and 3329 (983-6430) mL in the ≥ mSS cohort; median TSS was 13.0 and 17.6, respectively. Spleen volume data were available at BL and EOC6 for 37 (82%) and 38 (75%) pts in the < mSS and ≥ mSS cohorts, respectively. Median spleen volume reduction (SVR) at EOC6 was -38% [95%CI -43%, -31%] in the < mSS group and -40% [-40%, -28%] in the ≥ mSS group (Figure). Changes in MF symptom scores at EOC6 were similar in the < mSS (n = 37) and ≥ mSS (n = 34) cohorts, with median TSS reductions of -49% and -51%, respectively. For individual symptoms, median reductions in abdominal discomfort, bone/muscle pain, and early satiety were similar between BL SS cohorts, whereas changes were greater in the < mSS group for pruritus and pain under ribs-left side, and greater in the ≥ mSS group for night sweats. In JAKARTA2, 97 pts received FEDR 400 mg/d (starting dose); BL mSS for all pts was 18 cm (range 5-36). Median (range) BL spleen volumes were 1937 (737-4305) and 4002 (1821-7815) mL for pts with < mSS and ≥ mSS, respectively; and BL TSS was 17.2 (0.7-48.0) and 23.6 (1.0-44.0). Spleen volume and MFSAF TSS data were available at BL and EOC6 for 41 and 29 pts, respectively, in the < mSS cohort, and for 41 and 22 pts in the ≥ mSS group. At EOC6, median SVR from BL was -35% [95%CI -40%, -29%] for pts with < mSS at BL and -30% [-37%, -17%] for pts with ≥ mSS (Figure). Median TSS changes were -36% and -49% in the < mSS and ≥ mSS cohorts, respectively; pts with ≥ mSS at BL had similar or greater reductions from BL in 5/6 MFSAF symptoms (all except pruritus) vs those with < mSS. Conclusions: These analyses demonstrate that extent of splenomegaly at BL in JAKARTA and JAKARTA2 did not influence the likelihood of achieving improvements in spleen volume or MF symptom severity for pts receiving FEDR 400 mg/d as 1L MF Tx or as post-RUX salvage Tx. For pts who completed 6 FEDR Tx cycles, reductions in spleen volume and TSS at EOC6 in the ≥ mSS cohorts in both studies were similar to those in the < mSS cohorts, even though BL spleen volumes and TSS were higher in the ≥ mSS groups. Figure 1 Figure 1. Disclosures Kiladjian: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Passamonti: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Janssen: 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, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi: BMS: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Talpaz: Imago: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: 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; Takeda: Other: Grant/research support . Cervantes: Bristol Myers Squibb: Consultancy, Honoraria. Harrison: Roche: 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; Constellation Pharmaceuticals: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: 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; CTI BioPharma: 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; Incyte Corporation: Speakers Bureau; Sierra Oncology: Honoraria; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mesa: AOP: Consultancy; La Jolla Pharma: Consultancy; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Genentech: Research Funding; Samus: Research Funding; CTI: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Gilead: Research Funding; CTI: Research Funding; Pharma: Consultancy; Promedior: Research Funding. Mascarenhas: Geron: Consultancy; Merus: Research Funding; Geron: Consultancy, Research Funding; Merck: 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; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Consultancy; Galecto: Consultancy; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: 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; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; Sierra Oncology: 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; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek: Promedior: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; Celgene: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Devos: Alexion, AstraZeneca Rare Disease Inc.: Consultancy; Incyte: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb - Celegene: Consultancy; Novartis: Consultancy. Rose: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zhang: Bristol Myers Squibb: Current Employment. Sy: Bristol Myers Squibb: Current Employment.

SummaryFedratinib, an oral Janus kinase‐2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400‐mg daily was based on results of an updated analysis of the pivotal phase III, placebo‐controlled JAKARTA trial in patients with JAK‐inhibitor‐naïve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first‐line fedratinib in patients with myelofibrosis.

BACKGROUND: MF is characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib is an oral JAK2 inhibitor approved in the United States for treatment (Tx) of adult patients (pts) with intermediate (INT)-2 or high-risk MF. The randomized, placebo (PBO)-controlled, phase III JAKARTA trial evaluated clinical outcomes with fedratinib in pts with JAK-inhibitor-naïve MF. Initial findings from the JAKARTA study have been reported (Pardanani, JAMA Oncol, 2015). JAKARTA data were recently reanalyzed in preparation for regulatory review. OBJECTIVE: Evaluate the clinical efficacy and safety with fedratinib 400 mg/day in updated analyses of the JAKARTA study. METHODS: JAKARTA was an international, randomized, double-blind, PBO-controlled study that enrolled pts aged ≥ 18 years with INT-2 or high-risk primary, post-PV, or post-ET MF. Pts were randomly assigned 1:1:1 to fedratinib 400 mg, fedratinib 500 mg, or PBO, administered orally once-daily for ≥ 6 consecutive 4-week cycles ("randomized Tx period"). After completing 6 Tx cycles (or earlier in the case of disease progression), pts randomized to PBO could crossover to fedratinib. The primary endpoint was the spleen volume response rate (SVRR), the proportion of pts who achieved a ≥ 35% spleen volume reduction from baseline (BL) confirmed by MRI/CT at end of cycle 6 (EOC6), confirmed by follow-up scan 4 weeks later. Secondary endpoints included SVRR without 4-week confirmation, durability of spleen response, and symptom response rate (proportion of pts with a ≥ 50% reduction from BL in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF]) at EOC6. An exploratory analysis evaluated proportions of pts with ≥ 50% reductions from BL at EOC6 in individual MFSAF symptom scores: night sweats, pruritus, abdominal discomfort, early satiety, pain under ribs on left side, and bone or muscle pain. These analyses are limited to pts randomized to fedratinib 400 mg (the approved starting dose of fedratinib) or to PBO. Efficacy analyses were performed for the intention-to-treat (ITT) population and safety was assessed in all pts who received ≥ 1 dose of study drug. RESULTS: 96 pts were randomized to fedratinib 400 mg and 96 pts to PBO. In the fedratinib and PBO arms, median ages at BL were 63 (range 39-86) and 66 (27-85) years, respectively, 65% and 60% of pts had primary MF, 76% and 73% had constitutional symptoms, median spleen volumes were 2652 (316-6430) and 2660 (662-7911) mL, and median TSS were 15.3 (0-57) and 12.4 (0-53). Median durations of exposure were 15.5 months in the fedratinib 400 mg arm and 6 months in the PBO arm. With a confirmation scan 4 weeks after EOC6, SVRR was significantly higher in the fedratinib arm (37% [95%CI 27%, 46%]) vs. the PBO arm (1% [0%, 3%]) (P < 0.0001). Without the confirmation scan, SVRR at EOC6 was 47% (95%CI 37%, 57%) in the fedratinib 400 mg arm and 1% (0%, 3%) in the PBO arm (P < 0.0001; Figure). Estimated median duration of spleen response with fedratinib was 18.2 months. Symptom response rate at EOC6 for evaluable pts (ie, with TSS data available at BL and EOC6) was 40% (36/89) with fedratinib and 9% (7/81) with PBO (P < 0.0001). Fedratinib was associated with higher response rates vs. PBO in all 6 MFSAF symptoms: abdominal discomfort (41% vs. 15%, respectively), night sweats (58% vs. 22%), bone or muscle pain (33% vs. 14%), early satiety (51% vs. 18%), pruritus (39% vs. 20%), and pain under the ribs on the left side (42% vs. 24%). The most common Tx-emergent adverse events (TEAEs) during the randomized Tx period were grade 1-2 gastrointestinal events (Table). New or worsening grade 3 anemia and grade ≥ 3 thrombocytopenia laboratory abnormalities were reported in 34% and 12% of fedratinib-treated pts, most (75%) occurring within 3-4 months of Tx initiation. Compared with PBO, fedratinib-treated pts more frequently experienced increased serum creatinine, amylase, and lipase; these were mainly grade 1-2 in severity. TEAEs led to Tx discontinuation for 14% of fedratinib pts and 8% of PBO pts. CONCLUSIONS: Fedratinib 400 mg/day significantly reduced splenomegaly and symptom burden in pts with JAK-inhibitor-naïve MF. Relatively few pts discontinued fedratinib therapy due to TEAEs, suggesting these events are manageable. These data corroborate results initially reported for the JAKARTA trial, and further support the efficacy and safety of fedratinib in this pt population. Disclosures Masszi: AbbVie: 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; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Drummond:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicine Corporation: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jourdan:Novartis: Honoraria, 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; Abbvie: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Blueprint: Membership on an entity's Board of Directors or advisory committees; Celgene/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; 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. Ribrag:AZD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; MSD: 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; gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; nanostring: Honoraria, Membership on an entity's Board of Directors or advisory committees; EPZ: Honoraria, Membership on an entity's Board of Directors or advisory committees; epizyme (EPZ): Research Funding; argenX: Research Funding; pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Consultancy; gustave roussy comprehensive cancer center: Current Employment. Rambaldi:Abbvie: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Omeros: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Roche: Honoraria; MSD: Honoraria. Rose:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Zhang:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Harrison:Promedior: Honoraria; Roche: Honoraria; Sierra Oncology: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; CTI Biopharma Corp: Honoraria, Speakers Bureau.