Goh, Yeow Tee

Introduction: Anemia is a cardinal feature of myelofibrosis (MF), along with splenomegaly and constitutional symptoms. Red blood cell (RBC) transfusions, often used to manage anemia in patients (pts) with MF, are a negative prognostic factor for overall survival and are associated with diminished quality of life and increased healthcare-related economic burden. Momelotinib (MMB), a Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor, has demonstrated clinically meaningful and durable improvements in anemia, splenomegaly, and symptoms. Prespecified anemia endpoints in MMB phase 3 studies prioritized achievement of a strict transfusion independence response, defined as no transfusions for ≥12 wk immediately before the end of wk 24, with all hemoglobin levels ≥8 g/dL. Longitudinal analysis of transfusion intensity (units per 28 days) in a phase 2 trial of MMB in pts with transfusion-dependent MF demonstrated a reduction in transfusion burden in most (85%) pts (Harrison C, et al. EHA 2023). Here, we further characterize the impact of MMB and comparators on transfusion burden in pts with JAK inhibitor-naive and -experienced MF from the phase 3 SIMPLIFY-1 and MOMENTUM trials. Methods: This analysis evaluated time-dependent transfusion burden in pts enrolled in the phase 3 SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494) trials. SIMPLIFY-1 included pts with JAK inhibitor-naive MF randomized (1:1) to receive MMB or ruxolitinib (RUX). In MOMENTUM, pts with symptomatic (Myelofibrosis Symptom Assessment Form Total Symptom Score ≥10), anemic (hemoglobin <10 g/dL), JAK inhibitor-experienced MF were randomized (2:1) to receive MMB or danazol (DAN). All RBC units transfused were collected during the 24-wk randomized treatment period of each study and during the 84 days before receipt of randomized treatment on study for baseline assessment. Time-dependent transfusion burden was quantified by number of RBC units administered, in a tabular display of baseline- and treatment-period intensity. Pts were grouped jointly based on the baseline- and treatment-period intensity of RBC units per 28 days into ordinal bins: exactly zero units, >0 to 1 unit, >1 to 2 units, >2 to 3 units, >3 to 4 units, and >4 units. Results: In SIMPLIFY-1 (JAK inhibitor-naive pts), 150 of 213 evaluable pts (70%) in the MMB arm and 163 of 216 evaluable pts (76%) in the RUX arm required zero units of RBC transfusion per 28 days at baseline. Of pts who required zero units of transfusion at baseline, a higher proportion in the MMB arm (142 of 150 [95%]) maintained a requirement of zero RBC transfusions during randomized treatment of 24 wks vs the RUX arm (93 of 163 [57%]). Overall, the mean RBC transfusion burden per 28 days declined 0.10 units (SD, 0.701) from baseline to randomized treatment in the MMB arm and increased 0.39 units (SD, 1.016) in the RUX arm. Using ordinal bins, 87% of pts in the MMB arm maintained (144 [67.6%]) or improved (41 [19.2%]) RBC transfusion intensity during randomized treatment compared with baseline vs 54% in the RUX arm (maintained, 94 [43.5%]; improved, 23 [10.6%]) (Figure). In MOMENTUM (JAK inhibitor-experienced pts), most pts had some transfusion requirement at baseline, with 26 of 130 (20%) in the MMB arm and 11 of 65 (17%) in the DAN arm requiring zero units of RBC transfusion per 28 days. During randomized treatment, a higher proportion of pts in the MMB arm (46 of 130 [35%]) required zero units of RBC transfusion vs the DAN arm (11 of 65 [17%]), including a higher proportion of those who had zero RBC transfusion requirement at baseline who maintained zero RBC transfusion requirement during randomized treatment (MMB, 92%; DAN, 64%). The mean RBC transfusion burden per 28 days declined 0.86 units (SD, 1.748) from baseline to randomized treatment in the MMB arm and declined 0.28 units (SD, 1.584) in the DAN arm. Using ordinal bins, 85% of pts in the MMB arm maintained (25 [19.2%]) or improved (85 [65.4%]) RBC transfusion intensity compared with baseline vs 63% in the DAN arm (maintained, 7 [10.8%]; improved, 34 [52.3%]). Conclusions: These data demonstrate that MMB was associated with better maintenance of RBC transfusion intensity and zero RBC transfusion status vs RUX in pts with MF who were JAK inhibitor naive and showed greater reduction in RBC transfusion burden from baseline vs DAN in pts with MF who were JAK inhibitor experienced. Across both trials, ≥85% of pts treated with MMB maintained or improved transfusion intensity.

PURPOSE Hematopoietic stem-cell transplantation–associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with significant mortality and no approved therapy. HSCT-TMA results from endothelial injury, which activates the lectin pathway of complement. Narsoplimab (OMS721), an inhibitor of mannan-binding lectin-associated serine protease-2 (MASP-2), was evaluated for safety and efficacy in adults with HSCT-TMA. METHODS In this single-arm open-label pivotal trial ( NCT02222545 ), patients received intravenous narsoplimab once weekly for 4-8 weeks. The primary end point (response rate) required clinical improvement in two categories: (1) laboratory TMA markers (both platelet count and lactate dehydrogenase) and (2) organ function or freedom from transfusion. Patients receiving at least one dose (full analysis set [FAS]; N = 28) were analyzed. RESULTS The response rate was 61% in the FAS population. Similar responses were observed across all patient subgroups defined by baseline features, HSCT characteristics, and HSCT complications. Improvement in organ function occurred in 74% of patients in the FAS population. One-hundred-day survival after HSCT-TMA diagnosis was 68% and 94% in FAS population and responders, respectively, whereas median overall survival was 274 days in the FAS population. Narsoplimab was well tolerated, and adverse events were typical of this population, with no apparent safety signal of concern. CONCLUSION In this study, narsoplimab treatment was safe, significantly improved laboratory TMA markers, and resulted in clinical response and favorable overall survival.

Abstract Background LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM kinase gene family encodes 3 serine/threonine protein kinases that have roles in cell cycle progression and survival. In human disease, elevated levels of Pim1 and Pim2 are associated with hematologic malignancies, with MM showing the highest level of Pim2 expression. In preclinical studies, a majority of MM cell lines proved sensitive in vitro to LGH447-mediated Pim inhibition, exhibiting a dose-dependent decrease in cell proliferation. Furthermore, LGH447 was well tolerated and demonstrated significant inhibition of tumor growth in xenograft mouse models of MM as compared with control animals, supporting the clinical development of LGH447 in MM patients. Methods Patients with relapsed/refractory MM for whom no effective treatment options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses of single-agent LGH447 were administered orally on a continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of LGH447 administered as a single agent, orally, once daily. Secondary objectives included assessing the safety, tolerability, preliminary antimyeloma activity, and pharmacokinetic (PK) profiles of LGH447. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events v4.03. Efficacy assessments were made by investigators according to International Myeloma Working Group (IMWG) uniform response criteria with modifications. Following determination of the MTD for LGH447, additional patients will be enrolled in an expansion cohort to further characterize the safety and tolerability profile of LGH447. Results At the data cutoff, 19 patients have been treated at the following doses: 70 mg (n = 5), 150 mg (n = 6), 200 mg (n = 4), 250 mg (n = 4), with enrollment ongoing in dose escalation. Median age was 66 years (range, 41-75 years). Most patients (94.7%) presented with baseline Eastern Cooperative Oncology Group performance status 0-1. Most patients (73.7%) had received ≥ 2 prior regimens (median 4; range, 1-11), 89.5% had received prior bortezomib, and 84.2% had received prior lenalidomide and/or thalidomide (68.4% and 47.4%, respectively). Ten patients are ongoing at doses between 150-250 mg, with a median duration of exposure of 6 weeks (range, 1-26.6 weeks), and 9 patients discontinued (disease progression [n = 6], AEs [n = 2], withdrawal of consent [n = 1]). There was 1 DLT consisting of grade 3 thrombocytopenia at the 200 mg dose level and no reported suspected unexpected serious AEs. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were thrombocytopenia (31.6%), anemia (21.1%), and neutropenia (15.8%). No deaths have occurred on study. LGH447 displayed time-dependent PK with a 3- to 6-fold accumulation from day 1 to steady state (day 14). After a single oral dose, area under the curve and maximum concentration increased somewhat more than in proportion to the dose from 70 to 250 mg. Evidence of single-agent activity, as determined by investigators using IMWG criteria, has been seen in multiple patients, with best response to date being a very good partial response (VGPR). Conclusion In heavily treated patients with relapsed/refractory MM, LGH447 was generally well tolerated and exhibited evidence of single-agent efficacy in multiple patients, validating Pim kinase inhibition as a promising therapeutic rationale and supporting its further clinical development in patients with MM and other hematologic malignancies. Dose escalation is ongoing and updated results will be presented. Disclosures: Ocio: BMS: Consultancy; Arry-520: Consultancy; Pharmamar: Research Funding; Celgene: Honoraria, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Honoraria. Thomas:Novartis: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; Millenium: Research Funding. Günther:Novartis: Consultancy, Research Funding. Lebovic:Celgene: Speakers Bureau; Allos/Spectrum: Speakers Bureau; Genentech: Speakers Bureau; Onyx: Speakers Bureau. Kumar:Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Jakubowiak:Onyx: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria. Song:Novartis: Employment. Xiang:Novartis: Employment. Hynds:Novartis: Employment. Vanasse:Novartis: Employment. Goh:Jannsen: Research Funding; BMS: Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Hospira: 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, Research Funding.

Abstract Background: LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM (Provirus Integration site for Moloney leukemia) kinase gene family encodes 3 serine/threonine protein kinases that have roles in cell cycle progression and survival. In human disease, elevated levels of Pim1 and Pim2 are associated with hematologic malignancies, with MM showing the highest level of Pim2 expression. In preclinical studies, a majority of MM cell lines proved sensitive in vitro to LGH447-mediated Pim inhibition, exhibiting a dose-dependent decrease in cell proliferation. LGH447 demonstrated significant tumor growth inhibition in xenograft mouse models of MM as compared with control animals, supporting the clinical development of LGH447 in MM patients. Methods: Patients with relapsed/refractory MM for whom no effective treatment options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses of single-agent LGH447 were administered orally on a continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of LGH447 administered as a single agent, orally, once daily. Secondary objectives included assessing the safety, tolerability, preliminary anti-myeloma activity, and pharmacokinetics of LGH447. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Efficacy assessments were made by investigators according to International Myeloma Working Group (IMWG) uniform response criteria with modifications. Results:At the data cutoff, 54 patients have been treated at the following doses: 70 mg (n = 5), 150 mg (n = 6), 200 mg (n = 6), 250 mg (n = 7), 300 mg (n = 4), 350 mg (n=10), 500 mg (n=10), 700 mg (n=6), with the MTD determined to be 500 mg once daily. Median age was 65 years (range, 41-87 years). Most patients (92.6%) presented with baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated with a median of 4 prior lines of therapy (range, 1-16). 81.5% had received prior proteasome inhibitor therapy, 83.3% had received prior immunomodulatory therapy (70.4% lenalidomide and 48.1% thalidomide), 68.5% were treated with both proteasome inhibitor and immunomodulatory therapies, and 87.0% had received prior stem cell transplant. Seventeen patients are ongoing at doses between 250-700 mg, with a median duration of exposure of 10.6 weeks (range, 0.1-56.1 weeks), and 37 patients discontinued (disease progression [n = 29], AEs [n = 4], withdrawal of consent [n = 4]). There were 8 DLTs, consisting of four grade 3/4 thrombocytopenia (1 each at 200, 250, 350, 500 mg dose levels), two grade 3 fatigue (1 each at 500 and 700 mg dose levels), one grade 3 hypophosphatemia (300 mg), and one episode of vaso-vagal syncope (700 mg). This last event was the only reported unexpected serious AE that was suspected to be due to LGH447 treatment. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were thrombocytopenia (18.5%), anemia (18.5%), neutropenia (13%), and fatigue (11.1%). No deaths have occurred on study. Forty-eight individuals (70-500 mg) were evaluable for disease response assessments. Evidence of single agent activity was noted at doses ≥ 150 mg, including 1 VGPR at 200 mg (exposure duration > 55 weeks) and 4 PRs noted at doses ranging from 150-500 mg (respective exposure durations of 32, 29, 24, and 21 weeks). Five additional patients achieved MR, resulting in a clinical benefit rate (≥ MR) of 20.8%, and 23 patients were noted to have SD, resulting in a remarkable disease control rate (≥ SD) of 68.8%. In addition, of those patients with SD, 8 had exposure durations for > 20 weeks. Conclusions:In heavily treated patients with relapsed/refractory MM, LGH447 was generally well tolerated and exhibited evidence of durable single-agent efficacy in multiple patients, with the best response being a VGPR. These findings validate Pim kinase inhibition as a promising therapeutic rationale in MM patients and support further clinical development in patients. Disclosures Ocio: Novartis: Honoraria. Thomas:Novartis: Research Funding; Celgene: Consultancy, Research Funding; Millennium: Research Funding; Idera Pharmaceuticals: Research Funding; Immunomedics: Research Funding. Günther:Novartis: Consultancy, Research Funding. Goh:Gilead Sciences: 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; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Lebovic:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millennium: Consultancy. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, 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; SkylineDx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Song:Novartis: Employment. Xiang:Novartis: Employment. Patel:Novartis: Employment. Vanasse:Novartis: Employment, Equity Ownership. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Research Funding; Array: Research Funding; Cephalon: Research Funding.

BACKGROUNDNVP‐AUY922 (AUY; Luminespib) with or without bortezomib showed preclinical activity against multiple myeloma (MM) cells. This phase 1/1B study assessed NVP‐AUY922 alone and with bortezomib in patients with relapsed or refractory MM.METHODSDose escalation was guided by an adaptive Bayesian logistic regression model. In phase 1, patients who progressed after 2 to 4 prior therapies received NVP‐AUY922 intravenously once weekly. In phase 1B, patients who progressed after 2 or fewer prior therapies received NVP‐AUY922 plus bortezomib. The primary objective was to determine the maximum tolerated dose (MTD) of NVP‐AUY922.RESULTSTwenty‐four patients received NVP‐AUY922 monotherapy at doses of 8 to 70 mg/m2. One dose‐limiting toxicity (DLT) was observed (grade 3 blurred vision at 70 mg/m2); no MTD was reached. The recommended phase 2 dose was 70 mg/m2. The most frequent drug‐related adverse events (AEs) were diarrhea, nausea, and ocular toxicities. Grade 3/4 AEs were uncommon (<10%). Eight patients discontinued treatment because of AEs; 5 had ocular toxicities (≥45 mg/m2). The best response was stable disease in 66.7% of the patients. There were no partial or complete responses. Five patients received NVP‐AUY922 (which was started at 50 mg/m2) plus bortezomib (1.3 mg/m2). Three of these patients experienced DLT. No further dose escalation was performed; the MTD for NVP‐AUY922 plus bortezomib was not established.CONCLUSIONSThis study showed disease stabilization with NVP‐AUY922 in patients with relapsed or refractory MM. The MTD for NVP‐AUY922 was not reached, but reversible ocular toxicity has been reported at high dose levels. Bortezomib at the standard recommended dose plus NVP‐AUY922 was not tolerated. Cancer 2015;121:2185–2192. © 2015 American Cancer Society.