Cohort 2b Research Articles

Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis

AbstractThe 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.

Real-world treatment patterns and outcomes in US patients (pts) with advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy (PBC) and anti–PD-(L)1 treatment.

8627 Background: Effective treatment options for advanced or metastatic NSCLC are limited, especially for pts who progress after treatment with PBC and an anti–programmed cell death 1 protein (PD-1) or ligand 1 (PD-L1) regimen. Examining real-world treatment patterns and long-term outcomes, we report on progression-free survival (PFS) and overall survival (OS) in pts with NSCLC who previously received PBC and anti–PD-(L)1 regimens. Methods: This study used the nationwide Flatiron Health electronic health record–derived deidentified database. Pts included in the analysis were ≥18 years old with an initial diagnosis of advanced or metastatic NSCLC and an ECOG PS of 0 or 1 who had received prior PBC and anti–PD-(L)1 therapy in 1 (in combination) or 2 (in sequence) lines and had initiated ≥1 subsequent line of treatment between 2018 and 2023; the start date of subsequent treatment (defined as the index regimen) was the index date. Pts were followed up until death or last available data through Mar 31, 2023. Pt characteristics, treatment patterns, and outcomes were analyzed for the overall pt group and according to initial treatment cohort (cohort 1: first-line [1L] PBC plus anti–PD-(L)1; cohort 2a: 1L PBC and second-line [2L] anti–PD-(L)1; or cohort 2b: 1L anti-PD-(L)1 and 2L PBC). PFS and OS were estimated using Kaplan-Meier methods. Results: Of 1793 pts, most were in cohort 1 (73.5%), with fewer pts in cohorts 2a (22.5%) and 2b (4.1%). The majority of pts in cohort 2b had PD-L1 ≥50% (n = 57, 78.1%), while the percentage was lower in cohorts 1 (n = 262, 19.9%) and 2a (n = 72, 17.9%). Most pts (n = 1626, 90.7%) had stage IV disease. Median time from advanced diagnosis to index date was 10.5 months (range, 1.1-103.8); median follow-up from index date was 7.8 months (range, 0.0-65.0). A broad range of treatments were used after PBC and anti–PD-(L)1 regimens; among all pts, the most common were docetaxel + ramucirumab and docetaxel monotherapy. Among all pts, median PFS and OS from the time of starting these index regimens were 5.29 and 11.20 months, respectively; PFS and OS were similar across cohorts. Conclusions: A broad range of subsequent treatments were used following PBC and anti–PD-(L)1 regimens, most commonly docetaxel with or without ramucirumab. Short median PFS and OS underscore a significant unmet need among pts previously treated with PBC and anti–PD-(L)1. [Table: see text]

Updated results of a phase 1/2 study of AU-007, a monoclonal antibody (mAb) that binds to IL-2 and inhibits CD25 binding, in patients with advanced solid tumors.

2527 Background: AU-007 is a computationally designed human mAb that binds interleukin-2 (IL-2) on its CD25 binding epitope. AU-007 bound IL-2 cannot bind trimeric (CD25, CD122, CD132) IL-2 receptors (IL-2R) on regulatory T cells (Tregs), vascular endothelium, or eosinophils, but IL-2’s binding to dimeric IL-2R (CD122, CD132) on effector T (T eff) and NK cells is unhindered. AU-007 thus redirects IL-2 towards T eff and NK cell activation, while diminishing Treg activation and vascular leak. AU-007 uniquely redirects IL-2 generated from T eff cell expansion, converting a Treg-mediated autoinhibitory loop into an immune stimulating loop. Methods: The study consists of three dose escalation arms followed by cohort expansion. Arm 1A evaluates escalating doses (0.5 – 12 mg/kg) of AU-007 (IV every 2 weeks [Q2W]). Arm 1B evaluates AU-007 Q2W + escalating doses (15K – 270K IU/kg) of one aldesleukin subcutaneous (SC) dose. Arm 1C evaluates AU-007 + escalating doses of SC aldesleukin, both Q2W. Nineteen solid tumor types are allowed in escalation. Cohort expansion Arm 2B evaluates 9 mg/kg AU-007 + one 135K IU/kg aldesleukin dose. Results: Fifty-three patients were enrolled as of 23 January 2024: 15 in Arm 1A, 12 in Arm 1B, 25 in Arm 1C, and 1 in cohort expansion. AU-007 (+/- aldesleukin) was well-tolerated, with no dose limiting toxicities through all Arm 1A and 1B cohorts and the 3rd cohort (of 4) in 1C. Enrollment is ongoing in the final Arm 1C cohort and Arm 2B expansion. All drug related adverse events (AE) were Grade 1 or 2 except for 4 patients with transient lymphopenia (Grade 3 and 4) and 1 patient with Grade 3 anemia. The most common drug-related AEs were pyrexia (18%), fatigue (16%), nausea (14%), lymphopenia (8%), and chills (6%). Two patients had transient Grade 2 drug-related serious AEs: pyrexia Arm 1B and cytokine release syndrome Arm 1C; both patients continued therapy. A confirmed partial response (32% decrease) occurred in a nasopharyngeal carcinoma patient in Arm 1C who progressed on anti-PD-1 therapy. Tumor shrinkage occurred in patients with non-small cell lung, bladder, head and neck, colorectal (CRC), and renal cancer. A melanoma patient (Arm 1B) who progressed on anti-CTLA-4 + anti-PD-1 therapy had a 48% decrease in target tumors; a small brain metastasis was found and irradiated at week 16 and the patient remains on treatment. A patient with microsatellite stable CRC had a 26% tumor shrinkage after the first cycle (Arm 1C). Serum Tregs and eosinophils decreased in patients while NK and CD8 cell counts trended upwards. The CD8:Treg ratio trends upward in all cohorts. Conclusions: The mild toxicity profile and promising early efficacy observed in dose escalation across multiple tumor types in heavily pretreated patients, along with initial pharmacodynamic data, warrant continued evaluation of AU-007 + low dose SC aldesleukin in the Phase 2 expansion cohorts of the study. Clinical trial information: NCT05267626 .

BIOLUMA: A phase II trial of nivolumab and ipilimumab in lung cancer—Results from the SCLC TMBhigh cohort.

8099 Background: Therapeutic options and prognosis for patients with small-cell lung cancer (SCLC) remain poor. Treatment with checkpoint inhibition can achieve remarkable responses, but this holds true for a small percentage of SCLC patients only. While tumor mutation burden (TMB) emerged as possible predictive biomarker for nivolumab and ipilimumab combination therapy in SCLC patients, to our knowledge, tissue-based TMB has never been evaluated prospectively in SCLC patients. Here, we present the results of the cohort 2b of the BIOLUMA trial, which evaluates efficacy and safety of nivolumab in combination with ipilimumab in SCLC patients with high tumor mutation burden. Methods: BIOLUMA is an investigator initiated multicentre non-randomised phase II trial in 2nd line patients with SCLC. The initial all-comer SCLC cohort was amended for inclusion of patients with high TMB only. FFPE tumor tissue was used for TMB pre-screening by whole exome sequencing (WES) at time of first diagnosis. TMBhigh was defined as the upper tertile of total missense mutations. After progression on platinum-based therapy, patients received 4 cycles of nivolumab 1 mg/kg q3w in combination with ipilimumab 3 mg/kg q3w and subsequently nivolumab 240 mg flat dose as monotherapy. Primary endpoint was overall response rate (ORR) of the combination therapy. Additionally, exploratory analyses of sequential tumor biopsies and blood samples were performed at different time points. Results: TMB analysis was feasible for most patients without necessity of performing additional tumor biopsy. Evaluation of TMB on FFPE tumor tissue obtained at first diagnosis was sufficient for TMB analysis in 92.5% of cases. TMB status was determined for 297 patients: 45.8% belonged to the TMB high group, while 54.2% had low or medium TMB. In total, 45 TMBhigh patients were enrolled in the study with 44 subjects evaluable for primary endpoint analysis. Six patients (13.6%) showed response to therapy, of whom in 4 patients (9%) response could be confirmed according to RECIST 1.1 criteria. One patient, who is not evaluable for endpoint analysis experienced a remarkably long lasting PR, which is still ongoing for more than three years. This patient received concomitant palliative radiation during induction with nivolumab and ipilimumab. Disease control rate (DCR) was 20.4% (n=9), three more patients showed unconfirmed SD. Three patients with confirmed PR or SD experienced long lasting treatment benefit, which is still ongoing at data cut-off. Conclusions: This represents the first trial to prospectively evaluate the combination therapy of nivolumab and ipilimumab in TMBhigh SCLC patients. The primary endpoint ORR was not reached. However, we observed an impressive clinical benefit in single patients, which warrants further investigation in order to get more insight into the mechanisms leading to these long-lasting tumor responses. Clinical trial information: NCT03083691 .

Prevalence of elevated lipoprotein(a) in cardiac rehabilitation patients - results from a large-scale multicentre registry in Germany.

Lipoprotein(a) (Lp(a)) is an independent risk factor for myocardial infarction and aortic valve stenosis. European guidelines recommend assessing it at least once in a lifetime, particularly in premature atherosclerotic heart disease. A non-interventional registry was conducted at MEDIAN rehabilitation facilities in Germany to assess the frequency of Lp(a) testing in referring acute care hospitals and the prevalence of elevated Lp(a) levels in aortic valve stenosis or premature myocardial infarction. All consecutive patients referred after coronary intervention or aortic valve surgery were included in four cohorts: aortic valve intervention (cohort 1), current/previous myocardial infarction at < 60 years of age (cohorts 2a/2b), and myocardial infarction at ≥ 60 years of age (control). The analysis included 3393 patient records (cohort 1, n = 1063; cohort 2a, n = 1351; cohort 2b, n = 381; control, n = 598). Lp(a) had been determined at the referring hospital in 0.19% (cohort 1), 4.96% (cohort 2a), 2.36% (cohort 2b), and 2.01% (control) of patients. Lp(a) levels were > 50 mg/dL or > 125 nmol/L in 28.79% (cohort 1), 29.90% (cohort 2a), and 36.48% (cohort 2b; p < 0.001) compared to 24.25% (control). Family history of premature cardiovascular disease was reported in 13.45% (cohort 1), 38.56% (cohort 2a), and 32.81% (cohort 2b) compared to 17.89% (control; p < 0.05 for each comparison). Lp(a) had been rarely assessed in acute management of aortic valve stenosis or premature myocardial infarction despite expanding scientific evidence and guideline recommendation. Given the above-average incidence of elevated Lp(a) levels, awareness for Lp(a) has to increase substantially to better identify and manage high-risk patients.

Abstract CT176: OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy induced deepening and durable responses without interleukin 2 (IL2) in patients (pts) with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma

Abstract Introduction: Treatment options are limited for pts with ICI-resistant metastatic melanoma. Investigational unengineered TIL cell therapy has shown promising activity in this setting, but co-administration of systemic high-dose IL2 limits pt eligibility and is associated with safety risks. OBX-115 is an investigational, autologous TIL cell therapy engineered to express membrane-bound IL15 (mbIL15) under pharmacologic regulation by the FDA-approved small-molecule drug acetazolamide (ACZ) using cytoDRiVE® technology, to induce cytokine-driven TIL expansion and persistence without co-administration of IL2. Methods: This Phase 1 first-in-human study (NCT05470283) is assessing the safety, tolerability, and efficacy of the OBX-115 regimen in pts with unresectable or metastatic melanoma progressing after ICI. Initial pts are enrolled into dose-escalation cohorts (n=3 each; maximum doses: Cohort 1 [C1], 30 × 109 cells + ACZ 125 mg; Cohort 2b [C2b], 100 × 109 cells + ACZ 125 mg). OBX-115 is manufactured using the pt’s tumor tissue (procured by surgical excision or core needle biopsy) and infused after completion of cyclophosphamide and fludarabine lymphodepletion. ACZ is administered orally once daily for up to 7 days, with redosing (Week 6, up to 7 days) permitted for pts without radiographic response at Week 6. No systemic IL2 is administered. The primary objective is to evaluate safety (dose-limiting toxicities [DLTs] and treatment-emergent adverse events [TEAEs]). Results: As of 1 December 2023, 6 pts (age, 28-64 y; C1, n=3; C2b, n=3) with ICI-resistant metastatic melanoma completed the DLT-evaluation period. Median lines of prior therapy was 2.5 (range, 1-5). OBX-115 was successfully manufactured for all 6 pts, including from core needle biopsy tumor tissue (n=5). At 20 weeks median study follow-up (range, 11-51 weeks), no DLTs were observed; 3 pts experienced Gr 3 nonhematologic TEAEs (abdominal pain, ALT elevation, hypokalemia, hyponatremia, syncope) and no Gr 4 nonhematologic TEAEs were reported. Four pts received and tolerated ACZ redosing. ORR per RECIST 1.1 was 50% (2 CR, 1 PR, 3 SD); responses were established between Week 6-18 and ongoing at the time of data cut. All pts had consistent reduction of lesions at each assessment through Week 18. One pt developed new metastatic disease (liver) and progressed at Week 24, despite continued target lesion reduction. Updated data will be presented. Conclusions: OBX-115, a one-time, IL2-free, regulatable, engineered TIL cell therapy, was well-tolerated and induced consistently deepening and durable responses, with the potential to fulfill the unmet need in ICI-resistant advanced melanoma. These early results support continued investigation of the OBX-115 regimen in this and an ongoing Phase 1/2 multicenter study (NCT06060613). Citation Format: Rodabe N. Amaria, Jennifer L. McQuade, Michael A. Davies, Isabella C. Glitza Oliva, Steffy Jose, Erik N. Cressman, Ashlynd L. Clausell, Roland Bassett, Sapna Patel, Adi Diab, Hussein A. Tawbi, Michael K. Wong, Alexandra P. Ikeguchi, Madan Jagasia, Giridharan Ramsingh, Prakash Prabhakar, Raina Duan, Parameswaran Hari. OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy induced deepening and durable responses without interleukin 2 (IL2) in patients (pts) with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT176.

Results from the phase 1b/2 SGNTUC-024 study: Assessment of tucatinib, trastuzumab, and FOLFOX for HER2+ GI cancers.

100 Background: HER2 is overexpressed in various GI tumors. Tucatinib (TUC), which is approved in combination with trastuzumab (Tras) in the US for previously treated RAS WT HER2+ metastatic colorectal cancer (mCRC), is a tyrosine kinase inhibitor highly selective for HER2. Preliminary safety and antitumor activity results of TUC + trastuzumab + FOLFOX in patients (pts) with HER2+ GI cancers are presented. Methods: The phase 1b/2 SGNTUC-024 (NCT04430738) study evaluated TUC + Tras + FOLFOX in pts with HER2+ metastatic GI cancers in Cohorts 1A, 1B, 1D (pts in Japan), and 2B. For Cohorts 1A, 1B, and 1D (enrolled sequentially), eligible pts had unresectable or metastatic HER2+ GI malignancies, including mCRC. Cohort 2B is still enrolling, and pts with HER2+ mCRC are eligible. Pts received a combination of TUC 150 mg orally twice a day (PO BID; Cohort 1A) or TUC 300 mg PO BID (Cohorts 1B, 1D, and 2B) + Tras + FOLFOX. Pts in Cohort 2B were enrolled to further assess the study regimen. Antidiarrheal prophylaxis was required for Cohort 1D. Results: As of July 10, 2023, 25 pts were treated (5, 11, 7, and 2 in Cohorts 1A, 1B, 1D, and 2B, respectively). In Cohort 1A (TUC 150 mg PO BID), the most common TEAEs were diarrhea, fatigue, nausea, and proteinuria (each in 60.0% [3/5]). For pts receiving TUC 300 mg PO BID, the most common TEAEs were diarrhea (90.0% [18/20]) and fatigue (65.0% [13/20]). Table 1 presents the overall summary of adverse events. In Cohort 1A, Treatment-emergent adverse events (TEAEs) leading to any treatment discontinuation were reported in 40.0% (2/5) pts, with 20.0% (1/5) discontinuing tucatinib. For pts treated with TUC 300 mg, TEAEs leading to treatment discontinuation were reported in 35.0% (7/20), with 15.0% (3/20) discontinuing tucatinib. One TEAE leading to death (aspiration) in Cohort 1A was unrelated to study treatment. Grade ≥3 diarrhea was observed in 45.5% (5/11) pts in Cohort 1B; most were observed in elderly pts or pts with gastric, gastroesophageal, or esophageal cancer or pts who were generally noncompliant with antidiarrheal treatment. No grade ≥3 diarrhea was observed in Cohort 1D. Among pts receiving TUC 300 mg, confirmed objective response rate was 83.3% (5/6) for mCRC, 40.0% (4/10) for gastroesophageal cancers, and 0% (0/4) for biliary tract cancer. Conclusions: TUC + Tras + FOLFOX showed manageable safety in the enrolled pt population and preliminary antitumor activity in pts with HER2+ mCRC and gastroesophageal cancer. This regimen will be compared with the standard of care (FOLFOX with or without bevacizumab/cetuximab) in the ongoing randomized, phase 3 study (MOUNTAINEER-03; NCT05253651) for pts with HER2+ RAS WT mCRC. Clinical trial information: NCT04430738 . [Table: see text]

Transitioning insomnia patients from zolpidem to lemborexant: A multicenter, open-label study evaluating a next-dose transition approach to insomnia pharmacotherapy

ObjectiveFew clinical studies have assessed real-world abrupt transitioning between insomnia medications. This study assessed strategies for directly transitioning patients from zolpidem tartrate (ZOL) immediate/extended release to the dual orexin receptor antagonist, lemborexant (LEM). MethodsThis randomized, open-label, multicenter study (Study 312; E2006-A001-312) enrolled 53 adults age ≥18 years with insomnia disorder and ≥1-month history of intermittent (3–4 nights/week) or frequent (≥5 nights/week) ZOL use. Subjects recorded their ZOL use in a 3-week Pretreatment Phase, followed by a 2-week Treatment Phase (TRT; Titration) during which ZOL was discontinued. Intermittent ZOL users transitioned to LEM 5 mg (LEM5), Cohort 1, and frequent ZOL users were randomized 1:1 to LEM5, Cohort 2A, or LEM 10 mg (LEM10), Cohort 2B. One dose adjustment was permitted during the TRT. Subjects completing the TRT could continue LEM in the 12-week Extension Phase (EXT). The primary outcome was proportion of subjects who successfully transitioned and remained on LEM at the end of the TRT. ResultsMost subjects (43 [81.1 %]) successfully transitioned to LEM (9 [90 %], 17 [81.0 %], and 17 [77.3 %] in Cohorts 1, 2A, and 2B, respectively). By the end of the EXT, 66.7 % in Cohort 1 and 60.0 % in Cohort 2A up-titrated to LEM10, whereas 41.2 % in Cohort 2B down-titrated to LEM5; 61.0 % were receiving LEM10 at study end. At the end of the TRT, more subjects taking LEM reported that it helped them return to sleep after waking, compared with those taking ZOL (71.7 % vs. 49.1 %). There were no important differences between treatments regarding how subjects reported feeling as they fell asleep. Most of the treatment-emergent adverse events with LEM were mild in severity. ConclusionsMost subjects transitioned successfully to LEM from ZOL (intermittent or frequent use). LEM was well tolerated.

Predictive Biomarkers of Response to Luspatercept in Patients with Myelofibrosis- (MF) Associated Anemia: Biomarker Analysis from the ACE-536-MF-001 Study

Introduction: MF is a clonal myeloproliferative neoplasm that results in fibrosis of the bone marrow and impaired hematopoiesis. Among other clinical manifestations, ineffective erythropoiesis leads to anemia resulting in poor quality of life and reduced overall survival (Passamonti et al., Blood 2010). Current treatment options for MF-associated anemia with most agents lack optimal efficacy and durability of response (Cervantes et al., Expert Rev Hematol., 2016). Luspatercept is a transforming growth factor-β (TBF-β) family ligand trap that inhibits the TGF-β-Smad signaling axis and promotes late-stage erythropoiesis. Luspatercept is approved in low-risk MDS with ring sideroblasts and β-thalassemia requiring red blood cell (RBC) transfusion. The ACE-536-MF-001 study investigates the safety and efficacy of luspatercept in the treatment of MF-related anemia. Here, through mutational and cytokine analysis of ACE-536-MF-001 biomarker samples, we sought to identify mutational and cytokine profiles associated with response. Methods: Eligible patients were divided into 4 cohorts based on transfusion dependence (TD) and treatment with ruxolitinib (RUX). Cohorts 1 and 3A were non transfusion dependent (NTD) while cohorts 2 and 3B were TD patients receiving 4-12 RBC units/84 days up to C1D1. Cohorts 3A and 3B received a stable dose of RUX. All patients received 1.0 mg/kg of luspatercept (1.33 mg/kg for cohort 3B) with titration up to 1.75 mg/kg once every 21 days. Primary endpoint was anemia response (defined as an increase of ≥ 1.5 g/dL hemoglobin (Hgb) from baseline for cohorts 1/3A or RBC transfusion free for ≥ 12 consecutive weeks for cohorts 2/3B). Secondary endpoint was mean Hgb increase ≥ 1.5 g/dL from baseline for ≥ 12 consecutive weeks for cohorts 1/3A, or ≥ 50% decrease in RBC transfusions from baseline for ≥ 12 consecutive weeks and duration of RBC transfusion-free period for cohorts 2 and 3B. Mutational analysis was performed in DNA from peripheral blood mononuclear cells using a panel targeting 74 genes. Rules-Based Medicine's Human Inflammation panel was used to measure changes in 54 serum cytokines. Nexelis custom panel was used for detection of GDF8, GDF15, erythroferrone, soluble transferrin receptor 1 (sTfR1) and hepcidin. Changes in soluble factors from cycle 1 to end of week 24 (day 169) were examined for correlation with clinical response. Results: All 4 cohorts (N = 95) displayed improvement in anemia and TD patients receiving RUX had the greatest benefit (Gerds et al. EHA 2023 S167). In the biomarker cohort (n = 63 across all 4 cohorts), mutational analysis revealed that most patients carried the JAK2 V617F mutation, and patients with SF3B1 or SF3B1 with co-occurring DTA mutations ( DNMT3A, TET2 or ASXL1) had a favorable prognosis related to anemia response (p= 0.0260, 0.0495; OR= 3.54, 3.86). In addition, JAK2 V617F patients in cohort 3B showed clinical benefit with luspatercept (OR= 6.75, p= 0.0445). Across cohorts and endpoints, the general trend of responders was low baseline (2-3-fold lower relative to nonresponders) levels of key inflammatory cytokines. Low levels of IL-10 (TD patients) and VCAM-1, TNFR2, CRP and IL-18 (NTD patients) were significant ( P &amp;lt; 0.01) predictors of response. Paired analysis between cycle 1 and week 24 revealed increases in alpha-2-macroglobulin, haptoglobin, TIMP1, and decrease in C3, vitamin D-binding protein, hepcidin and sTfR1 associated with anemia response. When transfusion burden reduction was used as a response criterion, ferritin, hepcidin, thrombopoietin, von Willebrand Factor, sTfR1, and beta-2-microglobulin were significantly ( P &amp;lt; 0.05) associated with response (Figure). In addition, Hgb increase was associated with increased TGF-β1 and VEGF levels and decreased GDF-15 and ERFE. These cytokines are implicated in iron metabolism (ferritin, hepcidin, alpha-2-macroglobulin), Hgb catabolism (haptoglobin), anemia (vitamin D-binding protein, C3), and luspatercept-target engagement (hepcidin, sTfR1). Conclusions: Our analysis identifies unique predictors of response to luspatercept treatment in patients with MF. While the data describe our findings across cohorts, cohort 3B (TD, receiving RUX), which had the highest response rate, also had higher levels of RANTES and TPO at baseline in responders. The ongoing phase 3 study, INDEPENDENCE (NCT04717414), would validate these observations in a larger cohort of patients

Phase 1/2 Multicenter, Open-Label Study of CTX-712 in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Background and Significance Dysregulation of alternative splicing, caused by abnormal expression or mutation of splicing factors, has been identified as an important contributor to the genesis and progression of cancer, and suggested as a novel target for anticancer treatment. CDC2-like kinases (CLK) represent a family of dual-specificity tyrosine and serine-threonine kinases that are involved in the regulation of splicing by phosphorylation of serine/arginine-rich splicing factors (SRSFs) which play a central role in exon recognition. CTX-712 is an orally available, potent, selective, and a first-in-class pan-CLK inhibitor (CLK 1-4), that inhibits phosphorylation of SRSFs resulting in significant antitumor activity in vitro and multiple xenograft models in vivo. CTX-712 formulated in capsules is currently being evaluated in an ongoing first-in-man study in Japan, evaluating tolerability and early efficacy in patients with solid tumors or hematologic malignancies (JapicCTI-184188). Preliminary data from the Japanese study were presented during ASCO 2022 and ASH 2022, and showed an acceptable safety profile (doses up to 175 mg (MTD 140 mg) twice a week in 28-day cycles, observed DLTs included dehydration, decreased platelets, hypokalemia, and pneumonia) with early signs of clinical antitumor activity (2 partial responses / 26 treated solid tumor patients, 5 complete remissions and complete remission with incomplete hematologic recovery/ 8 treated patients with AML or MDS), warranting further clinical investigations.. (J Clin Oncol (2022) 40(16_suppl):3080. Blood (2022) 140(Supplement 1):6211-2.). This abstract details a second study with CTX-712 that has just been initiated. Study Design and Methods A new film-coated tablet formulation will be evaluated in this phase 1/2 multicenter, open-label study of CTX-712 in patients with (mutated or wild type spliceosomes genes) relapsed/refractory AML, higher risk MDS (IPSS-R intermediate, high, or very high), or high marrow blast (≥5 %) MDS/MPN (including CMML). The phase 1 part of the study will be conducted at 4 US sites, and all sites are currently open for enrolment. The study allows patients with performance status 0, 1, or 2, adequate organ function, and up to four prior lines of therapy. Due to potential risk of interactions (in vitro studies suggest CYP3A4 as main metabolic pathway for CTX-712), concomitant use of strong CYP3A4 inhibitors is prohibited. Use of azole antifungals that are not strong CYP3A4 inhibitors (e.g., isavuconazole) is permitted. The phase 1 part of the study consists of dose-escalation (sequential standard 3 + 3 design), where cohorts of 3 (or 6) patients will receive ascending doses of CTX-712 once weekly in a 28-day cycle with continuous monitoring of emerging clinical PK, PD, safety, and efficacy data, to determine the recommended phase 2 dose (RP2D) based on the suggestion by the Safety Review Committee (SRC). The protocol defines five different dose levels (20-140 mg, once weekly) but also authorizes the SRC to suggest up to two interim dose levels or alternate schedules (e.g., dosing two times a week) if supported by emerging data. The suggested RP2D will be used in a confirmatory phase 1 expansion cohort where an additional 10 patients (total n = 16; 8 patients with AML and 8 patients with MDS) will be treated to gain further confidence in the selected dose level. The phase 2 part of the study will commence after the RP2D has been identified and confirmed and aims at evaluating therapeutic activity in R/R AML (Cohort 2a) or R/R HR-MDS (Cohort 2b), in addition to confirmation of the safety profile. Clinical trial registry number: NCT05732103

Tailor: Interventional Study Evaluating Physician's Choice of Ibrutinib Monotherapy or Ibrutinib-Venetoclax Combination Using Dose Modifications and Alternate Dosing Approaches in Patients with Untreated Chronic Lymphocytic Leukemia

Background: Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor (BTKi) that has changed the treatment paradigm for patients with chronic lymphocytic leukemia (CLL) with durable responses and improved overall survival (OS). In the pivotal Phase 3 GLOW and Phase 2 CAPTIVATE trials, fixed-duration combination of ibrutinib-venetoclax (I+V) resulted in deep and sustained clinical responses, and a broadly manageable safety profile in patients with CLL. Several factors including genetic features, disease status, comorbidities, patient preferences, and safety profiles contribute to selection of the optimal therapeutic option for patients with CLL in the first-line setting. Adverse events (AEs), such as atrial fibrillation, bleeding, and hypertension, have been seen with the BTKi therapeutic class.Long-term clinical and real-world experience with ibrutinib has led to specific guidance regarding AE management, which has been included in the updated ibrutinib prescribing information (US PI, May 2022; EU SmPC, April 2023). Retrospective evidence, including post-hoc analyses of clinical trial data, demonstrates that dose reduction of ibrutinib mitigates recurrence or worsening of AEs while preserving efficacy. Thus, these findings together support the rationale to prospectively evaluate the impact of regimen and dosing flexibility of ibrutinib in patients with untreated CLL. Aim: The key objective of the TAILOR study (NCT05963074) is to assess the efficacy and safety of I+V and ibrutinib monotherapy regimens with both a proactive and reactive dose adjustment in patients with untreated CLL. Methods: TAILOR is a phase 2, two-arm, four-cohort interventional study designed to provide physicians the choice of ibrutinib monotherapy or I+V combination therapy for previously untreated patients with CLL and prospectively evaluate proactive and reactive dose adjustment approaches. Eligible patients will have previously untreated active CLL, needing therapy as per iwCLL 2018 criteria. Key exclusion criteria include significant active or history of cardiovascular disease, uncontrolled hypertension, and ECOG performance status &amp;gt; 2. Patients will be randomized after selection of regimen: I+V fixed-duration regimen (2 cohorts, 80 patients in each cohort) or ibrutinib monotherapy (2 cohorts, 80 patients in each cohort), as per physician's choice. Patients in the I+V arm will receive ibrutinib 420 mg QD as lead-in for 3 cycles plus 12 cycles of either ibrutinib 420 mg QD (Cohort 1a) or 280 mg QD (Cohort 1b) in combination with venetoclax, which will be initiated in cycle 4 with dose ramp-up per label over 5 weeks (20, 50, 100, 200, and 400 mg/day) and continued at 400 mg/day dose from cycle 5 onward. In addition, patients with deletion 17p and/or mutated TP53 will receive optional ibrutinib maintenance. Patients in the ibrutinib monotherapy arm will receive ibrutinib 420 mg QD (Cohort 2a) or 420 mg QD for 3 cycles, then 280 mg QD (Cohort 2b) until progressive disease or unacceptable toxicity ( Figure). All cohorts will follow the dose modification guidance as per protocol based on the US PI/ EU SmPC. The primary endpoint is best overall response rate as assessed by investigators and compared with historic controls. Secondary endpoints include: complete response rate, duration of response, PFS, and OS; undetectable minimal residual disease rate (I+V cohorts only); safety (AEs, discontinuation due to AEs, adherence rates); and patient reported outcomes. The study is currently recruiting patients.

A Prospective Ukrainian Multicentre Cohort Study of Pet Value Prognostic Role in Primary Patients with Hodgkin Lymphoma (HL): Six-Year a Brief Review

Introduction : The PET-adapted approach for the treatment of patients with Hodgkin's lymphoma has long been used around the world. In Ukraine, this method has recently become actively used at all stages of treatment, which allows it to meet modern standards. Airms. The primary endpoint was to assess the effectiveness of individualized approaches as a correlation between PET findings and response to therapy, type of regimen and clinical outcome (Event free (EFS) and overall survival (OS)). The second endpoint was to evaluate the impact of risk factors on the survival. Methods. Of 278 evaluable patients, 64% were female; median age 43 years (range, 17-69 years). Patients received a treatment with ABVD or ABVD/AVD (more than 50% pts); BEACOPP-14/esc or “switched-regimens” (ABVD+BEACOPP-esc/14, BEACOPP-esc/14+ABVD). Metabolic PET imaging was performed to routine protocols using Deauville criteria for response assessment. Results. Bulky disease (&amp;gt;10 cm in any dimension) were presented in 74/278 (26.6%) of pts, B symptoms - in 126/278 (45.3%) and extranodal disease had 57/278 (20.5%). 93.8% of patients achieved remission (CR/PR) during the follow-up period (median timeline: 27 months). The ORR for patients with stage I-II was 87.2% (137/157) vs 80.1% (97/121) for patients with stage III-IV. We recorded a disease progression in 44 (15.8%) patients during and after the 1st line therapy, (median time to relapse - 8 months). Only 6 pts died due to HL. In the study group, PET was performed at the beginning of treatment in 150 pts, interim in 248 and at the end of treatment in 190 pts. We found a trend in improved outcome after treatment in patients with at least two follow-up PETs (interim and EOT), indicating the effectiveness of individualized PET-adapted therapy. Interim PET-CT was assessed as DS 1-2 in 127 patients (48.4%), DS 3 in 88 (33.6%), DS 4-5 in 47 pts (17.9%). In total, the disease progression occurred in 48.3% (15/31) of interim PET-positive (PET2+) patients and 11.5% (20/174) of interim PET-negative (PET2-) patients (p&amp;lt;0.05). After 6 year of follow-up EFS decreased in patients with PET2+ by 10% than the previously reported (PET2- pts 85% and vs 44% PET2+ pts, p=0.0001). Perhaps, despite the achievement of a partial metabolic response (DS-4), patients in this group still require intensification of treatment. Intermediate-risk group cohort (2B stage) to improve the EFS levels when the regimens was given BEACOPP-esc/14+ABVD vs ABVD+BEACOPP-esc/14 vs ABVD (80% vs 60% vs 55% respectively, p=0.03) and was independent of PET2 status. Also, a more intensified treatment for patients with stage III-IV of HL showed a significantly better level of EFS compared to the ABVD regimen, and it did not depend on PET2 status (Log-rank test, p=0.0003). OS is the most patient-relevant outcome in oncology; large sample sizes and extended follow-up durations are needed to detect statistically significant differences in OS. After a median follow up of 70 months, the study met its primary endpoint in the PET-2 negative cohort, with 6-year OS of 97% versus 60% (p=0.004). Interestingly, we did not find any correlation between EFS between risk groups 2B+bulky vs 2B without bulky (p=0.9) and also 2A+ (vs) - bulky (p=0.2). But we confirmed OS higher in pts with stage 2A vs 2B (98% vs 75%, respectively, p=0.03). Conclusions . The results of the use of PET in patients with primary HL showed a high predictive value of PET, which affects event-free and overall survival.

Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemias: Efficacy and Safety Results from the Augment-101 Phase 1/2 Study

Background: Revumenib (SNDX-5613), a potent, selective small-molecule inhibitor of the menin-histone-lysine N-methyltransferase 2A (KMT2A) interaction, is being investigated in patients (pts) with relapsed/refractory (R/R) KMT2A-rearranged ( KMT2Ar) and nucleophosmin 1-mutated ( NPM1m) acute leukemias. An initial analysis of the phase 1 of AUGMENT-101 (NCT04065399) has been reported ( Nature. 2023;615:920-924). Here we report an update of &amp;gt;1 year additional experience in the phase 1 portion of the study, which has completed enrollment, with safety data from 131 treated pts and efficacy data in 80 pts with R/R KMT2Ar leukemia. Demographic data from pivotal phase 2 cohorts are included; safety and efficacy data of a preplannedanalysis will be reported at the meeting. Methods: In phase 1, pts aged ≥30 days with R/R acute leukemias were assigned to 1 of 6 dose-escalation arms designed to identify a recommended phase 2 dose (RP2D) for concomitant administration of weak, moderate, or strong cytochrome P450 3A4 inhibitor (CYP3A4i) azole antifungal or no CYP3A4i. Pts received revumenib every 12 hours (q12h) or 3 times a day at a flat dose (≥40 kg) or a body surface area-based dose (&amp;lt;40 kg). Safety was assessed in all pts who received ≥1 dose of revumenib; responses are reported for all treated pts with KMT2Ar. In pts who underwent hematopoietic stem cell transplant (HSCT), responses reported are those achieved before HSCT. The Phase 2 study was initiated following identification of an RP2D of 163 mg (95 mg/m 2 if &amp;lt;40 kg) q12h with a strong CYP3A4i in 28-day cycles until unacceptable toxicity, lack of at least morphological leukemia-free state (MLFS) by end of cycle 4, or progressive disease without clinical benefit as defined by the investigator. The phase 2 primary objectives are evaluation of safety and tolerability of revumenib and assessment of the complete remission (CR) + CR with partial hematologic recovery (CRh) rate. The safety and efficacy of revumenib at an RP2D is being explored in 3 expansion cohorts: Cohort 2A, KMT2Ar acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia; Cohort 2B, KMT2Ar acute myeloid leukemia (AML); and Cohort 2C, NPM1m AML. A preplanned pooled analysis of adult and pediatric pts with KMT2Ar acute leukemia will be conducted when a subset of Cohorts 2A+2B pts have completed a minimum of 4 cycles or have discontinued therapy. Results: Phase 1: As of June 19, 2023, 80 pts with R/R KMT2Ar acute leukemia were treated with revumenib in the 6 dose-escalation arms (Table 1). In adults with AML (n=51), the largest KMT2Ar subgroup, CR+CRh was 28% and overall response rate (ORR) was 59%. Responses were consistent in ALL/other leukemia subtype (n=15), with 27% CR+CRh and 53% ORR. ORR (61%) was similar in pediatric pts (&amp;lt;18 years, n=18), with 22% proceeding to HSCT. Although similar percentages of adult and children proceeded to transplant, consistent with common clinical practice in pediatrics, 75% of children transplanted went on to HSCT prior to achieving a CR/CRh (2 MLFS, 1 CRp) versus 17% of adults. In the safety population (n=131), 24% of pts had a ≥Grade 3 treatment-related adverse event (TRAE), with Grade 3 QTc prolongation in 8% and differentiation syndrome in 2% (Table 1). QTc prolongation remained as the only dose-limiting toxicity; no patients experienced ventricular arrhythmias. In addition, based on updated phase 1 pharmacokinetics, clinical activity, and safety data, an RP2D of 276 mg q12h without a strong CYP3A4i was established. Phase 2: In a preliminary analysis of Cohorts 2A and 2B (June 19, 2023), 88 pts with KMT2Ar acute leukemia were enrolled and treated with revumenib at an RP2D (Table 2). Ages ranged from 1.3 to 75 years (22 aged &amp;lt;18 y; Table 2). Leukemia subtypes included ALL (15%), AML (81%), and other (3%). Pts were heavily pretreated, having received a median of 3 prior lines of therapy (range 1-12); 38% received ≥4 prior lines and 48% had prior HSCT. Conclusions: These phase 1 data continue to demonstrate deep responses to revumenib and a manageable safety profile in heavily pretreated patients with R/R KMT2Ar acute leukemia across ages and subtypes. The lack of targeted therapies approved for KMT2Ar leukemia indicate the need for further investigation of novel, potentially transformative therapies such as revumenib. Enrollment in the AUGMENT-101 trial is ongoing. Pivotal Phase 2 safety and efficacy data for the KMT2Ar population will be reported at the meeting.

Longitudinal Safety of Luspatercept in the Treatment of Anemia in Patients with Myelofibrosis: Results from the ACE-536-MF-001 Study

Introduction Luspatercept (LUSPA) is approved for the treatment of anemia in some adults with β-thalassemia or myelodysplastic syndrome who require red blood cell transfusion and has a well characterized safety profile for these indications. The primary readout from the phase 2 ACE-536-MF-001 study (NCT03194542) demonstrated manageable safety and promising efficacy of LUSPA for treatment of myelofibrosis (MF)-related anemia with 19.0%-31.6% of patients (pts) achieving transfusion independence (defined as 84 consecutive days transfusion free), and 18.2%-21.4% of non-transfusion-dependent (NTD) pts achieving anemia response (defined as 84 consecutive days ≥ 1.5 g/dL hemoglobin increase from baseline without transfusion) in the entire treatment period (Gerds ASCO 2023 7016). To characterize further the safety profile of LUSPA in MF and provide data on adverse event (AE) management, we present a detailed longitudinal safety analysis of the MF-001 study. Methods Pts were enrolled into 4 cohorts based on transfusion dependence (TD) and stable ruxolitinib (RUX) treatment - cohort 1: NTD, no RUX; cohort 2: TD, no RUX; cohort 3A: NTD, RUX; cohort 3B: TD, RUX. All pts received LUSPA 1.0 mg/kg subcutaneously with titration up to 1.75 mg/kg in 21-day cycles; the starting dose was 1.33 mg/kg in the cohort 3B expansion group. Response was assessed at day 169 (24 weeks), with treatment extended for pts showing clinical benefit. The primary endpoint was anemia response; AEs alongside LUSPA and RUX dosing were also assessed. On dosing days, seated blood pressure was assessed prior to LUSPA administration. In the case of ≥ grade 3 hypertension (systolic ≥ 160 mmHg, diastolic ≥ 100 mmHg), dosing was delayed until hypertension had resolved to ≤ grade 1 or baseline, followed by dose reduction by 1 dose level. If ≥ 2 dose reductions were implemented due to any suspected treatment-related AE (TRAE), LUSPA was discontinued. Results In the safety population (N = 95; cohort 1, n = 22; cohort 2, n = 14; cohort 3A, n = 21; cohort 3B, n = 38), the most frequently used prior medications for anemia treatment were erythropoiesis-stimulating agents (23.2%, most frequently epoetin alfa [14.7%]), followed by danazol (11.6%), lenalidomide (2.1%), and thalidomide (1.1%). Prior history of hypertension was recorded in 50.5% of pts. Median follow-up duration was 546 days. A total of 47.4% of pts had ≥ 1 TRAE; the most common were hypertension (17.9%), bone pain (7.4%), and diarrhea (6.3%). Incidence of treatment-related grade ≥ 3 diarrhea was low (2.1%). Overall, 13.7% of pts received concomitant antidiarrheals. LUSPA was discontinued in 9 pts due to AEs; 1 event of cerebral toxoplasmosis was considered treatment related by the investigator. Among pts receiving RUX (cohorts 3A/3B), hypertension was the most frequently occurring grade ≥ 3 TRAE ( Table 1) and 5 pts had LUSPA dose modifications related to hypertension events; considered related to LUSPA in 4 pts ( Table 2). In contrast, among pts not receiving RUX (cohorts 1/2), no pts experienced grade ≥ 3 hypertension events. Hypertension was manageable with clinical intervention; during the study the most frequent concomitant medications for hypertension were angiotensin-converting enzyme inhibitors (26.3%), beta-blocking agents (selective, 23.2%; non-selective, 3.2%), and angiotensin II receptor blockers (alone, 20.0%; plus diuretics, 5.3%). Among NTD pts (cohort 3A), there were no changes in RUX dose. Among TD pts (cohort 3B), 25 (65.8%) pts maintained their RUX dose and 6 (15.8%) pts had ≥ 1 dose increase. Overall, 9 deaths occurred during treatment; none were considered treatment related. Causes of death were pneumonia, septic shock, intracranial hemorrhage, ischemic stroke, organ dysfunction, post-procedural hemorrhage, myelofibrosis, renal failure, and pneumonitis (n = 1 each). Conclusions The safety profile of LUSPA in the ACE-536-MF-001 study was consistent with previous studies in other indications, and AEs were mostly low grade. In addition to benefits in anemia, the safety profile of LUSPA allowed most pts receiving RUX to maintain or increase their RUX dose, supporting maintenance of Janus kinase inhibitor therapy for adequate disease control of MF. Study support: Bristol Myers Squibb.

Clinical Parameters, Anemia, and Spleen Response in Patients with MF-Related Anemia Treated with Luspatercept: Efficacy Sub-Analysis from the ACE-536-MF-001 Study

Introduction: Approximately 24% of patients with myelofibrosis (MF) have anemia requiring red blood cell (RBC) transfusion at initial diagnosis. For patients with MF, chronic anemia and RBC transfusion dependence (TD) often increase throughout the disease course and are an indicator of poor prognosis. Luspatercept (LUSPA) is an erythroid maturation agent approved to treat anemia in adults with β-thalassemia and myelodysplastic syndrome requiring RBC transfusions. Primary results from the phase 2 ACE-536-MF-001 study (NCT03194542) demonstrated reductions in MF-related anemia and transfusion dependence (Gerds et al. ASCO 2023 7016). Here we provide an extended analysis of the impact of LUSPA on clinical parameters and transfusion burden over time, and associated management of MF disease symptoms. Methods: Patients were enrolled into cohorts based on TD and ruxolitinib (RUX) treatment. Patients received LUSPA 1.0 mg/kg subcutaneously (with titration up to 1.75 mg/kg), administered on day 1 of each 21-day cycle (starting dose was 1.33 mg/kg for cohort 3B expansion). Patients were defined as TD if receiving an average of 4-12 RBC units/84 days immediately up to cycle 1 day 1 (C1D1). For non-transfusion dependent (NTD) patients, anemia was defined as 3 or more hemoglobin (Hgb) level measurements of ≤ 9.5 g/dL recorded on at least 3 different days in the 84-day period immediately preceding C1D1. The primary endpoint was anemia response, assessed at day 169 (week 24) and defined as 84 consecutive days without RBC transfusion for TD patients, and 84 consecutive days with Hgb increase of ≥ 1.5 g/dL from baseline without transfusion for NTD patients. Treatment was extended if clinical benefit was observed at day 169. Secondary and exploratory endpoints included anemia response for the entire treatment period, transfusion burden, and clinical and laboratory parameters. Results: A total of 95 patients were enrolled: cohort 1 (NTD, no RUX, n = 22), cohort 2 (TD, no RUX, n = 21), cohort 3A (NTD, RUX, n = 14), and cohort 3B (TD, RUX, n = 38). A total of 63 (66.3%) patients continued to the follow-up period. The mean (SD)/median (range) duration of treatment was 42.8 (47.6)/24.0 (2.0-232.0) weeks and mean/median (range) follow-up duration after first dose was 101.1/78.0 (2.1-232.1) weeks. Anemia response was seen across all cohorts. Among transfusion-dependent patients (cohorts 2 and 3B), transfusion independence ≥ 12 weeks was observed in 4 (19.0%, 95% CI 5.45-41.91) and 12 (31.6%, 95% CI 17.5-48.7) patients, respectively, in the entire treatment period. Additionally, approximately half of patients with TD achieved a 50% reduction in transfusion burden; 10 (47.6%) patients in cohort 2 and 20 (52.6%) patients in cohort 3B had ≥ 50% reduction in transfusion burden over any 84-day period in the entire treatment period, including 16 patients from cohorts 2 and 3B who achieved transfusion independence (100% reduction) (Figure). Changes in laboratory parameters of Hgb, serum erythropoietin, serum ferritin, and platelet count at day 169 are summarized in the Table; in addition, patients with clinical benefit continuing LUSPA treatment after day 169 showed ferritin decreases with longer follow-up from cycle 13 (n = 20) to cycle 33 (n = 6). Additionally, there was minimal (~1 cm) to no increase in median spleen size across patients in all cohorts. Of the 3 patients in cohort 3B who increased their RUX dose during LUSPA treatment, spleen size remained stable, with a -4.0 cm, 1.0 cm, and 3.0 cm change from baseline during the entire treatment period, respectively. Conclusions: In the phase 2 ACE-536-MF-001 study, LUSPA demonstrated improvements in anemia and transfusion burden in patients with MF. Further analysis of clinical and laboratory parameters may reveal differences between responders and non-responders. Spleen size stability was observed in all patients; this suggests that LUSPA does not worsen splenomegaly and may support continual use of RUX for MF disease and symptoms. Study support: Bristol Myers Squibb.

TIPS-22 A TWO-PART, PHASE 1 STUDY OF RHENIUM (186RE) OBISBEMEDA (186RNL) DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) FOR RECURRENT, REFRACTORY, OR PROGRESSIVE CHILDHOOD EPENDYMOMA AND HIGH-GRADE GLIOMA (HGG)

Abstract INTRODUCTION: Childhood ependymoma and HGG are difficult tumors to treat. Recurrent ependymoma is treated with re-resection and multiple rounds of EBRT. HGG is treated with chemoradiation followed by clinical trials, if available. While EBRT remains a central component of management, it is limited by tolerance of the surrounding normal brain tissue. 186RNL permits the selective delivery of beta-emitting radiation with excellent tumor retention. In an adult Phase 1/2 trial for recurrent glioblastoma (NCT01906385), the mean absorbed dose to the tumor was ~300-500 Gy, markedly higher than absorbed doses typically delivered by EBRT. Despite this, no dose-limiting toxicity was observed, and no treatment-related serious adverse events have occurred. Here, we describe the first pediatric trial using a two-part, Phase 1 dose-finding study followed by expansion cohorts to explore efficacy. Enrolling subjects will be 6 to 21 years of age with a diagnosis of recurrent ependymoma or HGG. Subjects will be allowed to enroll either if they have exhausted standard of care options or if they are clinically stable and surgical resection can be deferred by 4 weeks. Part 1 will enroll up to 24 subjects to determine the maximum feasible dose (MFD) of 186RNL administered by CED. Tumor size and concentration of infusate will be escalated in each cohort (A-D) to a maximum tumor diameter of 6 cm (114.1 mL) and a concentration of 2mCi/ml. Up to 4 CED catheters will be used. Part 2 will independently evaluate 186RNL in 2 different expansion cohorts: Cohort 2A: recurrent ependymoma; Cohort B: recurrent HGG. The primary endpoint for Cohort 2A is overall response rate (ORR) by Radiographic Assessment in Pediatric Neuro-Oncology (RAPNO) criteria and the primary endpoint for Cohort 2B is progression free survival. Planned enrollment will begin in early 2023.

Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis: Results from the ACE-536-MF-001 study.

7016 Background: Many patients (pts) with myelofibrosis (MF) experience anemia resulting from disease or JAK inhibitor therapy. The open-label, phase 2 ACE-536-MF-001 study (NCT03194542) evaluated the safety and efficacy of luspatercept (LUSPA) for the treatment of MF-related anemia. Methods: Eligible pts comprised 4 cohorts based on transfusion dependence (TD, defined as receiving 4–12 red blood cell [RBC] units/84 days [d] immediately up to cycle 1 d 1) and stable ruxolitinib (RUX) treatment; cohort 1: no TD, no RUX; cohort 2: TD, no RUX; cohort 3A: no TD, RUX; cohort 3B: TD, RUX. Pts received subcutaneous LUSPA 1.0 mg/kg (1.33 mg/kg for pts in cohort 3B expansion) with titration up to 1.75 mg/kg in 21-d cycles. Disease response was assessed at d 169 and treatment extended for pts showing clinical benefit; pts were followed for ≥ 3 years (y) post last dose. The primary endpoint was anemia response (defined as 84 consecutive d: ≥ 1.5 g/dL hemoglobin [Hgb] from baseline without transfusion [cohorts 1 and 3A] or RBC transfusion-free [cohorts 2 and 3B]); secondary endpoints included duration of response (DOR), transfusion frequency, change in Hgb level, and symptom response. Results: Of 95 pts in the ITT group, the most common reason for treatment discontinuation was lack of clinical benefit at d 169 (n = 28). Median (range) age was 71.0 (50–89) y. Most (54.7%) pts had primary MF, intermediate-risk 2 disease (75.8%), and &gt; 2 y since initial diagnosis (74.7%). Median prior RUX therapy was 18.1 months (cohorts 3A/3B) and 84.7% of pts had baseline transfusion burden 6–12 units/84 d (cohorts 2/3B). Mean treatment duration was 42.8 weeks. Cohort 3B had the highest anemia response rate with 26.3% (95% CI, 13.4–43.1) of pts transfusion independent during the primary treatment period and 31.6% (95% CI, 17.5–48.7) transfusion independent during the entire treatment period; median (range) DOR was 448 d (85–1582). In cohort 3B: 19 (50.0%) pts had reduced transfusion burden by ≥ 50% during the primary treatment period; 8 (21.1%) pts achieved mean Hgb increase ≥ 1.5 g/dL from baseline throughout the entire treatment period and 6 (15.8%) achieved a mean ≥ 50% reduction in symptom score from baseline. Overall, 47.4% of pts had ≥ 1 treatment-related adverse event (TRAE), most frequently hypertension (17.9%, 5.3% grade ≥ 3); 3.2% of pts had a serious TRAE. One TRAE led to LUSPA discontinuation. Two (2.1%) pts had transformation to acute myeloid leukemia. Nine pts died on treatment from: post-procedural hemorrhage, pneumonia, intracranial hemorrhage, septic shock, ischemic stroke, multiple organ dysfunction syndrome, renal failure, pneumonitis, and myelofibrosis (n = 1 each); no deaths were considered related to the study drug. Conclusions: In pts with MF, the safety profile of LUSPA was consistent with previous studies and efficacy results showed promising improvements in anemia and transfusion burden in all cohorts. Clinical trial information: NCT03194542 .

A phase II study of durvalumab re-treatment +/- prednisone in patients who discontinued prior checkpoint therapy due to immune related toxicity (CCTG IND.238A).

TPS2673 Background: Up to 18% of patients permanently discontinue immune checkpoint blockade (ICB) therapy following G3/G4 immune-related adverse events (irAEs) even if reversible / easily managed with replacement therapy or steroids. Safety concerns exist with ICB re-treatment. Given the potential benefit of ICB and evidence that patients with irAEs may exhibit greater efficacy, there is interest in ICB rechallenge following successful management of G3/G4 irAEs in patients who have had benefit, and trials to prospectively investigate ways to prevent irAE recurrence are needed. Durvalumab is a human monoclonal antibody of IgG1κ subclass that binds to PD-L1. Canadian Cancer Trials Group (CCTG) IND.238A is a phase 2, open label, multicentre study of durvalumab +/- prednisone rechallenge in patients who were benefitting from prior ICB but discontinued due to irAEs. Methods: Eligible patients have received prior anti-PD-(L)1 ICB alone or in combination with anti-CTLA-4 ICB, with or without chemotherapy/targeted therapy, and experienced either: 1) G3 or selected G4 irAEs (i.e. endocrinopathies manageable with replacement therapy; hematologic toxicity) that required drug discontinuation; 2) prolonged G2 irAEs where therapy was discontinued due to poor tolerability. Prior irAE must have resolved to ≤G1, patients must have completed steroid therapy and have documented RECIST 1.1 CR, PR, or prolonged SD (≥8 weeks) to initial ICB. Patients with prior (neo)adjuvant/consolidation ICB are eligible provided there has been ≥6-month treatment free interval before enrollment. Based on prior irAE, patients are allocated into either: 1) the High Risk cohort, receiving durvalumab (1500mg IV Q4W in all cohorts) + prednisone 0.5mg/kg/day for C1-2, or; 2) the Standard Risk cohort, where they are randomized to receive either durvalumab + prednisone 10mg/day for C1-2 (Cohort 2A) or durvalumab alone (Cohort 2B). Three to 6 patients are enrolled into each cohort initially, then each cohort expands up to a total of 60 evaluable patients (20 per cohort). Safety review takes place following enrollment of the 1st, 3rd, 6th and 10th patient in each cohort. Safety review occurs 4 weeks after the 1st patient treated on each cohort and subsequently once the last patient has been followed for at least 4 weeks. The primary endpoint is the incidence of treatment-related AEs (CTCAE v5.0), estimated as percentages of patients with each AE (90% exact CI will be calculated). Secondary objectives are ORR (RECIST 1.1 and iRECIST) and efficacy of corticosteroids in preventing recurrent or new ≥G2 irAEs (90% exact CI will be calculated). Exploratory endpoints include PFS / iPFS by Kaplan-Meier method, exploration of blood- and stool-based irAE biomarkers and PD-L1 expression. As of January 30, 2023, 12 of planned 60 patients have been enrolled. Clinical trial information: NCT03847649 .

Epcoritamab + R2 regimen and responses in high-risk follicular lymphoma, regardless of POD24 status.

7506 Background: Follicular lymphoma (FL) is a heterogeneous disease. Early progression after initial treatment (tx) with chemoimmunotherapy (CIT), POD24, occurs in around 20% of patients (pts) and strongly predicts poor outcomes. There is no standard tx approach for high-risk, relapsed or refractory (R/R) FL (high-risk subgroups in Table). Novel options are needed to improve efficacy in pts with high unmet need. Epcoritamab, a subcutaneous (SC) T-cell–engaging bispecific antibody, demonstrated impressive single-agent antitumor activity and a manageable safety profile in R/R FL (Hutchings et al, Lancet 2021) and shows promise combined with standards of care. Here we present pooled analyses from cohorts 2a and 2b of the ongoing phase 1/2 EPCORE NHL-2 trial (NCT04663347) of epcoritamab with rituximab + lenalidomide (R2). Methods: Pts with R/R CD20+ FL received epcoritamab SC + R2 for 12 cycles (Cs; 28 d each). Epcoritamab was dosed QW in C1–3, Q2W in C4–9, and Q4W in C≥10 (2a) or QW in C1–2 and Q4W in C≥3 (2b) for ≤2 y. Results: As of Oct 31, 2022, 109 R/R FL pts had received epcoritamab 48 mg + R2 in 2a and 2b. Median age was 65 y, 56% of pts had FLIPI 3–5, 61% had stage IV disease, and 59% had only 1 prior tx. Most had received alkylating agents (92%) or anthracyclines (62%); 2 had prior CAR T. At a median follow-up of 8.8 mo (range, 1.2–18.5), 82% were still on tx. The most common tx-emergent AEs were: CRS and neutropenia, 48% each; injection-site reactions, 38%; and fatigue, 33%. CRS events were mostly low grade (G; 46% G1–2, 2% G3) and mostly occurred following the first full dose on C1D15; all resolved and none led to discontinuation. ICANS occurred in 2 pts (G1, G2) and resolved. In 101 efficacy-evaluable pts, overall response rate (ORR) was 97%, with complete metabolic response (CMR) in 86%. Notably, pts achieved higher ORR/CMR rates with epcoritamab + R2 vs their immediate prior tx line (ORR, 97% vs 85%; CMR, 86% vs 60%). Estimated 6-mo progression-free survival was 93%. In second-line (2L) pts with POD24, ORR/CMR rates were 95%/90% (additional high-risk subgroup data in Table). Additional data with longer follow-up will be presented. Conclusions: Epcoritamab + R2 showed potent antitumor activity and a manageable safety profile in a large R/R FL population. Encouraging responses were seen in pts with high-risk disease, suggesting epcoritamab SC may abrogate negative effects of high-risk features. A separate POD24 cohort is planned, and epcoritamab + R2 is being studied in the phase 3 EPCORE FL-1 trial (NCT05409066). Clinical trial information: NCT04663347 . [Table: see text]

Cardiovascular outcomes with SGLT2 inhibitors versus DPP4 inhibitors and GLP-1 receptor agonists in patients with heart failure with reduced and preserved ejection fraction

BackgroundNo study has compared the cardiovascular outcomes for sodium–glucose cotransporter-2 inhibitors (SGLT2i) head-to-head against other glucose-lowering therapies, including dipeptidyl peptidase 4 inhibitor (DDP4i) or glucagon-like peptide-1 receptor agonist (GLP-1RA)—which also have cardiovascular benefits—in patients with heart failure with reduced (HFrEF) or preserved (HFpEF) ejection fraction.MethodsMedicare fee-for-service data (2013–2019) were used to create four pair-wise comparison cohorts of type 2 diabetes patients with: (1a) HFrEF initiating SGLT2i versus DPP4i; (1b) HFrEF initiating SGLT2i versus GLP-1RA; (2a) HFpEF initiating SGLT2i versus DPP4i; and (2b) HFpEF initiating SGLT2i versus GLP-1RA. The primary outcomes were (1) hospitalization for heart failure (HHF) and (2) myocardial infarction (MI) or stroke hospitalizations. Adjusted hazards ratios (HR) and 95% CIs were estimated using inverse probability of treatment weighting.ResultsAmong HFrEF patients, initiation of SGLT2i versus DPP4i (cohort 1a; n = 13,882) was associated with a lower risk of HHF (adjusted Hazard Ratio [HR (95% confidence interval)], 0.67 (0.63, 0.72) and MI or stroke (HR: 0.86 [0.75, 0.99]), and initiation of SGLT2i versus GLP-1RA (cohort 1b; n = 6951) was associated with lower risk of HHF (HR: 0.86 [0.79, 0.93]), but not MI or stroke (HR: 1.02 [0.85, 1.22]). Among HFpEF patients, initiation of SGLT2i versus DPP4i (cohort 2a; n = 17,493) was associated with lower risk of HHF (HR: 0.65 [0.61, 0.69]) but not MI or stroke (HR: 0.90 [0.79, 1.02]), and initiation of SGLT2i versus GLP-1RA (cohort 2b; n = 9053) was associated with lower risk of HHF (0.89 [0.83, 0.96]), but not MI or stroke (HR: 0.97 [0.83, 1.14]). Results were robust across range of secondary outcomes (e.g., all-cause mortality) and sensitivity analyses.ConclusionsBias from residual confounding cannot be ruled out. Use of SGLT2i was associated with reduced risk of HHF against DPP4i and GLP-1RA, reduced risk of MI or stroke against DPP4i within the HFrEF subgroup, and comparable risk of MI or stroke against GLP-1RA. Notably, the magnitude of cardiovascular benefit conferred by SGLT2i was similar among patients with HFrEF and HFpEF.