Treatment-related Treatment-emergent Adverse Events Research Articles

Abstract PO2-04-13: TWT-203: PHASE 1b/2 STUDY OF CFI-402257 AS MONOTHERAPY IN ADVANCED SOLID TUMORS AND IN COMBINATION WITH FULVESTRANT IN PATIENTS WITH ER+/HER2- ADVANCED BREAST CANCER AFTER PROGRESSION ON PRIOR CDK4/6 INHIBITORS AND ENDOCRINE THERAPY

Abstract Background: TTK (Threonine Tyrosine Kinase also known as Monopolar spindle 1), is a dual-specificity serine-threonine kinase critical for anaphase promoting complex inhibition at the spindle assembly checkpoint and is required for chromosome alignment and error correction. TTK inhibition results in premature mitosis exiting with unattached chromosomes potentially leading to aneuploidy and cell death. High TTK tumor levels correlate with worse prognosis and contribute to the survival and proliferation of aneuploid cells. CFI-402257, a potent and selective inhibitor of TTK, inhibits the growth of a variety of human cancer-derived cell lines. A first-in-human phase 1 study of CFI-402257 (NCT02792465) demonstrated a tolerable safety profile when enrolled as a monotherapy in solid tumors, and in combination with fulvestrant in hormone receptor positive, HER2 negative (HR+/HER2-) breast cancer1. The dose for expansion was 168 mg, dose limiting toxicity was dose-dependent neutropenia which was manageable and reversible. Investigator-confirmed partial responses (cPR) were observed in 5 pts (8%) with 32 (50.8%) exhibiting disease control. In the HR+/HER2- breast cancer population previously treated with cyclin dependent kinase 4/6 inhibitors (CDK4/6i) and aromatase inhibitors (N=25), there were 4 cPR’s with a median duration of response of 223 days, with responses emerging after 2 cycles of therapy. Responses were observed with CFI-402257 as a single agent and in combination with fulvestrant. Based on these data, study TWT-203 will focus on advanced solid tumors for dose confirmation then focus on advanced HR+/HER2- breast cancers in combination with an approved endocrine therapy. Methods: In TWT-203 study, safety and clinical activity of CFI-402257 monotherapy will be evaluated in patients (pts) with advanced solid tumors (Part A) or in combination with fulvestrant in pts with HR+/HER2- advanced breast cancer (Part B). Part A will confirm the RP2D using a 3+3 design with a starting dose of 126 mg daily. Part B evaluates CFI-402257 in combination with fulvestrant in pts with HR+/HER2- advanced breast cancer following progression on prior CDK4/6i and endocrine therapy. Efficacy endpoints include overall response rate and disease control rate. Safety endpoints include incidence of treatment emergent adverse events. Exploratory objectives include characterization of protein and molecular alterations relevant to the cell cycle and CFI-402257 response. Results: At data cutoff of 11 May 2023, 14 pts were enrolled. All received monotherapy treatment. Median treatment duration was 2.1 months (range, 0.2-7.3+). Median age was 67 years (57-76). Median number of prior regimens was 3.5 (2-12). Tumor types enrolled were colorectal (n=6, 43%), breast (3, 21%), and endometrial, hepatocellular, leiomyosarcoma, pancreatic, and sarcoma (1 each, 7%). 4 dose levels, from 126 to 252 mg, were studied. Most pts (12, 86%) experienced ≥1 treatment emergent adverse event (TEAE). More than half of pts (8, 57%) experienced ≥1 treatment related TEAE. Most common TEAEs were fatigue (5, 36%) and nausea (4, 29%). 5 pts (36%) experienced TEAEs grade ≥3, most common were fatigue, neutrophil count decrease, white blood cell count decrease (2 pts each, 14.3%). 1 pt (7%) experienced a serious adverse event (hematuria), not related to study therapy. No patients discontinued treatment due to TEAE. All pts who ended treatment were due to disease progression (8, 57%). No grade 5 TEAEs occurred. No dose limiting toxicities were reported. Disease control rate (CR, PR, or SD ≥ 6 weeks from baseline) was 54.5% (6 pts/11): all achieved SD. 3 of the 6 pts remain on study. Conclusion: CFI-402257 is a potent inhibitor of TTK. It is well tolerated with manageable TEAEs, no dose limiting or treatment limiting toxicities, and no treatment related deaths. Dose expansion in the patient population of interest will commence. 1. John Hilton et al. Cancer Res 2023;83(5 Suppl): P6-10-13. Citation Format: Justin Call, Muralidhar Beeram, Alexander I. Spira, Mark Bray, Dih-Yih Chen, Long Kwei, Emily Roberts-Thomson, Trisha Denny, Roger Sidhu, Robert Wesolowski. TWT-203: PHASE 1b/2 STUDY OF CFI-402257 AS MONOTHERAPY IN ADVANCED SOLID TUMORS AND IN COMBINATION WITH FULVESTRANT IN PATIENTS WITH ER+/HER2- ADVANCED BREAST CANCER AFTER PROGRESSION ON PRIOR CDK4/6 INHIBITORS AND ENDOCRINE THERAPY [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-13.

Abstract PS16-02: Efficacy and safety of first-line atezolizumab + bevacizumab + paclitaxel in patients with advanced triple-negative breast cancer: the ATRACTIB phase 2 trial

Abstract BACKGROUND Triple-negative breast cancer (TNBC) is an aggressive tumor characterized by poor outcomes and new treatment strategies are urgently required. The programmed cell death-ligand 1 (PD-L1) antibody (Ab) atezolizumab (ATZ) combined with first-line (1L) nab-paclitaxel (nab-PTX) is approved in multiple countries for the treatment of PD-L1-positive patients (pts) with advanced TNBC (aTNBC) based on a significant improvement in progression-free survival (PFS) and a numerically higher and clinically meaningful median overall survival (OS). A synergism between antiangiogenic therapy and immunotherapy (IO)-based strategies has been observed preclinically and in different tumor types, but data in aTNBC is lacking. METHODS ATRACTIB (NCT04408118) is an international, open-label, single-arm, phase 2 trial evaluating the efficacy and safety of 1L ATZ + BVZ + PTX for pts with aTNBC, regardless of their tumors’ PD-L1 status. Adult pts with untreated, unresectable locally advanced/metastatic TNBC were included. Pts who had received (neo)adjuvant taxane-based chemotherapy (CT) and/or IO and/or an antiangiogenic agent had to have had a relapse with a disease-free interval beyond 12 months (mo). Pts received intravenous ATZ 840 mg + BVZ 10 mg/kg on days (D)1 and D15 + PTX 90 mg/m2 on D1, 8, and 15 of every 28-day cycle until disease progression, intolerable toxicity, death, or patient withdrawal. Tumor assessments were performed every 8 weeks for the first 12 mo and every 12 weeks thereafter. Baseline PD-L1 expression was centrally assessed using 22C3 (combined positive score [CPS]) and SP142 (expression on tumor-infiltrating immune cells [ICs]) Abs. The primary endpoint was investigator-assessed PFS by RECIST v.1.1. Key secondary endpoints included OS, objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR), and safety. Median PFS was analyzed with exponential maximum likelihood estimation (H0: ≤7.0 mo; HA: ≥9.5 mo). We estimated that enrolling 100 pts would provide 80% power at one-sided α nominal level of 5%, assuming a 10% drop-out rate. RESULTS Between October 2020 and May 2022, 100 female pts from 28 centers across 5 European countries were included. Median age was 55.0 years (32.0 - 84.0), 57.0% of pts had visceral disease, 46.0% had ≥3 metastatic sites, and 70.0% had received prior treatment for early BC (taxane-based CT in 87.1% of them). A total of 82 and 85 tumor samples out of 100 pts were available for PD-L1 assessment using 22C3 and SP142 assays, respectively. Most pts had PD-L1-negative tumors (87.8% with 22C3 [CPS < 10] and 97.6% with SP142 [expression on < 1% positive of ICs]). At data cutoff (15th September 2023), 23 pts were still on therapy. With a median follow-up of 16.7 mo (1.1 - 34.1), median PFS was 11.0 mo (95% CI, 9.0 - 13.2). OS data were immature at data cutoff, with 30 events. Estimated 18-month OS was 69.4% (95% CI, 58.4% - 78.1%). ORR was 63.0% (95% CI, 52.8% - 72.4%), CBR was 79.0% (95% CI, 69.7% - 86.5%), and median DoR was 10.0 mo (95% CI, 7.2 - 13.8). Regarding safety, the most common treatment-emergent adverse events (TEAEs) were peripheral neuropathy (68.0%) and fatigue (62.0%). Grade (G) 3/4 treatment-related TEAEs occurred in 47.0% of pts, mainly peripheral neuropathy (13.0%) and neutropenia (12.0%). Any-grade immune-related TEAEs, thrombosis or embolism, and bleeding occurred in 13.0% (5.0%; G≥3), 4.0% (1.0%; G≥3), and 10.0% (0.0%; G≥3) of pts, respectively. There were no drug-related deaths. CONCLUSIONS 1L ATZ + BVZ + PTX demonstrated encouraging anti-tumor activity in aTNBC pts, most of them presenting with PD-L1-negative tumors. Median PFS seems to be much higher compared with that previously reported with other IO-based regimens in a similar patient population. The safety profile was consistent with the known safety data of ATZ and BVZ combined with CT, without significant added toxicity. These results merit further research of this combination for PD-L1-negative aTNBC. Citation Format: Maria Gion, Patricia Cortez-Castedo, Isabel Blancas, Alfonso Cortés, Frederik Marmé, Salvador Blanch, Serafin Morales Murillo, Nieves Díaz, Isabel Calvo-Plaza, Sabela Recalde, Alejandro Martínez-Bueno, Manuel Ruiz-Borrego, Elisenda Llabres, María Teresa Taberner, Michelino de Laurentiis, José Ángel García-Sáenz, Jana Repkova, Antonio Antón, Joseph Gligorov, Susana de la Cruz, Oliver Hoffmann, Jacques Medioni, Melissa Phillips, Miguel Sampayo-Cordero, Daniel Alcalá-López, José Manuel Pérez-García, Antonio Llombart-Cussac, Javier Cortés. Efficacy and safety of first-line atezolizumab + bevacizumab + paclitaxel in patients with advanced triple-negative breast cancer: the ATRACTIB phase 2 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-02.

Efficacy and Safety of Fibroblast Growth Factor-21 Analogs for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis: A Systematic Review and Meta-Analysis.

Fibroblast growth factor (FGF)-21 analogs are potential therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). This systematic review and meta-analysis aimed to assess the efficacy and safety of the FGF-21 analogs, efruxifermin, pegbelfermin, and pegozafermin for MASH treatment. A comprehensive systematic review and meta-analysis of randomized controlled trials from five major databases was conducted. Primary efficacy outcomes focused on liver histological improvement, while secondary efficacy outcomes encompassed reductions in liver fat content and improvements in biochemical parameters. Safety outcomes examined included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Eight eligible studies involving 963 patients were included in this review. Compared with the placebo group, the FGF-21 analog-treated group exhibited significantly improved primary efficacy outcomes, specifically ≥1 stage improvement in fibrosis with no worsening of MASH (risk ratio [RR] = 1.83; 95% confidence interval [CI] = 1.27-2.62) and at least two-point improvement in the non-alcoholic fatty liver disease activity score with no worsening of fibrosis (RR = 2.85; 95% CI = 2.06-3.95). Despite an increased risk of TEAEs (RR = 1.17; 95% CI = 1.08-1.27) and treatment-related adverse events (RR = 1.75; 95% CI = 1.40-2.19), FGF-21 analogs exhibited an acceptable safety profile. FGF-21 analogs were significantly better in achieving liver histological improvements and beneficial biochemical outcomes compared with placebo, with a tolerable safety pattern. These findings shed light on the efficacy and safety of FGF-21 analogs and provide valuable evidence for their application as MASH therapeutics.

Efficacy and Safety of Fixed-Dose Triple-Combination Clindamycin Phosphate 1.2%/Adapalene 0.15%/Benzoyl Peroxide 3.1% Gel for Moderate-to-Severe Acne Vulgaris in Children and Adolescents

Background: Topical clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% (CAB) gel is the first fixed-dose triple-combination formulation approved for acne vulgaris and is indicated for use in patients aged 12 years and older. As topical acne treatment in pediatric patients may be complicated by tolerability issues and/or a perceived lack of efficacy, the objective of this post hoc analysis was to investigate the efficacy and safety of CAB in children and adolescents.
 Methods: Data were pooled from two phase 3 double-blind, randomized, 12-week studies (NCT04214639; NCT04214652). Eligible participants ≥9 years of age with moderate-to-severe acne were randomized (2:1) to once-daily CAB or vehicle gel. This analysis evaluated adolescents aged 12-17 years (CAB: n=123; vehicle: n=50). Endpoints included ≥2-grade reduction from baseline in Evaluator’s Global Severity Score and clear/almost clear skin (treatment success), least-squares mean percent change from baseline in inflammatory/noninflammatory lesions, and treatment-emergent adverse events (TEAEs). Descriptive efficacy and safety data for five children aged 10-11 years enrolled in the study are also summarized (CAB: n=3; vehicle: n=2).
 Results: At week 12, 51.5% of CAB–treated participants aged ≥12 years achieved treatment success vs 24.9% with vehicle gel (P<0.01). CAB treatment resulted in significant reductions of >70% in inflammatory and noninflammatory lesion counts in adolescents (78.3% and 73.7%, respectively) vs vehicle (50.5% and 42.9%; P<0.001, both). Most TEAEs were of mild-to-moderate severity, and the most common (>3% in any treatment) treatment-related TEAE was application site pain. Less than 2.5% of participants withdrew due to AEs. For the 5 children aged <12 years, all 3 treated with CAB achieved treatment success, with reductions in inflammatory/noninflammatory lesions ranging from 76%-100%; neither vehicle-treated participant achieved treatment success. Only one CAB–treated younger participant experienced TEAEs (application site pain/dryness, and erythema [all mild/moderate]) and none discontinued the study.
 Conclusions: In two pooled phase 3 studies, once-daily CAB gel—the first approved fixed-dose, triple-combination topical formulation for acne vulgaris—was well tolerated and efficacious in pediatric participants with moderate-to-severe acne, with over half achieving treatment success at week 12.
 Funding: Ortho Dermatologics

Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS.

Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment. Patients with nmCRPC were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval-specific new and cumulative event rates were determined during the first 24 months of the double-blind period. Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months. Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment-related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment. ClinicalTrials.gov identifier NCT02200614.

ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma.

Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG. Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review. The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred. ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.

Safety of teriflunomide in Chinese adult patients with relapsing multiple sclerosis: A phase IV, 24-week multicenter study.

Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. Eighty-two patients were assigned to variant (n = 42) and wild type groups (n = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUCtau) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. NCT04410965, https://clinicaltrials.gov.

A phase 1 study of fianlimab (anti-LAG-3) in combination with cemiplimab (anti-PD-1) in patients with advanced ccRCC.

434 Background: Concurrent blockade of lymphocyte-activation gene 3 (LAG-3) may enhance efficacy of anti–programmed cell death protein 1 (PD-1) therapies. We present safety and clinical activity data from a Phase 1 study in patients with clear cell renal cell carcinoma (ccRCC) treated with anti–LAG-3 (fianlimab) + anti–PD-1 (cemiplimab). Methods: Patients with advanced or metastatic ccRCC who had received no more than 2 previous regimens of anti-angiogenic therapy who were anti–PD-1/PD-L1-naïve (cohort 3) or anti–PD-1/L1-experienced with most recent dose within 3 months prior to screening (cohort 4) were eligible. All patients were to receive fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks for up to 24 months. Tumor measurements were performed by RECIST 1.1 every 6 weeks for 24 weeks, then every 9 weeks. Results: 15 patients (median age: 64 years) each in cohort 3 and 4 (total N=30) were enrolled and treated with fianlimab + cemiplimab as of 01 Nov 2022 data cutoff.For cohorts 3 and 4 respectively, 80% and 87% of patients were male, and 40% and 87% were White. All patients had prior cancer-related systemic therapy. 60% (9/15) and 93% (14/15) of patients in cohorts 3 and 4 had ≥2 lines of prior therapies, respectively. For cohorts 3 and 4, median treatment duration was 27 weeks and 18 weeks, and median follow-up was 13 months and 24 months, respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 53% and 33% of patients in cohorts 3 and 4, respectively. Serious TEAEs occurred in 33% and 13% of patients in cohorts 3 and 4, respectively. Treatment-related TEAEs (TRAEs) were reported in 80% of patients in cohorts 3 and 60% of patients in cohort 4. The most common TRAEs (any grade) were rash (27%) and infusion related reaction (grade 1 and 2) (27%) in cohort 3 and fatigue (20%) in cohort 4. Grade ≥3 TRAEs occurred in 27% of patients in cohorts 3. Treatment was discontinued due to any TEAE in 3 patients in cohort 3 and 1 patient in cohort 4. In cohort 3, there was one death. The patient was a 79-year-old woman with a history of antiphospholipid syndrome who died from complications of biopsy-proven ischemic colitis attributed to study treatment. RECIST 1.1-based investigator-assessed objective response rate (ORR) was 20% (3 partial responses [PRs]) in cohort 3 and 7% (1 PR) in cohort 4. The disease control rate (DCR) was 60% and 73% in cohorts 3 and 4, respectively. Kaplan–Meier estimation of median progression-free survival was 4 months (95% confidence interval [CI], 1–10) in cohort 3 and 4 months (95% CI, 1–7) in cohort 4 patients. Duration of responses were 4, 7, and 26 months in 3 responders in cohort 3; and 6 months in one responder in cohort 4. Conclusions: Fianlimab + cemiplimab demonstrated promising signs of clinical activity with durable responses among patients with anti–PD-1/PD-L1-naïve (cohort 3) and anti–PD-1/L1-experienced (cohort 4), with an acceptable safety profile. Clinical trial information: NCT03005782 .

P628 Vedolizumab in Indian patients with Inflammatory Bowel Disease: Interim results from a prospective, multicentre, open-label, phase 4 study

Abstract Background Although anti-tumour necrosis factor (TNF)-α agents have revolutionised the management of ulcerative colitis (UC) and Crohn’s disease (CD), they have demonstrated a therapeutic ceiling with numerous safety concerns. Vedolizumab (VDZ) has consistently demonstrated safety and efficacy in patients with UC and CD in pivotal clinical trials, but its efficacy and safety data are very limited in the developing world where infectious diseases predominate. Methods This prospective, multicentre, open-label, single-arm, phase 4 study (Clinicaltrial.gov: NCT04804540) included patients (aged 18-65 years [yrs]) with moderate-to-severe active UC and CD who were non-responsive to available conventional therapies and/or anti-TNF agents. Patients received VDZ 300 mg through intravenous infusion for induction (Week [W]0, W2, W6) and maintenance (W14, W22, W30, W38, and W46) treatment phase. This interim analysis included data collected till the last patient completed W14 visit. Safety endpoints including incidence of adverse events (AE), serious AEs (SAE), adverse drug reactions (ADR), and adverse events with special interest (AESI), and efficacy endpoints including clinical response and clinical remission were analysed. Results Of 215 patients screened, 150 were eligible (UC, 102 [68.0%], median age: 39 yrs; CD, 48 [32.0%], median age: 31 yrs). Median VDZ treatment duration was 155 days in UC and 143 days in CD groups. Overall, 71 (47.3%) patients (UC, 49 [48.0%]; CD, 22 [45.8%]) experienced ≥1 AE; of these, 40.7% patients had mild AEs (UC, 40.2%; CD, 41.7%). Forty-six (45.1%) patients with UC and 22 (45.8%) patients with CD had ≥1 treatment-emergent AE (TEAE); 5 (4.9%) patients with UC had treatment-related TEAEs. Seven (4.7%) patients (UC, 6 [5.9%]; CD, 1 [2.1%]) had ≥1 SAE (2 [1.3%] were treatment-related), 5 (3.3%) had ≥1 ADR, and 4 (2.7%) had ≥1 AESI. One patient (0.7%) each reported pulmonary tuberculosis and tuberculous pleural effusion as ADR/AESI. Anaemia and small intestinal obstruction were the frequently reported TEAE and SAE, respectively. Most of the AEs were resolved and no AE-related death was reported during study (Table 1). Overall, 90 (60.0%) patients (UC, 56 [54.9%]; CD, 34 [70.8%]) at W14, 37 (63.8%) patients (UC, 29 [61.7%]; CD, 8 [72.7%]) at W30, and 4 (57.1%) patients (UC, 4 [66.7%]) at W46 had the clinical response. Similarly, 62 (41.3%) patients (UC, 40 [39.2%]; CD, 22 [45.8%]) at W14, 23 (39.7%) patients (UC, 19 [40.4%]; CD, 4 [36.4%]) at W30, and 3 (42.9%) patients (UC, 3 [50.0%]) at W46 had the clinical remission (Figure 1). Conclusion Treatment with vedolizumab was safe and effective in Indian patients with moderate-to-severe active UC and CD as per this first multicentre prospective study on vedolizumab from India.

Tislelizumab plus chemotherapy (chemo) versus placebo plus chemo as first-line treatment for locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: RATIONALE-305 European/North American patient subgroup.

330 Background: Tislelizumab (TIS), an anti-programmed cell death protein 1 monoclonal antibody, plus chemo, demonstrated significant overall survival (OS) benefit vs placebo (PBO) plus chemo (15.0 vs 12.9 months [mo], hazard ratio [HR]=0.80, 95% confidence interval [CI]: 0.70, 0.92, P=0.0011) as first-line therapy in patients (pts) with advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) in the randomized, double-blind, global, phase 3 RATIONALE-305 study (NCT03777657). Here we present results from the European/North American (Eu/NA) pts subgroup analysis. Methods: This double-blind, global, phase 3 study evaluated adult pts with previously untreated, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable, or metastatic GC/GEJC, regardless of programmed death-ligand 1 (PD-L1) expression status. Eligible pts were randomized (1:1) to receive TIS 200 mg or PBO intravenously once every 3 weeks plus investigator chosen chemo (5-fluorouracil + cisplatin or capecitabine + oxaliplatin). The primary endpoint was OS in the PD-L1+ (patients with tumor area positivity score ≥5%) and intent-to-treat (ITT) analysis sets. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Results: Of 997 pts enrolled, 249 (25.0%) were from Eu/NA (TIS plus chemo arm, n=125; PBO plus chemo arm, n=124). In the Eu/NA pts subgroup, after a minimum follow-up of 26.6 mo at final analysis, TIS plus chemo resulted in OS improvements vs PBO plus chemo in the PD-L1+ (HR=0.75, [95% CI: 0.52, 1.07]; 24 mo rate 27.6% vs 12.5%) and ITT analysis sets (HR=0.71, [95% CI: 0.54, 0.94]; 24 mo rate 27.6% vs 13.6%). TIS plus chemo resulted in favorable PFS vs PBO plus chemo (HR=0.84, 95% CI: 0.63, 1.11), numerically higher ORR (36.0% vs 31.5%), and longer DoR (median 7.5 mo [95% CI: 4.4, 12.0] vs 5.0 mo [95% CI: 3.9, 6.7]). Sixty (48.8%) pts in the TIS plus chemo arm and 61 (49.2%) pts in the PBO plus chemo arm experienced grade ≥3 treatment-related treatment-emergent adverse events (TRAEs). Sixteen (13.0%) and seven (5.6%) pts discontinued treatment due to TRAEs in the TIS plus chemo and PBO plus chemo arms, respectively. Deaths due to TRAEs occurred in two (1.6%) pts in the TIS plus chemo arm and one (0.8%) pt in the PBO plus chemo arm. Conclusions: TIS plus chemo showed OS benefit compared with PBO plus chemo and a manageable safety profile in pts in the Eu/NA subgroup with previously untreated, HER2-negative, locally advanced unresectable, or metastatic GC/GEJC. These findings are consistent with the published results in the overall study population. Clinical trial information: NCT03777657 .

Safety and Tolerability of Fixed-Dose Clindamycin Phosphate 1.2%/Adapalene 0.15%/Benzoyl Peroxide 3.1% Gel in Black Participants With Acne

Background: As acne can cause inflammation-associated sequelae (eg, post-inflammatory hyperpigmentation) in individuals with melanin-rich skin, effective and rapid management must be balanced with minimization of skin irritation. Clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% (IDP-126) polymeric mesh gel is the first fixed-dose, triple-combination topical acne product in development. In clinical studies, over half of participants achieved treatment success with IDP-126 gel after 12 weeks. The objective of this pooled, post hoc analysis was to evaluate safety and tolerability of IDP-126 gel in Black participants.
 Methods: In two identical phase 3, double-blind, randomized, 12-week studies (NCT04214639; NCT04214652), participants aged ≥9 years with moderate-to-severe acne were randomized (2:1) to receive once-daily IDP-126 or vehicle gel. Assessments included treatment-emergent adverse events (TEAEs) and cutaneous safety/tolerability (hyperpigmentation, hypopigmentation, erythema, scaling, itching, burning, and stinging; graded from 0 [none] to 3 [severe]). Post hoc analyses were based on participants’ self-identification of race as ‘Black or African American’ (hereafter referred to as Black).
 Results: Of 363 randomized participants, 54 (14.9%) self-identified as Black. No serious TEAEs were reported and no TEAEs led to discontinuation. Treatment-related TEAEs were reported in 7 (17.5%) IDP-126-treated Black participants; the most common were application site pain (n=5 [12.5%]) and application site pruritus (n=2 [5.0%]). No vehicle-treated participants reported treatment-related TEAEs. TEAEs in Black participants were generally similar to the overall population.
 Mean severity scores for all cutaneous safety/tolerability assessments following IDP-126 treatment were <0.55 at all study visits (1=mild). Rates of hyperpigmentation remained relatively unchanged throughout the study while erythema decreased by over 10% from baseline to week 12 with IDP-126 treatment. Rates of all other cutaneous safety/tolerability assessments were low (<9%) at both baseline and week 12.
 Conclusions: Clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% (IDP-126) gel was safe and well tolerated in Black participants with moderate-to-severe acne over 12 weeks, with no discontinuations or serious TEAEs. Additionally, IDP-126 treatment led to improved erythema in Black participants and no substantial increases in hyperpigmentation. These post hoc analyses add valuable information to the limited literature describing treatment effects and tolerability of novel acne therapeutics in Black individuals.
 Support: Ortho Dermatologics.

Efficacy and safety of linaclotide in treating functional constipation in paediatric patients: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Linaclotide, a guanylate cyclase C agonist, has been approved in the USA for the treatment of chronic idiopathic constipation and irritable bowel syndrome with predominant constipation in adults. We aimed to assess the efficacy and safety of linaclotide in paediatric patients aged 6-17 years with functional constipation. This randomised, double-blind, placebo-controlled, multicentre, phase 3 study was done at 64 clinic or hospital sites in seven countries (USA, Canada, Israel, Italy, the Netherlands, Ukraine, and Estonia). Patients aged 6-17 years who met modified Rome III criteria for functional constipation were randomly assigned (1:1), with a block size of four and stratified by age (6-11 years and 12-17 years), to receive either oral linaclotide 72 μg or placebo once daily for 12 weeks. Participants, investigators, and data assessors were masked to assignment. The primary efficacy endpoint was change from baseline (CFB) in the 12-week frequency rate of spontaneous bowel movements (SBMs; occurring in the absence of rescue medication on the calendar day of or before the bowel movement) per week and the secondary efficacy endpoint was CFB in stool consistency over the 12-week treatment period; efficacy and safety were analysed in all patients in the randomised population who received at least one dose of study intervention (modified intention-to-treat population and safety population, respectively). The study is registered with ClinicalTrials.gov, NCT04026113, and the functional constipation part of the study is complete. Between Oct 1, 2019, and March 21, 2022, 330 patients were enrolled and randomly assigned to linaclotide (n=166) or placebo (n=164). Two patients in the linaclotide group did not receive any treatment; thus, efficacy and safety endpoints were assessed in 328 patients (164 patients in each group). 293 (89%) patients completed the 12-week treatment period (148 in the linaclotide group and 145 in the placebo group). 181 (55%) of 328 patients were female and 147 (45%) were male. At baseline, the mean frequency rate for SBMs was 1·28 SBMs per week (SD 0·87) for placebo and 1·16 SBMs per week (0·83) for linaclotide, increasing to 2·29 SBMs per week (1·99) for placebo and 3·41 SBMs per week (2·76) for linaclotide during intervention. Compared with placebo (least-squares mean [LSM] CFB 1·05 SBMs per week [SE 0·19]), patients treated with linaclotide showed significant improvement in SBM frequency (LSM CFB 2·22 SBMs per week [0·19]; LSM CFB difference 1·17 SBMs per week [95% CI 0·65-1·69]; p<0·0001). Linaclotide also significantly improved stool consistency over placebo (LSM CFB 1·11 [SE 0·08] vs 0·69 [0·08]; LSM CFB difference 0·42 [95% CI 0·21-0·64]; p=0·0001). The most reported treatment-emergent adverse event (TEAE) by patients treated with linaclotide was diarrhoea (seven [4%] of 164 vs three [2%] of 164 patients in the placebo group) and by patients treated with placebo was COVID-19 (five [3%] vs four [2%] in the linaclotide group). The most frequent treatment-related TEAE was diarrhoea (linaclotide: six [4%] patients; placebo: two [1%] patients). One serious adverse event of special interest (treatment-related severe diarrhoea resulting in dehydration and hospitalisation) occurred in a female patient aged 17 years in the linaclotide group; this case resolved without sequelae after administration of intravenous fluids. No deaths occurred during the study. Linaclotide is an efficacious and well tolerated treatment for functional constipation in paediatric patients and has subsequently been approved by the US Food and Drug Administration for this indication. AbbVie and Ironwood Pharmaceuticals.

TQB2450 in patients with advanced malignant tumors: results from a phase I dose-escalation and expansion study.

Immune checkpoint inhibitor therapy has demonstrated impressive clinical benefits in multiple tumor types. TQB2450, a novel monoclonal antibody targeting programmed cell death ligand 1, has shown safety and efficacy in preclinical studies. This first-in-human study aimed to evaluate the safety/tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of TQB2450 in patients with advanced malignant tumors. In this phase I study, eligible patients with advanced malignant tumors received intravenous TQB2450 once every 3 weeks. This study consisted of a 3 + 3 dose-escalation phase (1-30 mg/kg) and a specific dose-expansion phase (1200 mg). The primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety. The secondary endpoints were PK, immunogenicity, and investigator-assessed response rate. Between April 2018 and February 2020, 40 patients were enrolled (22 in the dose-escalation phase and 18 in the dose-expansion phase). No DLT was reported and the MTD was not reached. Grade ⩾3 or worse treatment-related treatment-emergent adverse events (AEs) occurred in 11 (27.50%) patients, with the most frequent being aspartate aminotransferase increased (5.00%), leukopenia (5.00%), and anemia (5.00%). Treatment-related serious AEs were reported in six patients, the most common of which was decompensated liver function (5.00%). No treatment-related death was reported. The maximum serum concentration of TQB2450 increased in a dose-proportional manner. Treatment-induced anti-drug antibodies were detected in 31.58% (12/38) of patients. The investigator assessed the objective response rate as 5.00% and the disease control rate was 52.50%, including 2 partial responses and 19 stable diseases. The median progression-free survival was 2.69 (95% confidence interval, 2.07-6.14) months. TQB2450 has a manageable safety profile with favorable PK and immunogenicity and has shown early evidence of clinical activity in advanced malignant tumors. NCT03460457.

Long-Term Safety of Dupilumab in Patients With Moderate-to-Severe Asthma: TRAVERSE Continuation Study

Previous clinical trials have demonstrated dupilumab efficacy and safety in adults and adolescents with moderate to severe asthma for up to 3 years. The TRAVERSE continuation study (NCT03620747), a single-arm, open-label study, assessed safety and tolerability of dupilumab 300 mg every 2 weeks up to an additional 144 weeks (∼3 years) in patients with moderate to severe asthma who previously completed TRAVERSE (NCT02134028). Primary end points were incidence and event rates per 100 patient-years of treatment-emergent adverse events (TEAEs). Secondary end points included adverse events (AEs) of special interest, serious AEs, and AEs leading to study discontinuation. A total of 393 patients participated in the TRAVERSE continuation study (cumulative dupilumab exposure, 431.7 patient-years; median treatment duration, 309 days). A total of 29 patients (7.4%) received more than 958 days of treatment. A total of 214 (54.5%) patients reported at least 1 TEAE (event rate: 171.4); 37 (9.4%) experienced at least 1 treatment-related TEAE, none of which were considered severe; 2 patients reported 6 TEAEs of moderate intensity. A total of 22 (5.6%) patients reported serious AEs (event rate: 6.9). AEs of special interest were reported in 24 patients (6.1%; event rate: 6.0). Five (1.3%) deaths occurred (event rate: 1.2) following serious AEs of coronavirus disease 2019 (COVID-19)-related pneumonia (3 patients), pancreatitis (1 patient), and pulmonary embolism (1 patient). None of the TEAEs leading to death were considered treatment-related. Dupilumab treatment was well tolerated for up to an additional 3 years. Safety findings were consistent with the known safety profile of dupilumab. These findings further support the long-term use of dupilumab in patients with moderate to severe asthma.

Valemetostat for Relapsed or Refractory B-Cell Lymphomas: Primary Results from a Phase 1 Trial

Introduction: B-cell non-Hodgkin lymphomas (B-NHLs), including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), are among the most common NHLs. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze the trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional mark is broadly associated with gene silencing. EZH2 is involved in mediating B-cell development. Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1. The clinical activity of valemetostat in patients (pts) with relapsed or refractory (R/R) NHL was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary clinical outcomes for the subgroup of pts in J101 with R/R B-NHLs, including DLBCL and FL. Methods: This phase 1, open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were aged ≥ 18 years (y; US) or ≥ 20 y (Japan), had confirmed B-NHL or T-cell NHL (T-NHL), and were relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation portion (Japan only) followed by a dose-expansion phase (Japan &amp; US). Pts with a histological diagnosis of B-NHL were enrolled in the dose-escalation phase and received valemetostat once daily at doses of 150-300 mg/day (d) in continuous 28-d treatment (Tx) cycles. Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, and duration of response (DOR). DOR was estimated for responding pts using Kaplan-Meier methods. Due to the small number of pts with B-NHL, safety was assessed among all enrolled pts, including those with T-NHL in the dose-escalation and dose-expansion cohorts. Results: At the primary trial cutoff (Dec 31, 2022), 19 pts with R/R B-NHLs were registered and had received ≥ 1 dose of study drug, including 7 with DLBCL, 7 with FL, 3 with indolent B-NHL, and 2 with other B-NHLs. Median age was 66 (range 44-88) y. Most (79%) pts had an Eastern Cooperative Oncology Group performance status score of 0. Median number of prior therapies was 2.0 (range 0-6); no pt in this cohort had received prior hematopoietic cell transplantation. Overall, 90 pts with R/R NHLs were enrolled. All pts experienced at least 1 treatment-emergent adverse event (TEAE), including 78 (87%) who had treatment-related TEAEs. The most common TEAEs (any grade) were decreased platelet count (64%), dysgeusia (50%), anemia (43%), decreased neutrophil count (34%), and alopecia (33%). The most common grade ≥ 3 TEAEs were cytopenias, including decreased neutrophil count (24%), platelet count (24%), and lymphocyte count (19%). TEAEs required Tx interruption for 42 (47%) pts, dose reduction for 9 (10%) pts, and Tx discontinuation for 7 (8%) pts. The overall response rate in pts with R/R B-NHL was 47% (9/19; 95% confidence interval [CI], 24.4-71.1). Clinical responses were seen in 3/7 pts with DLBCL and 4/7 pts with FL; 1 pt in each of these groups achieved CR ( Table). Of 19 pts, 9 (47%) achieved reductions of ≥ 50% from baseline in the sum of target lesion areas during valemetostat Tx ( Figure). A gain-of-function EZH2 mutation was identified in 1 pt with FL, and this pt achieved a partial response. Median time to response overall was 3.7 (range 1.9-10.1) months (mo) and estimated median DOR for the 9 responding pts was 18.4 mo (95% CI, 5.3 mo to not reached). Among all pts who received valemetostat 200 mg/d with pharmacokinetic (PK) data available (n = 74), mean [standard deviation; SD] maximum plasma concentration (C max) on cycle 1 day 1 was 2140 [1620] ng/mL, with a median time to C max (T max) of 3.9 (range 0.2-27.8) h and a mean [SD] AUC tau of 17,500 [21,400] ng × h/mL. Conclusions: Valemetostat demonstrated encouraging clinical activity in pts with R/R B-NHLs. The safety profile of valemetostat was acceptable; cytopenias were common but manageable and did not require Tx discontinuation between 150-300 mg/d. Clinical responses were durable, with a median DOR of &amp;gt; 1.5 y. Results for pts in this trial with R/R T-NHLs are presented in another abstract (Jacobsen et al.) at this congress. Ongoing trials of valemetostat in pts with R/R B-NHLs include a phase 2 monotherapy trial in France and Belgium (NCT04842877) and a phase 1/2 trial of valemetostat plus rituximab and lenalidomide (R 2) in the US (NCT05683171).

Pirtobrutinib, a Non-Covalent (reversible) BTK Inhibitor, in Mantle Cell Lymphoma Patients Previously Treated with a Covalent BTK Inhibitor: Results from a China Phase 2 Study

Background Pirtobrutinib, a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi), inhibits both wildtype and C481-mutant BTK and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of protein turnover, and shows promising efficacy and favorable safety profile in patients with pre-treated B-cell malignancies including a covalent BTKi (cBTKi). This study (NCT04849416) was a China only phase 2, open-label, multi-center trial aiming to evaluate the safety and efficacy of oral pirtobrutinib as a monotherapy for patients with B-cell malignancies. This abstract summarizes the findings on the efficacy in a cBTKi pre-treated mantle cell lymphoma (MCL) population and safety outcomes among all enrolled patients. Methods Eligible Chinese patients with relapsed/refractory B-cell malignancies were enrolled and assigned to one of three cohorts based on tumor histology and prior treatment history. All enrolled patients received pirtobrutinib monotherapy at a daily dose of 200 mg, until disease progression (PD), unacceptable side effects, or other reasons for discontinuation. The primary analysis set (PAS) comprised patients with centrally confirmed non-blastoid MCL, who received a prior cBTKi, and with measurable lesion(s) at baseline. The efficacy analysis set (EAS) was extended into all MCL patients treated with a prior cBTKi. The safety population included all patients who received at least one dose of pirtobrutinib. The primary objective was to evaluate the effectiveness by assessing the overall response rate (ORR) based on Lugano criteria and was conducted by an independent review committee (IRC). Secondary objectives included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety profile. Results As of April 10, 2023, of 39 enrolled MCL patients, 28 were in the PAS and 35 were in the EAS for efficacy analysis. The safety analysis included a total of 87 enrolled patients and the median duration of therapy was 4.2 months. In the PAS population (N=28) with cBTKi pre-treated non-blastoid MCL, patients had a median of 3.0 prior lines of therapy (range, 1-8). The majority received prior chemotherapy (96.4%) and an anti-CD20 antibody (85.7%). The most common reason for discontinuation from the prior cBTKi was PD (85.7%). The IRC-assessed ORR was 71.4% (95% CI, 51.3-86.8), with 4 patients (14.3%) achieving complete responses (CR) and 16 patients (57.1%) achieving partial responses (PR). The median DOR assessed by IRC was not reached at the cut-off date with a 6-month DOR rate of 66.02% (95% CI, 39.29-83.14). The median IRC-assessed PFS was 9.43 months (95% CI: 5.32-not evaluable [NE]), and the median OS was 15.47 months (95% CI, 8.67-NE). The EAS (N=35), demonstrated similar efficacy results with IRC-assessed ORR 62.9% (95% CI, 44.9-78.5) and the 6-month DOR rate was 64.45%. In the safety population (N=87) of all enrolled B-cell malignancy patients, common treatment-emergent adverse events (TEAEs) of any grade included decreased neutrophil count (40.2%*), anemia (31%), and increased bilirubin (23.0%, with 2.3% grade ≥3 and none led to dose modification). The most frequent grade ≥3 TEAE was decreased neutrophil count (25.3%*). All grade hemorrhage was observed in 19.5% patient (n=17, with 2.3% grade ≥3), while all grade hypertension was 5.7% (n=5, with 2.3% grade ≥3), and no patient developed atrial fibrillation/flutter. Three patients (3.4%) stopped treatment due to treatment-related TEAEs, and 2 patients (2.3%) experienced treatment related fatal TEAEs (one infection and one patient with reported tumor lysis syndrome, tumor necrosis, and hemorrhage). Conclusion Pirtobrutinib demonstrated clinically meaningful and durable antitumor activity in a cBTKi pre-treated MCL Chinese population and showed a well-tolerated safety profile in patients with B-cell malignancies. * Aggregate of neutropenia and neutrophil count decreased

Preliminary Results from a Multicenter Phase 2/3 Study of Next-Generation HbS Polymerization Inhibitor GBT021601 for the Treatment of Patients with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a lifelong inherited disorder resulting in polymerization of sickle hemoglobin (HbS) and is characterized by chronic hemolytic anemia, vaso-occlusive crises (VOCs), and cumulative end-organ damage. Voxelotor is a first-in-class HbS polymerization inhibitor approved in the US for the treatment of patients with SCD aged ≥4 years and in Europe for the treatment of hemolytic anemia due to SCD in patients aged ≥12 years. GBT021601 is a next-generation HbS polymerization inhibitor with improved pharmacokinetic (PK) properties that increases hemoglobin (Hb)-oxygen affinity and stabilizes Hb in the oxygenated state to inhibit polymerization. GBT021601 has the potential for higher Hb occupancies at lower doses than voxelotor and could potentially reduce treatment burden and improve clinical outcomes. Here we report preliminary safety, efficacy, and pharmacodynamic (PD) data from an ongoing phase 2/3 study of orally administered GBT021601 (NCT05431088) in patients with SCD. Methods: This is a 3-part, multicenter phase 2/3 study in SCD. Part A is a randomized, open-label, 12-week, dose-finding study of GBT021601 in adult participants. Part B is a placebo-controlled study in adult and adolescent participants. Part C is an open-label study in pediatric participants. Here, we report data at Week 12 from Part A, which enrolled participants aged 18-65 years with SCD (HbSS/HbSβ 0 genotype) and Hb 5.5-10.5 g/dL at screening. Eligible participants were randomly assigned 1:1 to GBT021601 100 mg or 150 mg and received a loading dose twice daily for 4 days followed by once-daily maintenance doses through to Week 12. The primary endpoint was change from baseline in Hb at Week 12; secondary endpoints included Hb response (increase from baseline &amp;gt;1 g/dL) and change from baseline in hemolysis markers at Week 12, PK, PD, and safety. Vascular cell adhesion molecule-1 (VCAM-1) levels are elevated during VOCs, with flow adhesion of whole blood on VCAM-1 previously reported as a prognostic biomarker for VOC risk. The effect of GBT021601 on adherent cells was evaluated using a microfluidic device coated with VCAM-1. Results: At data cutoff (June 20, 2023), 35 patients were treated in Part A; 28 had completed 12 weeks of treatment. The 100-mg group consisted of 17/35 patients (48.6%), with a mean (range) age of 29.1 (18-49) years; 7/17 patients (41.2%) were on hydroxyurea (HU). The 150-mg group had 18/35 patients (51.4%), with a mean (range) age of 30.2 (18-59) years; 9/18 patients (50.0%) were on HU. Most patients (32/35 [91.4%]) had the HbSS genotype. After 12 weeks of treatment, the mean (SD) increase in Hb from baseline was 2.67 (1.52) g/dL for the 100-mg group (n=12) and 3.17 (1.82) g/dL for the 150-mg group (n=11). A favorable trend towards reduction from baseline was observed in markers of hemolysis. Flow adhesion data showed patients taking GBT021601 had a reduction in adherent cells, which could correlate with a reduction in the probability of a VOC event (Figure). At data cutoff, the safety data showed GBT021601 was well tolerated. For 27 patients with ≥1 VOC at baseline, the baseline annualized VOC rate was 2.30 (95% CI 1.81-2.92), and the on-study annualized VOC rate was 1.16 (95% CI 0.55-2.43) with a median (range) on-study duration of 0.4 (0.03-0.41) years. Treatment-emergent adverse events (TEAEs), predominantly grade 1 and 2 (15/35 [42.9%]) and unrelated to treatment (14/35 [40.0%]), were reported for 22 patients (62.9%). Treatment-related TEAEs in 8/35 patients (22.9%) were headache (n=4), diarrhea (n=2), and abdominal discomfort, nausea, suspected seizure (uncoded), sickle cell anemia with crisis, upper abdominal pain, and urticaria (n=1 each). There was 1 TEAE, unrelated to treatment, that led to study discontinuation (sepsis, in the 100-mg group). One death deemed unrelated to GBT021601 was due to a cerebrovascular (CVA) event, in a patient with history of CVA and seizures, after new onset high fever and no change from baseline Hb 8.0 g/dL. Conclusions: Loading and daily doses of GBT021601 for 12 weeks were well tolerated in adult participants with SCD. Despite large increases in mean Hb levels, pain episodes did not increase and there was a reduction of adherent cells in a flow adhesion assay with VCAM-1, a potential biomarker for VOC risk. Data from Part A of this phase 2/3 study support the ongoing clinical development of GBT021601 as a potential treatment for individuals with SCD.

Long-Term Evaluation of Luspatercept in Erythropoiesis-Stimulating Agent (ESA)-Intolerant/Refractory Patients (pts) with Lower-Risk Myelodysplastic Syndromes (LR-MDS) in the Phase 3 MEDALIST Study

Background: Pts with LR-MDS receiving luspatercept in the phase 3 MEDALIST trial previously reported durable, long-term red blood cell (RBC) transfusion independence (RBC-TI) (Fenaux P, et al. J Clin Oncol 2022;40[suppl 16]. Abstract 7056). MEDALIST pts were eligible to enroll in a follow-up study to evaluate long-term efficacy and safety. Aims: To report long-term efficacy and safety outcomes in ESA-refractory/intolerant pts with LR-MDS treated with luspatercept in the MEDALIST trial with an additional 26 mo of follow-up from the final MEDALIST data cutoff. Methods: Eligible pts were ≥ 18 y of age; IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with ring sideroblasts; were refractory, intolerant, or unlikely to respond to ESAs, and required regular RBC transfusions. Pts were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg, with titration up to 1.75 mg/kg) or placebo. Efficacy outcomes include RBC-TI ≥ 8 wk and ≥ 16 wk. Cumulative duration of response was determined by Kaplan-Meier (KM) analysis. Rates of longest single and cumulative duration of RBC-TI ≥ 1 y and exposure-adjusted incidence rates (EAIR) of treatment-emergent adverse events (TEAEs) and AEs of special interest (AESIs) were calculated. Rates of high-risk (HR)-MDS and acute myeloid leukemia (AML) progression were calculated from LR-MDS diagnosis to HR-MDS/AML diagnosis, or to last HR-MDS/AML follow-up date for pts who did not progress. Results: As of January 2, 2023, 11 pts remained on luspatercept treatment; 8 pts randomized to luspatercept and none from placebo continued in post-treatment follow-up. The median (range) follow-up time was 39.9 (2.8-76.0) mo for luspatercept arm pts and 38.7 (1.7-68.6) mo for placebo arm pts. The median (range) duration of treatment was 50.9 (5.9-332.9) wk for luspatercept pts and 24.0 (9.0-103.0) wk for placebo pts. Seventy-five of 153 (49.0%) luspatercept pts achieved RBC-TI ≥ 8 wk during the entire treatment period and 53/75 (70.7%) had ≥ 2 response periods with a median cumulative duration of 110.14 wk (95% confidence interval [CI], 53.71-154.14; Figure A). Overall, 31/75 (41.3%) luspatercept pts had the longest RBC-TI duration ≥ 1 y, and 44/75 (58.7%) had a cumulative RBC-TI duration ≥ 1 y. In total, of the 48/153 (31.4%) pts receiving luspatercept who achieved RBC-TI ≥ 16 wk during the entire treatment period, 32/48 (66.7%) had ≥ 2 response periods with a median cumulative duration of 129.29 wk (95% CI, 79.86-240.43). Grade 3/4 treatment-related TEAEs were reported in 14/153 (9.2%; EAIR, 5.3 per 100 pt-y [PYs]) and 3/76 (3.9%; EAIR, 6.6 per 100 PYs) luspatercept and placebo pts, respectively; TEAEs of any grade leading to permanent treatment discontinuation were reported in 24/153 (15.7%; EAIR, 8.6 per 100 PYs) luspatercept and 6/76 placebo pts (7.9%; EAIR, 13.0 per 100 PYs). The most common TEAEs of any grade reported in &amp;gt; 5% of luspatercept pts were fatigue (47/153 [30.7%]; EAIR, 22.1 per 100 PYs; vs placebo, 11/76 [14.5%]; EAIR, 27.1 per 100 PYs), diarrhea (47/153 [30.7%]; EAIR, 23.5 per 100 PYs; vs placebo, 8/76 [10.5%]; EAIR, 18.4 per 100 PYs), asthenia (41/153 [26.8%]; EAIR, 18.8 per 100 PYs; vs placebo, 9/76 [11.8%]; EAIR, 21.5 per 100 PYs), peripheral edema (40/153 [26.1%], EAIR, 17.6 per 100 PYs; vs placebo, 13/76 [17.1%]; EAIR, 32.0 per 100 PYs), and back pain (38/154 [24.7%]; EAIR, 16.8 per 100 PYs; vs placebo, 5/76 [6.6%]; EAIR, 11.7 per 100 PYs; Figure B). During the entire treatment period, 26/44 (59.1%), 9/23 (39.1%), and 12/86 (14.0%) pts who received ≤ 1 mg/kg, 1.33 mg/kg, and 1.75 mg/kg luspatercept, respectively, reported fatigue of any grade. No new progression to HR-MDS or AML events have been reported since the last data cutoff (Santini V et al. Blood 2022;140[suppl 1]:4079-4081). Conclusions: Pts with LR-MDS who received luspatercept for &amp;gt; 2 years longer than in the original MEDALIST study, continued to experience sustained periods of RBC-TI with more than half of pts experiencing cumulative RBC-TI for ≥ 1 year. The long-term safety profile of luspatercept is consistent with previous shorter-term reports, and AEs were mostly lower grade with rates of fatigue decreasing with increasing luspatercept dose. These data demonstrate the long-term efficacy and safety of luspatercept in pts with LR-MDS intolerant/ineligible for ESA treatment.

Efficacy and Safety of Luspatercept in Patients with HbE/β-Thalassemia from the BELIEVE Study: A Subgroup Analysis

Background: Thalassemias are a group of inherited blood disorders caused by impaired production of the globin chains of hemoglobin (Hb), resulting in anemia. HbE/β-thalassemia results from the co-inheritance of a specific point mutation in the β-globin gene with a second β-thalassemia mutation. The combination of mutations influences disease severity, ranging from mild to severe, with HbE/β-thalassemia accounting for about half of all cases of severe thalassemia. Patients (pts) with severe disease have higher red blood cell (RBC) transfusion requirements, which can be associated with increased risk of related morbidities. Treatments that can reduce dependence on RBC transfusions are needed to improve pt outcomes. Primary results from the BELIEVE study (NCT02604433) demonstrated the efficacy and safety of luspatercept to treat anemia in transfusion-dependent pts with β-thalassemia across genotypes including HbE (Cappellini MD, et al. HemaSphere 2020;4[S1]:108-109). A subsequent analysis of the final BELIEVE data for pts with β 0/β 0 mutations, a form of severe β-thalassemia, demonstrated similar results with longer treatment in this subgroup (Sheth S, et al. Blood 2022;140 [S1]:1946-1948). The aim of this post hoc sub-analysis was to investigate the efficacy and safety of longer-term luspatercept treatment in pts in the BELIEVE trial with HbE/β-thalassemia. Methods: The BELIEVE trial included adult pts with β-thalassemia or HbE/β-thalassemia (compound heterozygous β-thalassemia with mutation and/or multiplication of α-globin genes allowed) who required regular RBC transfusions (6-20 RBC units in the 24 wk before randomization with no transfusion-free period &amp;gt; 35 days). Pts were randomized 2:1 to receive luspatercept (1.0-1.25 mg/kg) or placebo subcutaneously every 3 wk and evaluated for response (defined as reduction in RBC transfusion burden ≥ 33% or ≥ 50% from baseline during any 12-wk interval over the entire study) and safety. Data were evaluated up to the final pt visit (Jan 5, 2021). Results: The BELIEVE trial enrolled 336 pts, 52 (15.5%) of whom had HbE/β-thalassemia; 31 were randomized to the luspatercept group of the overall intent-to-treat (ITT) population (13.8%; N = 224). At baseline, pts receiving luspatercept with HbE/β-thalassemia were similar in age compared with the overall ITT population (median 32 y vs 30 y, respectively) and had similar transfusion burden (median 13.0 units vs 14.0 units over 24 wk), but had higher median fetal Hb (6.1% vs 5.1%), higher median serum ferritin (2087.0 vs 1441.3 μg/L), and higher median liver iron content (10.8 vs 6.1 mg/g dry weight). The median (range) duration of luspatercept treatment for pts with HbE/β-thalassemia was similar to the overall ITT population (157.7 [51.0-207.1] wk vs 153.6 [1.7-215.0] wk). A similar proportion of pts with HbE/β-thalassemia as in the overall ITT population achieved ≥ 33% reduction in transfusion burden (83.9% vs 77.2%) and ≥ 50% reduction in transfusion burden (61.3% vs 50.0%) over any 12-wk interval with luspatercept treatment (Figure A). Median total duration of ≥ 33% reduction in transfusion burden response was longer for HbE/β-thalassemia pts versus the overall ITT population (722.0 days vs 586.0 days). In the HbE/β-thalassemia subgroup, 67.6% of pts experienced ≥ 1 treatment-emergent adverse event (TEAE) related to treatment versus 60.5% of pts in the overall luspatercept safety population. The proportion of pts experiencing grade ≥ 3 treatment-related TEAEs was 25.8% in the HbE/β-thalassemia subgroup and 12.1% in the overall safety population. Treatment-related TEAEs resulted in discontinuation of luspatercept in 6.5% and 9.0% of the HbE/β-thalassemia and overall safety populations, respectively. No treatment-related TEAEs resulted in death in either group (Figure B). Summary: The HbE/β-thalassemia sub-group of the BELIEVE study had rates of response that were consistent with the larger ITT population. Furthermore, pts with HbE/β-thalassemia experienced a longer median total duration of response compared with the overall ITT population with a similar safety profile. Additional evaluation of the efficacy and safety of luspatercept in a larger population of HbE/β-thalassemia pts would be valuable as the number of pts in this sub-analysis was small, yet these results suggest that luspatercept is as safe and effective for this subgroup of pts as for the wider β-thalassemia population.

Lacutamab in Patients with Relapsed and Refractory Sèzary Syndrome: Results from the Tellomak Phase 2 Trial

Introduction Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Sézary syndrome (SS) is a rare, aggressive and advanced type of CTCL. It has a unique biology, with high expression of KIR3DL2, a killer immunoglobulin-like receptor, reported in more than 85% of patients. SS is characterized by erythroderma, significant blood involvement with malignant SS cells, and lymphadenopathy. These patients suffer from debilitating itching and recurrent skin infections, often affecting quality of life (QoL). SS is distinguished by its poor prognosis, as the median survival of patients is approximately 5 years. Lacutamab is a first-in-class monoclonal antibody designed to specifically deplete KIR3DL2-expressing cells via antibody-dependent cell-cytotoxicity and phagocytosis. Methods TELLOMAK is an international, open-label, Phase 2 trial with multiple cohorts (NCT03902184). We report here results from Cohort 1, designed to evaluate safety and efficacy of single agent lacutamab in patients with relapsed/refractory (R/R) SS after at least 2 prior systemic therapies including mogamulizumab. Patients had blood stage B2 (≥1000 circulating Sézary cells/mm 3) at screening based on central evaluation by flow cytometry. Patients with evidence of large cell transformation were excluded. Lacutamab 750 mg is administered as an intravenous infusion weekly × 5 weeks (w), every 2 w × 10, then every 4 w until progression or unacceptable toxicity. Primary endpoint was Objective Response Rate (ORR) by global response score based on the evaluation of 4 compartments: skin, blood, lymph nodes and viscera according to International Consensus criteria (Olsen 2011). Secondary endpoints included but not limited to additional efficacy endpoints, safety, QoL assessments. Results At the data cut-off of May 1, 2023, 56 SS patients were enrolled treated and evaluated in Cohort 1. Median age was 69 years (range: 42-86), the median prior lines of systemic therapies was 6.0 (range: 2-15), 60.7 % (n=34) had stage IVA1, 32.1 % (n=18) had stage IVA2 and 7.1% (n=4) had stage IVB disease at baseline, all patients (100%) had blood involvement (B2), 67.9% (n=38) had confluence of erythema covering ≥ 80% body surface area (T4), 35.7% (n=20) had lymph node lymphoma involvement (N3). Median follow-up was 14.4 months (95% CI 9.0-18.4). In the ITT population (n=56), Global confirmed ORR was 37.5% (n=21; 95% CI 26.0-50.6) including 2 CRs, with a median time to response of 2.8 months (range 1-9; Figure 1). Confirmed ORR in skin was 46.4% (n=26; 95% CI 34.0-59.3) including 5 CRs. Confirmed ORR in blood was 48.2% (n=27; 95% CI 35.7-61.0) including 15 CRs. Clinical Benefit Rate (CBR, defined as CR+PR+SD) was 87.5 % (n=49; 95% CI 76.4-93.8). Median PFS was 8.0 months (95% CI 4.7-21.2). Grade ≥ 3 Treatment-related (TR) Treatment-Emergent Adverse events (TEAEs) were observed in 10/56 (17.9%) pts, Serious TR TEAEs were observed in 4/56 (7.1%) and 3/56 (5.4%) pts discontinued study drug due to TR TEAE. Data from additional key endpoints will be presented. Conclusion In this SS cohort from the TELLOMAK study, our data confirm that lacutamab monotherapy shows promising clinical activity in a R/R population previously treated with 2 or more prior systemic therapies including mogamulizumab, and an overall favourable safety profile. Continued evaluation of this new targeted treatment option for patients with SS is warranted.