OP10 Symptomatic improvement with intravenous guselkumab induction therapy is observed early in patients with moderately to severely active Ulcerative Colitis: post-hoc analysis of QUASAR

P0928 Improvements in patient-reported work productivity and activity impairment among patients with moderately to severely active ulcerative colitis (UC) treated with obefazimod induction therapy: pooled results from the 8-week ABTECT-1 and ABTECT-2 Phase 3, double-blind, placebo-controlled induction trials

Background: Decline in renal function is common in patients (pts) with transthyretin amyloidosis (ATTR) and is a marker of disease progression associated with mortality in ATTR with cardiomyopathy (ATTR-CM). The TTR-silencing RNAi therapeutic vutrisiran reduced risk of all-cause mortality (ACM) and cardiovascular (CV) events vs placebo (PBO) in pts with ATTR-CM in the Phase 3 HELIOS-B study (NCT04153149). Aims: To assess the potential impact of vutrisiran on renal function and efficacy/safety of vutrisiran in pts who advanced to CKD Stage 4 during the HELIOS-B double-blind (DB) period. Methods: HELIOS-B eligibility criteria included eGFR ≥30 mL/min/1.73m 2 . Pts were randomized 1:1 to vutrisiran 25 mg or PBO Q3M. In this post hoc analysis of the DB period (up to 33–36 months), the proportion of pts with eGFR decline ≥40% from baseline was assessed. The primary composite endpoint of ACM and CV events, as well as ACM, CV events, and safety, were also assessed in pts who progressed to CKD Stage 4 (eGFR <30 mL/min/1.73m 2 ) during the DB period. Outcomes were assessed overall and by baseline tafamidis use (monotherapy and baseline tafamidis subgroups). Results: Median (IQR) eGFR at baseline in pts receiving vutrisiran and PBO was 64 (50–81) and 65 (53–81) mL/min/1.73m 2 , respectively. In the overall population, fewer pts in the vutrisiran group experienced a ≥40% decline in eGFR from baseline vs PBO (12.7% vs 21.2%, respectively); results were consistent in monotherapy and baseline tafamidis subgroups ( Figure 1 ). Among pts who advanced to CKD Stage 4, in the overall population, vutrisiran reduced the risk of composite ACM and CV events vs PBO (HR [95% CI] 0.47 [0.26, 0.85]); similar results were seen in ACM and CV events, separately, and in the monotherapy and baseline tafamidis subgroups ( Figure 2 ; CV-related death: 34.3% with PBO; 9.7% with vutrisiran in the overall population). The safety profile of vutrisiran in pts who advanced to CKD Stage 4 was comparable with PBO. No new safety signals were reported. Conclusion: Vutrisiran appeared to preserve renal function in pts with ATTR-CM. Consistent with results from the overall population, vutrisiran reduced the risk of ACM and CV events vs PBO in pts with ATTR-CM and advanced CKD in HELIOS-B; results require corroboration in a larger pt population.

Reduction in corticosteroid use with rilzabrutinib and sustained response in adults with persistent/chronic immune thrombocytopenia in the long-term extension period of the Phase 3 LUNA3 study

Efficacy and safety of benralizumab in patients with hypereosinophilic syndrome: Results from the Phase 3 natron study

Abstract Background and Aims C3 glomerulopathy (C3G) and primary (idiopathic) immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases where uncontrolled C3 activation results in excessive glomerular deposition of C3 breakdown products. Current treatments, such as mycophenolate mofetil (MMF) and corticosteroids, are used off-label, primarily targeting inflammatory changes rather than the underlying disease mechanism. These treatments are associated with adverse effects and lack robust clinical evidence of efficacy. As a result, up to 50% of patients progress to kidney failure within 10 years. Pegcetacoplan (PEG) binds selectively to C3 and C3b to strongly block C3 activation by classical/lectin/alternative pathways, C3/C5 convertase activity and activation of downstream effectors. PEG targets the pathogenic process in C3G/primary IC-MPGN with the aim of stopping kidney damage. In the Phase 3 VALIANT study (NCT05067127) in pts aged ≥12 years with native or post-transplant recurrent C3G/primary IC-MPGN, PEG led to glomerular C3 clearance in 71% of pts and achieved significant and sustained reduction in proteinuria across all pt subgroups with stabilization of estimated glomerular filtration rate (eGFR). Change in proteinuria has been proposed as a predictor of progression to kidney failure [1]. Registry data show that a ≥50% reduction in proteinuria over time correlated with a significantly lower risk of kidney failure in C3G pts [1]. Pts with urine protein-to-creatinine ratio (UPCR) of <0.88 g/g 12 months after diagnosis have an 87% [2] reduction in kidney failure risk over 20 years. The aim of this analysis was to investigate the indicators suggesting a potential long-term protective effect of PEG in preventing kidney failure. Method Pts were randomized 1:1 to receive PEG (subcutaneous infusion twice weekly) or placebo (PBO) for 26 weeks as add-on to their stable treatment regimen. The primary endpoint was the log-transformed ratio of UPCR at Week 26 vs baseline. Secondary endpoints included the proportion of pts achieving a reduction in C3c staining on kidney biopsy and change in eGFR from baseline vs PBO. We present a pre-specified analysis on the effect of PEG on complement dysregulation and a post-hoc analysis on changes in proteinuria across the VALIANT population. Results Overall, 124 pts enrolled in VALIANT (63 PEG, 61 PBO). After PEG treatment, there was a rapid response in serum complement C3 and sC5b-9 from Week 4 that was maintained through 26 weeks. On treatment, C3 increased in all pts with a mean (standard deviation [SD]) change of 308.7 (94.7) mg/dL and soluble C5b-9 decreased with a mean (SD) reduction of 612.3 (614.7) ng/mL at Week 26 vs baseline, while no change was observed in PBO pts. Improvement in circulating complement biomarkers was associated with 25/35 (71%) PEG pts achieving 0 glomerular C3c staining at Week 26. Significant proteinuria reduction was observed as early as Week 4 in the PEG arm and remained stable up to Week 26 with no discernible change in UPCR over time in the PBO arm. Pts were categorized by proteinuria range at baseline and Week 26, and shift in proteinuria was evaluated. In the PEG arm, pt distribution across proteinuria ranges shifted towards lower values with 50.8% (32/63) achieving UPCR <1 g/g, including 31.7% (20/63) <0.5 g/g, and a decrease in proportion of pts in all higher UPCR ranges >1.5 g/g. In contrast, in the PBO arm at Week 26, there was no increase in the number of pts in the low proteinuria ranges while the proportion of pts in higher ranges either stabilized or increased, as expected (Figure). Conclusion PEG treatment led to an increase in serum C3 levels, a reduction in serum sC5b-9 and clearance of glomerular C3 deposition. Further, PEG treatment resulted in a significant and clinically meaningful decrease in UPCR to <0.5 g/g. These findings demonstrate a profound disease-modifying effect, regardless of baseline proteinuria levels. Based on registry data, the observed reduction in proteinuria across the cohort at 26 weeks suggests PEG treatment is likely to significantly lower the long-term risk of patients progressing to kidney failure.

Abstract Background and Aims C3 glomerulopathy (C3G) and primary (idiopathic) immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases where uncontrolled C3 activation results in excessive glomerular deposition of C3 breakdown products. Current treatments, such as mycophenolate mofetil (MMF) and corticosteroids, are used off-label, primarily targeting inflammatory changes rather than the underlying disease mechanism. These treatments are associated with adverse effects and lack robust clinical evidence of efficacy. As a result, up to 50% of patients progress to kidney failure within 10 years. Pegcetacoplan (PEG) binds selectively to C3 and C3b to strongly block C3 activation by classical/lectin/alternative pathways, C3/C5 convertase activity and activation of downstream effectors. PEG targets the pathogenic process in C3G/primary IC-MPGN with the aim of stopping kidney damage. In the Phase 3 VALIANT study (NCT05067127) in pts aged ≥12 years with native or post-transplant recurrent C3G/primary IC-MPGN, PEG led to a 68.1% relative proteinuria reduction vs placebo (PBO), glomerular C3 clearance in 71% of pts and stabilization of estimated glomerular filtration rate (eGFR). Pts with native or post-transplant recurrent C3G/primary IC-MPGN who present with nephrotic range proteinuria (urine protein-to-creatinine ratio [UPCR] ≥3 g/g) are at high risk of rapid disease progression to kidney failure, constituting a patient population with a high unmet medical need. The aim of this analysis was to evaluate the efficacy and safety of PEG vs placebo (PBO) in pts presenting with nephrotic range proteinuria at baseline. Method VALIANT study participants were randomized 1:1 to receive PEG (subcutaneous infusion twice weekly) or PBO for 26 weeks as add-on to their stable treatment regimen. The primary endpoint was the log-transformed ratio of UPCR at Week 26 vs baseline. Secondary endpoints included the proportion of pts achieving a reduction in C3c staining on kidney biopsy, change in eGFR from baseline vs PBO, and normalization of serum albumin. Results Overall, 124 pts were randomized in VALIANT (63 PEG; 61 PBO). At baseline, there were 24 (38.1%) and 16 (26.2%) pts in the PEG and PBO arm, respectively, who had UPCR ≥3 g/g. Baseline characteristics are shown in the Table. At Week 26, PEG-treated pts with baseline UPCR ≥3 g/g achieved a significant and clinically meaningful 72.1% relative reduction in proteinuria vs PBO (p < 0.0001). 66.7% (16/24) of pts in the PEG group vs 0% (0/16) in the PBO group had a ≥50% reduction in proteinuria from baseline (p < 0.0001). Furthermore, 66.7% (10/15) of PEG-treated pts with baseline UPCR ≥3 g/g and low baseline serum albumin achieved normalization of serum albumin at Week 26 vs 0% (0/12) for PBO. 84.6% (11/13) of pts achieved a reduction in glomerular C3c staining with PEG vs 0% (0/9) with PBO (p = 0.0002). PEG-treated pts experienced a mean change of +4.7 mL/min/1.73 m2 in eGFR, showing a relative improvement of +16.2 mL/min/1.73 m2 (p = 0.0046) vs PBO. Rates of treatment-emergent adverse events were comparable between PEG vs PBO pts with UPCR ≥3 g/g, similar to the overall study population, with no study discontinuations or deaths. Conclusion In the VALIANT trial, C3G/primary IC-MPGN pts presenting with nephrotic range proteinuria demonstrated robust reductions in proteinuria and glomerular C3, eGFR stabilization, and serum albumin normalization, confirming a disease-modifying effect of PEG in this severe subpopulation. PEG was well-tolerated and the safety profile was consistent with previous reports.

Introduction and Objective: HRS-7535, an oral small molecule GLP-1RA, is under development for T2DM and obesity. The study evaluated its efficacy and safety in T2DM participants (pts) inadequately controlled on metformin. Methods: In this randomized, double-blind, multicenter phase 2 study, 194 pts were randomized (1:1:1:1:1) to receive once-daily doses of HRS-7535 at 15, 30, 60, 90, or placebo (PBO). The 60 and 90 mg doses were targeted dose via titration. Primary endpoint was change from baseline in HbA1c at wk 16. Results: 177 (91.2%) completed 16-wk treatment period. At baseline, mean age was 52.3 yrs, HbA1c was 8.5%, BMI was 26.7 kg/m², body weight (BW) was 73.4 kg, 59.3% were men, and ~80% were taking ≥ 1500 mg/day metformin. At wk 16, the PBO-adjusted least-squares (LS) mean changes in HbA1c for HRS-7535 doses of 15, 30, 60, and 90 mg were -0.94%, -1.34%, -1.57%, and -1.39%, respectively (P<0.001 for all doses vs. PBO). At wk 16, the LS mean percentage change in BW reached -2.63% for the 90 mg group vs. -1.30% for PBO. At wk 16, HRS-7535 showed dose-related reductions in FPG, 2h-PG, and waist circumference. During the 16-wk treatment, 3.2% of HRS-7535 and 30.8% of PBO pts required rescue therapy. TEAEs occurred in 71.8-84.6% of HRS-7535-treated pts vs. 76.8% with PBO. Most TEAEs were gastrointestinal-related (nausea: 7.7-34.2% on HRS-7535 vs. 2.6% on PBO; diarrhea: 5.1-15.4% vs. 0%; vomiting: 2.6-15.8% vs. 0%), and mild to moderate. 9 pts (5.8%) on HRS-7535 had documented hypoglycemia; no Level 2 or higher events were reported. Pts on HRS-7535 showed a trend toward increased serum amylase and lipase levels, with no cases of pancreatitis observed. At wk 16, pts on HRS7535 had a mean pulse rate increase of 0.21-3.18 bpm from baseline. Conclusion: HRS-7535 significantly resulted HbA1c in Chinese pts with T2DM inadequately controlled on metformin and exhibited an acceptable safety profile consistent with other GLP-1RAs. Disclosure L. Guo: Research Support; Abbott, AstraZeneca, Bayer Pharmaceuticals, Inc, Eli Lilly and Company, Innovent Biologics, Merck & Co., Inc, MSD Life Science Foundation, Novo Nordisk A/S, Sanofi, Jiangsu Hengrui Pharmaceuticals Co., Ltd, Tonghua Dongbao. Z. Sun: None. L. Zhang: None. G. Qin: None. Y. Li: None. Z. Ye: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y. Xu: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. C. Shu: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. P. Liu: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Funding Jiangsu Hengrui Pharmaceuticals Co., Ltd.

LBA8010 Background: The phase 3 CheckMate 77T study demonstrated statistically significant and clinically meaningful improvement in EFS with perioperative NIVO vs PBO in pts with resectable NSCLC. pCR rates were also improved. Here, we report updated EFS, OS from the first prespecified interim analysis, and exploratory biomarker analyses. Methods: Pts with resectable stage IIA–IIIB (N2; AJCC v8) NSCLC were randomized 1:1 to neoadjuvant (neoadj) NIVO + chemotherapy (chemo) Q3W (up to 4 cycles [cyc]) followed by adjuvant (adj) NIVO Q4W (up to 13 cyc) or neoadj PBO + chemo Q3W (up to 4 cyc) followed by adj PBO Q4W (up to 13 cyc). The primary endpoint was EFS per BICR. Secondary endpoints included pCR, OS, and safety. Exploratory analyses included efficacy by pCR status, presurgery ctDNA clearance (CL), and tumor genomic alterations. Results: At a median follow-up of 41.0 mo (database lock, 16 Dec 2024), NIVO continued to provide EFS benefit vs PBO (HR [95% CI], 0.61 [0.46–0.80]; 30-mo EFS rates, 61% vs 43%) in all randomized pts and regardless of disease stage, tumor histology, or PD-L1 expression (Table). EFS from surgery (HR [95% CI]) continued to favor NIVO vs PBO in pts with pCR (0.90 [0.19–4.15]) or without (w/o; 0.72 [0.50–1.05]). In biomarker-evaluable pts (NIVO, 98; PBO, 92), pts with ctDNA CL had greater EFS benefit (assessed from randomization) vs pts w/o (HR [95% CI]: NIVO, 0.41 [0.20–0.86]; PBO, 0.62 [0.31–1.22]); pts with ctDNA CL with or w/o pCR had improved EFS vs pts w/o ctDNA CL and pCR (data to be presented). EFS (HR [95% CI]) favored NIVO vs PBO in pts with tumor genomic alterations ( KRAS , and/or STK11 , and/or KEAP1 mutations; 0.63 [0.32–1.23]) or w/o (0.65 [0.39–1.10]). Higher ctDNA CL and pCR rates were seen with NIVO vs PBO regardless of mutation status; additional efficacy and ctDNA outcomes will be presented. At the first prespecified interim OS analysis, NIVO showed a trend of OS improvement vs PBO in all randomized pts (HR [97.63% CI], 0.85 [0.58–1.25]; median OS, not reached in both tx arms; 30-mo OS rates, 78% vs 72%). Safety outcomes were consistent with previous reports. Conclusions: In this update, perioperative NIVO continued to show long-term EFS benefit and a favorable OS trend vs PBO in pts with resectable NSCLC; no new safety signals were observed. In exploratory analyses, presurgery ctDNA CL was associated with EFS benefit. EFS favored NIVO vs PBO regardless of KRAS , STK11 , and KEAP1 mutation status. Clinical trial information: NCT04025879 . All pts Stage II Stage III Squamous Non-squamous PD-L1 < 1% PD-L1 ≥ 1% NIVO (N = 229) vs PBO(N = 232) NIVO (n = 80) vs PBO(n = 81) NIVO (n = 149) vs PBO(n = 149) NIVO (n = 116) vs PBO(n = 118) NIVO (n = 113) vs PBO(n = 114) NIVO (n = 93) vs PBO(n = 93) NIVO (n = 128) vs PBO(n = 128) Median EFS, mo 46.6 vs 16.9 NR vs NR 42.1 vs 13.4 NR vs 16.4 40.1 vs 16.9 40.1 vs 19.8 46.6 vs 15.1 HR (95% CI) 0.61(0.46–0.80) 0.77(0.46–1.30) 0.54(0.39–0.74) 0.53(0.35–0.80) 0.69 (0.48–1.00) 0.79(0.52–1.21) 0.53(0.36–0.76)

6004 Background: The addition of PD-1 inhibitor to gemcitabine and cisplatin (GP) showed promising activity as first-line therapy for R/M NPC. Here, we first report the PD-L1 inhibitor Tagitanlimab (KL-A167) plus GP compared with placebo plus GP in a randomized phase 3 study (KL167-Ⅲ-08, NCT05294172). Methods: Eligible patients (pts) with previously untreated R/M NPC were in 2:1 ratio randomly assigned to receive tagitanlimab or placebo (1200 mg, D1) in combination with cisplatin (80 mg/m 2 , D1) and gemcitabine (1000 mg/m 2 , D1 and D8) every 3 weeks (Q3W) for up to 6 cycles followed by tagitanlimab or placebo monotherapy Q3W until disease progression, unacceptable toxicity, or withdrawal of consent. After disease progression, pts from the placebo arm could crossover to receive tagitanlimab monotherapy. The primary endpoint was progression-free survival (PFS) assessed by the blinded independent central review (BICR) according to RECIST version 1.1. Results: Between Jun 16, 2022, and May 27, 2023, 295 pts were assigned to tagitanlimab plus GP arm (n = 197) or placebo plus GP arm (n = 98). The median age was 52 years, and 79.7% were male. As of Feb 4, 2024, 47.2% of pts in tagitanlimab plus GP arm vs 23.5% of pts in placebo plus GP arm were still on treatment, 36.7% of pts in placebo plus GP arm were crossed to receive tagitanlimab monotherapy after disease progression. The median follow-up time was 11.7 months. The PFS per BICR was met at the prespecified interim analysis with a 53% reduction in risk of progression or death (HR 0.47; 95% CI, 0.33 to 0.66; one-sided P <0.0001). The median PFS was not reached (95% CI, 10.9-NE) in tagitanlimab plus GP arm and 7.9 months (95% CI, 6.9-8.3) in placebo plus GP arm; the 12-month PFS rate was 56.7% vs 26.7%. The objective response rate (ORR) per BICR was 81.7% (95% CI, 75.6-86.9) in tagitanlimab plus GP arm and 74.5% (95% CI, 64.7-82.8) in placebo plus GP arm, with a median duration of response (DoR) of 11.7 months (95% CI, 8.2-NE) and 5.8 months (95% CI, 5.6-6.9; HR 0.48, 95% CI, 0.32-0.70), respectively. The overall survival (OS) benefit was observed in tagitanlimab plus GP arm vs placebo plus GP arm (median OS not reached for either arm; HR 0.62, 95% CI 0.32-1.22). The most common ≥ grade 3 treatment-related adverse events (tagitanlimab plus GP arm vs placebo plus GP arm) were neutrophil count decreased (57.9% vs 49.0%), white blood cell count decreased (52.8% vs 46.9%), and anemia (38.6% vs 40.8%). Conclusions: The addition of tagitanlimab to GP demonstrated superior PFS efficacy compared to GP alone, supporting that tagitanlimab, as a PD-L1 inhibitor, could be the new standard of treatment for pts with R/M NPC in the first-line setting. The safety profile of tagitanlimab combined with GP was manageable and consistent with previous reports, with no new safety signals identified. Clinical trial information: NCT05294172 .

4000 Background: At 24.4-month (mo) median follow-up, adjuvant nivolumab demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) vs placebo with a well-tolerated safety profile in patients (pts) with resected EC/GEJC with residual pathologic disease following neoadjuvant CRT and surgery in the primary analysis from the global, phase 3 CheckMate 577 study (NCT02743494). We report the final analysis of the hierarchically tested secondary endpoint of OS along with longer follow-up of DFS. Methods: Adults with resected (R0) stage II/III EC/GEJC who received neoadjuvant CRT and had residual pathologic disease were randomized 2:1 to nivolumab 240 mg or placebo Q2W for 16 weeks, followed by nivolumab 480 mg or placebo Q4W. Maximum treatment duration was 1 year. The primary endpoint was DFS. OS was a secondary endpoint, and exploratory endpoints included safety, distant metastasis-free survival (DMFS), and progression-free survival on subsequent systemic therapy (PFS2). Results: 794 pts were randomized (nivolumab, n = 532; placebo, n = 262). With a median follow-up of 78.3 (range, 60.1–96.6) mo, adjuvant nivolumab continued to show DFS benefit vs placebo (HR 0.76 [95% CI 0.63–0.91]; Table). Median OS was numerically longer with nivolumab vs placebo (51.7 vs 35.3 mo), although the difference was not statistically significant (HR 0.85 [95.87% CI 0.70–1.04]; P = 0.1064; Table). OS rates at 3 and 5 years with nivolumab vs placebo were 57% vs 50% and 46% vs 41%, respectively. OS subgroup analyses will be presented. Clinically meaningful improvement in DMFS with nivolumab vs placebo was maintained (Table). PFS2 favored nivolumab vs placebo (HR 0.81 [95% CI 0.67–0.98]). In the nivolumab group, 46% of pts received subsequent therapy vs 60% in the placebo group; 5% vs 15% received subsequent immunotherapy. No new safety signals were identified. Conclusions: Adjuvant nivolumab demonstrated sustained long-term DFS benefit and numerical improvement in OS vs placebo in pts with resected EC/GEJC and residual pathologic disease following neoadjuvant CRT. The safety profile of adjuvant nivolumab remained well-tolerated with longer follow-up. These results further support the use of adjuvant nivolumab in this pt population. Clinical trial information: NCT02743494 . Efficacy Nivolumab(n = 532) Placebo(n = 262) Median DFS (95% CI), mo 21.8 (16.6–29.7) 10.8 (8.3–14.3) HR (95% CI) 0.76 (0.63–0.91) Median OS (95% CI), mo 51.7 (41.0–61.6) 35.3 (30.7–48.8) HR (95.87% CI; P value) 0.85 (0.70–1.04; P = 0.1064) Median DMFS (95% CI), mo 27.3 (21.4–36.0) 14.6 (10.9–20.3) HR (95% CI) 0.75 (0.62–0.90) Safety, n (%) n = 532 n = 260 Any-grade/grade 3–4 TRAEs 379 (71)/75 (14) 124 (48)/17 (7) Any-grade/grade 3–4 TRAEs leading to discontinuation 48 (9)/26 (5) 8 (3)/7 (3) TRAE, treatment-related adverse event.

3014 Background: No globally approved therapies exist for adults with NF1 and symptomatic, inoperable PN.KOMET is evaluating the efficacy and safety of selumetinib (SELU; ARRY-142886, AZD6244) in adults. Methods: KOMET is an ongoingPhase 3, randomized, double-blind, placebo-controlled trial. Adults (≥18 yrs) with NF1 and symptomatic, inoperable PN were randomized 1:1 to 28-day cycles of oral SELU 25 mg/m 2 BID or placebo (PBO) with crossover to SELU at progression or the end of Cycle (C) 12. Among others, baseline (BL) PAINS-pNF target PN chronic pain intensity score (< 3 or ≥3) was a stratification factor; 70% of patients (pts) were required to have a score ≥3. Primary analyses were conducted after the last pt completed C16 (data cutoff: Aug 5, 2024). The primary endpoint was objective response rate (ORR; confirmed partial/complete response) per ICR REiNS by the end of C16. Key secondary endpoints were change from BL to C12 in PAINS-pNF chronic pain score in pts with a BL score ≥3 and PlexiQoL total score in all randomized pts (SELU vs PBO). A planned sample of 73 pts per arm with a 2-sided 5% alpha Fisher’s exact test had > 99% power to detect the difference between a SELU ORR of 20% and PBO ORR of 0%. Key secondary endpoints were analyzed with a mixed model for repeated measures. Results: Of 145 randomized pts (SELU: 71; PBO: 74), 51.7% were male; median age was 29 yrs (range 18–60). SELU led to a rapid onset of response (median 3.7 mos), with an ORR of 19.7% (95% CI 11.2, 30.9) by C16 vs 5.4% (95% CI 1.5, 13.3) with PBO (p = 0.011). At C12, pts with a BL chronic pain score ≥3 had a greater reduction in pain score with SELU (LS mean −2.0; 95% CI −2.6, −1.4) vs PBO (LS mean −1.3; 95% CI −1.8, −0.7); and clinically meaningful improvement (meaningful score difference −2 points) vs BL, but this was not statistically significant vs PBO (p = 0.070). Reduction in chronic pain intensity was observed with SELU vs PBO in the full analysis set (all pts regardless of BL chronic pain intensity, nominal p = 0.024). Change from BL to C12 in PlexiQoL total score between treatment arms was not statistically significant (LS mean difference −0.1; 95% CI −1.2, 1.1). Adverse events (AEs) in the randomized period were consistent with the known safety profile of SELU. The most common AEs (≥10% of pts) were dermatitis acneiform (59%), increased blood creatine phosphokinase (45%), and diarrhea (42%) with SELU, and COVID-19 (20%), nausea (16%), and fatigue (14%) with PBO. Fourteen pts on SELU and 1 pt on PBO reported CTCAE Grade ≥3 treatment-related AEs; 9 SELU and 5 PBO pts discontinued due to AEs. Conclusions: In the first international, randomized, placebo-controlled trial in adults with NF1-PN, SELU achieved a significant ORR vs PBO (C16), meeting the primary endpoint, and a clinically meaningful reduction in PN-associated chronic pain (C12). Clinical trial information: NCT04924608 .

658 Background: In the phase 3, randomized, double-blind CheckMate 274 trial, adjuvant NIVO demonstrated statistically significant and clinically meaningful disease-free survival (DFS) benefit vs PBO in pts with high-risk MIUC after radical surgery (RS) ± prior neoadjuvant cisplatin-based chemotherapy (NAC). With extended 3-y median follow-up, continued improvements in DFS were seen with NIVO vs PBO in the primary efficacy populations (intent-to-treat [ITT], tumor programmed death ligand 1 [PD-L1] expression ≥ 1%) and in pts with MIBC. Early trends in interim OS favored NIVO vs PBO in ITT and tumor PD-L1 ≥ 1% pts. Here we report additional efficacy outcomes for pts with MIBC. Methods: Pts were randomized 1:1 to NIVO 240 mg every 2 wk or PBO for ≤ 1 y of adjuvant treatment, stratified by tumor PD-L1 expression, nodal status, and prior NAC. Primary endpoints were DFS in ITT and tumor PD-L1 expression ≥ 1% pts. OS in ITT and PD-L1 ≥ 1% pts was a secondary endpoint. Analysis of MIBC pts was exploratory. MIBC OS data are from preplanned interim analyses of ITT and PD-L1 ≥ 1% pts. OS follow-up is ongoing as the prespecified statistical boundaries for significance in ITT and PD-L1 ≥ 1% pts were not crossed at the time of these analyses. Results: Of 709 randomized pts (ITT), 560 (79%) had MIBC (NIVO, n = 279; PBO, n = 281); 284 (51%) of MIBC pts had prior NAC. With median follow-up of 36.1 mo (ITT), DFS improvement with NIVO vs PBO was consistent between all pts with MIBC (hazard ratio [HR] 0.63) and those with (HR 0.58) and without prior NAC (HR 0.69; Table). For OS, HRs favored NIVO vs PBO in all pts with MIBC (HR 0.70) and the tumor PD-L1 ≥ 1% subgroup (HR 0.48), as well as in pts with MIBC with (HR 0.74) and without prior NAC (HR 0.67). Safety was consistent with previous data in ITT pts; no new safety signals were identified. Conclusions: With 3-y median follow-up, consistent benefit in DFS was observed with NIVO vs PBO in all MIBC pts and across prior NAC subgroups. The HR for OS favored NIVO in all MIBC pts, in those with PD-L1 ≥ 1%, and regardless of prior NAC status. These results continue to support adjuvant NIVO as a standard of care for high-risk MIUC and MIBC, potentially providing an opportunity for a curative outcome. Clinical trial information: NCT02632409 . NIVOn NIVOMedian(95% CI), mo PBOn PBOMedian(95% CI), mo HR (95% CI) DFS All MIBC 279 25.6 (19.2–41.8) 281 8.5 (7.3–13.7) 0.63 (0.51–0.78) With prior NAC 142 19.6 (15.6–48.2) 142 8.3 (5.6–11.2) 0.58 (0.43–0.79) No prior NAC 137 25.9 (19.2–51.5) 139 13.7 (7.8–22.1) 0.69 (0.50–0.94) OS All MIBC 279 NR (45.0–NE) 281 39.9 (29.8–52.1) 0.70 (0.55–0.90) PD-L1 ≥ 1% 113 NR (NE–NE) 117 37.6 (26.9–NE) 0.48 (0.29–0.77) With prior NAC 142 55.2 (41.8–NE) 142 40.2 (28.8–53.7) 0.74 (0.53–1.03) No prior NAC 137 NR (40.7–NE) 139 37.7 (28.7–65.2) 0.67 (0.47–0.95) NE, not estimable; NR, not reached.

143 Background: In ARASENS, darolutamide (DARO) + ADT + docetaxel (DOC) significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P <0.0001) vs placebo (PBO) + ADT + DOC with similar incidence of treatment-emergent adverse events (TEAEs) between groups in patients (pts) with mHSPC. DARO + ADT + DOC has become one of the standards of care in mHSPC. We report post-hoc efficacy and safety in pts by age subgroups (<75 y, ≥75 y) in ARASENS. Methods: Pts were randomized to receive DARO 600 mg orally twice daily or PBO, with ADT + DOC. Age subgroups were analyzed for baseline characteristics including ongoing comorbidities, treatment duration, completion of DOC therapy, use of first subsequent therapy, key efficacy outcomes, and safety. Results: Of 1305 pts analyzed in ARASENS, ages ranged from 41–89 y, with 1086 pts <75 y (83%; DARO n=546; PBO, n=540) and 219 pts ≥75 y (17%; DARO n=105; PBO n=114). Baseline characteristics were generally similar in the DARO and PBO groups by age subgroup. The most common comorbidities by system organ class in pts <75 y and ≥75 y were vascular (55%, 67%), musculoskeletal/connective tissue (42%, 42%), and metabolism/nutrition (35%, 43%) disorders. Treatment duration was consistently longer with DARO vs PBO (<75 y: 41.2 vs 16.8 mo; ≥75 y: 38.5 vs 15.0 mo). Most patients completed 6 cycles of DOC (<75 y: 89%, 88%; ≥75 y: 80%, 76%). Among pts who entered follow-up, fewer DARO vs PBO pts initiated subsequent therapy independent of age (<75 y: 57% vs 76%; ≥75 y: 54% vs 73%). The overall survival (OS) benefit of DARO vs PBO was consistent across age subgroups (<75 y: HR 0.70, 95% CI 0.58–0.84; ≥75 y: HR 0.61, 95% CI 0.41–0.91). Time to metastatic castration-resistant prostate cancer (mCRPC) was longer with DARO vs PBO across age subgroups (<75 y: HR 0.35, 95% CI 0.30–0.43; ≥75 y: HR 0.42, 95% CI 0.28–0.64) as was time to initiation of subsequent therapy (<75 y: HR 0.40, 95% CI 0.34–0.48; ≥75 y: HR 0.35, 95% CI 0.22–0.54). TEAEs were generally similar between DARO and PBO, with slightly higher incidence rates in older pts. Few patients discontinued DARO or PBO due to TEAEs in both age subgroups (<75 y: 13.2%, 9.1%; ≥75 y: 15.1%, 17.7%). The most common grade 3/4 TEAEs were generally similar between DARO and PBO across age subgroups and occurred most frequently during overlapping DOC treatment. TEAEs commonly associated with androgen receptor pathway inhibitors occurred at similar incidences between treatment groups in both age subgroups. Conclusions: Pts with mHSPC benefited from DARO + ADT + DOC irrespective of age (<75 y and ≥75 y), with consistent improvements in OS, time to mCRPC, and time to initiation of subsequent therapy. DARO was well tolerated in both age subgroups, with similar incidences of TEAEs vs PBO. Clinical trial information: NCT02799602 .

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P1149 Guselkumab improves health-related quality of life as measured by PROMIS-29 in participants with moderately to severely active Crohn’s disease: Phase 3 GRAVITI study

DOP060 Early disease efficacy of guselkumab therapy in biologic-naïve patients with moderately to severely active Crohn’s disease: Post-hoc analysis from the phase 3 GALAXI 2 & 3 studies