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To elucidate mechanisms of renal excretion of pudexacianinium (ASP5354) and evaluate renal impairment effects on pharmacokinetics, safety, and tolerability of pudexacianinium. Transcellular transport and transporter-mediated uptake of pudexacianinium were investigated in cells expressing human renal drug transporters P-gp, BCRP, OAT1, OAT3, OCT2, MATE1, and MATE2-K. A Phase 1, open-label, parallel-group study (N = 28) was conducted in 6 participants each with mild, moderate, and severe renal impairment; 10 with normal renal function. Participants received a single intravenous dose of pudexacianinium 3 mg. Plasma and urine were collected post-dosing for pharmacokinetics. In vitro, pudexacianinium was not a substrate of the drug transporters tested. In humans, mean maximum concentration of pudexacianinium in plasma was comparable across study groups regardless of renal impairment. Systemic exposure was highest with severe renal impairment and decreased in parallel with renal impairment severity. Geometric least-squares mean ratios for area under the plasma concentration–time curve from time 0 to time infinity were 1.53, 2.30, and 3.69, respectively, for mild, moderate, and severe renal impairment, versus matched participants with normal renal function. During the 48-h collection, 64

Purpose: Avacincaptad pegol (ACP) is a pegylated RNA aptamer that inhibits complement C5. The efficacy and safety of ACP 2 mg was investigated in GATHER2, with positive year 1 results published. Herein, 2-year results are reported. Design: Phase 3, randomized, sham-controlled study (ClinicalTrials.gov identifier, NCT04435366). Participants: Patients with non-center point-involving geographic atrophy (GA). Methods: Eligible patients were randomized 1:1 to receive monthly ACP 2 mg (n = 225) or sham (n = 222) for 1 year. At month 12, patients who received ACP 2 mg were randomized again 1:1 to dosing every month (EM; n = 96) or every other month (EOM; n = 93) with ACP 2 mg. Patients who had received monthly sham continued with sham (n = 203). Main Outcome Measures: The safety and efficacy of ACP versus sham administration over 2 years and the effect of ACP EM or EOM dosing in year 2. Results: Overall, 175 and 184 patients in the ACP and sham group completed the study at year 2, respectively. At 2 years, treatment with ACP demonstrated a continued reduction in GA growth (slope) with both ACP EM and EOM versus sham. From baseline to year 2, the mean rate of GA area growth was 4.46 mm2 (standard error [SE], 0.25 mm2) with ACP EM and 5.18 mm2 (SE, 0.17 mm2) with sham, a difference in growth of 0.724 mm2 (95% confidence interval [CI], 0.133-1.315 mm2; P = 0.0165), representing a 14% difference. From baseline to year 2, the mean rate of GA area growth was 4.20 mm2 (SE, 0.25 mm2) with ACP EOM, a difference in growth of 0.976 mm2 (95% CI, 0.377-1.575 mm2; nominal P = 0.0015) versus sham, representing a 19% difference. The incidence of choroidal neovascularization (study eye) was 11.6% with ACP (all treated) versus 9.0% with sham over 2 years. No events of retinal vasculitis, ischemic optic neuropathy, or serious intraocular inflammation occurred over 2 years. Conclusions: Dosing of ACP 2 mg, either EM or EOM, continued to reduce GA growth versus sham therapy over 2 years with no new safety signals compared with year 1. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. Ophthalmology 2026;133:451-465 (c) 2025 by the American Academy of Ophthalmology. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

Zolbetuximab is a monoclonal antibody targeting claudin 18 isoform 2 (CLDN18.2) approved for first-line treatment of CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Here, we report efficacy and safety outcomes from the combined Japanese subgroup analysis of SPOTLIGHT and GLOW. Global, double-blind, phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials investigated zolbetuximab plus chemotherapy versus placebo plus chemotherapy in patients with CLDN18.2-positive, HER2-negative, LA unresectable or metastatic gastric or GEJ adenocarcinoma. The primary endpoint in both trials was progression-free survival (PFS); overall survival (OS) was a key secondary endpoint. Of 1072 patients enrolled, 116 Japanese patients (SPOTLIGHT, n = 65; GLOW, n = 51) comprised the combined Japanese subgroup. The baseline characteristics of Japanese patients were generally similar to those of the overall study populations. In the combined Japanese subgroup, PFS was improved with zolbetuximab plus chemotherapy versus placebo plus chemotherapy (20.53 months [95

BACKGROUND:Patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy proceed directly to radical cystectomy with pelvic lymph-node dissection. Perioperative therapy may improve outcomes in this population. METHODS:In this phase 3, open-label trial, participants with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy were randomly assigned to perioperative (neoadjuvant and adjuvant) enfortumab vedotin, an antibody-drug conjugate directed at nectin-4, plus pembrolizumab and surgery (9 total cycles of enfortumab vedotin [1.25 mg per kilogram of body weight on days 1 and 8] plus 17 total cycles of pembrolizumab [200 mg on day 1 every 3 weeks], with surgery after 3 cycles) or surgery alone (control). The primary end point was event-free survival. Key secondary end points were overall survival and pathological complete response (absence of viable tumor after surgical resection). Other secondary end points included safety. RESULTS:A total of 344 participants underwent randomization (170 in the enfortumab vedotin-pembrolizumab group and 174 in the control group). At data cutoff, median follow-up was 25.6 months (range, 11.8 to 53.7). Surgery was performed in 87.6% of participants in the enfortumab vedotin-pembrolizumab group and in 89.7% in the control group. At 2 years, estimated event-free survival was 74.7% in the enfortumab vedotin-pembrolizumab group and 39.4% in the control group (hazard ratio for an event or death, 0.40; 95% confidence interval [CI], 0.28 to 0.57; two-sided P<0.001); estimated overall survival was 79.7% and 63.1% (hazard ratio for death, 0.50; 95% CI, 0.33 to 0.74; two-sided P<0.001). A pathological complete response had occurred in 57.1% and 8.6% of the participants (estimated difference, 48.3 percentage points; 95% CI, 39.5 to 56.5; two-sided P<0.001). Adverse events occurred in all participants in the enfortumab vedotin-pembrolizumab group (grade ≥3, 71.3%; grade ≥3 drug-related, 45.5%) and in 64.8% in the control group (grade ≥3, 45.9%). CONCLUSIONS:Perioperative enfortumab vedotin plus pembrolizumab and surgery led to significantly better event-free and overall survival outcomes and a greater percentage of participants with pathological complete response than surgery alone in a predominantly cisplatin-ineligible population with muscle-invasive bladder cancer. Safety was also assessed. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-905 ClinicalTrials.gov number, NCT03924895.).

LBA630 Background: Enfortumab vedotin (EV) + pembrolizumab (pembro) is the established first-line standard of care for locally advanced/metastatic urothelial carcinoma and represents a novel neoadjuvant and adjuvant treatment strategy for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. The randomized phase 3 KEYNOTE-B15/EV-304 study (NCT04700124) evaluates neoadjuvant and adjuvant EV + pembro followed by radical cystectomy plus pelvic lymph node dissection (RC + PLND) vs neoadjuvant chemotherapy followed by RC + PLND in participants (pts) with MIBC who are eligible for cisplatin-based therapy. Methods: Pts with clinical stage T2-T4aN0M0 or T1-T4aN1M0 MIBC (confirmed by central pathology and central imaging assessment) who were eligible for cisplatin-based chemotherapy and RC + PLND were randomized 1:1 to receive either 4 cycles neoadjuvant EV 1.25 mg/kg IV on days 1 and 8 + pembro 200 mg IV on day 1 Q3W, followed by RC + PLND, and adjuvant 5 cycles EV + 13 cycles pembro (EV + pembro arm) vs 4 cycles neoadjuvant gemcitabine 1000 mg/m 2 on days 1 and 8 + cisplatin 70 mg/m 2 on day 1 Q3W, followed by RC + PLND (cis + gem arm). The primary endpoint was event-free survival (EFS) by blinded independent central review. Key secondary endpoints were pathological complete response (pCR) rate by blinded central pathological review and overall survival (OS). Safety was a secondary endpoint; AEs of special interest were based on distinct prespecified lists for each drug. Results: A total of 405 and 403 pts were randomized to EV + pembro and cis + gem, respectively. Median time from randomization to the data cutoff date of October 27, 2025 was 33.6 months (range, 22.5–53.6). Baseline characteristics were generally balanced between groups. EV + pembro significantly improved EFS (median NR vs 48.5 mo; 24-mo estimated EFS rate 79.4% vs 66.2%; HR 0.53, 95% CI 0.41–0.70; 1-sided P <.0001), OS (median NR vs NR; 24-mo estimated OS rate 86.9% vs 81.3%; HR 0.65, 95% CI 0.48–0.89; 1-sided P =.0029), and pCR rate (55.8% vs 32.5%; estimated difference 23.4%, 95% CI 16.7–29.8; 1-sided P <.0001) vs cis + gem. Grade ≥3 treatment-emergent AEs occurred in 75.7% of pts with EV + pembro and 67.2% with cis + gem. Most common grade ≥3 drug-related AE of special interest for EV was skin reactions (14.1%); most common grade ≥3 AE of special interest for pembro was severe skin reactions (13.9%). Conclusions: Neoadjuvant and adjuvant EV + pembro significantly improved EFS, OS, and pCR rate compared with neoadjuvant gem + cis in pts with MIBC who were eligible for cisplatin-based chemotherapy. The safety profile of EV + pembro was consistent with prior experience with the combination. These results support EV + pembro as an effective perioperative treatment option in this setting. Clinical trial information: NCT04700124 .