Citations

8094 Background: Patients with extensive-stage small cell lung cancer (ES-SCLC) who progress after platinum-based chemotherapy plus immunotherapy have limited options. Whether adding lurbinectedin while continuing immune checkpoint blockade at relapse improves outcomes is unknown. We report results for the platinum-resistant cohort (progression ≤3 months from last chemotherapy) of MC1923. Methods: MC1923 is a phase II trial using a Simon optimal two-stage design. Patients were assigned to a starting dose of durvalumab 1500 mg IV plus lurbinectedin 3.2 mg/m 2 IV on Day 1 of 21-day cycle. The primary endpoint was the 6-month progression-free survival rate (PFS6). Accrual continued to 22 eligible patients if ≥2/9 achieved PFS6; the regimen would be considered promising if ≥7/22 (32%) were alive and progression-free at 6 months. Secondary endpoints included adverse events (AEs), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Twenty-two patients enrolled (02/04/2022–05/21/2025); all were eligible and treated. Median age was 66 years; 32% were male; ECOG performance status was 0 in 9% and 1 in 91%; 96% had prior atezolizumab. Median cycles delivered were 4 (range 1–13). PFS6 was 4/22 (18.2%; 95% CI, 7.5–44.1%), below the prespecified threshold. Median PFS was 3.1 months (95% CI, 1.6–5.3). ORR was 13.6% (3/22; all partial responses; 95% CI, 2.9–34.9%). At data cutoff (12/18/2025), 4 patients were alive; median follow-up was 16.8 months (range 5.5–39.6). Median OS was 7.4 months (95% CI, 4.3–18.6) and 1-year OS was 33.1% (95% CI, 17.6–61.9%). One (1) patient discontinued treatment with durvalumab due to AE. No treatment-related Grade 5 AEs occurred; Grade 3–4 AEs at least possibly related to treatment occurred in 32% (7/22); Grade 4 AEs occurred in 5% (1/22), all hematologic. Most common Grade 3 AEs were decreased neutrophils and white blood cells (each 9%). Conclusions: Durvalumab plus lurbinectedin demonstrated manageable toxicity in platinum-resistant ES-SCLC after chemoimmunotherapy but did not meet the prespecified PFS6 efficacy threshold, supporting the need for alternative strategies in this high-risk population. Clinical trial information: NCT04607954 .

8049 Background: Multiple pulmonary nodules (MPN) pose significant challenges for accurate staging of non-small cell lung cancer (NSCLC). As next generation sequencing (NGS) technologies have become more widely available on smaller amounts of tissue, the prevalence and clinical implications of heterogeneity between MPNs are poorly understood. This study retrospectively evaluates the histopathological and NGS findings after MPN biopsy in a single robotic-assisted bronchoscopy (RaB) procedure. Methods: 191 patients were retrospectively enrolled at 6 geographically diverse centers in the US. All patients had 2+ pulmonary nodules biopsied and staging EBUS in the same procedure. An expert molecular pathologist reviewed NGS data between nodule pairs to determine if they were discordant, concordant, or indeterminate. Results: Of 191 patients, 85 patients had 2 malignant nodules with 15 of those demonstrating histopathologic heterogeneity (e.g., one adenocarcinoma, one squamous cell carcinoma). 26 patients with 2 malignant nodules of similar histopathology demonstrated molecular heterogeneity between nodules. These cases were reviewed by an expert molecular pathologist who determined the following breakdown: -15 discordant pairs (57.7%) -3 concordant pairs (11.5) -8 indeterminate pairs (30.8%) Breakdown by nodule density: -Discordant: 7 same density, 8 different density -Concordant: 3 same density -Indeterminate: 5 same density, 3 different density Breakdown by nodule laterality: -Discordant: 7 ipsilateral, 8 contralateral -Concordant: 2 ipsilateral, 1 contralateral -Indeterminate: 4 ipsilateral, 4 contralateral Staging EBUS was performed in all 26 cases with malignancy identified in 2 cases. NGS sufficiency for NSCLC from three sites with standardized NGS reporting was as follows: 1 st nodule biopsied: 42/54 (77.8%), 2 nd nodule biopsied: 37/51 (72.5%), 3 rd nodule biopsied: 2/4 (50%). In total, 90/109 (82.6%) NSCLC samples had adequate tissue for NGS. In 85 cases with 2 malignant nodules, 35 (41.2%) had all nodules Stage IIB or lower. Notably, 25 (29.4%) of the cases did not have NGS available on one or more of the nodules, thus precluding staging. Conclusions: This study highlights the frequency and clinical relevance of histopathologic and molecular heterogeneity among synchronous MPNs. Importantly, heterogeneity was not limited to contralateral or anatomically distant lesions, challenging the assumption that spatial proximity implies clonal relatedness. Further, this study shows that relying solely on density or radiographic features of a nodule is an incomplete discriminator between separate primary lung cancers and intrapulmonary metastasis. Our findings support the need for an integrated diagnostic paradigm in which sampling of multiple lesions is used to inform clonality, refine staging, and guide precision therapy.

8057 Background: The NCI Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST) study tested resected stage II-IIIB(N2) NSCLC for targetable EGFR and ALK alterations and PD-L1 expression to screen patients for biomarker-driven adjuvant therapy trials (NCT02194738). Local lab results were requested when available for comparison to central lab results. Methods: We identified patients with both central and local PD-L1 results in the ALCHEMIST adjuvant immunotherapy study screening population. Discrepancies in tumor proportion score (TPS) between central and local PD-L1 were defined using prespecified cut-points (granular: <1%, 1-<5%, 5-<10%, 10-<20%, 20-<30%, 30-<40%, 40-<50%, 50-60%, 60-<70%, 70-<80%, 80-<90%, 90-<100%; clinical: <1%, 1-<50%, 50-100%). Large discrepancies were defined as ≥ 50 percentage point differences; for these cases, local PD-L1 and hematoxylin & eosin-stained slides were requested. These and all central slides were digitally scanned at 40X. Three expert pathologists reviewed the scanned slides in a blinded fashion. Differences between patient or tumor characteristics were assessed by Chi-square and Wilcoxon rank sum tests. Percent agreement was computed within and between the reviewers. Results: Central and local PD-L1 results were available for 497 patients. 177 cases (36%) had discrepancies that placed patients in different clinical TPS categories (<1%, 1-<50%, 50-100%). Among these, 43 cases had large TPS discrepancies; 14 had available local testing slides. 46 of the 320 cases without discrepancy were randomly selected as controls. No patient or tumor characteristics were associated with discrepancy, including tumor location, histology, grade or cancer stage (p > 0.05). Pairwise comparisons of TPS according to three pathologists re-reading the same scanned PD-L1 slides showed similar levels of disagreement in clinical TPS category whether there was initial discrepancy between central and local results (24%, 34%, and 23%; mean 27%) or not (33%, 30%, and 20%; mean 28%). Among the 14 cases with large initial discrepancies and local slides available, there was agreement in clinical TPS category when the anonymized central and local scanned slides were re-read by the pathologists in 54%, 38%, and 43% of cases, despite 100% non-agreement in initial reads. There were higher rates of agreement when the tested slides both originated from the same (100%) versus different (35%) blocks, when the same (48%) versus different (40%) PD-L1 antibodies were used, and when the cases were of non-squamous (52%) versus squamous (14%) cell carcinoma. Conclusions: There are substantial differences in PD-L1 TPS read by pathologists that can result in placement of patients in different categories commonly used for clinical management. These differences have clear implications in clinical trials and routine patient care.

8021 Background: Lung cancer is the leading cause of cancer-related mortality worldwide, primarily due to delayed diagnosis and diagnostic variability in histopathological assessment. Advances in deep learning applied to medical imaging offer the potential to enhance early detection accuracy, reduce interobserver variability, and improve diagnostic efficiency in lung cancer. Methods: In this retrospective study, we evaluated DAVINCI using a dataset of 8,962 patients with confirmed lung malignancies. The model utilizes a specialized architecture combining convolutional neural networks (CNNs) and residual blocks to optimize feature extraction from high-resolution pathological slides. Performance was measured via detection accuracy, recall, specificity, and Area Under the Curve (AUC). Results: A total of 8,962 patients were included in the analysis. The DAVINCI model correctly identified lung cancer in 93% of cases, corresponding to 8,334 of 8,962 patients, with a 95% confidence interval (CI) of 86%–100% (7,707–8,962 patients). Model specificity was also 93% (95% CI, 86%–100%), indicating a high true-negative rate. Sensitivity (recall) was 87%, with correct detection in 7,797 patients and a 95% CI of 80%–94% (7,170–8,425 patients). The model demonstrated strong discriminatory performance, achieving an area under the curve (AUC) of 0.91 (95% CI, 0.84–0.98). In comparison, active pathologists achieved a mean diagnostic accuracy of 83%, corresponding to 7,438 of 8,962 cases, with a 95% CI of 76%–90% (6,811–8,066 cases). In terms of efficiency, DAVINCI processed whole-slide images in 16–19 seconds, substantially faster than conventional manual review, which typically requires several minutes per slide. Conclusions: DAVINCI demonstrated superior accuracy, robust discriminatory performance, and markedly faster processing compared with human review, supporting its potential role in early lung cancer detection at scale.

7569 Background: MAIA and CEPHEUS trials demonstrated that daratumumab (Dara) with standard of care (SOC) VRd or Rd significantly improved clinical outcomes versus SOC in TIE NDMM. Here we describe efficacy and safety in TIE pts from both trials by age and baseline (BL) frailty using the latest data cuts. Methods: Pts were randomized 1:1 to DRd (n=368) or Rd (n=369) in MAIA and 1:1 to DVRd (n=144) or VRd (n=145) in CEPHEUS. Progression-free survival (PFS), complete response or better (≥CR), overall MRD negativity (neg) at 10 -5 with ≥CR, sustained MRD neg with ≥CR (confirmed MRD neg ≥12 ± 1 months [mo] apart without MRD positivity in between), and safety were assessed by age (<70, 70–<75, or ≥75 years [y]) and BL frailty (assessed by IFM simplified frailty score: 0–1, non-frail; ≥2, frail). Results: Median follow-up was 64.5 mo in MAIA and 76.0 mo in CEPHEUS. In MAIA, 155 (21%) pts were <70 y, 261 (35%) 70–<75 y, and 321 (44%) ≥75 y; 341 (46%) pts were frail, 88.0 % of whom were ≥70 y. In CEPHEUS TIE pts, 70 (24%) pts were <70 y, 133 (46%) 70–<75 y, and 86 (30%) ≥75 y; 83 (29%) pts were frail, 86% of whom were ≥70 y. DRd or DVRd improved PFS, MRD neg rates, sustained MRD neg rates, and ≥CR rates vs Rd or VRd arms across age and frailty subgroups in both trials (Table). Safety was consistent with established individual drug profiles, and adverse event rates were generally comparable across treatment arms and subgroups within both trials. Additional data on patient-specific factors relevant to these subgroups will be presented. Conclusions: Dara-based regimens improved efficacy outcomes across subgroups in MAIA and CEPHEUS trials, reinforcing Dara-based regimens as SOC in TIE NDMM regardless of age or frailty. These data offer clinically relevant insights to help guide treatment selection for TIE pts. Clinical trial information: NCT03652064 ; NCT02252172 . PFS, hazard ratio (95% CI) ≥CR rate, % MRD neg with ≥CR (10 -5 ) rate, % Sustained MRD neg with ≥CR (10 -5 ) rate, % Age/ Frailty status MAIA* CEPHEUS** MAIA* CEPHEUS ** MAIA* CEPHEUS** MAIA* CEPHEUS ** <70 y 0.35 (0.21–0.56) 0.60 (0.31–1.18) 56.4 vs 31.2 85.7 vs 68.6 35.9 vs 11.7 74.3 vs 42.9 25.6 vs 3.9 62.9 vs 28.6 70–<75 y 0.64 (0.45–0.89) 0.60 (0.37–0.99) 56.2 vs 31.3 77.9 vs 69.2 36.2 vs 12.2 55.9 vs 47.7 20.8 vs 5.3 45.6 vs 38.5 ≥75 y 0.59 (0.44–0.79) 0.46 (0.22–0.94) 44.4 vs 28.6 80.5 vs 44.4 26.9 vs 9.9 58.5 vs 26.7 13.8 vs 3.1 43.9 vs 15.6 Frail 0.64 (0.48–0.85) 0.62 (0.32–1.18) 44.8 vs 33.1 72.9 vs 54.3 25.6 vs 13.0 56.3 vs 34.3 15.7 vs 4.1 39.6 vs 17.1 Non-frail 0.48 (0.36–0.64) 0.51 (0.34–0.78) 56.6 vs 27.5 84.4 vs 63.6 37.8 vs 9.5 63.5 vs 41.8 21.4 vs 4.0 54.2 vs 32.7 *MAIA: DRd vs Rd; **CEPHEUS: DVRd vs VRd.

8001 Background: The ALCHEMIST clinical trial platform, launched by the National Clinical Trials Network (NCTN) in 2014, screened patients with resected non-small cell lung cancer (NSCLC) for molecular markers and tailored post-operative adjuvant therapy trials. A081105 evaluated whether adjuvant erlotinib improved overall survival (OS) following complete resection in patients with early stage EGFR mutated lung adenocarcinoma. Methods: A081105 was a randomized phase III trial enrolling patients with completely resected stage IB (≥4 cm), II, or IIIA non-squamous NSCLC (per the 7 th TNM staging classification) harboring EGFR exon 19 deletion or L858R mutations. Patients were randomized 1:1 to erlotinib 150 mg daily for up to 2 years or placebo/observation, stratified by stage, prior chemotherapy, EGFR mutation subtype, and ECOG performance status. The primary endpoint was OS in the per-protocol (PP) population with centrally confirmed EGFR mutations, designed to detect a hazard ratio (HR) of 0.67 in favor of erlotinib with a power of 86% and one sided type I error rate of 5%. Secondary endpoints included OS and disease free survival (DFS) in a modified intent-to-treat (mITT) population with local or centrally confirmed EGFR mutations, and safety. A prespecified backstop analysis was conducted after a minimum of 5 years of follow-up on all patients. Results: Trial enrollment was discontinued when 390 of the intended 450 patients had been enrolled due to the proven benefit of adjuvant osimertinib. Among 390 enrolled patients, the arms were balanced for age (median: 67.0 years), sex (70% female), race (70% white), stage (II: 51%, IIIA: 37%), prior chemotherapy (82%), ECOG PS 0 (60%), and exon 19 deletion (57%). Adjuvant erlotinib did not significantly improve OS compared with placebo/observation in the overall PP population (364 patients, 108 events, HR 0.89; 95% CI, 0.59–1.34; 1-sided P = 0.29) or within exon 19 deletion (HR: 0.94) or L858R mutation (HR: 0.82) subgroups. Five-year OS rates were 78.6% versus 77.9%, respectively. Results were consistent in the mITT analysis (379 patients, 113 events, HR 0.86; 95% CI, 0.58–1.28). Erlotinib improved DFS (mITT: 181 events, median: 68 vs 50 months, HR 0.74; 95% CI, 0.55–1.01). Across both arms, 11% of patients started non-protocol treatment (Osimertinib: 9%) prior to disease progression, and 9% withdrew consent for all follow-up prior to recurrence. In the erlotinib arm, 3 deaths on study were reported; grade 3 or higher adverse events were reported on 39% of patients. Median duration of treatment on Erlotinib arm was 16 months; only 37% of patients completed the planned treatment. Conclusions: In resected EGFR -mutant NSCLC, adjuvant erlotinib did not improve overall survival but improved DFS. Additional studies are exploring efficacy in selected subsets of patients using genomics and proteomic analyses. Clinical trial information: NCT02193282 .

8000 Background: The NCI’s ALCHEMIST program has screened thousands of patients with resected lung adenocarcinoma for mutations in EGFR and ALK. EA5142 studied the efficacy of adjuvant nivolumab after standard of care adjuvant therapy in patients with resected lung adenocarcinoma without sensitizing EGFR and ALK alterations and squamous cell carcinoma. Methods: Patients enrolled in the ALCHEMIST screening trial (A151216) with resected NSCLC tumors at least 4 cm and/or lymph node positive (N1/2) (for lung adenocarcinoma, without sensitizing EGFR and ALK alterations), were centrally tested for tumor cell PD-L1 expression using the DAKO 28-8 clone. After completion of all planned adjuvant therapy (chemotherapy and/or post-operative radiation) patients were randomized 1:1 to adjuvant nivolumab 480 mg IV every 4 weeks for up to 1 year or best supportive care. Patients were stratified by tumor histology, stage (AJCC 7 th edition IB/IIA vs IIB/IIIA), prior adjuvant treatment, and PD-L1 status (<1% vs ≥1%). The primary study endpoints were disease free survival (DFS) in all patients and in patients with high tumor PD-L1 expression (≥50%). Overall survival was powered to be tested hierarchically, if DFS was positive. Results: Between July 2016 and October 2019, 935 patients were randomized across 378 sites. The treatment arms were balanced for age (median 66 years), sex (52% male), smoking status (10% never smoked), histology (29% squamous), stage and PD-L1 expression (29% PD-L1 high). With a median follow-up of 72.6 months, nivolumab did not improve DFS in the intention to treat population (median DFS 71.3 months vs. 68.8 months in observation arm), hazard ratio (HR) 0.97 (95% CI 0.81-1.17, p=0.78) or the PD-L1 ≥50% subset (median DFS 89.8 months vs. 78.5 months in observation arm), HR 0.86 (95% CI 0.59-1.25, p=0.43). In multivariate analysis, adjusting for age, gender, and smoking history, the DFS HR was 0.99 (95% CI 0.82-1.19, p=0.89) in all randomized patients and 0.82 (95% CI 0.56-1.2, p=0.31) in the PD-L1 ≥50% subset. As the primary recurrence endpoint included any lung cancer, including new primaries, a sensitivity analysis was performed excluding new primary lung cancers, DFS HR 0.97 (95% CI 0.80-1.18, p=0.76) in all patients and HR 0.88 (95% CI 0.60-1.30, p=0.52 in the ≥50% subset. The median duration of treatment with adjuvant nivolumab was 9.4 months (range 0-12.7 months). The most common reasons for nivolumab discontinuation were adverse event (29%), patient withdrawal (11%), and disease progression while on treatment (10%). Treatment related grade 3-5 toxicities were reported in 25% of patients: Grade 3: 23%, Grade 4: 2%, Grade 5: <1%. Conclusions: In patients with resected NSCLC (≥4cm or LN+, EGFR/ALK -) adjuvant nivolumab did not improve DFS, irrespective of tumor PD-L1 expression. Clinical trial information: NCT02595944 .

7563 Background: Subcutaneous (SC) drug delivery options have become more widely available in multiple myeloma (MM). SC delivery of isatuximab (Isa), an anti-CD38 monoclonal antibody, has been investigated across clinical trials via a novel hands-free on-body injector (OBI). Isa SC OBI features a small, retractable needle, establishing the first device-enabled delivery of an oncologic treatment. The Phase 3 IRAKLIA, Phase 2 IZALCO, and Phase 1b (TCD15484) trials consistently demonstrated similar efficacy and safety of Isa SC OBI vs Isa IV in relapsed/refractory MM (RRMM) patients (pts). Here, we present a cross-trial analysis exploring safety and reliability of Isa SC OBI in RRMM pts. Methods: Pts with RRMM in IRAKLIA (N=263) and the Phase 1b expansion cohort (N=22) received 1400 mg Isa SC OBI plus pomalidomide and dexamethasone (d). In IZALCO, RRMM pts (N=64) received 1400 mg Isa SC OBI + carfilzomib (K)-d. Pts were monitored for 4 hrs (IRAKLIA) or 1-2 hrs (IZALCO) following first administration and for 1 hr for the following cycle (C) 1 administrations to assess local tolerability. Pre-infusion medications included montelukast (C1), steroids, acetaminophen and H1 antihistamines. Pts without systemic infusion-related reactions (IRRs) after 4 consecutive administrations of Isa SC OBI had subsequent pre-medication reassessed at investigator’s discretion. Safety and device performance explored in this cross-trial analysis of company sponsored studies were assessed in the Isa SC OBI cohorts by the duration of injection, IRRs, local injection-site reactions (ISRs), and injection/device success, which were defined similarly across all trials. Results: The median duration of Isa SC OBI injection was 13 mins in IRAKLIA, 12 mins in IZALCO, and 10 mins in the Phase 1b trial (6426 total injections, N=349 pts). IRRs across trials occurred in 6/6426 (0.09%) injections and 4/349 (1.15%) pts. IRRs were mostly grade 1 (G; 3/6426, 0.05%) with 1 G3 (0.02%); none leading to discontinuation. In IRAKLIA, 80/263 (30.4%) pts did not require premedication (931/5145 injections, 18.1%); no IRRs occurred in this group. Across trials, ISRs occurred in 21/349 (6.02%) pts resulting in 35 (0.54%) ISR events. Most ISRs were G1 (33, 0.51%), the remaining were G2 (2, 0.03%) and generally occurred on the day of injection. 99.9% (6421/6426) of injections in 98.6% (344/349) pts were successful (completed without interruption) across all trials. Conclusions: These findings support overall low, self-limiting rates of IRRs and ISRs across trials, with >6000 (99.9%) Isa SC OBI injections successfully delivered. Isa SC OBI shows reproducible safety and reliability in IRAKLIA, IZALCO and Phase 1b trials, supporting it as a novel administration option for MM pts and its potential for future exploration in at-home administration. Clinical trial information: NCT04045795 , NCT05405166 , and NCT05704049 .

7543 Background: Delayed neurotoxicity (DNT) after ciltacabtagene autoleucel (cilta-cel) is associated with severe morbidity and mortality occurring in 10-15% of patients. A high post-infusion peak absolute lymphocyte count (ALCpeak ≥3x10 9 /L; ALC hi ) is correlated with an increased risk of DNT (25-30%). We previously examined prophylactic dexamethasone (PPX DEX) administered for 3 days when ALC hi was reached and found no reduction in ALC expansion, DNT incidence or severity. Here, we report the use of prophylactic cyclophosphamide (PPX CTX) on ALC kinetics and DNT. Methods: We conducted a retrospective analysis of patients (pts) treated with cilta-cel at Mayo Clinic (09-12/2025; n =60). Pts with ALC hi received CTX 500 mg IV/PO once (n = 22). Outcomes and ALC kinetics including ALCpeak, ALC D28 (ALC D28 ), and area under the curve D1-D28 (ALC AUC ) were compared with PPX DEX cohort (12/2024-08/2025; n =50) and a historical cohort without PPX (04/2022-11/2024; n =116). Results: Pre-lymphodepletion (LD) demographics were similar across historical ALC hi , PPX DEX, and PPX CTX groups. Pre-LD CRP was higher in the historical ALC hi cohort; however, baseline ferritin, CRS, and ICANS, and disease burden did not differ significantly between groups. There were no statistically significant differences in time to ALCpeak or ALC kinetics among the 3 cohorts. Among pts with ALC < 3×10⁹/L treated during the PPX CTX study period, 2 developed cranial nerve palsy (IEC-CNP; 2/38, 5%). Both presented with unilateral facial nerve palsy and were treated with corticosteroids. One pt resolved symptoms by one month, while the second had persistent symptoms at 2 weeks and remains on follow-up. Among ALC hi patients in the PPX CTX cohort, DNT occurred in 4/22 pts (18%), including 1 case of IEC-CNP (5%) and 3 with parkinsonism (IEC-PKS, 14%). Within the PPX CTX cohort, baseline characteristics and post-infusion CRS or laboratory parameters did not differ between patients with and without DNT. Among patients who developed DNT, ALC kinetics were similar across PPX CTX, PPX DEX, and historical cohorts. PPX CTX was well tolerated, with 2 cases of grade 1 nausea reported. The incidence of DNT did not differ significantly between the PPX DEX (14/61, 23%) and PPX CTX (4/22, 18%) cohorts. However, DNT presentations in the PPX CTX cohort appeared milder and were responsive to treatment. Two of three patients (67%) presented with mild symptoms (one with dynamic dysphasia; second with flat affect) that responded to DEX. A third patient presented with typical parkinsonian features (hypomimia, bradykinesia, rigidity) and demonstrated clinical improvement following high-dose CTX. Conclusions: PPX CTX was well tolerated. While it did not significantly impact ALC expansion kinetics or DNT rates, first few cases of IEC-PKS suggest that the presentation may be milder and amenable to less toxic treatment. Larger cohorts are needed to refine optimal prophylactic strategies.

7501 Background: AL amyloidosis is a plasma cell dyscrasia (PCD) characterized by κ or λ Ig light chain amyloid fibrils that deposit in vital organs. Anselamimab is an investigational mAb designed to complement anti-PCD therapy through accelerated removal of amyloid fibrils. Cardiac Amyloid Reaching for Extended Survival (CARES) studies (NCT04512235 and NCT04504825) investigated the efficacy and safety of anselamimab compared with placebo, in addition to anti-PCD therapy. Methods: Alongside anti-PCD therapy with CyBorD (daratumumab was permitted) newly diagnosed patients with European modification of Mayo stage IIIa or IIIb AL amyloidosis were randomized 2:1 to receive anselamimab (1000 mg/m 2 ) or placebo (normal saline) IV every 7 days for 4 weeks followed by every 14 days for the remainder of the blinded study (18 months after the last participant enrolled). The primary endpoint was a hierarchical combination of time to all-cause mortality (ACM) and frequency of adjudicated cardiovascular hospitalizations (CVH) using the Finkelstein-Schoenfeld test and win-ratio in the combined study population. Subgroup analysis by involved κ or λ free light chain (iFLC) was prespecified. Results: 271 patients were randomized to receive anselamimab and 135 placebo. Baseline characteristics were similar between treatment arms. The median duration of treatment was 21.4 months and 21.1 in the anselamimab and placebo arms, respectively. Daratumumab was used in 79.3% and 83.7% of the anselamimab and placebo arms, respectively. Results of the primary efficacy analyses are shown in the table. Anselamimab-treated patients with κ iFLC had a 62% reduction in ACM (HR = 0.38; 95% CI, 0.17, 0.86; nominal P = 0.012) and a 71% reduction in risk for CVH (estimated CVH rate ratio = 0.29; 95% CI, 0.10, 0.87; nominal P = 0.028). Patients with λ iFLC had a 10% reduction in risk for CVH; none in ACM. Safety data were comparable between both treatment arms. In anselamimab-treated patients, safety findings were similar between κ subgroup and full population. Conclusions: Anselamimab, a κ light chain–directed anti-fibril monoclonal antibody used alongside standard of care chemotherapy, offers a first-in-class, new therapeutic option for patients with newly diagnosed κ AL amyloidosis. Clinical trial information: NCT04512235 and NCT04504825 . Summary of primary efficacy endpoints. Endpoint Overall κ Isotype λ Isotype Anselamimab (N=271) Placebo (N=135) P -value Anselamimab (N=48) Placebo (N=24) P -value Anselamimab (N=219) Placebo (N=109) P -value ACM and CVH win ratio (95% CI) 1.1 (0.8, 1.5) 0.332 2.06 (0.98, 4.31) 0.100 0.9 (0.6, 1.3) 0.848 ACM n (%) 90 (33.2) 52 (38.5) 15 (31.3) 14 (58.3) 73 (33.3) 37 (33.9) HR (95% CI) 0.8 (0.6, 1.1) 0.290 0.38 (0.2, 0.9) 0.012 1.0 (0.7, 1.5) 0.647 CVH Frequency/year (95% CI) 0.6 (0.4, 0.8) 0.9 (0.6, 1.4) 0.145 0.41 (0.2, 0.8) 1.4 (0.6, 3.4) 0.028 0.7 (0.4, 1.0) 0.8 (0.4, 1.3) 0.664 Incidence risk ratio (95% CI) 0.7 (0.4, 1.2) 0.29 (0.1, 0.9) 0.9 (0.5, 1.7)