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Optimization of immunotherapy duration for advanced melanoma: The prospective OTIMAS trial.
1608 Background: Anti-PD1 monotherapy is a common option for first-line treatment for advanced melanoma in resource-constrained settings. A shorter duration of therapy and associated biomarkers of response can reduce financial burden for healthcare systems. Methods: In this phase 2 single-arm trial, pts with unresectable stage III-IV melanoma received pembrolizumab (Pem) 200mg intravenously every 3 weeks for a maximum of 12m. Primary endpoint was 24m progression-free survival (PFS); secondary endpoints included overall response rate per RECIST 1.1 and overall survival (OS) and safety. An additional course of therapy was allowed if progression was observed after 6m of treatment interruption. Exploratory analysis included miRNA cargo of small extracellular vesicles (sEVs) and cost-effectiveness analysis of 12m vs. 24m in the context of the universal Brazilian health system. Results: 29 pts were enrolled from Jan 2022 to Jan 2025. As of Sep 2025, all had completed treatment, with a median follow-up of 19.1m (0.6-45.3). Median age was 59 years (28-85), 55.2% were male, 72.4% had metastatic disease and 20.7% had ECOG-PS >1. 41.4% presented with high baseline LDH. 2 pts had acral melanoma. 20.6% had received previous chemotherapy. Median PFS was 5.7m (IC95% 3.1-8.4) and 24m-PFS, 23.8%. 2-y OS was 42.8% (IC 95% 24.2-61.4). ORR was 34.5% (10/29), with 51.7% DCR. Among 24.1% who completed 12m of Pem, only one pt experienced PD less than 6m after completion of Pem. One death due to immune related pneumonitis was observed. The percentage of variable expressed regions in sEVs differed according to immunotherapy (IO) response profile. Cost analysis showed that the medication cost was reduced by 53.75% when compared to the 2-year strategy. Conclusions: This trial demonstrated that one year treatment with IO is feasible and provides comparable outcomes to a standard 24m treatment (mPFS 5.6 range 3.4–8.2; 2-year OS 55% IC 95% 49-61%), regardless of response. This strategy can be cost effective and provide broader access to immunotherapy and improve resource allocation in public health systems. Specific miRNAs were identified for a potential response signature to select patients with long-term benefit. Clinical trial information: NCT07376317 .
Genomic landscape of <i>KRAS</i> mutations: A retrospective clinico-genomic database analysis.
e15085 Background: Since the approval of KRAS G12C inhibitors, there is ongoing interest in trials for combination treatments with these agents beyond lung cancer, KRAS G12D and pan-RAS inhibitors. In this context, we present the genomic landscape of KRAS mutations to inform future clinical studies. Methods: We searched the American Association for cancer research project genomics evidence neoplasia information exchange (AACR GENIE) version 19.0, for distribution of KRAS mutations across tumor types, race and sex; as well as mutation subtypes, copy number alterations (CNA), and co-mutations. For patients with multiple samples, only one was retained. The data was filtered for p-value < 0.001 and odds ratio > 2 or < 0.5. Results: We identified KRAS alterations in 33,391 patients, mostly missense mutations ( > 99%). 52.1% of these were females, 63.1% white and 6.6% were black. 54% of mutated samples were from primary tumors and 31% from metastatic sites. The most common cancers with KRAS alterations were colorectal cancer (CRC) (26.8%), pancreatic cancer (PAC) (24.7%), non-small cell lung cancer (NSCLC) (23.3%), endometrial cancer (4.6%) and cancer of unknown primary (3.9%). 584 different KRAS variants were identified. The most common alterations were G12D, G12V, and G12C in both sexes, with females harboring more G12C and males more G12D. Similarly, Asians were ore enriched in G12D and G13D compared to black and white patients but the p values were not statistically significant due to smaller representation of minority races in the data. Most common KRAS mutations in NSCLC were G12C, G12V, G12D and G12F. Most common KRAS mutations in pancreatic cancer were G12D, G12V, G12R and Q61H. The frequencies of relevant co-mutations in CRC, PAC and NSCLC are described in the table. Relevant CNA observed were FLT1/3, MYC, BRCA2 amplifications and SMAD4 deletions for CRC; CDKN2A/B, MTAP and SMAD4 deletions and GATA6 amplifications for PAC. These patterns were similar for both sexes and races with slightly higher prevalence of TP53 mutations in Asians. PTEN, EGFR, ERBB2, MET and BRAF were mutually exclusive with KRAS. Conclusions: The distribution of KRAS mutations in our study is consistent with known literature. We found higher prevalence of KRAS G12D mutations in Asians, which is informative for future clinical trial designs. With KRAS G12D inhibitors on the horizon, and ongoing research for pan-RAs inhibitors and combination therapies, it is important to review the current genomic landscape of KRAS mutations in diverse cohorts of patients to address any disparities, and ideally lead to better insight into the reasons for these differences. Relevant Co-mutations with KRAS in major solid tumors. Tumor Type Gene Frequency (%) Colorectal cancer APC 73.1 TP53 63.6 NDRG1 33.3 PIK3CA 26.3 Pancreatic cancer SET 89.5 NDRG1 84.2 STIL 84.2 TP53 77.1 FGFR1 73.7 Non-small cell lung cancer TP53 40.9 FGFR1 21.8 STK11 21.4 KEAP1 19.5
Treatment outcomes for non-metastatic colorectal cancer in Nigeria: A 10-year retrospective study.
e15655 Background: Although the role of chemotherapy in the treatment of non-metastatic colorectal cancer (CRC) has been established little is known on its role and treatment outcomes in the Nigerian cohort. Recent data shows a unique biology and a prevalence of 28% of mismatch repair deficient CRC in the Nigerian population. It is unclear if this unique biology informs similar treatment approach in established guidelines. We set out to study the treatment outcomes of surgery, and chemotherapy in stage II and III CRC in Nigeria. Methods: This is a retrospective study on 381 patients with stage 2 and 3 CRC from 2013 to 2023. Patients were staged using the 8 th edition AJCC TNM. Data on these patients were retrieved from the African Research Group for Oncology (ARGO) database. Patients in each stage were subdivided into 5 groups based on the modality of treatment received (surgery alone; neoadjuvant therapy + surgery; surgery + adjuvant therapy; neoadjuvant therapy + surgery + adjuvant therapy; and chemotherapy alone). Primary end points of the study were overall survival (OS) and disease-free survival (DFS); and secondary end point was to identify the modality of treatment most appropriate for each stage. Data was analysed using Kaplan Meier curves and log rank test for survival outcomes. Results: The study showed that 40.6% of stage 2 and 40.4% of stage 3 CRC patients had surgery alone, while 59.4% and 59.6% of stage 2 and 3 respectively had combined chemotherapy and surgery. The median disease-free survival and overall survival was similar for both stages (10 months, p = 0.508; 9 months, p = 0.722 respectively). Patients with stage 3 who had either neoadjuvant chemotherapy or adjuvant chemotherapy had better OS when compared with patients who had surgery alone (p = 0.021; p = 0.001 respectively). Conclusions: This study advocates for the use of (neo)adjuvant chemotherapy for stage 3 CRC in Nigeria. This is in line with current NCCN and ASCO guidelines for stage 3 CRC. Prospective studies would be needed to fully explore the role of combined treatment modality (surgery and chemotherapy) in the non-metastatic setting.
NEO-ERA-01(CLEAP2507): A multi-center, single-arm, phase II study with neoadjuvant therapy of HAIC (GEMOX) combined with adebrelimab and lenvatinib for resectable intrahepatic cholangiocarcinoma with high-risk recurrence factors.
e16295 Background: The high recurrence rate after resection compromises survival in patients with resectable intrahepatic cholangiocarcinoma (ICC). Propensity score–matched studies indicate that neoadjuvant chemotherapy improves overall survival (OS) in high-risk resectable ICC. This study evaluates the efficacy and safety of neoadjuvant hepatic artery infusion chemotherapy (HAIC) combined with adebrelimab and lenvatinib in this population. Methods: This multicenter, single-arm, phase II trial was conducted for Pts with resectable, high-risk ICC, defined as tumor size > 5 cm, multiple tumors, presence of radiographic major vascular invasion, or lymph node involvement. Pts received 2-4 cycles of neoadjuvant therapy, consisting of HAIC-GEMOX (Oxaliplatin 85mg/m 2 and Gemcitabine 800mg/m 2 on Days 1 Q3W), Adebrelimab (1200mg on Days 3 Q3W) and Lenvatinib (8mg on Days 5-21 Q3W), followed by curative-intent surgical resection. The primary endpoint was completion rate of study treatment，defined as proportion of patients receive both neoadjuvant therapy and subsequently curative-intent surgical resection. Secondary endpoints included safety, R0 resection, OS, objective response rate (ORR), event-free survival (EFS), complete pathological response (pCR) and major pathological response (MPR) defined as ≤50% residual viable tumor cells in resection bed. Results: As of January 15, 2026, 31 Pts (median age 58 and 58% male) were enrolled from 4 sites in China. 27 Pts completed all neoadjuvant therapy (mean 2.5 cycles), followed by surgery. 1 Pts were still undergoing neoadjuvant therapy, and 3 Pts did not undergo surgery: one due to disease progression, one due to adverse events and another chronic heart failure. According to RECIST 1.1, 30 Pts underwent imaging evaluation. The ORR and DCR were 43.3% and 93.3% respectively (CR:3.3%, PR:40.0%, SD: 50%, PD:6.7%). Among 27 Pts, 25 (92.6%) Pts achieved MPR (2 Pts achieved pCR). The R0 resection rate was 96.3%. Median size of largest tumor was 5.9 cm and 44.4% were lymph node positive. 11 (35.5%) Pts experienced grade 3 treatment-related adverse events, with the most common being hypertension, thrombocytopenia, ALT elevated, GGT elevated and cough, with no grade 4/5 adverse events. One patient experienced Clavien-Dindo grade 3b complications of wound ulceration. No treatment-related mortality occurred. EFS and OS are immature. Conclusions: Neoadjuvant HAIC (GEMOX) combined with adebrelimab and lenvatinib showed good feasibility, acceptable safety, and promising pathological responses in high-risk resectable ICC. Perioperative safety was not compromised. Long-term survival outcomes require ongoing follow-up. Clinical trial information: NCT06208462 .
NRG-GY037: A phase III randomized trial of induction chemotherapy and pembrolizumab followed by chemoradiation and pembrolizumab maintenance versus standard chemoradiation and pembrolizumab maintenance in high-risk locally advanced cervical cancer.
TPS5632 Background: Concurrent chemoradiation therapy (CCRT) is the standard of care for locally advanced cervical cancer (LACC); however, outcomes remain suboptimal in patients with high-risk disease. Recent studies suggest that integration of immunotherapy (IO) with definitive chemoradiation, or induction chemotherapy prior to CCRT improves outcomes. Whether treatment intensification with induction systemic therapy and IO prior to CCRT and IO further improves disease control remains unknown. Induction chemotherapy may reduce tumor burden, eradicate micrometastatic disease, and improve tumor immunogenicity prior to definitive CCRT. Preclinical and clinical data support synergy between systemic therapy or radiotherapy and immune checkpoint blockade, providing the rationale for evaluating an induction strategy incorporating chemotherapy and immunotherapy before standard CCRT with immunotherapy, followed by maintenance immunotherapy. Optional tumor tissue and blood samples will be collected for exploratory correlative analyses, including immune and molecular biomarkers associated with response, resistance, and patterns of failure. Methods: NRG-GY037 is a prospective, multi-institutional phase III randomized trial conducted through NRG Oncology. A total of 336 patients will be enrolled (168 per arm). Patients will be stratified by FIGO stage (III vs. IVA) and presence or absence of para-aortic lymph nodes (N2). The primary endpoint is progression free survival (PFS). The study has 90% power to detect PFS hazard ratio of 0.65 in the experimental arm. Treatment: Patients with previously untreated, high-risk LACC are randomized to receive either induction chemotherapy with pembrolizumab for 6 weeks followed by CCRT with pembrolizumab and pembrolizumab maintenance, or standard CCRT with pembrolizumab followed by pembrolizumab maintenance. Major Eligibility Criteria: Eligible patients have histologically confirmed cervical carcinoma (squamous, adenocarcinoma, or adenosquamous), TNM T3 and T4 disease, N0-2, ECOG performance status 0–1, and no prior definitive therapy for cervical cancer. Current Enrollment Status: The trial is actively accruing patients. No efficacy or safety data are available at the time of submission. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT07061977. Clinical trial information: NCT07061977 .
Influence of precision treatment with artificial intelligence–assisted subtyping on first-line therapeutic efficacy in HR+/HER2– breast cancer.
e13054 Background: The combination of CDK4/6 inhibitors and endocrine therapy (ET) has become the first-line standard treatment for HR+/HER-2- advanced breast cancer (ABC). A certain number of patients who are not sensitive to endocrine therapy and progress rapidly during CDK4/6 inhibitor treatment 20% to 30% of the patients experienced disease progression within 12 months. Screening of those insensitive individuals and further exploration of the optimal treatment strategies is currently the greatest challenge faced by HR+ ABC. Methods: This is a randomize, open-labeled, multi-center phase Ib/II trial (NCT05759572). AI-assisted digital pathology classified of SNF4 subtype patients had pathologically confirmed hormone receptor-positive, HER2-negative with untreated ABC were enrolled. In safety lead-in phase, 9 patients were enrolled (following the 3+3+3 protocol) to receive oral apatinib (250 mg per day) with dalpiciclib (125 mg per day for 3 weeks, followed by 1 week off) and endocrine therapy to determine the safety and dose for subsequent phase II part. In pahse II patients were randomly assigned (1:1) to receive dalpiciclib (125 mg per day for 3 weeks, followed by 1 week off) and endocrine therapy with or without oral apatinib (250 mg per day). Randomisation was stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting. Safety was analyzed in all randomly assigned patients who received at least one dose of study treatment. Results: Between March 1, 2023, and August 1, 2024, 157 patients were screened and 145 were eligible and enrolled. In safety lead-in phase 9 patients were enrolled and the recommended phase 2 dose was determined as oral apatinib (250 mg per day) and dalpiciclib (125 mg per day for 3 weeks, followed by 1 week off) with endocrine therapy. In phase II part 136 patients were randomly assigned to the apatinib+dalpiciclib with ET ( precision group, n = 68) or dalpiciclib with ET (control group, n = 68). Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (27.8m vs 19.4m; stratified hazard ratio 0.57 [95% CI 0.36–0.91]; two-sided log-rank p = 0.017). Adverse events of grade 3 or 4 were reported in 72(93.5%) of 77 patients in the precision group and 62 (91.1%) of 68 patients in the control group. The most common adverse events of grade 3 or 4 were neutropenia (71 [92.2%] in the precision group vs 62 [91.1%] in the control group) and leukopenia (70 [91.0%] in the precision group vs 60 [88.2%]). Conclusions: AI-assisted digital pathology classification identified SNF4 patients who were resistant to ET combined with CDK4/6 inhibitor. The first-line treatment of apatinib combined with ET and CDK4/6 inhibitor, significantly improved the prognosis of these SNF4 patients with tolerated toxicity. Further prospective phase III trial has currently been conducted. Clinical trial information: NCT05759572 .
A targeted phosphoproteomic assay to enable the prediction of response to intensive chemotherapy in acute myeloid leukemia.
6521 Background: Intensive chemotherapy (IC; cytarabine plus an anthracycline) remains a standard first-line therapy for fit patients with acute myeloid leukemia (AML), a heterogeneous hematologic malignancy with poor long-term survival. IC induces composite complete remission (cCR) in ~60–70% of cases, and IC response variability persists within genetic/ELN risk strata. As emerging regimens increasingly challenge IC as a default therapy, biology-informed predictors are needed to identify patients unlikely to benefit from IC to avoid unnecessary toxicity. Mass spectrometry (MS)-based phosphoproteomics enables quantitative profiling of phosphopeptides (PPs) from patient samples, providing a functional readout of tumor biology. Thus, we sought to develop a PP-based clinically-deployable assay, orthogonal to genetic risk stratification, to predict response to IC in AML. Methods: 261 retrospective samples were collected from patients with newly-diagnosed AML (Table) treated with standard “7+3” IC in 9 centers in Europe, Australia, and North America. Response was assessed at the end of induction by the treating physician. Samples underwent phosphoproteomics using: 1) global MS for biomarker discovery or 2) targeted, clinically-compatible MS for validation. Predictive model performance was evaluated using rebalanced leave-one-out cross-validation. Results: During discovery, 3205 PPs were detected. Using Bayesian approaches, we identified an 80-PP multi-analyte signature of IC response (refractory vs cCR), and achieved an AUROC of 0.68 (95% CI 0.54-0.83). The signature was enriched for DNA damage signalling and repair (DNA-PK-S2612, ATM/cohesin, nucleotide excision and double-strand break repair proteins), and cellular stress pathways (phospho-p38, IL-16, AP-1/c-Jun). In an independent validation cohort, the targeted assay reliably detected the biomarker set and preserved its association with outcome (AUROC 0.69; 95% CI 0.53-0.84). Biomarker-based classification was associated with improved event-free survival (HR 0.45; 95% CI 0.26-0.78). Conclusions: We identified and validated a signature of response to IC in AML, and translated it into a targeted, clinically-deployable assay. This approach captures signaling states relevant to IC mechanisms of action that are not directly inferred from standard clinical or genetic variables. Ongoing analyses are evaluating its relationship to established genetic and ELN risk stratification. These findings support diagnostic phosphoproteomics and suggest functional biomarkers may complement existing approaches for treatment selection in AML. Cohort characteristics. Cohort Discovery Validation Median age at diagnosis (years, quartiles) 54 (23, 65) 59 (47, 68) Median diagnosis year (range) 2014 (1999, 2023) 2013 (2001, 2024) No of patients/samples 135/165 102/106 No of cCR/Refractory 94/41 79/23 PPs 3205 80
Immunohistochemical profile and age distribution of breast cancer at a tertiary referral center in Abuja, Nigeria: A two-year retrospective study.
e13116 Background: Breast cancer outcomes in sub-Saharan Africa are often poor, driven by late presentation and aggressive tumor biology. Immunohistochemistry (IHC) plays a critical role in guiding treatment; however, data on tumor subtype distribution in Nigerian populations remain limited. This study describes the socio-demographic characteristics and IHC patterns of breast cancer patients managed at the National Hospital Abuja and examines the association between age and tumor biological subtype. Methods: A retrospective descriptive study was conducted among 425 breast cancer patients diagnosed between 2024 and 2025 at the National Hospital Abuja. Data on age, sex, and IHC subtype were extracted from pathology records. Tumors were classified by Scarff–Bloom–Richardson (SBR) grade and receptor status. Associations between age groups (≤30, 31–40, 41–50, ≥51 years) and IHC subtypes were analyzed using chi-square statistics. Results: The mean age at diagnosis was 49.6 ± 13.3 years in 2024 and 47.8 ± 12.0 years in 2025, with the highest burden observed among women aged ≥51 years (41.9%). Females accounted for 96.5% of cases. Triple Negative Breast Cancer (TNBC) was the predominant subtype, comprising 58.8% of all tumors (48.7% SBR II and 10.1% SBR III). Hormone receptor–positive tumors (ER/PR positive) accounted for 33.4%, while HER2-positive tumors were rare ( < 3%). TNBC remained the dominant subtype across all age groups, including younger women, with no statistically significant association between age and IHC subtype (χ² = 32.68, p = 0.208). Conclusions: Breast cancer in this Nigerian population is characterized by a striking predominance of aggressive TNBC across all age groups, with low rates of hormone receptor and HER2 positivity. The absence of age-related differences in tumor biology suggests widespread aggressive disease irrespective of age. These findings highlight the urgent need for improved early detection, expanded diagnostic capacity, and context-specific treatment strategies to improve breast cancer outcomes in Nigeria.
Improving immunotherapy response with direct-acting antiviral therapy in patients with advanced hepatocellular carcinoma and chronic hepatitis C virus infection.
e16181 Background: Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) carries a poor prognosis. Immune checkpoint therapy (ICT) enhances antitumor activity through CD8⁺ T-cell proliferation. Direct-acting antivirals (DAAs) have been associated with a remarkable HCV cure rate and have been shown to enhance hepatic and systemic immune responses by reversing the exhaustion of the HCV-specific CD8 + T-cell response. HCV guidelines do not address the optimal timing of DAAs in patients with advanced HCC undergoing ICT. We conducted a phase IV clinical trial in patients with HCV-associated HCC to determine whether clearing HCV with early DAA therapy improves ICT response and enhances the immune response against liver cancer cells by reversing T-cell exhaustion. Methods: In this open-label single-arm clinical trial (NCT05717400), patients with HCV-related HCC received atezolizumab plus bevacizumab and DAAs (sofosbuvir/velpatasvir [SV] or SV/voxilaprevir [SVV]). Peripheral blood samples were collected at baseline and at weeks 4 (W4) and 12 (W12) after DAA initiation for high-dimensional flow cytometry. Tumor biopsies were obtained before and after DAA therapy. Multiplex immunofluorescence quantified intertumoral CD8⁺ T-cell densities and immune-cell phenotypes. Primary endpoints were objective response rate (ORR), disease control rate (DCR), and sustained virological response (SVR). Results: Between March 17, 2023, and August 28, 2024, 11 patients were screened, and 2 were enrolled. Patient 1 was a 74-year-old Black man with metastatic HCC and HCV genotype 2 treated with SV. Patient 2 was a 64-year-old White man with stage IIIB HCC and HCV genotype 1a treated with SVV after initial DAA failure. Both were ICT-naïve, started DAAs within weeks of ICT initiation, experienced no grade 3 or 4 adverse events, had stable disease as their overall best response (DCR 100%; ORR 0%), and had SVR. In both patients, CD4⁺ and CD8⁺ T-cell frequencies increased over time, whereas monocyte frequencies decreased. At all times, both patients had high CD4:CD8 ratios but low natural killer (NK) cell frequencies. We observed no changes in proliferation or in the expression of the activation markers 41BB, OX40, ICOS, or CD69 on T-cell subsets or NK cells. The expression of inhibitory markers in T and NK cell subsets is shown. At W12, patient 1 had increased T-cell densities, while patient 2 had pronounced tumor infiltration by cytotoxic T lymphocytes (CD3⁺CD8⁺) and macrophages (CD68⁺). Conclusions: Early DAA therapy after ICT in patients with advanced HCC was safe and resulted in enhanced CD4⁺ and CD8⁺ T-cell responses with excellent virologic control but did not impact tumor response. Larger clinical trials are warranted to determine whether HCV clearance with DAA therapy enhances ICT response in patients with HCV-related HCC. Clinical trial information: NCT05717400 .
Adaptive targeting of lung cancer using the anti-P329G adapter CAR T-cell platform.
e14514 Background: Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic malignancies but remains less effective in solid tumors such as lung cancer due to antigen heterogeneity, on-target/off-tumor toxicities, and immunosuppressive tumor microenvironments (TME). Adapter CAR systems offer a strategy to improve flexibility and toxicity control by separating antigen recognition from CAR signaling. Anti-P329G adapter CAR T cells recognize a P329G point mutation in the Fc region of engineered human IgG1 antibodies, permitting precise and reversible retargeting through P329G-Fc–mutated antibodies against multiple tumor antigens. This work investigates the anti-P329G CAR platform in lung cancer, emphasizing its performance against the clinically relevant and therapeutically validated target EGFR. Methods: Anti-P329G CAR T cells demonstrated strong, antibody-dependent in vitro activation and effector functions against EGFR-positive lung cancer cells and recombinant EGFR protein. CAR T cell activity required presence of the P329G-Fc–engineered antibody, confirming reversible and modular antigen control. To further explore controllability, antibody displacement experiments with mock binders were conducted to assess reversibility. In vivo, EGFR-redirected anti-P329G CAR T cells induced significant tumor regression and prolonged survival in lung cancer–bearing mice without systemic toxicity. In both TCS-PCLS and TD-PCLS, EGFR-directed anti-P329G CAR T cells effectively reduced EdU+ tumor proliferation and enhanced TUNEL+ apoptosis, while sparing adjacent nonmalignant tissue despite EGFR co-expression. Results: Anti-P329G CAR T cells showed strong, antibody-dependent in vitro activation and effector functions against EGFR-positive tumor cells and recombinant EGFR protein. Activity required the P329G-Fc–engineered antibody, confirming modular and reversible antigen control. To explore controllability, antibody displacement experiments with mock binders were performed. In vivo, EGFR-redirected anti-P329G CAR T cells induced significant tumor regression and prolonged survival in lung cancer–bearing mice without systemic toxicity. In both TCS-PCLS and TD-PCLS, EGFR-directed anti-P329G CAR T cells reduced EdU+ tumor proliferation and increased TUNEL+ apoptosis, while sparing nonmalignant lung tissue despite EGFR co-expression. Conclusions: The anti-P329G adapter CAR platform provides a tunable, specific, and reversible approach for EGFR-targeted immunotherapy in lung cancer. Demonstrated efficacy across in vitro, in vivo, and ex vivo models, together with feasibility testing of antibody displacement, highlights its translational potential to overcome key barriers of CAR T therapy in solid tumors while maintaining improved safety and controllability.
Twenty years of metastatic uveal melanoma management: Real-world experience from a comprehensive cancer center in a low- and middle-income country (LMIC).
9545 Background: Uveal melanoma (UM) is a rare malignancy arising from melanocytes of the uveal tract and accounts for 85% of primary ocular malignancies. Despite effective local control, 10-50% of patients develop metastatic disease, which is associated with poor prognosis and a median overall survival (OS) of approximately one year. Until recently, no effective standard systemic therapy existed for metastatic UM. Real-world data especially from LMICs remain lacking. This study evaluates the clinical characteristics, treatment patterns, and survival outcomes of patients with metastatic UM treated in a LMIC. Methods: This retrospective study included adult patients with metastatic UM treated and followed at King Hussein Cancer Center in Amman, Jordan between January 2006 and December 2025. Collected data included baseline demographic and clinical characteristics, metastatic and treatment patterns. Descriptive and survival analyses were conducted using JASP software (version 0.95.4). A two-sided P value <0.05 was considered statistically significant. Results: Among 125 patients with UM, 31 (24.8%) had metastatic disease, including two patients with metastasis at initial presentation. Median age at diagnosis was 51 years, and 61.3% were males. ECOG performance status was 0–2 in 81.5% of patients. Hepatic-only metastasis occurred in 51.6% of patients, combined hepatic and extrahepatic in 38.7%, and extrahepatic-only in 9.7%, with 58.6% classified as M1a disease. Median time to distant metastasis was 25 months. Median OS from initial UM diagnosis was 35 months, while median post-metastatic OS (PM-OS) was 10 months. First-line Immunotherapy was associated with significantly improved PM-OS compared to Dacarbazine (median 11 vs 5 months; P = 0.034), with 24-month PM-OS of 44.4% vs 0% respectively. Treatments included Immunotherapy, chemotherapy, Targeted therapy in one patient, local interventions, and best supportive care (Table). Conclusions: Metastatic UM remains associated with poor survival outcomes in this real-world cohort. First-line Immunotherapy was associated with longer survival compared to chemotherapy. This study highlights ongoing unmet outcomes needs and underscores disparities in access to emerging therapies, such as Tebentafusp, in LMICs. Broader availability of novel agents and inclusion of patients from LMICs in clinical trials are required. First-line Treatments Second-line Treatments Third line Treatments Additional Local interventions Pembrolizumab (n=15) Dacarbazine (n=7) Carboplatin plus Paclitaxel (n=1) Radiotherapy (n=9) Nivolumab and Ipilimumab (n=4) Nivolumab and Ipilimumab (n=1) Single agent Paclitaxel (n=1) Microwave ablation (n=1) Dacarbazine (n=3) Surgery (n=1) Darovasertib and Crizotinib (n=1) Best supportive care only (n=8)
Comprehensive plasma-based epigenomic profiling from INTR@PID Lung 037 study samples to identify pathways associated with response and resistance to pembrolizumab in PD-L1–high NSCLC.
e20547 Background: Pembrolizumab produces variable benefit in PD-L1-high metastatic NSCLC, and mechanisms of resistance remain insufficiently defined. Plasma-based epigenomic profiling could potentially identify pathway-level biology not captured by PD-L1 IHC or genomic mutations alone. An exploratory post hoc analysis was performed using comprehensive epigenomic profiling from 1 mL of plasma to characterize pathways associated with pembrolizumab response and resistance from INTR@PID Lung 037 study samples. Methods: 192 longitudinally collected plasma samples (baseline, on-treatment, and end-of-treatment [EOT]) were analyzed using Precede’s comprehensive epigenomic liquid biopsy platform. 99% of samples passed analyte-specific QC metrics and 55% samples had detectable ctDNA, consistent with previous reports. Differential promoter and enhancer activation and pathway enrichments were evaluated across PFS-stratified groups. Pathway activity dependence on ctDNA levels was used to investigate whether signals originated from tumor or stroma. Pathway activities were profiled across gain of function (GOF) and loss of function (LOF) alterations. Epigenomic activation of ADC targets was also assessed. Results: Baseline plasma from non-responders (lowest PFS tertile) showed enrichment of MYC and proliferative pathways, and an RNA-based intrinsic IFN-resistance signature, whereas responders showed reduced KRAS and EMT signalling. Despite patients being selected for PD-L1 expression ≥50%, higher epigenomic PD-L1 promoter activation trended with greater tumor shrinkage. Differential pathway activities for 86 mutations were identified, including 68 linked to immune-related programs (IFN, TNFα, JAK/STAT). NF1 and ARID1A LOF mutations exhibited immune-enriched profiles, whereas KEAP1 LOF and MDM2 GOF showed immune-depleted profiles, consistent with poor ICB response. Paired baseline-EOT samples showed acquired resistance characterized by squamous-like differentiation and keratinization pathways, consistent with lineage plasticity and immune exclusion. ADC target profiling demonstrated a subset of patients exhibiting co-activation of MUC1 and EGFR , suggesting potential suitability and combination potential for bispecific or targeted ADC strategies. Conclusions: Plasma epigenomic profiling resolved genes and pathways associated with pembrolizumab response, in PD-L1-high NSCLC, including intrinsic IFN-driven resistance and acquired squamous-like resistance. This approach also captured functional immune and tumor-associated biology not evident from PD-L1 IHC or mutation status. These findings provide a clear rationale for the use of plasma epigenomics for non-invasive monitoring, patient stratification, and future evaluation of combination and targeted strategies.
Real-world outcomes of neoadjuvant concurrent chemoradiotherapy with epirubicin–ifosfamide in localized high-grade soft tissue sarcoma: A single-center retrospective series (N=57).
e23547 Background: Neoadjuvant chemotherapy combined with radiotherapy (nCRT) is an established strategy for selected patients (pts) with localized high-risk soft tissue sarcoma (STS). However, real-world data on this concurrent multimodal approach remain limited. We evaluated clinicopathologic characteristics and outcomes in high-risk localized STS pts treated with nCRT using the regimen reported by Gronchi et al. (JCO 2012). Methods: We conducted a retrospective single-center study of consecutive pts with localized high-grade STS treated with nCRT at Hospital Gregorio Marañon (2014-2024). Treatment (Tx) was 3 cycles of epirubicin-ifosfamide concurrent with RT. Clinical and treatment variables, toxicity, RECIST 1.1 response, and recurrence patterns were analyzed. Primary outcomes included R0 resection and pathologic response; secondary outcomes were local control, DFS and OS. Results: Fifty-seven pts were included (M 31/F 26), median age of 51 years (21-70), 93.0% had tumors >5 cm. Primary sites were extremities (84.2%), head/neck (5.3%), and other non-retroperitoneal sites (10.5%). Most common histologies were undifferentiated pleomorphic sarcoma (19.3%), liposarcoma (17.5%), undifferentiated sarcoma NOS (15.8%), synovial sarcoma (14.0%), and malignant peripheral nerve sheath tumor (10.5%). Neoadjuvant treatment was completed in 94.7% (3 discontinuations due to toxicity). Grade 3–4 chemo-related adverse events (AEs) occurred in 56.1%, mainly hematologic. RT (50 Gy/25 fx) was delivered in 87.7%; grade 3–4 RT-related AEs occurred in 12.3%, with discontinuation in 10.5%. By RECIST 1.1, partial response was 49.1%, stable disease 24.6%, and complete response 3.5%. Definitive surgery was performed in 93.0%, with an R0 rate of 86.8%. Major pathologic response (>90% necrosis) was 22.6%. Intraoperative RT was delivered in 81.1%. Postoperative grade ≥3 acute and late complications occurred in 15% and 34%, mostly infections (7.5%, 13.2%) and wound-healing disorders (9.4%, 11.3%). After a median follow-up of 38 months, 45.3% relapsed, mainly distant (41.5% vs 13.2% local). The median progression-free survival and recurrence-free survival were 28.45 and 24.73 months, respectively. Four-year overall survival (OS) was 79% (95% CI 63-95). No significant OS differences were observed by margins (R0 vs R1), tumor size (<5, 5–10, >10 cm), necrosis (≥90% vs <90%), or complications in univariate or multivariate analysis, likely due to small sample size and cohort heterogeneity. Conclusions: In this real-world retrospective cohort of localized high-grade STS, epirubicin-ifosfamide-based nCRT was feasible and associated with encouraging surgical and disease-control outcomes. These data support prospective evaluation and may help refine patient selection for intensified multimodality tx strategies.
Real-world outcomes and cross-resistance of sequential antibody-drug conjugate therapy in HER2-low and triple-negative breast cancer: A systematic review.
e12548 Background: Antibody–drug conjugates (ADCs) have demonstrated superior efficacy over chemotherapy in HER2-low and triple-negative breast cancer (TNBC). However, real-world outcomes of sequential ADC use and the extent of cross-resistance remain poorly defined. We performed a systematic review to evaluate randomized and real-world evidence on efficacy, safety, and cross-resistance of ADC sequencing. Methods: Phase III randomized controlled trials and retrospective real-world studies evaluating ADCs in HER2-low and TNBC were reviewed. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled using an inverse-variance method. Response rates, safety outcomes, and real-world sequencing data were synthesized narratively. Risk of bias was assessed using ROB-2. Results: Pooled analysis of three phase III trials demonstrated a significant OS benefit with ADCs compared with chemotherapy (HR 0.66, 95% CI 0.50–0.87; P = 0.004), representing a 34% reduction in mortality risk. PFS was also significantly improved (HR 0.45, 95% CI 0.33–0.63; P < 0.00001), with substantial heterogeneity (OS I² = 80%; PFS I² = 87%). ADCs showed higher objective response rates, including sacituzumab govitecan in ASCENT (31% vs 4%) and trastuzumab deruxtecan with ORR up to 57.3% in DESTINY-Breast studies. All trials were open-label, resulting in some risk of bias. Real-world data revealed reduced efficacy with sequential ADC therapy. In a multicenter retrospective cohort, 53% of patients exhibited cross-resistance to a second ADC. A separate institutional cohort showed shorter real-world PFS with second ADC use in ~75% of patients, with PTEN loss associated with resistance. ADCs demonstrated manageable toxicity profiles and favorable patient-reported outcomes compared with chemotherapy. Conclusions: Although ADCs improve survival outcomes in HER2-low and TNBC, real-world evidence suggests substantial cross-resistance with sequential use. Prospective sequencing trials are essential for defining optimal treatment strategies and overcoming resistance.
Reducing effort through informatics-driven identification, recruitment, and data capture on a trial to improve adjuvant endocrine therapy adherence.
11025 Background: Adjuvant endocrine therapy (AET) improves outcomes in HR+ breast cancer. Nonadherence to AET is common, but manual screening for nonadherence is fraught. High-specificity structured cancer electronic health record (EHR) data, particularly if it includes key variables like stage, could streamline these steps for both clinical care and research purposes. We conducted an analysis of approaches to identifying patients as eligible for a multi-site AET adherence study to understand how variation in structured data informatics-supported screening impacts coordinator time. Methods: Mayo Clinic implemented a two-step identification: (1) EHR structured data (diagnosis date, stage, ER/PR/HER2 positivity, medication script) to prescreen for eligibility; (2) SureScripts fills to flag nonadherence using proportion of days covered < 80% across early fills. Medical College of Wisconsin (MCW) implemented a more manual screening process for Step 1 using only medication scripts. Coordinators at both sites then conducted a medical record review to assess if the resulting list of patients had a plan to continue AET for at least two additional years. Opt-out clinician permission preceded patient contact; pharmacists delivered a patient reported outcome (PRO)-guided intervention and documented encounters. Results: At Mayo, 829 patients were prescreened for study eligibility through informatics workflow; 120 (14.5%) met eligibility criteria. At MCW, 1,763 patients were prescreened; 168 (9.5%) were eligible. EHR filters included non–breast cancer encounters (50% at MCW) and ineligible based on time since cancer (36% at Mayo; 26% at MCW). At Mayo, screening required 5.6 minutes/patient for experienced coordinators. At MCW, experienced coordinators averaged 6.67 minutes/patient and inexperienced coordinators averaged 9.33 minutes/patient. Conclusions: Structured EHR data, pharmacy-fill information, and standardized workflows allowed consistent prescreening, intervention and recruitment processes across sites. Higher-specificity informatics-supported screening reduced the percentage of patients requiring manual review and reduced coordinator screening time. It also supported timely provider-permission steps and patient outreach. These workflows were feasible to implement at both institutions, and study enrollment is ongoing. Clinical trial information: NCT06765707 .
A phase I/IIa dose-escalation, dose-optimization, and dose-expansion study to evaluate the safety and preliminary efficacy of tri-specific antibody (SOA101) in subjects with advanced solid tumors.
TPS2671 Background: SOA101 is a nanobody (VHH)-based tri-specific T cell engager targeting programmed death-ligand 1 (PD-L1), Human Leukocyte Antigen G (HLA-G), and Cluster of Differentiation 3 (CD3) to modulate the immunosuppressive tumor microenvironment and enhance T-cell activation and recruitment. In vitro, SOA101 showed potent, broad-spectrum anti-tumor activity, enhancing peripheral blood mononuclear cells mediated cytotoxicity against non–small cell lung cancer (NSCLC) cells with varying PD-L1/HLA-G expression. In vivo, SOA101 demonstrated superior anti-cancer efficacy compared with relevant monoclonal antibodies and bispecific T-cell engagers in a humanized NSCLC mouse model, achieving effective tumor control and prolonged survival. The pharmacologically active dose did not increase cytokine secretion ex vivo, indicating a manageable safety profile with low cytokine release syndrome risk. Methods: This first-in-human clinical study, regulated by FDA and TFDA, is being conducted in subjects with locally advanced or metastatic solid tumors, including NSCLC ovarian cancer, head and neck cancer, breast cancer, and colorectal cancer with PD-L1 expression ≥1%. The dose-escalation phase is a six-cohort study designed to determine the maximum tolerated dose or pharmacoactive dose, enrolling up to 36 subjects who receive bi-weekly SOA101 for up to six doses. The dose-optimization phase randomizes approximately 40 subjects into low- or high-dose cohorts to further evaluate safety, pharmacokinetics, preliminary antitumor activity, and to determine the recommended Phase 2 dose. Part 2 may include up to four disease-specific expansion cohorts (up to 27 subjects each) to further characterize safety and antitumor activity. The study is currently in the dose-escalation phase. Cohort 1 has been completed without DLT, and enrollment for Cohort 2 has begun following approval by the independent Safety Review Committee. Clinical Trial Registry Number: NCT07055594. Clinical trial information: NCT07055594 .
Two decades of change: Trends and disparities in breast cancer surgical outcomes.
e12742 Background: Breast cancer is the most commonly diagnosed malignancy among women in the United States, and surgery remains the cornerstone of treatment. Although advances in surgical care have reduced morbidity and mortality, contemporary analyses of perioperative outcomes are limited, highlighting the need for an updated evaluation. This study aims to examine trends in breast cancer surgical outcomes and associated disparities over the past two decades. Methods: This retrospective, cross-sectional study utilized the National Inpatient Sample database. The study population included females aged ≥18 years with stage I–III breast cancer, who underwent inpatient lumpectomy or mastectomy, with or without breast reconstruction, between 2001 and 2021. Multivariable regression analyses adjusted for patient- and hospital-level confounders to evaluate in-hospital mortality, length of stay (LOS), cost, and postoperative complications. In-hospital mortality following complications was compared across racial groups using chi-squared tests with Non-Hispanic (NH) White patients as the reference group. Results: Among 993,551 patients, in-hospital mortality declined (6.24 to 5.67 per 10,000 patients), while median hospitalization costs increased ($7,379.34 to $23,362.62) over the study period. Most surgical complications rates remained stable; however, reported deep vein thrombosis increased 0.023% per year (Confidence Interval (CI): 0.016–0.030). Private insurance was associated with a lower risk of surgical complications [adjusted Odds Ratio (aOR) = 0.86, (CI: 0.83–0.89)] and in-hospital mortality (aOR = 0.40, CI: 0.27–0.59). NH Black patients had higher odds of in-hospital mortality (aOR = 2.20, CI: 1.69–2.87), longer LOS (RR = 1.12, CI: 1.11–1.12), and higher systemic (aOR = 1.13, CI: 1.09–1.18) and surgical complications (aOR = 1.50, CI: 1.46–1.54); specifically higher rates of postoperative hemorrhage/hematoma (+0.70% - 1.06%). NH Asian American/Pacific Islander (AAPI) patients also demonstrated higher odds of surgical complications [aOR = 1.19 (CI: 1.12–1.24)]. Hispanic patients experienced lower hemorrhage/hematoma complication rates compared with NH White patients across the study period (2001-2010: 1.65% vs 2.33%; 2010-2021: 2.84% vs 3.77%). All results p < 0.001. Yearly trend analyses demonstrated a narrowing disparity in postoperative hemorrhage/hematoma rates for NH Black patients (p = 0.006) and widening disparity among NH AAPI (p = 0.045). Conclusions: Over the past two decades breast cancer surgical outcomes have improved, overall; however, substantial racial/ethnic and socioeconomic disparities persist. Despite narrowing of specific gaps, inequities remain pronounced, emphasizing the importance of targeted, equity-focused interventions to improve postoperative outcomes.
Clinical outcomes of patients with cell cycle alterations by treatment type: The MD Anderson Cancer Center IMPACT 2 study.
3149 Background: Cell cycle pathway alterations are a hallmark of cancer. Disruption of cell cycle checkpoints results in genomic instability, uncontrolled proliferation and tumor progression to aggressive and treatment-resistant phenotypes. We report the clinical outcomes of patients with cell cycle pathway alterations treated in the IMPACT 2 study (2014-2023; NCT02152254). Methods: Patients with advanced cancer underwent tumor biopsy and molecular profiling (CLIA-certified lab). Pathway analysis was conducted using the maftools R package. Cell cycle pathway alterations were defined as those involving the CCND1 , CCND2 , CCNE1 , CDK4 , CDK6 , CDKN2A , CDKN2B , and RB1 genes. Cases were discussed at Molecular Tumor Board meetings. Patients were treated on clinical trials with investigational agents that included matched targeted therapies (MTTs) when available. We analyzed the following outcomes by treatment type (MTT vs. non-matched targeted therapy [NTT] and immunotherapy [IO] vs. non-IO): objective response rate (complete response + partial response), clinical benefit rate (CBR; ORR + stable disease≥4 months), progression-free survival (PFS), and overall survival (OS). Results: Of 491 treated patients with targetable alterations, 157 (32.0%) had cell cycle pathway alterations (median age, 61 years [range, 21-82]; female, 46.5%; ECOG performance status 1, 85.4%; median number of prior therapies, 3 [range, 0-9]; liver metastases, 40.8%; >2 metastatic sites, 36.3%; high LDH, 33.1%; low albumin, 10.8%). The most common cancers were sarcoma (19.7%), other gastrointestinal (17.2%), head and neck (14.0%), lung (9.6%), and breast (8.3%). Other tumor characteristics included PD-L1 ≥1%, 45.6% (41/90); MSI-H, 2.0% (2/102); and TMB-H, 13.0% (13/100). Concomitant pathway alterations were TP53 (67.5%), PI3K (29.9%), and RTK-RAS (47.1%). MTT targeted CDK4/6, n=9; BET, n=2; ATR, n=1; PKMYT1, n=1; and ACAT, n=1. Clinical outcomes are shown in the Table. Conclusions: Very few investigational therapies that target the cell cycle pathway were available. No differences were noted in tumor response, PFS, or OS by type of therapy, likely owing to the limited antitumor activity of the MTTs and the complexity of targeting this pathway. Novel and effective MTTs are needed for tumors with cell cycle dysregulation. Clinical trial information: NCT02152254 . All patients MTT NTT P IO Non-IO P N=157 N=14 N=143 N=40 N=117 ORR (%) 7/135 (5.2) 0/12 (0) 7/123 (5.7) 1.00 4/33 (12.1) 3/102 (2.9) 0.14 CBR (%) 76/135 (56.3) 6/12 (50.0) 70/123 (56.9) 0.76 19/33 (57.6) 57/102 (55.9) 1.00 Median PFS, months(95% CI) 3.75(2.66, 5.49) 3.75(1.81, NA) 3.58(2.66, 5.52) 0.81 2.96(1.81, 8.98) 3.75(2.66, 5.59) 0.98 Median OS, months(95% CI) 8.48(7.1, 11.21) 6.66(5.56, NA) 8.61(7.17, 11.57) 0.40 7.46(5.19, 17.42) 8.48(7.1, 11.57) 0.72
Glucagon-like peptide-1 receptor agonist (GLP-1 RA) and hematologic cancer risk among older adults with type 2 diabetes.
6592 Background: Recent preclinical and clinical evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1 RA) may reduce cancer risk through inflammation modulation. However, comparative effectiveness research evaluating hematologic malignancy risks of GLP-1 RAs remain limited in real-world populations. Methods: Using 15% random samples of Medicare Part D beneficiaries from 2013 to 2022, we identified older adults with type 2 diabetes who initiated GLP-1 RA or DPP-4i. The primary outcomes included myelodysplastic syndromes (MDS), lymphoma, and leukemia. We performed 1:1 propensity score matching for confounding control. We estimated the hazard ratios (HR) and 95% confidence intervals (CI) with Cox proportional hazard model. We examined the heterogeneity in treatment effects by pre-specified patient demographic and baseline factors. Subgroup analyses were conducted for: a) age (≥75 vs. <75 years), b) sex (female vs. male), c) race/ethnicity (non-Hispanic Black vs. non-Hispanic White vs. Hispanic ethnicity), d) obesity status (overweight vs. obese vs. severe obesity), and e) specific GLP-1 RA class (e.g., liraglutide, dulaglutide, and semaglutide). In the sensitivity analysis, we used cause-specific Cox model to account for death as a competing risk and calculated E-values to examine the potential influence of unmeasured confounders. Results: After propensity score matching, there were 29,212 patients included in the cohort (14,606 GLP-1 RA users and 14,606 DPP-4i users). Of the cohort, mean (SD) age was 77.3 (7.4) years; 53.9% were female, 69.9% were non-Hispanic White, 11.1% were non-Hispanic Black, and 3.9% were Hispanic. Compared to DPP4i, GLP-1 RA showed reduced risks in MDS (HR: 0.70, 95% CI [0.53-0.94]), lymphoma (0.71 [0.57-0.89]), and leukemia (0.85 [0.74-0.99]). Overall, no statistically significant heterogeneity of treatment effect was detected in subgroup analyses. After accounting for death as a competing event, the hazard ratios are consistent with the conventional Cox models except monocytic leukemia (HR: 1.4 [0.45-4.56], p=0.48). E-values suggest moderate robustness to potential unmeasured confounding. Conclusions: GLP-1 RA initiation was associated with a reduced risk of hematologic malignancies compared with DPP-4i use among real-world patients with type 2 diabetes. These findings suggest a potential protective effect of GLP-1 RAs on hematologic cancer risk and warrant further mechanistic and prospective investigation.
Evaluating the incidence and predictors of chronic opioid use in early survivorship for patients with diffuse large B-cell lymphoma.
7087 Background: Exposure to opioids during cancer treatment is common and may lead to new persistent opioid use (NPOU) in a subset of patients in survivorship. There are limited data on the incidence and predictors of NPOU in a diffuse large B-cell lymphoma (DLBCL) cohort. Methods: We conducted a population-based cohort study utilizing health administrative datasets from Ontario, Canada. We included patients ≥18 years old with DLBCL who received first-line rituximab-based chemoimmunotherapy from 2014 to 2021 and survived >365 days after treatment. We considered patients to be opioid exposed if they filled ≥1 opioid prescriptions from 90 days prior to and 180 days after first rituximab-based chemoimmunotherapy (the exposure window). The primary outcome was NPOU defined as filling ≥1 opioid prescriptions in each of the two half-years of follow up after the exposure window (i.e. within both 0-180 days and 181-365 days). We used a multivariable Poisson regression model with robust error variance to assess the relative risk (RR) of NPOU while controlling for covariates. Results: Our cohort consisted of 4,988 patients with DLBCL. The median age was 66 years and 32.3% had relapsed/refractory disease. Opioid exposure occurred in 55.0% of the entire cohort. Of the entire cohort, 6.7% fulfilled criteria for NPOU including 10.4% of exposed patients compared to 2.4% of unexposed patients. In the multivariable analysis, exposed patients were four times more likely to develop NPOU (RR 3.81, 95% CI 2.85-5.07). After adjustment, other statistically significant predictors of NPOU included palliative care use in follow-up (RR 2.77, 95% CI 2.21-3.47), relapsed/refractory disease (RR 1.63, 95% CI 1.33-1.99), comorbid disease burden (RR 1.50, 95% CI 1.01-2.23), and prior mental health diagnoses (RR 1.27, CI 1.01-1.58). Conclusions: Over 1 in 2 DLBCL patients were exposed to opioids during treatment and 1 in 10 exposed patients developed NPOU. Exposed patients were four times more likely to develop NPOU. Our study identified several clinically relevant predictors of NPOU in DLBCL, which may enable clinicians to identify high-risk patients who would benefit from early intervention.