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Assessing a survival paradox in young-onset lung adenocarcinoma: Racial and ethnic disparities in SEER analysis.
e20114 Background: Survival outcomes in young adults with lung adenocarcinoma (LUAD) are poorly characterized, particularly across racial and ethnic groups. It remains unclear whether disparities observed in the general lung cancer population persist in younger patients. Improved understanding of stage distribution and survival patterns in young-onset LUAD is needed to inform risk stratification and clinical decision-making. Methods: We analyzed patients aged 15–49 years diagnosed with LUAD between 2004 and 2016 using the SEER 17 Registries. Patients were stratified by race/ethnicity (non-Hispanic White [NHW], non-Hispanic Black [NHB], Hispanic, and non-Hispanic Asian or Pacific Islander [NHAPI]), sex, age group, and stage at diagnosis (localized, regional, distant). Five-year cause-specific survival was estimated using Kaplan–Meier methods and compared with log-rank tests. Multivariable Cox proportional hazards models evaluated associations between demographic and clinical factors and mortality. Statistical significance was defined as p < 0.05. Results: Survival differed significantly by race and ethnicity among young-onset LUAD patients (log-rank p < 0.001). Median survival was 15.0 months (95% CI,13.7–16.3) for NHB patients, 18.0 months (95% CI,16.9–19.1) for NHW patients, 23.0 months (95% CI,20.8–25.2) for Hispanic patients, and 27.0 months (95% CI,24.4–29.6) for NHAPI patients. Across all racial and ethnic groups, advanced stage at diagnosis was the strongest predictor of mortality, with distant-stage disease associated with markedly increased hazards of death compared with localized disease (NHB HR2.98; NHW HR3.49; Hispanic HR3.33; NHAPI HR3.80; all p < 0.001). Male sex was independently associated with higher mortality across all groups. Among NHW patients, younger age (15–39 vs 40–49 years) was associated with lower mortality (HR0.81;95%CI,0.74–0.89). Despite adjustment for these factors, NHAPI patients consistently demonstrated superior survival. Conclusions: NHAPI patients with young-onset LUAD experience significantly improved survival compared with other racial and ethnic groups, while NHB and NHW patients have poorer outcomes. These findings reveal persistent survival disparities in young-onset LUAD and highlight the need for tailored early detection strategies and biologic and treatment-focused research to address these differences.
Molecular profiling of colorectal cancer in a clinical diagnostic cohort: RAS/RAF alterations, microsatellite instability, and mismatch repair status.
e15644 Background: Molecular characterization of colorectal cancer (CRC) is essential for therapeutic stratification, particularly for selecting patients eligible for anti-EGFR therapy. Beyond canonical hotspot mutations in KRAS and BRAF, evaluation of microsatellite instability (MSI) and deficient mismatch repair (dMMR) provides prognostic information and guides immunotherapy. Because RAS and certain RAF alterations predict resistance to EGFR-directed antibodies, comprehensive gene assessment is routine. Rare non-hotspot RAS/RAF variants are increasingly identified and present interpretive challenges. This study describes the molecular landscape of CRC in a real-world diagnostic cohort, emphasizing standardized variant curation and implications for anti-EGFR therapy. Methods: We retrospectively analyzed 285 CRC specimens submitted for routine molecular testing. Somatic variants in KRAS, NRAS, BRAF, and PIK3CA were detected using Sanger-sequencing. MSI testing was performed by PCR-fragment analysis, and MMR protein expression (MLH1, PMS2, MSH2, MSH6) by immunohistochemistry (IHC). Variant interpretation followed ACMG and AMP/ASCO/CAP somatic guidelines. Results: KRAS mutations were identified in 37.0% of tumors, including rare KRAS p.Gln22Lys (Q22K, 2 cases) and p.Lys147Asn (K147N, 1 case). BRAF mutations occurred in 7.5% of cases, mainly p.Val600Glu (V600E), with one p.Asn581Ile (N581I). NRAS and PIK3CA mutations were 1.1% and 5.7%, respectively. Overall, 51.3% of tumors harbored one mutation in KRAS, BRAF, NRAS, or PIK3CA. MSI tumors were 37.9% and largely concordant with dMMR IHC (32.3%). Among mutation-positive cases, 13.8% were dMMR and 16.6% MSI-H. 15% of dMMR-positive cases were associated with Lynch syndrome. KRAS Q22K and BRAF N581I were classified as oncogenic gain-of-function variants, while KRAS K147N was likely oncogenic gain-of-function. Alterations occurred across diverse histopathologic subtypes. Conclusions: This cohort highlights the clinical significance of molecular testing in CRC. Canonical hotspot mutations in KRAS, NRAS, PIK3CA and BRAF, detected in 51.3% of cases, are critical for guiding anti-EGFR therapy, as these mutations predict resistance to EGFR-directed monoclonal antibodies. Additionally, 13.8% of mutation-positive tumors were dMMR and 16.6% MSI-H, identifying patients who may benefit from immune checkpoint inhibitors. Rare non-hotspot gain-of-function variants—including KRAS Q22K, BRAF N581I, and KRAS K147N—were also observed and may impact therapy selection. Overall, comprehensive molecular testing, including both hotspot mutation analysis and MSI/dMMR evaluation, is essential for informed treatment planning in CRC.
C-POST study of adjuvant cemiplimab for high-risk cutaneous squamous cell carcinoma (CSCC): Disease-free survival (DFS) analyses per high-risk criteria and per start time after radiotherapy.
6083 Background: C-POST, a phase 3 trial (NCT03969004) in patients (pts) with high risk CSCC after surgery and radiotherapy (RT), demonstrated superior disease-free survival (DFS) for adjuvant cemiplimab (cemi) vs placebo (pbo) (HR, 0.32; P <0.0001); treatment discontinuation due to adverse events occurred in 9.8% vs 1.5% of pts (Rischin, et al. N Engl J Med . 2025). With approximately 6 months of additional follow-up, we present exploratory analyses of DFS per high-risk criteria and per the interval between completion of prior RT and study randomization (2-6 wk vs >6 wk). These additional analyses provide key data to understand the importance of risk factors and the impact of time post RT. Methods: Pts were randomized 1:1 (N=415) to adjuvant cemi or pbo (350 mg cemi or pbo Q3W for 12 wk, then 700 mg cemi or pbo Q6W for 36 wk). All pts had nodal high-risk disease (with extracapsular extension [ECE] and ≥1 node ≥20 mm, or ≥3 nodes regardless of ECE) and/or non-nodal high-risk disease (in-transit metastases, perineural invasion, T4 lesions, or recurrent CSCC with ≥1 other feature). Tumors could meet ≥1 high-risk criteria. Randomization occurred within 2-11 wk after completion of RT. Data cutoff was April 7, 2025. Results: Among 415 pts (209/206 cemi/pbo) randomized, the DFS HR was 0.35 (95% CI, 0.23-0.55) at a median follow-up of 30 months. The most common high-risk criterion was nodal ECE, present in 48.4% of pts (201/415). DFS was improved with cemi vs pbo across all high-risk features, including both nodal and non-nodal criteria (Table 1). A consistent benefit was observed regardless of whether the interval between prior RT completion and study randomization was 2-6 wk (DFS events, 17/117 [14.5%] vs 37/112 [33.0%]; HR, 0.39; 95% CI, 0.22-0.70) or >6 wk (DFS events, 12/91 [13.2%] vs 31/93 [33.3%]; HR, 0.36; 95% CI, 0.19-0.71). Conclusions: In this phase 3 study, adjuvant cemi demonstrated a DFS benefit vs pbo across all high-risk features and regardless of the interval between prior RT completion and randomization. Clinical trial information: NCT03969004 . DFS with cemi vs pbo: Analyses per high-risk criteria. Criteria a Met high risk criteria, n/N (%) DFS events in cemi arm, n/N (%) DFS events in pbo arm, n/N (%) DFS HR (95% CI) Nodal high risk ECE with ≥1 node ≥20 mm 201/415 (48.4) 14/105 (13.3) 27/96 (28.1) 0.44 (0.23-0.84) ≥3 nodes 71/415 (17.1) 7/34 (20.6) 18/37 (48.6) 0.34 (0.13-0.92) Non-nodal high risk In-transit metastases 41/415 (9.9) 2/20 (10.0) 9/21 (42.9) 0.07 (0.01-0.58) T4 lesion 33/415 (8.0) 6/17 (35.3) 5/16 (31.3) 0.58 (0.16-2.11) Perineural invasion 64/415 (15.4) 3/32 (9.4) 8/32 (25.0) 0.27 (0.07-1.04) Recurrent CSCC with ≥1 additional high-risk criteria 105/415 (25.3) 9/55 (16.4) 22/50 (44.0) 0.19 (0.08-0.45) a Tumors could meet ≥1 high-risk criteria.
Clinical activity of REM-422, a MYB mRNA degrader, in recurrent/metastatic adenoid cystic carcinoma: Final results from the phase 1/2 dose-escalation cohort.
6009 Background: Adenoid cystic carcinoma (ACC) is a malignant neoplasm characterized by dysregulation of MYB, with the majority of tumors containing a hallmark t(6:9) rearrangement resulting in a MYB:NFIB fusion oncogene, or aberrant MYB overexpression. There are no FDA approved systemic therapies for the treatment of ACC. REM-422 is a first-in-class, potent, selective, oral small molecule mRNA degrader of MYB. Methods: This Phase 1/2 study aims to determine the safety, PK/PD and efficacy of REM-422 in patients (pts) with recurrent or metastatic (R/M) ACC. During Phase 1 Dose Escalation and Optimization, patients received oral REM-422 once daily (3-48mg) in 28-day cycles. Enrollment was biomarker-agnostic; MYB mRNA transcripts targetable by REM-422 (biomarker positive) were retrospectively assessed in tumor specimens. Results: In the Phase 1 study, 69 pts were enrolled (median age 57 [range 20-82]); 75% received ≥1 prior line of systemic therapy. Fifty-nine pts were efficacy evaluable: 32 biomarker positive, 24 biomarker negative, and 3 unknown. Fifteen patients received REM-422 at the recommended phase 2 dose (RP2D) of 24 mg. REM-422 was generally well-tolerated. No dose-limiting toxicities were observed. The most common treatment-related adverse events at the RP2D included epistaxis (60%), fatigue (60%) and anemia (40%), all of which were grade 1 or 2. Pharmacodynamic analysis in peripheral blood and on-treatment tumor biopsy confirmed robust target engagement including reduction in MYB mRNA and protein at efficacious exposures. In the biomarker positive population, tumor regression was observed at doses ≥12mg, with 21/30 pts (70%) experiencing reduction in target lesions and 14/30 (47%) achieving at least ≥20% shrinkage. Clinical activity was seen across both molecular subtypes (ACC-I and II) and in pts previously treated with antibody-drug conjugates. At the RP2D of 24 mg, 3 PRs were observed among 7 biomarker positive pts (ORR 42%). Time to response ranged from 4-8 months with durations up to 12 months and ongoing at the data cutoff (07 January 2026). Conclusions: REM-422 is the first small molecule MYB mRNA degrader to demonstrate clinical activity in R/M ACC and is generally well-tolerated. These findings support further evaluation of REM-422 in a biomarker-selected population. Accrual to the Phase 2 Confirmatory Cohort is ongoing. Clinical trial information: NCT06118086 .
Overall survival for patients with pre-treated platinum-resistant ovarian cancer receiving gotistobart in combination with pembrolizumab.
5511 Background: Gotistobart, an investigational tumor microenvironment-selective Treg depletion antibody targeting CTLA-4 with a novel mechanism of action, demonstrated anti-tumor activity when combined with prembrolizumab in the PRESERVE-004/GOG-3081 trial in patients (pts) with platinum-resistant ovarian cancer (PROC; Barlin et al., ESMO 2024). Here, we present overall survival (OS) and updated safety data from the Phase 2 trial (NCT05446298). Methods: Pts with PROC, tubal, or peritoneal cancer who previously received 1 line of platinum-based therapy and progressed between 3-6 months or received ≥1 line and progressed within 6 months of last dose, were treated with gotistobart (1, 2, 3, or 6 mg/kg, Q3W) and pembrolizumab (200 mg, Q3W). Here we present data from patients that received 1 or 2 mg/kg gotistobart Q3W and pembrolizumab. Primary endpoints included objective response rate (ORR) based on RECIST 1.1 and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS) and OS. Results: As of November 12, 2025, 83 pts were treated with ≥1 dose of gotistobart in combination with pembrolizumab. Among them, 62 pts (85.5% White with a median age of 65 years and 83.9% with high grade serous OC) had received 1 or 2 mg/kg gotistobart, and 75.8% had received ≥3 lines of prior therapy (median 4, range: 1-10). The median time from randomization to database cutoff was 22.3 months (range 17.8, 27.2). Median OS was 18.9 m (95% CI 3.9, NE) and 8.3 m (95% CI 3.9 – 17.1) with the OS rates at 18 months at 54.3% (95% CI 35.1, 70.0) and 26.9% (95% CI 11.7 - 44.7) in pts that received 1 or 2 mg/kg gotistobart, respectively. Efficacy data are summarized in the table below. Grade ≥3 treatment-related (gotistobart or pembrolizumab) adverse events (TRAEs) were observed in 51.5% and 55.2% pts treated with 1 mg/kg or 2 mg/kg, respectively. Common (≥5%) grade ≥3 TRAEs were colitis (1 mg/kg: 12.1%, 2 mg/kg: 10.3%), hyponatremia (1 mg/kg: 12.1%, 2 mg/kg: 3.4%), increased ALT (1 mg/kg: 9.1%, 2 mg/kg: 3.4%), increased AST (1mg/kg: 9.1%, 2 mg/kg: 3.4%), adrenal insufficiency (1 mg/kg: 9.1%, 2 mg/kg: 3.4%), diarrhea (1 mg/kg: 9.1%, 2 mg/kg: 3.4%), and hypokalemia (1 mg/kg: 0%, 2 mg/kg: 6.9%). Conclusions: The chemotherapy-free combination of gotistobart and pembrolizumab demonstrated clinically meaningful ORR, OS and a manageable safety profile in pts with PROC, where the majority were heavily pretreated with no further standard-of-care treatment options. Clinical trial information: NCT05446298 . 1 mg/kg gotistobart + pembrolizumab(n=33) 2 mg/kg gotistobart + pembrolizumab(n=29) Confirmed ORR, % (95% CI) 21.2 (9.0, 38.9) 20.7 (8.0, 39.7) Median DoR, m (95% CI) 10.8 (3.3, NE) 11.6 (4.0, NE) Median PFS, m (95% CI) 2.2 (2.0, 4.2) 2.5 (1.9, 6.0) Median OS, m (95% CI) 18.9 (3.9, NE) 8.3 (3.9, 17.1) OS rate at 18 months, % (95% CI) 54.3 (35.1, 70.0) 26.9 (11.7, 44.7)
Use of KMT2 family mutations to define a distinct epithelial-high, stromal-depleted, and interferon-active gene expression state in colorectal cancer.
3671 Background: The KMT2A–D (MLL1–4) family of H3K4 methyltransferases are critical epigenetic regulators of enhancer landscapes and cell identity. At least one of the genes is mutated in 20-25% of colorectal cancer. Their role in shaping the tumor microenvironment (TME) remains distinct from their established roles in leukemia, where they are better described. We tested whether KMT2 mutations are associated with specific immune/stromal phenotypes that could inform therapeutic stratification. Methods: We analyzed a retrospective institutional CRC cohort using targeted NGS (n = 2,267; 565 KMT2 -mutant [MUT], 1,702 wild-type [WT]) and a transcriptomic subset with matched RNA-seq (n = 353; 73 MUT, 280 WT) from primary and metastatic specimens. Differential expression (DESeq2) and pathway enrichment (Hallmark GSEA) compared MUT vs. WT, adjusting for batch and tissue site. VST-based module z-scores (cancer associated fibroblast [CAF]/stroma, epithelial, IFN response, cell-cycle) were computed. xCell, EPIC, CIBERSORTx, and ESTIMATE scores were analyzed by linear regression on z-scored outcomes (MUT vs WT) adjusted for batch and tissue site; Benjamini–Hochberg false discovery rate (FDR). β denotes the adjusted mean difference in standardized score (MUT–WT) in SD units. Overall survival was assessed by Cox proportional hazards models. Results: KMT2 -MUT tumors demonstrate a unique tumor biology, with higher epithelial (β = 0.30, FDR = 0.011), IFN response (β = 0.24, FDR = 0.021), and cell-cycle (β = 0.24, FDR = 0.021) modules with lower CAF/stroma (β = −0.29, FDR = 0.011). Consistent with this, GSEA showed enrichment of IFN-α/γ and proliferation programs (MYC/E2F/G2M) and depletion of epithelial-mesenchymal transition (EMT), myogenesis, and apical junction pathways (FDR < 0.05). TME composition tools demonstrated lower stromal content [lower CAFs (EPIC, β = −0.288, FDR = 0.102), lower fibroblasts/stroma scores (xCell, β≈−0.36/−0.35, FDR = 0.079), and trend toward lower StromalScore (ESTIMATE, β = −0.24, FDR = 0.20)], and trends to higher Th2 (xCell, β = 0.40, FDR = 0.059) and NK cells (xCell, β = 0.38, FDR = 0.079). After adjusting for age, sex, ECOG performance status, primary tumor site, stage, RAS and BRAF mutation status, and MSI status, overall survival did not differ significantly between tumors with and without KMT2 family mutations, although there was a trend toward improved outcomes (HR 0.85, 95% CI 0.70–1.00; p = 0.078). Conclusions: KMT2 family mutations in CRC characterize a tumor subset with retained epithelial identity, active proliferation, and interferon signaling, but markedly reduced stromal infiltration and EMT programs. This distinct biology suggests KMT2 loss may impede the acquisition of aggressive mesenchymal features, highlighting a potential biomarker for stromal-modulating or immune-based therapies.
A phase II trial evaluating liposomal irinotecan combined with capecitabine as second-line therapy for biliary tract cancer.
e16261 Background: Gemcitabine plus cisplatin remains the standard first-line therapy for advanced biliary tract cancers (BTCs). However, disease progression within 8 months in most patients underscores the critical unmet need for effective second-line therapies. Compared to traditional irinotecan, the liposomal irinotecan offers a superior therapeutic profile characterized by higher efficacy and lower toxicity. The combination of liposomes irinotecan with capecitabine(a standard treatment) is currently being explored as a novel therapeutic option in ongoing clinical studies. Methods: This multicenter, single-arm, phase II trial enrolled patients with advanced BTCs (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer) who had progressed on first-line gemcitabine-based therapy. Patients received the combination of liposomal irinotecan and capecitabine. Treatment continued until disease progression. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS) and safety. Results: Between April 2024 and November 2025, 20 patients were enrolled and treated. The median age was 62.5 years (51-74), and 65% were male (13/20). Tumor types included extrahepatic cholangiocarcinoma (20%), intrahepatic cholangiocarcinoma (40%), and gallbladder cancer (40%). The combination therapy demonstrated promising efficacy, with a median PFS (mPFS) of 5.5 months（95%CI [4.50-NA]）. And the longest duration of continuous treatment observed was 14.1 months. which compares favorably to historical benchmarks in this setting. Of the 14 evaluable patients, 3 (21.4%) achieved a partial response, 8 (57.2%) maintained stable disease, and 3 (21.4%) experienced progressive disease. The ORR was 21.4%. Treatment was well-tolerated, with a 30% incidence of grade≥3 treatment-related adverse events (TRAEs). Including decreased white blood cell count(5.0%), neutropenia(10.0%) and diarrhea(5.0%). No fatal TRAEs were observed. Conclusions: The regimen of liposomal irinotecan plus capecitabine showed encouraging anti-tumor activity with a manageable safety profile in patients with gemcitabine-pretreated advanced BTCs, suggesting a potential new therapeutic option for the second-line setting. The follow-up work on patient survival is underway, and more data will be disclosed in the future. Clinical trial information: NCT06430827 .
Metastatic prostate cancer and heart failure hospitalizations: An intersection.
e17144 Background: Prostate cancer (PC) is the second most frequently diagnosed cancer in men. Those patients with metastatic prostate cancer(mPC) require cancer treatment for several months or years, which results in cardiac adverse effects, including heart failure (HF). We aim to identify the outcome of heart failure in mPC. Methods: We conducted a retrospective analysis utilizing the 2022 National Inpatient Sample (NIS) database. We analyzed hospitalizations from mPC with and without HF. We compared hospitalization characteristics and clinical outcomes employing T-tests and Chi-square tests. Results: In 2022, there were 16,996 hospitalizations of mPC, of which 2899 had associated HF. The mean age of mPC with HF was seen in older patients compared to those without HF (78 vs 74 years, p-value<0.001). In this cohort, racial distribution differed significantly between PC patients with and without HF (p < 0.001), with a higher proportion of White patients and a lower proportion of Hispanic patients observed in the HF group. The mortality rates of mPC patients with HF were 8.83% vs 6.60% in those without HF, with a p-value of <0.001. The multivariate logistic regression on the cohort showed an adjusted odds ratio of 1.36 ( 95% CI 1.28-1.48, p-value 0.002). A significant difference in insurance coverage was observed between groups (p < 0.001), with 85% of PC patients with HF insured through Medicare compared to 77% without HF. In comparison, those without HF had nearly twice the rate of private insurance coverage (15.4% vs. 8.8%). Disposition at discharge differed significantly between groups (p < 0.001); patients with HF were less frequently discharged home routinely (30.5% vs. 38.7%) and more often transferred to skilled nursing facilities (27.5% vs. 22.7%) compared to those without HF. The mean length of stay and total charge were significantly higher in mPC, averaging 7 days and $91034, compared to those without HF, who had an average of 6 days and $81851 (p-value<0.001). Conclusions: Our analysis revealed that mPC with HF had worse clinical outcomes and increased health care burden when compared to mPC hospitalizations without. This necessitates more aggressive treatment in patients with mPC with HF. Epidemiological characteristics of prostate cancer with and without heart failure. Variables Prostate Cancer with Heart Failure[2899](%) Prostate Cancer without Heart Failure[14097](%) p-Value Mean Age (Years) 78 74 <0.001 Mean LOS (Days) 7 6 0.002 Total Charges ($) 91,034 81,851 <0.001 Mortality (%) 8.83 6.60 <0.001 Race <0.001 White 68.76 66.08 African-American 20.79 20.12 Hispanics 6.11 8.69 Asian or Pacific Islander 2.26 2.33 Native American 0.32 0.39 Other 1.76 2.39 Insurance <0.001 Medicare 85.08 76.71 Medicaid 4.95 6.35 Private, including HMO 8.82 15.41 Self-pay 1.15 1.53 Region of the Hospital <0.001 Northeast 20.35 21.11 Midwest 28.04 22.69 South 30.56 35.68 West 21.04 20.52
Association of inpatient outcomes with cannabis use disorder in head and neck cancer.
e18112 Background: Cannabis is the most commonly used illicit substance worldwide and has recently been identified as a risk factor for head and neck cancer (HNC), joining established risk factors such as HPV, tobacco, and alcohol use. Whether cannabis use disorder (CUD) affects inpatient outcomes is unknown. We evaluated clinical characteristics associated with CUD among hospitalized HNC pts and hypothesized that CUD is associated with worse inpatient outcomes. Methods: We queried the National Inpatient Sample from 2016 to 2022 to identify adult hospitalizations for HNC with or without CUD using ICD-10 codes. Baseline characteristics were compared using chi-square and t-tests. The primary outcome was mortality; secondary outcomes included length of stay and major complications. Multivariable logistic regression assessed the association between CUD and mortality, adjusting for demographics, insurance, income, hospital characteristics, Charlson Comorbidity Index (CCI) excluding cancer, metastatic disease, alcohol and tobacco use, and an HPV-associated anatomic site proxy based on oropharyngeal tumor location. Sensitivity analyses stratified by HPV-associated site were performed. Results: Among 108,344 HNC hospitalizations, 1,596 (1.47%) involved CUD. Compared with non-CUD pts, those with CUD were younger (mean age 57.1 vs. 64.6 yrs), more often male (80.7% vs. 72.0%), Black (20.3% vs. 12.0%), and Medicaid insured (39.1% vs. 15.7%) (all p<0.001). Tobacco use (50.6% vs. 21.3%) and alcohol use disorder (26.8% vs. 7.9%) were more prevalent in the CUD cohort (both p<0.001). Unadjusted in-hospital mortality was lower among CUD pts (2.01% vs. 4.73%, p<0.001), while LOS was longer (7.48 vs. 7.05 days, p=0.041). Rates of major complications were similar, with lower pneumonia and acute kidney injury in the CUD group and no differences in sepsis, respiratory failure, aspiration, or venous thromboembolism. After adjustment, CUD was independently associated with lower in-hospital mortality (aOR 0.47, 95% CI 0.33-0.68; p<0.001). Metastatic disease, higher CCI, alcohol use disorder, and non-Medicare status were associated with increased mortality, while younger age, female sex, tobacco use, and HPV-associated tumor site were associated with lower odds in HNC pts. Stratified analyses showed no significant association between CUD and mortality among HPV-associated HNC, while a significant association persisted among non-HPV-associated HNC. Conclusions: Despite a higher burden of substance use and socioeconomic disadvantage, CUD was not associated with increased inpatient complications and was independently associated with lower in-hospital mortality, particularly in non-HPV-associated HNC, potentially reflecting younger age and lower comorbidity burden at hospitalization. Limitations include possible incomplete ascertainment of CUD use. These findings are important given the growing prevalence of CUD.
Clinicopathological characteristics and targeted therapy response in <i>ALK</i> fusion–positive lung squamous cell carcinoma: A multicenter retrospective real-world study.
e20709 Background: Anaplastic lymphoma kinase (ALK) rearrangements are rare in lung squamous cell carcinoma (SqCC), and real-world data on the clinicopathological features and therapeutic efficacy of ALK tyrosine kinase inhibitors (TKIs) in this subset are limited. This study aimed to characterize ALK-positive SqCC and evaluate the outcomes of ALK-targeted therapies. Methods: This multicenter, retrospective real-world study analyzed 15 patients with advanced ALK-rearranged SqCC (including 4 adenosquamous carcinoma) treated with ALK-TKIs. Clinicopathological features were collected. The primary objective was to assess progression-free survival (PFS) and objective response rate (ORR). A pooled analysis integrated data from published literature, creating a combined cohort of 54 patients (including 39 historical controls treated with crizotinib/alectinib) for broader comparison. Statistical analysis included Kaplan-Meier method for PFS estimation and log-rank test for comparisons, with a two-sided p<0.05 considered significant. Results: Among 19 TKI treatment events in our cohort, the overall ORR was 52.6% and disease control rate (DCR) was 100.0%. Lorlatinib (n=10 events) showed superior efficacy vs. alectinib (n=7): ORR 70.0% vs. 28.6%; median PFS (mPFS) 16.0 vs. 12.0 months (hazard ratio [HR]=0.43, 95% CI: 0.21–0.96; P=0.026). The pooled analysis (n=54 patients) confirmed the significant advantage of lorlatinib-based strategy (n=10) over earlier-generation TKIs (crizotinib/alectinib, n=49): mPFS 16.0 vs. 7.1 months (HR=0.21, 95% CI: 0.10–0.44; P<0.0001), representing a 79% reduction in progression/death risk. The cohort was characterized by a predominance of never-smoking (53.3%) and female (60.0%) patients. Conclusions: This real-world study provides the first evidence suggesting that lorlatinib may offer improved efficacy over earlier-generation ALK inhibitors in patients with ALK-rearranged SqCC. These exploratory findings highlight the clinical activity of lorlatinib in this rare subset and underscore the necessity of ALK testing in SqCC patients with relevant clinicopathological features. Prospective studies are warranted to validate these observations and define the optimal therapeutic strategy. Efficacy outcomes of ALK-TKIs in the study and pooled analysis. Treatment Group n (Events) ORR,% (n) DCR,% (n) Median PFS,months (95% CI) Lorlatinib 10 70.0 (7/10) 100.0 (10/10) 16.0 (11.0–26.0) Alectinib 7 28.6 (2/7) 100.0 (7/7) 12.0 (10.7–15.0) Crizotinib 2 50.0 (1/2) 100.0 (2/2) Not reported All TKIs (Study Cohort) 19 52.6 (10/19) 100.0 (19/19) 15.0 (11.0–20.4) Earlier-gen TKIs (Pooled Data) 49 Not pooled Not pooled 7.1 (6.0–9.0)
Measurable residual disease (MRD) by circulating tumor (ct) DNA in patients (pt) with R/R follicular lymphoma (FL) treated with lisocabtagene maraleucel (liso-cel) in TRANSCEND FL.
7025 Background: ctDNA is a minimally invasive method for detecting MRD in various malignancies. MRD negativity (MRD neg ) has been linked to improved PFS and durable disease control, including after liso-cel treatment in R/R large B-cell lymphoma. The prognostic value of MRD after chimeric antigen receptor (CAR) T cell therapy in R/R FL has not been established. We report an exploratory MRD analysis from TRANSCEND FL (NCT04245839), in which pts had high rates of deep and durable responses after liso-cel. Methods: Of 103 efficacy-evaluable pts with third-line or later (3L+) FL, 89 (86%) had ctDNA samples, of whom 90% (80/89) had evaluable ctDNA and efficacy data after liso-cel infusion. Tumor-derived phased variants were primarily identified from screening (baseline) plasma or tumor tissue when plasma was insufficient, using PhasED-Seq. Post-treatment ctDNA-MRD was assessed at months (M) 1 and 3 after infusion for all pts, and at M24 for ongoing responders. MRD positivity (MRD pos ) was defined as ctDNA above the assay detection threshold (lower limit of detection of 0.7 parts per million, with sample-specific sensitivity dependent on DNA input). Results: MRD neg was achieved by 89% (71/80) of evaluable pts from TRANSCEND FL. Among pts with a best overall response of CR, 93% (71/76) of them achieved MRD neg . ctDNA clearance increased over time, with MRD neg rates of 68% (52/76) at M1, 83% (63/67) at M3, and 97% (57/59) at M24. In contrast, pts with PR, SD, or PD (n=4) never achieved MRD neg . Baseline ctDNA levels were not associated with PFS after liso-cel treatment. MRD neg after infusion was associated with longer PFS compared with MRD pos ( P <0.001). In addition, MRD status at M3 (HR, 7.0 [95% CI, 3.0–16.2]) showed a stronger correlation with PFS than at M1 (HR, 3.0 [95% CI, 1.3–6.8]), with 36-M PFS rates of 80% for MRD neg (n=63) versus 38% for MRD pos (n=13) pts. Multivariate analysis controlling for PET findings confirmed the independent prognostic value of MRD for PFS. Importantly, PFS was longer for pts with both CR by PET and MRD neg at M3 (n=62) compared to pts with CR and MRD pos (n=9; HR, 5.0, [95% CI, 1.8-13.4]), with 36-M PFS rates of 81% versus 56%, respectively, suggesting that combining MRD with PET may provide additional prognostic information for long-term outcomes. Conclusions: Liso-cel induced deep molecular responses in pts with 3L+ FL with most pts (89%) achieving MRD neg after infusion. Although baseline ctDNA levels were not associated with PFS, MRD neg after infusion was significantly associated with improved PFS, highlighting the therapeutic benefit of liso-cel regardless of tumor burden before treatment. These findings support the potential of ctDNA-based MRD as a prognostic biomarker in FL and underscore that liso-cel is a key treatment option capable of inducing MRD neg and durable clinical outcomes in pts with 3L+ R/R FL. Clinical trial information: NCT04245839 .
Neutropenic diet (ND) versus liberalized diet (LD) in patients with cancer: A systematic review and meta-analysis.
e18574 Background: ND has historically been recommended to reduce infectious complications in cancer patients (pts). While the adoption of ND has declined over the last decade, recent studies - particularly in pts undergoing hematopoietic stem cell transplantation (HSCT) - have raised uncertainty regarding the safety of LD. Herein, we performed a meta-analysis of studies directly comparing ND with LD in pts with cancer. Methods: We conducted a systematic search of MEDLINE, Embase, and Cochrane databases from inception through January 2026. Comparative retrospective and prospective studies were included if they were comparing ND with LD in adults or children with cancer. Primary outcomes were major infections and bacteremia/fungemia. Secondary outcomes were pneumonia, diarrhea, and all-cause mortality. Random-effects meta-analyses were performed to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). The review followed PRISMA 2020 guidelines. Results: Fifteen studies enrolling 4,320 patients were included in the primary analysis. Six studies enrolled only adult patients, three were restricted to pediatric populations, and six included mixed adult and pediatric cohorts. Across these studies, ND was not associated with a significant reduction in major infections (RR 1.02, 95% CI 0.88–1.18; p=0.795), bacteremia/fungemia (RR 0.97, 95% CI 0.78–1.22; p=0.805), pneumonia (RR 0.98, 95% CI 0.59–1.63; p=0.933), diarrhea (RR 1.12, 95% CI 0.96–1.31; p=0.159), or all-cause mortality (RR 0.94, 95% CI 0.77–1.15; p=0.632). Sensitivity analyses restricted to RCTs showed consistent results. Subgroup analysis of hematological/HSCT studies (9 studies; 1,769 pts) also showed no differences across outcome. Analysis restricted to RCTs in hematologic/HSCT pts (6 studies; 855 pts) showed no differences in major infections, pneumonia, diarrhea, or mortality; however, ND was associated with a lower risk of bacteremia/fungemia (RR 0.67, 95% CI 0.47–0.95; p=0.023). Heterogeneity across studies was low to moderate. Conclusions: ND was not associated with reductions in major infections, pneumonia, diarrhea, or mortality compared with LD. A reduction in bacteremia/fungemia was observed in RCTs of hematologic malignancy and HSCT pts. Overall, these findings suggest that routine ND implementation is unnecessary for most cancer pts, although cautious dietary practices may remain reasonable in selected high-risk hematologic malignancy/HSCT populations.
Malnutrition and deaths associated with cancer in the United States.
e22579 Background: Patients with cancer have a heightened risk of malnutrition. The prevalence of malnutrition among cancer patients ranges from approximately 40% to 80%. Consequently, our analysis using CDC data aims to investigate mortality trends in patients facing both conditions from 1999 to 2023 in the United States. Methods: We accessed the CDC WONDER Multiple Cause of Death database spanning from 1999 to 2023, identifying all individuals who died of malignant neoplasm (ICD-10: C00-D48) listed as the primary cause of death, while malnutrition (ICD-10: E40-E46) was documented as a contributing factor. We assessed disparities across different racial/ethnic groups, census regions, and urban versus rural locations. Age-adjusted mortality rates (AAMRs) were calculated per 100,000 individuals. The annual percent change (APC) and average APC were determined using the Joinpoint regression software (Version 5.4). Results: There were a total of 163,907 deaths related to malnutrition among cancer patients. Overall, the AAMR rose from 2.81 (95% CI: 2.73 to 2.89) in 1999 to 6.03 (95% CI: 5.94 to 6.12) in 2023 (AAPC: 3.31; 95% CI: 2.64 to 3.99; p< 0.000001), with the most significant increase observed between 2013 and 2023 (APC: 11.79; 95% CI: 11.18 to 12.41; p<0.000001). The rise in mortality was slightly more pronounced in women than in men (AAPC: 3.37 vs 2.99). The highest incidence rates were noted among the non-Hispanic (NH) Black or African American population, followed by NH White and Hispanic or Latino. Geographic disparities were apparent, with the South experiencing the greatest impact, while the Northeast was the least affected. Rural regions consistently showed higher AAMR compared to urban areas, though urban locations experienced a steeper increase between the two (AAPC: 2.34 vs 1.49). Conclusions: Black men encounter significantly elevated rates of malnutrition-related cancer incidence and mortality when compared to other racial groups. This upward trend highlights the pressing need for focused interventions and resource distribution to tackle these disparities and achieve favorable outcomes. Deaths and AAMRs per 100,000 for trends related to malnutrition in cancer patients from 1999 to 2023. Variable Deaths AAMR (95%CI)1999 AAMR (95% CI)2023 Overall 163,907 2.81(2.71 to 2.89) 6.03(5.94 to 6.12) Male 87,961 3.64(3.49 to 3.78) 7.28(7.13 to 7.43) Female 75,946 87,961 2.31(2.22 to 2.40) 4.99(4.87 to 5.10) NH Blacks 23,335 5.30(4.93 to 5.68) 7.50(7.17 to 7.83) NH White 123,137 2.59(2.51 to 2.68) 6.19(6.08 to 6.30) Hispanic or Latino 11,282 2.39(2.05 to 2.73) 2.86(1.67 to 4.06) South 70,248 3.07(2.94 to 3.21) 6.22(6.07 to 6.37) West 41,542 2.70(2.53 to 2.88) 6.97(6.76 to 7.10) Midwest 38,769 3.25(3.08 to 3.42) 6.8096.58 to 7.18) Northeast 19,138 2.06(1.91 to 2.20) 3.51(3.35 to 3.68) Urban 94,409 2.65(2.56 to 2.73) 4.13(4.05 to 4.22) Rural 25,566 3.70(3.49 to 3.91) 4.87 (4.66 to 5.08)
Comparative efficacy of immune checkpoint inhibitor–anti-VEGF inhibitor combinations in non–small cell lung carcinoma: A network meta-analysis of randomized trials.
e20629 Background: Concomitant inhibition of the vascular endothelial growth factor (VEGF) pathway together with PD-1 or PD-L1 immune checkpoint blockade has demonstrated synergistic activity in non-small cell lung cancer (NSCLC). However, comparative evidence across individual immune checkpoint inhibitor (ICI) and anti-VEGF combinations remains limited. This network meta-analysis (NMA) aimed to evaluate and compare the efficacy of available ICI plus anti-VEGF combination strategies in NSCLC. Methods: A systematic search of three electronic databases and two clinical trial registries was conducted to identify randomized controlled trials evaluating combinations of ICIs with anti-VEGF agents. A frequentist NMA framework was applied using the netmeta package in R. Hazard ratios (HRs) were used for overall survival (OS) and progression-free survival (PFS), while odds ratios (ORs) were used for objective response rate (ORR). Treatment ranking was performed using P scores. Results: A total of 24 randomized controlled trials were included in the network. For survival outcomes, the combination of nivolumab plus bevacizumab demonstrated significantly improved OS (HR = 0.66, 95% CI 0.50–0.88) and PFS (HR = 0.46, 95% CI 0.27–0.81) compared with standard chemotherapy. In addition, atezolizumab plus bevacizumab was associated with a significant OS benefit over chemotherapy (HR = 0.79, 95% CI 0.65–0.95). Indirect comparisons showed that nivolumab plus bevacizumab significantly improved PFS compared with pembrolizumab monotherapy, as well as pembrolizumab combined with lenvatinib or chemotherapy. Furthermore, nivolumab combined with sitravatinib demonstrated significantly superior OS and PFS compared with ramucirumab and chemotherapy. For ORR assessed using RECIST 1.1, nivolumab-based combinations could not be incorporated into the network due to insufficient data, and no other combination demonstrated a statistically significant advantage over chemotherapy. However, indirect comparisons showed that pembrolizumab plus lenvatinib was superior to lenvatinib monotherapy (OR = 4.76, 95% CI 1.04–25.0). P-score rankings identified nivolumab plus bevacizumab as the top-ranked regimen for survival outcomes, followed by atezolizumab plus bevacizumab. For ORR, pembrolizumab plus lenvatinib ranked highest, followed by atezolizumab plus bevacizumab. Conclusions: Nivolumab-based ICI and anti-VEGF combinations, particularly with bevacizumab and sitravatinib, demonstrate the most favorable survival outcomes in NSCLC. Evidence for ORR remains limited, and further randomized comparisons are required to better define the relative efficacy of these combinations.
Chemotherapy use among women < 50 years with node-negative early-stage hormone receptor–positive breast cancer with intermediate OncotypeDX 21-gene recurrence score: A National Cancer Database analysis.
e12546 Background: The Oncotype DX recurrence score (RS) multigene assay is widely-used to guide adjuvant chemotherapy (CT) decisions in early-stage hormone receptor–positive (HR+), HER2-negative breast cancer (BC). As RS does not explicitly account for the key prognostic factors of age or menopausal status, its use among premenopausal women < 50 years with intermediate scores (16–25) remains unclear. Specifically, while CT benefit may increase toward the upper end of this range, the magnitude of benefit has not been clearly defined. To this end, we sought to examine CT treatment patterns among women < 50 years with node-negative BC and intermediate RS utilizing National Cancer Database (NCDB). Methods: This retrospective NCDB analysis queried data from 2018-2022 for patients < 50 years (surrogate for premenopausal status) and clinically and pathologically node negative (pN0) stage I-III HR+ HER2-negative BC who underwent upfront surgery and had RS 16-25. Intermediate RS was further categorized using two subgroups: 16-20 and 21-25. Multivariable binary logistic regressions were used to examine the associations between clinical factors and receipt of CT stratified by each RS subgroup. Results: Data from 3,586 premenopausal women with pN0 and intermediate RS were analyzed: 2,382 patients had RS 16-20 and 1,204 had RS 21-25. A greater proportion of patients with RS 21-25 received CT compared to RS 16-20 (49.2% vs 10.6%, p < .001). Among those with RS 16-20, older age (aOR 0.92, 95% CI 0.89-0.94), higher pathologic tumor stage (aOR 6.33, 95% CI 2.90–13.82, pT3/4 vs pT1/2), higher grade disease [i.e. moderately (vs well) differentiated (aOR 1.89, 95% CI 1.34–2.67); poorly (vs well) differentiated vs (aOR 5.17, 95% CI 3.27–8.16)], and residing > 50 miles from the treatment facility (aOR 1.81, 95% CI 1.11-2.94) were associated with greater odds of CT receipt. While most of those factors were also associated with CT receipt among those with RS 21-25, distance from treatment facility did not retain significance for this cohort. Conclusions: Among women < 50 years with pN0 and intermediate RS, CT receipt was strongly associated with clinicopathologic factors for scores 16-20 and 21-25. These findings indicate that even in node-negative disease, clinicopathological factors continue to be accounted for in guiding CT decisions and are considered alongside RS when individualizing treatment in this population.
Association between physician characteristics and likelihood of caring for underserved patients with cancer.
1646 Background: Despite evidence that a diverse workforce may improve access to care for underserved patients, emerging policies threaten to limit diversity in the physician workforce. We assessed whether nonwhite and foreign-born physicians were more likely than White and US-born physicians to care for underserved (minority race, low-income, rural) Medicare beneficiaries with cancer. Methods: Using SEER-Medicare, we analyzed Medicare beneficiaries aged 18+ newly diagnosed with breast, colorectal, lung, or prostate cancer from 2015-2019. We linked patients to cancer physicians (medical, radiation, and surgical oncology) using claims in the 6 months after diagnosis. We assessed physician race/ethnicity (data from Association of American Medical Colleges) and country of birth (American Medical Association). For each physician race and foreign-born status, we calculated the standardized treatment ratio (STR) as the percent of that group's dyads with a given patient characteristic divided by the percent of all dyads with that patient characteristic. Thus, STR > 1 indicates physicians in that group are more likely than the average physician to treat patients with the given characteristic. Results: We linked 434,923 patients (30% breast, 16% colorectal, 29% lung, 25% prostate) to 35,257 physicians. The patient population (mean age 74.7) was 79% White, 8% Black, 7% Hispanic, 3% Asian, 17% Medicaid dual-eligible, and 16% rural. Black physicians were more likely than expected to care for Black patients (STR 2.55; 95% CI 2.48–2.63; Table) and dual-eligible patients (STR 1.26; 1.22–1.29). Hispanic physicians were more likely to care for Hispanic (1.97; 1.91–2.03) and dual-eligible (1.11; 1.08–1.14) patients. Asian physicians were more likely to care for Asian (1.93; 1.89–1.96) and Hispanic (1.18; 1.16–1.20) patients and less likely to care for rural (0.73; 0.72-0.74) patients. Foreign-born physicians (20.7% of physicians) were more likely to care for Asian (1.36; 1.33–1.39), Hispanic (1.25; 1.23–1.27), and dual-eligible (1.20; 1.18–1.21) patients and less likely to care for rural patients (0.90, 0.89-0.91). Conclusions: Nonwhite and foreign-born cancer physicians disproportionately care for nonwhite and low-income patients. Policies restricting entry of minority and foreign-born physicians into the oncology workforce may hinder access to care for underserved cancer patients. Standardized treatment ratios (STRs) by physician race, ethnicity and country of birth. Physician characteristic Patient Characteristic Asian Black Hispanic White Dual eligible Rural Race & ethnicity Asian 1.93 1.00* 1.17 0.95 1.09 0.73 Black 0.60 2.55 1.08 0.85 1.26 1.04 Hispanic 0.79 0.97* 1.97 0.94 1.11 1.01* White 0.68 0.92 0.81 1.04 0.88 1.09 Foreign born No 0.86 0.96 0.89 1.02 0.88 1.04 Yes 1.36 1.05 1.25 0.96 1.20 0.90 *Denotes STRs NOT significantly different from 1.0; all other values are significant (P<0.05).
Impact of GLP-1 receptor agonists on outcomes in hepatocellular carcinoma patients treated with atezolizumab plus bevacizumab: A multicenter propensity-matched real-world analysis.
e16180 Background: First-line treatment of advanced unresectable or metastatic hepatocellular carcinoma (HCC) is now defined by immune checkpoint inhibitor (ICI) based combinations, particularly atezolizumab plus bevacizumab. Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used in type 2 diabetes mellitus (T2DM), may favorably modulate immune and metabolic pathways, potentially enhancing ICI efficacy and improving cardiovascular safety. We evaluated the real-world impact of GLP-1RA exposure on clinical outcomes in patients with HCC treated with atezolizumab plus bevacizumab. Methods: We conducted a multicenter retrospective cohort study using the TriNetX Global Collaborative Network, a federated electronic health record database, including data from January 1, 2018, to December 31, 2025. Adult patients with HCC and T2DM initiating atezolizumab plus bevacizumab were stratified into two cohorts: those prescribed any GLP-1RA within 12 months prior to treatment initiation (GLP-1RA group) and those treated with alternative antihyperglycemic agents without GLP-1RA exposure (non-GLP-1RA group). Alternative agents included metformin, SGLT2 inhibitors, DPP-4 inhibitors, insulin, thiazolidinediones, alpha-glucosidase inhibitors, and sulfonylureas. One-to-one propensity score matching was performed to balance demographics, HCC etiology, comorbidities, laboratory parameters, and concurrent antidiabetic therapies. Outcomes were assessed over a 5-year follow-up period. The primary endpoint was overall survival (OS). Secondary endpoints included major adverse cardiovascular events (MACE), excluding patients with pre-existing events. All analyses were conducted within the TriNetX analytics platform. Results: Among 920 eligible patients, 106 (11.5%) received GLP-1RA therapy and 814 (88.5%) comprised the non-GLP-1RA cohort. After 1:1 propensity score matching, 70 patients were included in each group. GLP-1RA exposure was associated with a improvement in OS compared with the non-GLP-1RA group at 5 years (hazard ratio [HR] 0.51; 95% CI, 0.32–0.82). In the MACE analysis, which excluded patients with prior cardiovascular events (GLP-1RA, n = 45; non-GLP-1RA, n = 48), GLP-1RA therapy was associated with a lower risk of MACE at 5 years (HR 0.49; 95% CI, 0.24–0.98). Conclusions: In patients with T2DM and HCC treated with atezolizumab plus bevacizumab, prior GLP-1RA exposure was associated with significantly improved overall survival and a reduced risk of major adverse cardiovascular events compared with alternative antihyperglycemic therapies. These findings support a potential synergistic role of GLP-1RAs in this population and warrant prospective validation.
Influence of pelareorep on mutant KRAS-specific blood TIL clonal expansion.
2664 Background: Pelareorep (pela) is an intravenously delivered unmodified oncolytic reovirus that selectively infects cancer cells and is being developed as an immunotherapy for multiple cancers. We report here the analysis of tumor and blood samples from breast and pancreatic cancer patients that demonstrate a multi-step process of innate, viral, and tumor-specific immune activation culminating in the expansion of tumor-specific mutant KRAS (mKRAS) T cell clones that are associated with reductions in tumor volume. Methods: Translational samples were obtained from subjects enrolled in breast cancer (AWARE-1 ClinicalTrials.gov ID NCT04102618) and pancreatic (PDAC) cancer trials (GOBLET ClinicalTrials.gov ID NCT07280377). Analysis of tumor gene expression was performed on extracted RNA from Formalin-Fixed Paraffin-Embedded (FFPE) obtained from AWARE-1 clinical samples collected at baseline, day 3 and day 21 of therapy. Changes in tumor gene expression were determined using a customized code-set including the 50 PAM50 genes + other genes (as immune panels). Translational data from GOBLET PDAC subjects included anti-reovirus T cell responses, which were assessed by ELISPOT using whole inactivated reovirus antigen stimulation. Enumeration of the T cell fractions was performed by Adaptive Biotechnologies (Seattle, WA, USA). TCRβ CDR3 DNA was isolated from tissue and blood at baseline and from blood collected post-treatment from both studies. Antigenic specificity of selected T cell clones for mKRAS was determined by the MIRA assay (Adaptive Biotechnologies). Results: Sequential genetic analyses of breast cancer tumor biopsies pre- and post-pelareorep therapy demonstrated significant increases in anti-viral and immune gene expression consistent with the activation of toll-like receptor 3 (TLR3). Activation of TLR3 also induced the production of CXCL13, a chemokine critical for the formation of tertiary lymphoid structures (TLS). TLS in the tumor were confirmed by imaging mass cytometry of tumor biopsies following pelareorep treatment. Expansion of tumor-infiltrating lymphocytes (TILs) in both tumor and blood was also observed. Analysis of serial blood samples from a cohort of pelareorep-treated pancreatic cancer patients showed expansion of anti-viral T cells by ELISPOT. In addition, clonal expansion of tumor-specific T cells was observed after one cycle of treatment. The expansion of pre-existing TIL clones in the blood correlated with reductions in tumor volume in pancreatic cancer. Analysis of TCR sequences for antigen specificity confirmed the expansion of mKRAS clones in these samples. Conclusions: These findings suggest that pelareorep immunotherapy, through the combined activation of TLR3 and infection of the tumor, induces innate and adaptive antiviral and anti-tumor-specific immune responses capable of controlling tumor growth.
New IMS/IMWG risk criteria by next-generation sequencing (NGS): Analysis of daratumumab benefit in both high- and standard-risk patients (pts) in the PERSEUS study.
7505 Background: IMS/IMWG recently proposed novel Consensus Genomic Staging (CGS) high-risk criteria for newly diagnosed multiple myeloma (NDMM), including genetic alterations not identifiable by fluorescence in situ hybridization (FISH) but by NGS (eg, TP53 mutations). PERSEUS/EMN017 (NCT03710603) evaluated the addition of daratumumab to VRd induction/consolidation and to R maintenance (DVRd arm) vs VRd+R (VRd arm) in transplant-eligible (TE) pts. PERSEUS previously reported that DVRd significantly improved progression-free survival (PFS) regardless of cytogenetic risk as defined by previous criteria. Methods: 709 pts with NDMM were randomized 1:1 to DVRd vs VRd. Unique molecular assay (UMA)-NGS target panel was used on DNA extracted from CD138+ bone marrow (BM) cells. Of 664 pts from whom BM was collected, 434 patient DNA samples were available for NGS testing. Per the new IMS/IMWG CGS criteria, high risk was defined post-hoc by the presence of del17p/ TP53 mutations; t(4;14) or t(14;16) or t(14;20) with additional amp1q or del1p; amp1q and del1p; biallelic del1p; and high β2 microglobulin with normal renal function. Classic FISH high risk was defined per-protocol by the presence of del17p, t(14;16), and/or t(4;14). Minimal residual disease negativity (MRD neg) was assessed by NGS (Adaptive) in pts with complete response or better. Results: Of 434 pts evaluated, 152 (35%) were high risk by CGS. The most common genetic lesions were del17p/ TP53 (n=59, 14%), IgH translocation with amp1q/del1p (12%), and del1p with amp1q (9%); 2% had biallelic focal del1p. Using CGS criteria, 17% of pts were reclassified from standard risk to high risk; additionally, 4% of pts previously classified as high risk were reclassified as standard risk. DVRd was associated with increased MRD neg rates at 10 -6 compared to VRd in both CGS standard-risk (67% vs 39%, P =0.0001) and high-risk pts (56% vs 26%, P =0.0003). Sustained MRD neg (10 -6 ) rates for ≥12 months (+/-1 mo) were higher with DVRd vs VRd for both CGS standard-risk (57% vs 24%; P <0.0001) and high-risk pts (41% vs 19%; P <0.0001), and pts who achieved sustained MRD negativity (10 -6 ) had superior PFS outcomes versus those who did not, regardless of CGS risk status ( P <0.0001). DVRd led to improved PFS in both CGS standard-risk (HR 0.38, 95% CI 0.20–0.73; P =0.001) and high-risk pts (HR 0.54, 95% CI 0.31–0.95; P =0.039), adjusting for ISS, lactate dehydrogenase, and age (>65 years). Conclusions: DVRd improved MRD negativity and PFS over VRd in both the new IMS/IMWG CGS high-risk and standard-risk subgroups. UMA-NGS panel successfully stratified risk according to CGS criteria, identifying nearly twice as many high-risk pts in the PERSEUS study. These data further support DVRd induction/consolidation and DR maintenance as standard of care for TE-NDMM, regardless of cytogenetic risk. Clinical trial information: NCT03710603 .
Phase IIa, open-label, multi-center study of the DNA polymerase theta inhibitor ART6043 administered orally in combination with olaparib to patients with HER2-negative breast cancer with a germline BRCA1/2 mutation (randomized expansion of study NCT05898399).
TPS1165 Background: Microhomology-mediated end joining (MMEJ) repair of DNA double-strand breaks is reliant on DNA polymerase theta (Polθ). ART6043 inhibits Polθ and hence MMEJ without affecting other forms of DNA double-strand break repair (DSBR) such as homologous recombination (HR) and non-homologous end joining (NHEJ). MMEJ becomes essential for tumor survival in patients with germline BRCA1/2 mutations being treated with poly adenosine diphosphate ribose polymerase (PARP) inhibitors. Polθ inhibition is therefore a powerful strategy to target HR-deficient cancers by potentiating the DNA damage induced by PARP inhibition. Combination of Polθ inhibition with PARP inhibition may also delay or prevent emergence of PARP inhibitor resistance through circumvention of MMEJ-mediated BRCA1/2 gene reversions that restore HR activity. The restricted expression profile of the POLQ gene in normal tissues compared with tumor tissues predicts a high therapeutic index for combining Polθ inhibition with DNA damaging agents without synergistic toxicity. Data from 61 pts dosed in the ART6043 dose escalation as monotherapy and in combination with the PARP inhibitor, olaparib, in a tumor agnostic population were presented at ESMO 2025 (Yap et al 2025). These data showed that ART6043 was well-tolerated alone and with the approved dose of olaparib; good ART6043 exposure with no evidence of drug-drug interaction with olaparib; pharmacodynamic engagement as monotherapy and enhanced with olaparib and promising signals of anti-tumor activity for the combination of ART6043 + olaparib. These data support a randomized expansion of ART6043 + olaparib compared to olaparib alone to demonstrate the first proof of concept for Polθ inhibition in HR-deficient cancers. Methods: In this expansion to study NCT05898399, approximately 80 pts with locally advanced or metastatic HER2 negative breast cancer with a germline BRCA1/2 mutation will be randomized to ART6043 + olaparib vs olaparib (stratified by use of prior platinum). Patients must have received prior chemotherapy and no or ≤1 month of prior PARP inhibitor. Patients with hormone receptor positive breast cancer should have been treated with prior endocrine therapy. Patients in the investigational arm will receive ART6043 600 mg once daily with olaparib 300 mg twice daily. Patients on the olaparib-alone arm may cross over to receive ART6043 + olaparib on progression. Key objectives include preliminary efficacy (progression-free survival, objective response rate etc), safety and tolerability. Cell free DNA samples will be collected to assess stratification biomarkers, response and compare the occurrence of resistance mechanisms (eg BRCA reversion) between the two arms. Enrollment will continue until Q4-2027. Clinical trial information: NCT05898399 .