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Role of microbiota in response to treatment in anal squamous cell carcinoma.
3518 Background: Anal squamous cell carcinoma (ASCC) is a rare tumor whose management and treatment have not changed since the 1970s, consisting of classical chemotherapy combined with radiotherapy. Microbiota has been recently included as a hallmark of cancer, playing a relevant role in oncogenesis and tumor progression. Therefore, the aim of this study is the characterization of tumor microbiota in ASCC. Methods: Paraffin samples from seventy-six ASCC patients were analyzed. First, DNA was extracted, followed by 16S rDNA sequencing to identify microbiota. Then, a bacterial reference proteome was built, including the bacteria genera identified by 16S, and proteins from human and microbiota were identified and quantified by mass-spectrometry proteomics. Results: Seventy-six ASCC patients were included in this study: 46 (60%) female; median age 61 years; 62 (81%) HPV-positive; 1 (1%) stage I, 30 (40%) stage II, 43 (57%) stage III, 1 (1%) stage IV, and 1 (1%) unknown stage. Of these, sixty-nine (stages II-III, treated with chemoradiotherapy) were considered for survival analyses. One thousand and fifty-seven bacteria genera were identified by 16S sequencing, with Cutibacterium , Bacteroides , and Fusobacterium being the most abundant. Using proteomics and after applying quality criteria, 1735 proteins were identified and quantified. Of them, 1727 were human proteins and eight were bacterial proteins. Two oncomicrobiota protein profiles were identified in ASCC, ASCC-OMP1 (36 [47%] pts) and ASCC-OMP2 (40 [53%] pts). ASCC-OMP1 presented a higher expression of proteins from Sutterella and Staphylococcus whereas ASCC-OMP2 showed higher expression of proteins from Dialister , Campylobacter A , and Dysosmobacter . In addition, the two microbiota profiles showed differences in human proteins related to immune response, adhesion, extracellular matrix, translation, and metabolism. Interestingly, significant differences in disease-free survival (DFS) (p=0.02, HR= 2.73, DFS at 5 years: ASCC-OMP1 78.43%, ASCC-OMP2 52.33%) were shown between ASCC-OMP1 and ASCC-OMP2. Overall survival (OS) is not significant between the two groups but a trend can be observed (p=0.06, HR=2.55, OS at 5 years: ASCC-OMP1 79.28%, ASCC-OMP2 62.92%). In a multivariate analysis including the classical clinical prognostic factors, the prognostic value in disease-free survival of the oncomicrobiota profiles remains. Conclusions: Two different oncomicrobiota protein profiles with implications in disease-free survival exist in anal squamous cell carcinoma.
Real-world outcomes of polatuzumab vedotin plus R-CHP versus R-CHOP in newly diagnosed diffuse large B-cell lymphoma: A propensity-matched analysis.
e19087 Background: Polatuzumab vedotin plus R-CHP (Pola-R-CHP) was approved as frontline therapy for diffuse large B-cell lymphoma (DLBCL) in 2022 after demonstrating improved progression-free survival compared with R-CHOP in the POLARIX trial, without a significant overall survival (OS) benefit at initial or long-term follow-up. However, real-world safety and survival outcomes in routine clinical practice, particularly among patients with higher comorbidity burden, remain incompletely characterized. Methods: A retrospective cohort study was conducted using the TriNetX research network. Adult patients with newly diagnosed DLBCL receiving Pola-R-CHP or R-CHOP were identified. Cohorts were balanced using 1:1 propensity score matching for age, sex, race/ethnicity, baseline comorbidities, and available laboratory data (standardized mean differences <0.1). The primary outcome was OS. Secondary outcomes included sepsis, tumor lysis syndrome (TLS), anemia, and major cardiovascular events. Kaplan–Meier, Cox regression, and logistic regression were used. Results: After matching, 533 patients were included in each group. Mean age was similar between Pola-R-CHP and R-CHOP (67.6 ± 12.4 vs 66.4 ± 14.4 years), with 54.4% male patients. Baseline comorbidities were common and well-balanced, including diabetes (~22%), chronic kidney disease (~13%), heart failure (~8%), and chronic lung disease (~7%). Mean baseline LDH levels were identical between groups (329 ± 294 U/L; 91% availability). Overall survival was comparable between Pola-R-CHP and R-CHOP, with no statistically significant difference on time-to-event analysis (HR 0.92; 95% CI 0.74–1.15; p = 0.47) and overlapping Kaplan–Meier curves. Anemia occurred at similar rates in the Pola-R-CHP and R-CHOP groups (36.8% vs 34.5%; OR 1.10; 95% CI 0.86–1.42; p = 0.44), with no difference on time-to-event analysis (HR 1.02; 95% CI 0.83–1.25; log-rank p = 0.86). Major cardiovascular events were also comparable (11.3% vs 10.0%; OR 1.14; 95% CI 0.76–1.72; p = 0.53; HR 1.04; 95% CI 0.71–1.54; log-rank p = 0.83). TLS occurred numerically less frequently with Pola-R-CHP compared with R-CHOP (3.9% vs 5.4%), though this difference was not statistically significant (OR 0.71; 95% CI 0.40–1.27; p = 0.25; HR 0.67; 95% CI 0.38–1.18; log-rank p = 0.16). Sepsis occurred at similar rates in both groups (13.5% vs 11.8%; OR 1.17; 95% CI 0.77–1.78; p = 0.46), with no difference on time-to-event analysis (HR 1.09; 95% CI 0.74–1.61; log-rank p = 0.66). Conclusions: In this large, real-world propensity-matched cohort of patients with newly diagnosed DLBCL, Pola-R-CHP demonstrated overall survival and safety outcomes comparable to R-CHOP in a population with substantial comorbidity burden. These findings support the feasibility of Pola-R-CHP in routine clinical practice and extend the external validity of POLARIX trial results.
Artificial intelligence–powered spatial analysis of endothelial cells and tumor-infiltrating lymphocytes to predict response to axitinib in adenoid cystic carcinoma.
6122 Background: Despite the limited systemic options for adenoid cystic carcinoma (ACC), VEGFR inhibitors remain a clinical mainstay. Although high stromal tumor-infiltrating lymphocyte (TIL) density has been identified as a predictive biomarker for improved progression-free survival (PFS), its predictive power remains to be fully optimized. We hypothesized that baseline vascular architecture, represented by endothelial cell (EC) density, might modulate the efficacy of axitinib. Methods: We performed a post-hoc exploratory analysis on H&E-stained whole-slide images (WSI) from 27 patients with R/M ACC treated with axitinib in a multicenter phase II trial (NCT02859012). An updated AI-powered analyzer (Lunit SCOPE IO), capable of multiple component TME profiling, was used to quantify the density (cells/mm²) of TILs and ECs within the tumor epithelium and stroma. Patients were stratified into subgroups based on the median values. The clinical impact of integrated immune and vascular architecture was evaluated by analyzing PFS and OS. Results: The analyzed cohort (N=27) had a best objective response of stable disease in 25 patients (92.6%) while 16 patients showed tumor shrinkage (59.3%). Stratification revealed that patients with concurrent High EC and High TIL density in the tumor stroma (n=9) derived exceptional clinical benefit compared to all other patients (N=18). The High EC/High TIL subgroup achieved a median PFS of 19.6 months compared to 11.1 months in the comparator group (HR 0.30; 95% CI: 0.11–0.87; P=0.026). Furthermore, this subgroup demonstrated significantly prolonged OS (median NR vs. 24.4 months; HR 0.12; 95% CI: 0.02–0.95; P=0.044). Stratification based on intratumoral densities of EC and TILs showed a similar trend with the High EC/High TIL subgroup (n=10) reporting prolonged PFS (HR 0.32; 95% CI: 0.12-0.87; P=0.025) but not OS (HR 0.46; 95% CI: 0.12-1.74; P=0.251). The individual biomarkers based on median TIL and EC showed a trend towards prolonged survival but were not statistically significant. Conclusions: The co-enrichment of stromal ECs and TIL is associated with significantly prolonged PFS and OS, suggesting that this unique TME architecture may identify R/M ACC patients who derive greater clinical benefit from axitinib. This AI-based spatial analysis using H&E slides offers a practical, scalable biomarker strategy to guide treatment selection in this rare cancer.
Comparative analysis of national cancer policy among low-income, low-middle-income, and high-middle-income countries.
e23045 Background: Despite lower incidence rates, under-resources and lower income countries bear a disproportionately high mortality burden due to cancer. The disparities stem from multiple factors: limited healthcare infrastructure and resources, lack of comprehensive cancer prevention strategies, inadequate screening programs, late-stage diagnosis, restricted access to treatment, insufficient trained workforce, and lower health expenditure. The aim of this analysis is to compare cancer-related policy in under-resourced parts of the world. Methods: The World Health Organization (WHO)’s International Agency for Research on Cancer and Noncommunicable Disease Repository (NCDR) was searched and data extracted on the incidence of national cancer policy or guidelines, timeline when policies were most recently updated and presence of plans pertaining to specific oncological conditions. The NCD Repository included data from 2015-2023. Countries were subdivided into low income (LIC), low-middle income (LMIC) and high-middle income (HMIC) according to the World Bank's 2025 categorizations. Incidence and mortality rates due to cancer in the different World Bank Classifications were derived from the WHO Data Repository. Descriptive statistics were utilized. Results: 131 countries were identified as part of the WHO LIC, LMIC and HMIC categories. Amongst these, 70.2% (N = 92) had national cancer policy or guidelines. 57.7% of LIC's, 76.4% LMIC's and 70.4% HMIC's had cancer-related policy or plan documented in the WHO Repository. There were no significant differences between the incidence of national cancer plans in different income categories. Furthermore, 38.5% LIC's, 27.5% LMIC's and 48.1% HMIC's had one or more cancer-specific plans. The most common cancer-specific plans pertained to cervical and breast cancer, with both lung cancer and colorectal occupying the third most frequently devised plan. Gastric and esophageal cancer was another organ-system where countries has specific plans. Amongst LIC's, The ratio between incidence and mortality were 1.38:1 in LIC's, 1.56:1 in LMIC's and 2.07:1 in HMIC's. There was no correlation between existence of plans and mortality rates. Conclusions: While there are marked differences in cancer related mortality, there were no significant differences in existence of policies between different income groups. Further studies should explore the content of the policies and execution of policies, especially pertaining to screening, early detection and treatment costs.
Efficacy and safety of immune checkpoint inhibitors in advanced non–small cell lung cancer: A systematic review and meta-analysis of randomized trials.
e20621 Background: Immune checkpoint inhibitors (ICIs) are standard first line therapy for advanced non small cell lung cancer (NSCLC), yet the magnitude and consistency of benefit across treatment strategies and agents remain incompletely defined. We conducted a comprehensive meta analysis of randomized trials to quantify survival benefit and evaluate key subgroups. Methods: We systematically searched PubMed, Embase, Cochrane Central, and major oncology conferences through January 2026 for randomized trials comparing first-line PD-1 or PD-L1 inhibitors, alone or combined with chemotherapy, versus platinum-based chemotherapy in advanced NSCLC. Random effects models were used to pool hazard ratios (HRs) for overall survival (OS) and progression free survival (PFS). Risk of bias was assessed using RoB 2, and certainty of evidence was graded using GRADE. Results: Twenty three randomized trials including 11,944 patients were analyzed. ICIs significantly improved OS compared with chemotherapy (pooled HR 0.73, 95% CI 0.68–0.78; I² = 46%), corresponding to a 27% reduction in mortality, with a prediction interval excluding the null. OS benefit was consistent across treatment strategies, with similar effects for ICI plus chemotherapy (HR 0.72) and ICI monotherapy (HR 0.76; interaction p = 0.54). PD-1 inhibitors demonstrated significantly greater OS benefit than PD-L1 inhibitors (HR 0.71 vs 0.81; interaction p = 0.03), although both classes improved survival. Survival benefit was consistent across squamous and non-squamous histologies. ICIs also significantly improved PFS (HR 0.60, 95% CI 0.53–0.67), with greater benefit observed for combination regimens compared with monotherapy. The pooled incidence of any grade immune-related adverse events was 37.3%, with higher rates in combination therapy. Results were robust across sensitivity analyses. Certainty of evidence was high for OS and moderate for PFS. Conclusions: First-line immune checkpoint inhibitors provide substantial and consistent overall survival benefit in advanced NSCLC across treatment strategies and histologies. PD-1 inhibitors appear to confer greater survival benefit than PD-L1 inhibitors, supporting their preferential use when clinically appropriate.
Long-term outcomes with addition of inotuzumab ozogamicin to HCVAD and sequential blinatumomab in adults with newly diagnosed B-ALL.
6515 Background: Despite high remission rates with intensive chemotherapy and blinatumomab (blina) in newly diagnosed (ND) Philadelphia-negative (Ph-) B-ALL, relapse remains a major cause of treatment failure. Inotuzumab ozogamicin (InO) demonstrates efficacy in the relapsed setting and may improve outcomes in frontline. We report long-term results with 4.5 years of follow-up from the phase II study of HCVAD plus blina +/- InO for adults with ND Ph- B-ALL. Methods: Patients (pts) 18-59 years (yrs) with ND Ph- B-ALL received HCVAD alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C) for up to 4 cycles, followed by 4 cycles of blina. Blina was initiated after 2 cycles of HCVAD for pts with high-risk features or persistent measurable residual disease (MRD) by multiparameter flow cytometry (FC). Starting with pt #39, InO was administered during the 2 MTX/Ara-C cycles and 2 blina cycles. Pts received 15 maintenance cycles with POMP and blina after every third cycle. Pts received 12 IT chemotherapies. Results: As of January 2025, 75 pts were treated (38 without InO [cohort 1] and 37 with InO [cohort 2]). The median age was 33 yrs (range, 18–59); 37 for cohort 1 (18-59) and 25 (18-57) for cohort 2 (p=0.01). All other characteristics were similar. All pts (100%) achieved complete remission (CR). MRD-negativity by FC was achieved in 95% of pts at any time (66% at CR): 97% (76%) in cohort 1 and 94% (56%) in cohort 2. By next generation sequencing (NGS), 76% achieved MRD-negativity (26% at CR): 50% in cohort 1 and 79% in cohort 2. There were no early deaths. The median follow-up for cohorts 1 and 2 was 76 months (28-109) and 47 months (31-61), respectively. Of the 38 pts in cohort 1, 14 (37%) proceeded to allogeneic stem cell transplantation (SCT); of these, 11 (79%) remain alive in CR, 1 (7%) died in CR and 2 relapsed, 1 of which died. A total of 24 pts (63%) did not proceed to SCT; of these, 16 (67%) remain alive in CR, 3 (13%) died in CR, and 5 (20%) relapsed, 4 of which died. Of the 37 pts in cohort 2, 10 (27%) proceed to SCT; all alive in CR. A total of 27 pts (65%) did not proceed to SCT; 24 (89%) remain alive in CR (1 pt received CAR T-cell) and 3 (11%) relapsed, all of them alive in CR2). Median OS and event-free survival (EFS) have not been reached for either cohort. 4-year OS rates for the entire cohort, cohort 1 and cohort 2 are 91%, 82% and 100% (p=0.007), respectively, with 4-year EFS rates of 83%, 74%, and 91% (p=0.034), respectively. At 24 months, CIR was with InO vs without InO (8.1% vs 18.4%; p = 0.18). No deaths were observed in the InO group, whereas pts without InO had a 24-month cumulative incidence of death of 7.9% ( p = 0.08). Conclusions: Incorporation of InO into frontline HCVAD with sequential blina is associated with improved survival and durable remission in adults with ND Ph- B-ALL, supporting its role in the frontline setting. Confirmatory randomized trial comparing HCVAD-blina to HCVAD-blina-Ino is ongoing. Clinical trial information: NCI-2017-00596 .
An international phase III randomized, double-blind, double-dummy trial comparing duloxetine and pregabalin for opioid-refractory neuropathic cancer pain.
12013 Background: Management of neuropathic cancer pain (NCP) refractory to standard-dose opioids remains a major clinical challenge, and direct comparative evidence between adjuvant analgesics is limited. This study aimed to compare the efficacy and safety of duloxetine and pregabalin in patients with opioid-refractory NCP. Methods: We conducted an international, multicenter, double-blind, randomized controlled trial. Adult cancer patients who continued to experience pain despite opioid analgesia were eligible to participate if they met the International Association for the Study of Pain criteria for neuropathic pain and had a Brief Pain Inventory (BPI) Item 3 (worst pain in the past 24 hours) score of ≥4. Inpatients and outpatients from Japan and Australia were randomized at a ratio of 1:1 to the duloxetine group (D group) or the pregabalin group (P group). The study drugs were titrated up to duloxetine 60mg daily or pregabalin 150mg twice daily until day 14 (D14). The primary endpoint was BPI item 3 at D14. Secondary endpoints included the change in BPI item 3 from baseline at D14, and the proportion of patients achieving ≥1 points, ≥2 points, ≥30% and ≥50% pain reduction. The primary endpoint was analyzed using a two-sided Student’s T-test (α=0.05) under the intention-to-treat principle. A sample size of 64 patients per group was estimated to detect a mean difference of 1.0 (SD 2.0) with 80% power. Results: Between February 2020 and June 2025, 147 patients were enrolled across 18 institutions. Baseline BPI item 3 scores were similar between the D and P groups (7.23 vs 7.04). At D14, mean scores were 5.62 and 5.45, with no significant difference (P=0.70), corresponding to mean reductions of 1.57 and 1.55, respectively. Rates of pain reduction (≥1 point, ≥2 points, ≥30%, ≥50%) were similar between groups (D: 53/45/36/25% vs P: 50/36/26/19%). Grade ≥2 adverse events included decreased appetite (29％), nausea (21％), fatigue (20％), in the D group, and constipation (23%), decreased appetite (16％), dizziness/fatigue (12％), in the P group. Conclusions: No significant difference in analgesic efficacy was observed between duloxetine and pregabalin in patients with opioid-refractory NCP. The magnitude of pain reduction exceeded the mean NRS change typically associated with placebo (approximately 0.5–1.0 points), and the response rates for ≥50% pain reduction were substantially higher than the ≈3% reported for placebo in a prior NCP study. The estimated numbers needed to treat were low (4.6 for duloxetine and 6.3 for pregabalin) and were smaller than those reported in non-cancer neuropathic pain, suggesting comparable or potentially greater efficacy. However, given the relatively high incidence of adverse events and the distinct adverse event profiles of each drug, careful and individualized treatment selection balancing efficacy and tolerability is warranted. Clinical trial information: jRCTs051190097.
Developing harmonized tumor microenvironment subtypes for patient stratification in clinical trials.
3120 Background: Accurate patient stratification by tumor microenvironment (TME) is critical for optimizing immunotherapy and targeted therapy outcomes. Existing transcriptome-based classification methods often focus on limited TME aspects and tumor types, restricting their clinical utility. Here, we developed a harmonized (H) TME classification by integrating findings from published pan-cancer TME profiling with reported immune evasion mechanisms. Methods: We used agglomerative clustering of gene signature scores (ssGSEA) and pathway activities (PROGENy) encompassing immune cells, fibrosis, vascularization, hypoxia, and other signals to acquire 9 transcriptomic HTME subtypes (Table 1) independently on TCGA (n=7,362) and internal (n=5,186) pan-cancer cohorts with high reproducibility (Spearman r =0.94). Next, we validated the subtypes on 29,875 solid cancer samples from open-source transcriptomic datasets by applying the K-Nearest Neighbors classifier. Differential expression analysis followed by Spearman correlation and PCA were used for comparison among classifications. Adjusted Cox models for survival and logistic regressions for response were applied. Results: Correlative analysis between existing classifications and HTME subtypes revealed patient stratification along 3 principal biological axes: adaptive immune response vs. tumor cell activity, fibrosis vs. antigen-presenting activity, and proliferation vs. vascularization, with, HTME uniquely covering all three axes. When applied to the selected clinical cohorts, HTME effectively distinguished patients by response (logOR) or progression-free survival (logHR) in a diagnosis- and therapy-specific manner (Table 1; showing values with p≤0.05). Conclusions: The proposed HTME patient stratification framework, publicly available and applicable to any RNA-seq sample, constitutes a practical tool for biomarker discovery and trial design across solid tumors. logOR and logHR metrics of HTME subtypes based on diagnosis and treatment type. BRCA Basal-like, Luminal, Normal-like; ICIlogOR [CI] BRCA HER2+; anti-HER2logOR [CI] ccRCC; TKIPFS logHR [CI] ccRCC; anti-VEGFR+anti-PDL1PFS logHR [CI] ccRCC; anti-mTORPFS logHR [CI] SKCM; ICIlogOR [CI] NSCLC; ICIlogOR [CI] Lymphoid-Cell-Enriched B-Cell-Enriched/Angiogenic -0.9 [-1.5, -0.3]** -0.7 [-1.4, -0.1]* 1.1 [0.2, 2.0]* Immune-Enriched/Hypoxic -1.8 [-3.2, -0.4]* 0.6 [0.1, 1.0]** 1.1 [0.4, 1.8]** -1.3 [-2.5, -0.1]* Highly Immune-Enriched/Inflamed -2.9 [-5.3, -0.4]* -1.5 [-2.3, -0.6]*** 1.1 [0.2, 1.9]* -2.1 [-3.6, -0.5]** -1.1 [-1.9, -0.2]* Immune-Enriched/Fibrotic 1.0 [0.5, 1.6]*** 2.3 [0.6, 4.1]** Fibrotic/Angiogenic/Myeloid 0.9 [0.4, 1.3]*** Fibrotic/Hypoxic 1.4 [0.4, 2.5]** Immune Desert 0.8 [0.0, 1.5]* 1.2 [0.2, 2.2]* 0.6 [0.1, 1.2]* Desert/Angiogenic 1.1 [0.1, 2.1]* -0.6 [-1.1, -0.1]* 1.1 [0.1, 2.1]* *p≤0.05; **p≤0.01; ***p≤0.001.
Intersectional analysis of race/ethnicity, geography, and socioeconomic status on colorectal cancer screening utilization and stage at diagnosis: A SEER analysis, 2016-2021.
e15714 Background: Despite effective screening modalities, colorectal cancer (CRC) remains the second leading cause of cancer-related mortality in the USA. Persistent disparities in CRC outcomes by race/ethnicity, socioeconomic status (SES), and geographic residence are well documented, these factors rarely operate independently. National data evaluating how intersecting social determinants jointly influence CRC stage at diagnosis and how these disparities have evolved over time remain limited. Understanding these synergistic effects is essential for designing precision public health strategies that equitably improve cancer prevention and early detection. Methods: We analyzed SEER data (2016–2021) including adults 50–75 diagnosed with CRC across 17 registries. Patients were classified by race/ethnicity (NHW, NHB, Hispanic/Latino, API, AI/AN), geography (metropolitan, urban, rural), and neighborhood deprivation (ADI quintiles). Stage at diagnosis (localized vs regional/distant) served as a downstream marker of screening access. Multivariable logistic regression estimated adjusted odds ratios (aORs) for late-stage diagnosis, adjusting for age, sex, insurance, and comorbidity. Interaction terms assessed synergistic effects; temporal trends evaluated disparity changes over time. Results: Among 156,847 patients, 39.4% were diagnosed at localized stage. NHB (aOR 1.31, 95% CI 1.26–1.36), Hispanic (aOR 1.21), and AI/AN patients (aOR 1.35) had higher odds of late-stage diagnosis, while API patients had lower odds (aOR 0.87). Rural residence (aOR 1.18) and highest ADI quintile (aOR 1.52) were independently associated with late-stage diagnosis. Intersectional analysis showed compounding effects: rural NHB patients in the highest ADI quintile had the greatest burden (71.4% late stage; aOR 2.34), with similar rates among rural AI/AN patients. Significant interactions were observed between race/ethnicity and geography (p = 0.003) and race/ethnicity and SES (p < 0.001). Although overall late-stage diagnoses declined modestly from 2016–2021, disparities widened over time. Conclusions: Race/ethnicity, geography, and socioeconomic deprivation exert synergistic effects on CRC stage at diagnosis. Disparities disproportionately affect rural NHB and AI/AN populations in highly deprived areas. Findings underscore the need for precision public health interventions—targeted outreach, patient navigation, and expanded access to at-home and mobile screening—to achieve equitable CRC prevention and early detection.
Real-world data on post-neoadjuvant trastuzumab emtansine to benchmark DESTINY-Breast-05 and -11 emerging paradigms.
e12516 Background: Post-neoadjuvant trastuzumab emtansine (T-DM1) is the standard of care for patients (pts) with HER2-positive early breast cancer (eBC) with residual disease (RD) after neo-adjuvant therapy (NAT). Emerging data show that trastuzumab deruxtecan (T-DXd) is redefining (neo-)adjuvant strategies according to DESTINY-Breast (DB)-05 and -11 trials. We conducted a real-world benchmarking study of post-neoadjuvant T-DM1 to quantify contemporary outcomes and contextualize emerging T-DXd strategies in routine practice. Methods: We included all consecutive pts with evidence of RD after trastuzumab-based NAT, receiving T-DM1 (≥1 cycle) from Jan-2020 to Aug-2024 at the European Institute of Oncology (Milan). The primary endpoint was the 3-year invasive disease-free survival (3y-iDFS) rate. Results: A total of 187 pts was included, of which 55% were premenopausal, 71% had hormone receptor (HR)-negative disease, 75% had HER2 3+, and 21% had node-positive eBC at diagnosis. Prior pertuzumab or anthracyclines-based NAT were used in 32% and in 82% of pts, respectively. Adjuvant ovarian function suppression was received by 84% of premenopausal pts with HR-positive eBC. At a median follow up of 30.4 months (range: 3.4-68.1), we observed a real-world 3y-iDFS rate of 97% (range: 95%-100%). Among the 6 pts with invasive disease recurrence, 5 had distant dissemination, including 1 brain recurrence. A high (> 30%) baseline Ki67 was detected in all pts with a relapse, compared to 44% of disease-free pts. Considering baseline characteristics, 41% of pts did not comply neither DB-11 nor DB-05 inclusion criteria; 32% were eligible only for DB-11 (“DB-11 only”); 25% were eligible for both; 3% were eligible only for DB-05. Among pts with a relapse, 4 were eligible for both trials, while 2 pts were ineligible for either. Conclusions: Post-neoadjuvant T-DM1 shows an excellent real-world effectiveness profile, with a low incidence of invasive disease recurrences. Notably, a large fraction of pts treated in routine practice would not have met DB-05/-11 trial eligibilities, and none with an iDFS event belonged to the “DB-11 only” population. These data highlight the value of real-world benchmarking to contextualize trial evidence and guide integration of antibody–drug conjugates in the curative scenario.
Prevalence of neurologic death in NSCLC patients with brain metastases treated with radiosurgery in the modern treatment era.
e20698 Background: Immune checkpoint blockade (ICB) and molecularly targeted therapies are increasingly integrated into the management of patients with non-small-cell lung cancer (NSCLC)in parallel with higher utilization of radiosurgery (SRS) for brain metastases. We report our experience with SRS for NSCLC brain metastases, contrasting the rate of post-treatment neurologic death in earlier versus recent years. Methods: We conducted a retrospective cohort study of patients treated with gamma knife (GK) SRS for NSCLC brain metastases at a single institution. Patients were grouped by treatment period: Period 1 (2013-2015), when early use of ICB and blood-brain-barrier (BBB) crossing molecular therapies was minimal, and SRS was more conservative; and Period 2 (2019-2021), when upfront ICB, BBB-crossing agents and SRS were increasingly utilized. The primary outcome was neurologic death, using cumulative incidence technique, treating non-neurologic death as a competing event. Cumulative incidence functions were estimated using the Aalen-Johansen estimator and compared at 6, 12, and 24 months. Absolute risk differences with 95% confidence intervals were estimated using nonparametric bootstrap resampling. A cause-specific Cox proportional hazards model was used as a secondary analysis. Results: A total of 125 patients were included (48 in Period 1; 77 in Period 2). Median follow-up among surviving patients was 51.1 months in Period 1 and 26.8 in Period 2. Neurologic death occurred more frequently in Period 1 than Period 2. At 12 months, the cumulative incidence was 11.7% and 1.5% in Period 1 and Period 2, respectively; at 24 months, the absolute risk difference widened to-−15.6 percentage points: 17.3% versus 1.5% (95% CI, -28.7 to -4.4). In cause-specific Cox analysis, treatment in Period 2 was associated with a significantly lower hazard of neurologic death (HR 0.09, 95% CI 0.01-0.72) p = 0.024. Conclusions: Patients treated with GK SRS during the modern period (2019-2021) of improved systemic therapy and increased SRS utilization experienced a substantially lower cumulative incidence and hazard of neurologic death compared with moderately earlier era (2013-2015). While causality cannot be concluded, these findings are consistent with emerging evidence supporting improved intracranial control with contemporary systemic therapies and SRS. Absolute risk differences in cumulative incidence of neurologic death at 6, 12, and 24 months. Time (months) CIF Period 1 (%) CIF Period 2 (%) ARD (%) 95% CI (%) p-value 6 6.5 0 -6.1 (-13.8, 0) 0.09 12 11.7 1.5 -10 (-20.6, -1.1) 0.023 24 17.3 1.5 -15.6 (-28.7, -4.4) 0.002 CIF: Cumulative Incidence Function. ARD: Absolute Risk Difference. CI: Confidence Interval. Absolute risk differences are reported as percentage-point differences between Period 2 and Period 1. 95% CI and p-values were estimated using nonparametric bootstrap resampling.
Efficacy with fruquintinib plus sintilimab versus axitinib or everolimus in advanced renal cell carcinoma: A post-hoc analysis from FRUSICA-2 trial by baseline tumor burden.
4533 Background: The multicenter randomized phase 2/3 FRUSICA-2 trial (NCT05522231) demonstrated that fruquintinib plus sintilimab (F+S) significantly improved progression-free survival (PFS) (22.2 months vs 6.9 months) and objective response rate (ORR) (60.5% vs 24.3%) by blinded independent central review (BIRC) assessment compared to axitinib or everolimus (A/E) in Chinese patients (pts) with advanced renal cell carcinoma (aRCC) who had failed prior tyrosine kinase inhibitor therapy (Ye D, et al; 2025 ESMO). Considering that baseline tumor burden may correlate with efficacy outcome, we present the results of a relevant post-hoc subgroup analysis. Methods: Overall, 234 eligible pts were 1:1 randomized to receive either F+S or A/E. The primary efficacy endpoint was PFS assessed by BIRC per RECIST 1.1; secondary endpoints included investigator-assessed PFS, ORR, disease control rate, duration of response, time to response, and overall survival. This subgroup analysis evaluated BIRC-assessed PFS and ORR across subgroups defined by the number of target lesions (TLs) and metastatic sites (METs) at baseline. Results: At baseline, 79, 79, 32 and 44 pts had 1, 2, 3 and ≥4 TL(s), respectively. Metastatic disease was present in 117 (98.3%) pts in F+S arm and 110 (95.7%) pts in A/E arm, with a higher proportion of pts in F+S arm (88, 73.9%) having ≥3 METs than in A/E arm (67, 58.3%). By the data cut-off date of Feb 17, 2025, median follow-up for PFS was 16.6 months. As summarized in the table, F+S demonstrated superior PFS versus A/E across all subgroups, with unstratified hazard ratios (HRs) ranged from 0.28 to 0.50, as well as consistently longer median PFS. Similarly, improvements in ORR were observed across subgroups with odds ratios (ORs) ranged 2.46~7.22. Notably, in F+ S arm, fewer baseline TLs and METs appeared to correlate with longer median PFS, though such trend was not observed for ORR. Conclusions: Consistent with the primary analysis, F+S showed superior efficacy compared to A/E in terms of PFS and ORR in the second-line treatment of aRCC, regardless of the amount of baseline TLs or METs. Clinical trial information: NCT05522231 . Subgroup(F+S v A/E) 1 TL(38 v 41) 2 TLs(38 v 41) 3 TLs(16 v 16) ≥4 TLs(27 v 17) 1 MET(29 v 43) 2 METs(39 v 28) ≥3 METs(49 v 39) PFS, HR (95% CI) a 0.39 (0.20, 0.76) 0.33 (0.17, 0.66) 0.43 (0.17, 1.10) 0.28 (0.12, 0.62) 0.28 (0.13, 0.60) 0.50 (0.24, 1.04) 0.31 (0.18, 0.545) Median PFS, months b 24.9 vs 8.3 22.2 vs 6.9 15.3 vs 4.2 13.8 vs 6.9 24.9 vs 8.3 22.2 vs 8.3 NE vs 4.2 ORR, OR (95% CI) c 3.95 (1.35, 11.91) 4.65 (1.63, 13.43) 7.22 (1.17, 52.78) 5.53 (1.21, 28.76) 7.18 (2.22, 23.84) 2.46 (0.81, 7.76) 6.12 (2.13, 18.44) ORR, % 52.6 vs 22.0 65.8 vs 29.3 62.5 vs 18.8 63.0 vs 23.5 65.5 vs 20.9 53.8 vs 32.1 61.2 vs 20.5 NE, not estimable. a Based on an unstratified Cox proportional risk model. b Estimated using Kaplan-Meier method. c Exact 95% CI for OR was calculated using Cochran-Mantel-Haenszel method.
National analysis of facility-level survival differences in elderly splenic marginal zone lymphoma patients.
e13740 Background: Splenic marginal zone lymphoma (SMZL) is an uncommon indolent B-cell lymphoma primarily affecting older adults. Although the prognosis is generally favorable, advanced age is associated with poorer outcomes. Limited data exist on the influence of treatment setting on survival in elderly patients. Academic centers often demonstrate advantages in broader lymphoma populations through specialized expertise and multidisciplinary care, but applicability to SMZL is unclear. We evaluated differences in treatment patterns and overall survival (OS) among patients aged ≥75 years with SMZL treated in Academic Cancer Programs (ACP) vs Community Cancer Programs (CCP). Methods: We performed a retrospective cohort study of National Cancer Database (NCDB) cases diagnosed from 2004–2022 with SMZL. Facility type was categorized as ACP or CCP. We compared demographics, socioeconomic indicators, comorbidity (Charlson–Deyo score), geography, management, and time from diagnosis to therapy initiation. OS was assessed by Kaplan–Meier estimates at 2, 5, and 10 years, and adjusted median OS by facility type. Results: Among 2,883 patients aged ≥75 with SMZL, 1,553 were treated at ACP and 1,330 at CCP. Median age was 80 (ACP) vs 81 (CCP). White patients were the majority in both cohorts (92% ACP vs 95% CCP). Only 3% of ACP and 2% of CCP patients were Hispanic (p = 0.158). Socioeconomic differences were notable, with CCP patients more often from lower-education areas and ACP patients from higher-income regions (p < 0.001). Most patients lived in metropolitan areas, with a higher representation in ACP. Median straight-line distance to the treating facility was slightly greater for ACP (9 vs 7 miles; P < 0.001). Charlson–Deyo scores were similar (0–1 in ~87%: 71% score 0 and 16% score 1 in ACP; 70% and 17% in CCP; p = 0.179). Primary payer was predominantly Medicare (90% ACP vs 91% CCP). Disease characteristics and management were similar between cohorts. Watchful waiting occurred in 15% vs 14%, and any treatment in 57% vs 57%. Median time to treatment was 24 days ACP vs 23 days CCP. Survival outcomes favored ACP. At two years, OS was 75% for ACP compared with 74% for CCP; at five years, 55% vs 51%; and at ten years, 25% vs 22%. Median OS was longer in ACP (5.8 vs 5.1 years, P = 0.041). Conclusions: Among elderly patients with SMZL, OS differed significantly by facility type, with a modest but statistically significant survival advantage observed at ACP. Despite largely similar disease characteristics and management strategies, differences in socioeconomic context and urban residence were evident and may influence access to specialized care and longitudinal disease management. These findings highlight the value of multidisciplinary expertise and support efforts to strengthen referral pathways and academic–community partnerships to ensure equitable access to high-quality care for older adults with indolent lymphomas.
Survival outcomes of neoadjuvant versus adjuvant chemotherapy in stage II-III hormone receptor-positive/HER2-negative breast cancer: A propensity score–matched analysis.
e12673 Background: The role of neoadjuvant chemotherapy (NACT) in stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer remains controversial due to low pathological complete response (pCR) rates. Recent evidence from the NATALEE trial subgroup analysis presented at San Gallen 2025 identified prior NACT as an independent negative prognostic factor for invasive disease-free survival (iDFS) in HR+/HER2- early breast cancer, raising concerns about the optimal sequencing of systemic therapy in this population. Whether NACT or adjuvant chemotherapy (ACT) provides better survival outcomes in HR+/HER2- breast cancer is an ongoing debate with significant clinical implications. Methods: Six hundred fifty-five patients (pts) with HR+/HER2- locally advanced breast cancer at stage II-III undergoing NACT (429 pts) or ACT (226 pts) between 2005 and 2021 were identified from Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome. Propensity score matching (PSM) was employed to create cohorts with balanced baseline characteristics across different categories (age, menopausal status, grading, stage, Ki67, ER, PgR, HER2). The efficacy of NACT and ACT in terms of overall survival (OS) and real-world invasive disease-free survival (rwiDFS) was evaluated using Kaplan-Meier analysis and the Cox proportional hazards model. Results: Using PSM, a total of 432 pts was ultimately included in the study (216 vs 216). OS was significantly longer for ACT versus NACT (NR vs 229 months mOS, 96.8% vs 90.6% survival rate at 5 years, HR 0.58, 95% CI 0.36-0.95, p = 0.03). The rwiDFS was longer for ACT versus NACT (NR vs 135 months, 91.6% vs 74.8% survival rate at 5 years, HR 0.63, 95% CI 0.43-0.92, p = 0.017). Patients who underwent ACT had significantly better OS compared to those who did not achieve pCR after NACT (HR 0.56, 95% CI 0.38-0.82, p = 0.016), while no significant difference was observed compared to patients who achieved pCR after NACT (HR 1.81, 95% CI 0.9-3.6, p = NS). Conclusions: In stage II-III HR+/HER2- breast cancer, NACT was associated with inferior OS and rwiDFS compared to ACT, consistent with NATALEE trial findings identifying NACT as an adverse prognostic factor. NACT should be reserved for selected cases requiring downstaging. While neoadjuvant CDK4/6 inhibitors have shown limited efficacy in replacing chemotherapy, emerging oral SERDs and PROTACs may improve pCR rates and bridge the efficacy gap in this subtype.
Overall survival after stereotactic radiosurgery versus whole-brain radiotherapy for patients with ≥5 brain metastases: A systematic review and meta-analysis.
e14017 Background: The role of stereotactic radiosurgery (SRS) is well established in the setting of one to four brain metastases (BM), offering effective control with reduced neurocognitive toxicity compared with whole-brain radiotherapy (WBRT). However, for patients with five or more BM, the optimal radiation strategy remains uncertain, and comparative outcome data are limited. We performed a systematic review and meta-analysis to compare overall survival (OS) between SRS and WBRT in patients with ≥ 5 BM. Methods: A systematic review was conducted to identify comparative studies of SRS versus WBRT in patients with ≥5 brain metastases. Retrospective and prospective studies reporting median OS with available cohort sizes were included. Comparative survival was summarized using pooled ratios of median survival within a random-effects meta-analytic framework. Results: Five comparative studies were included, comprising 226 patients treated with SRS and 261 treated with WBRT, including both retrospective and prospective cohorts. Sample-size–weighted summary (with reported medians) showed median OS was 8.1 months with SRS and 7.7 months with WBRT. Pooled analysis demonstrated no significant difference in OS between treatment strategies (ratio of median survival, 1.03; 95% CI, 0.73–1.46; p = 0.81). Conclusions: Among patients with ≥5 BM, SRS and WBRT were associated with comparable OS. These data suggest that OS alone may not guide treatment choice in this population, emphasizing the importance of careful patient selection. As focal therapies are increasingly incorporated into clinical practice for patients with higher intracranial disease burden, prospective, multi-institutional randomized clinical trials are needed to better define optimal management strategies. Summary of included studies reporting median overall survival (OS). Study Study Design SRS (n) WBRT (n) Median OS in SRS cohort (months) Median OS in WBRT cohort (months) Kim et al., 2009 Retrospective 29 39 5.6 7.2 Mizuno et al., 2019 Retrospective 24 20 7.3 7 .2 Li et al., 2020 Prospective, randomized 35 34 7.8 8.9 Bodensohn et al., 2023 Prospective, non-randomized 40 70 10.4 6.5 Aizer et al., 2025 Prospective, randomized 98 98 8.3 8.5
Structural determinants compared with genetic ancestry and self-reported race in triple-negative breast cancer disparities: A multilevel analysis in an admixed population.
617 Background: Triple-negative breast cancer (TNBC) exhibits marked racial disparities in outcomes. However, the contributions of genetic ancestry, self-reported race, and structural determinants remain unclear, particularly in admixed populations. We aimed to disentangle the independent and combined impact of these factors in a Brazilian cohort. Methods: We retrospectively studied 156 women with TNBC treated with neoadjuvant chemotherapy at a tertiary center in São Paulo, Brazil (2007-2022). Genetic ancestry was estimated using ancestry-informative markers (AIMs) from an unpublished dataset. Self-reported race followed national census categories. Healthcare system type (public/private) served as a proxy for socioeconomic status. Primary outcomes were pathologic complete response (pCR), overall survival (OS), and disease-free survival (DFS). Multivariable models were adjusted for age, stage, Ki-67, and year of diagnosis. Statistical techniques included multiple imputation, propensity score matching, LASSO regression, and causal mediation analysis. Results: The cohort was highly admixed: 27% had ≥20% African ancestry (AA). Discordance was observed between genetic and social classifications: 48% of self-identified Black patients had <20% AA, while 24% of non-Black patients had ≥20% AA. Patients with ≥20% AA had higher tumor proliferation (median Ki-67 90% vs 80%) and higher pCR (50.0% vs 41.2%, p=0.42) but higher mortality (35.7% vs 25.4%). Black patients more often to use public healthcare (48.4% vs 15.9%, p<0.001) present with stage III disease (45.2% vs 35.6%), and receive less dose-dense chemotherapy (41.9% vs 76.1%, p<0.001). In adjusted analyses, neither AA nor self-reported race independently predicted pCR, OS, or DFS. Public healthcare use was the strongest independent predictor of worse OS (HR 2.45, 95%CI 1.12-5.36, p=0.025) and DFS (HR 2.18, 95%CI 1.08-4.40, p=0.03). Clinical stage (OR 0.66, p=0.022) and carboplatin use (OR 2.8, p=0.018) were the only independent predictors of pCR. Causal mediation analysis showed that 60.1% of the detrimental effect of public healthcare on pCR was mediated by advanced stage at presentation. Conclusions: In this pre-immunotherapy Brazilian cohort, TNBC outcome disparities are primarily driven by structural determinants related to healthcare access rather than genetic ancestry or self-reported race. While ancestry and race capture relevant biological and social dimensions, delayed diagnosis and suboptimal treatment delivery were the main mechanisms underlying outcomes. These findings underscore the need to address structural inequities and ensuring equitable access to timely, evidence-based cancer care in admixed populations. Future prospective studies integrating genetic ancestry, socioeconomic factors, and tumor immune profiling are needed.
Ultra-refractory PD–PD pancreatic cancer: Clinical and molecular insights across first- and second-line therapy.
4206 Background: A subset of pancreatic cancer (PC) patients exhibits progressive disease (PD) as the best response to both first- and second-line chemotherapy (PD-PD), representing an ultra-refractory population with dismal outcomes. This group remains poorly characterized, highlighting a critical unmet need for novel therapeutic strategies. Methods: We retrospectively analyzed PC patients treated at Vall d’Hebron University Hospital (2012–2025) who received both first- and second-line chemotherapy with 5-FU- or gemcitabine-based regimens. Clinical, histopathological and molecular data were collected. Characteristics of PD-PD patients were compared with those achieving clinical benefit, defined as complete or partial response (CR/PR) in at least one treatment line. Progression-free survival (PFS2) was calculated from the start of first-line therapy to documented PD after second-line treatment. Overall survival (OS) was calculated from the start of first-line therapy to death or last follow-up. Survival curves were estimated using the Kaplan–Meier method. RNA-seq was performed on diagnostic tumor samples to explore transcriptomic features. Results: Median follow-up for the entire cohort was 58 months. Among 400 patients, 46 (12%) were classified as PD-PD. Median PFS2 was 5.4 months in PD-PD vs 14.5 months in CR/PR, and median OS was 8.1 vs 20.8 months, respectively (p < 0.001 for both). Treatment sequences in PD-PD patients included 5-FU followed by gemcitabine (18, 39%) and gemcitabine followed by 5-FU (28, 61%). Patients receiving 5-FU first were younger (median age 57 vs 72 years, p = 0.035). Histopathological features were similar in both groups. Inflammatory markers were largely comparable; however, median CRP/albumin ratio was higher in PD-PD, 0.86 vs 0.24 in CR/PR (p < 0.001). Molecular profiling was available for 34 (74%) of patients. Among these, KRAS mutations were present in 84% of patients, with G12V slightly more frequent in PD-PD than CR/PR (45% vs 31%, p = 0.5). TP53 mutations occurred in 81% vs 65% (p = 0.083), and SMAD4 alterations were more common in CR/PR (19% vs 6.3%, p = 0.082). DDR pathway alterations were rare in PD-PD patients. Exploratory RNA-seq of six PD-PD compared with CR/PR (n = 2) tumors revealed upregulation of coagulation and lipid metabolism genes ( FGB, APOA1 ) and downregulation of pancreatic function genes ( PNLIP, CPA1 ), suggesting potential alterations in inflammatory and metabolic pathways. Conclusions: PD-PD patients represent an ultra-refractory subset (~12%) of PC with very poor outcomes despite standard therapy. Differences in inflammatory markers and transcriptomic trends may reflect underlying biological features of this highly resistant phenotype. These findings underscore the need for further studies to clarify mechanisms of primary resistance and guide the development of novel therapeutic strategies in this high-risk population.
Are younger patients considered?: Geographic access and age-focused design in advanced PDAC trials for Appalachian populations.
e16384 Background: Younger-onset pancreatic ductal adenocarcinoma (PDAC) represents a clinically distinct population with rising incidence. Geographic and socioeconomic barriers limit trial access for young patients, while Appalachian regions experience disparities in cancer care access and outcomes. We evaluated age-focused trial design and access to interventional PDAC trials in Appalachian and socioeconomically deprived counties. Methods: Clinical trial data were obtained from ClinicalTrials.gov and restricted to interventional studies enrolling patients with advanced or metastatic PDAC. Trials were systematically and manually selected to include studies with at least one U.S. site and an overall status of Recruiting or Active, not recruiting. The final cohort of 275 trials was screened for age-focused design, including age-stratified cohorts or planned age-based subgroup analyses for adult PDAC patients under age 50. Appalachian status was evaluated at state and county levels using Appalachian Regional Commission (ARC) designations. County-level trial access was assessed via a trial desert framework (no eligible trial site within 50 miles). Socioeconomic deprivation was measured using the Area Deprivation Index (ADI) and rurality using Rural–Urban Continuum Codes (RUCC). Associations with trial desert status were evaluated using logistic regression. ChatGPT 5.2 (1/26/26) was used for code-writing assistance and troubleshooting R software. All statistical analyses were performed via R. Results: Among 275 interventional trials enrolling patients with advanced PDAC, none (0%) were designed to distinctly target younger-onset PDAC. Although trials permitted enrollment across broad adult age ranges, no trials incorporated age-focused design distinguishing younger patients. While 180 trials (65.5%) included at least one site in an Appalachian state, only 51 trials (18.5%) included a site in an ARC-designated Appalachian county. Trial sites were concentrated in metropolitan areas, and none met rural criteria (RUCC ≥5). Higher county-level socioeconomic deprivation was strongly associated with trial desert status. A 10-point increase in ADI increased the odds of being classified as a trial desert by 35% using a 50-mile definition (OR 1.35; p < 2×10⁻¹⁶), with similar findings at 100 miles (OR 1.28; p = 7.9×10⁻⁸). Associations persisted after accounting for rurality and did not differ by Appalachian designation. Conclusions: Interventional trials for advanced or metastatic PDAC lack age-focused design for young patients. Though state-level definitions suggest broad Appalachian representation, county-level ARC analysis shows that fewer than one in five trials include Appalachian sites. Younger PDAC patients, especially those in deprived or Appalachian regions, may be underserved by both trial design and trial geography.
SigVie-003: Phase 3 trial of frontline sigvotatug vedotin plus pembrolizumab vs pembrolizumab alone in non-small cell lung cancer (NSCLC) with PD-L1 TPS ≥50%.
TPS8660 Background: Integrin beta-6 (IB6) is a tumor-associated membrane protein linked to poor outcomes in solid tumors, including NSCLC, where it is expressed in >90% of cases. Sigvotatug vedotin (SV), a novel, IB6-directed, vedotin-based, antibody-drug conjugate, has shown manageable safety and encouraging antitumor activity as monotherapy in advanced NSCLC in the phase 1 SGNB6A-001 study (Peters, ASCO 2024). Based on preclinical studies, SV may induce immunogenic cell death and enhance antitumor activity when used in conjunction with pembrolizumab, a PD-1 inhibitor. Therefore, SV plus pembrolizumab is also being evaluated in the SGNB6A-001 study. Initial results of the combination demonstrated promising antitumor activity with a manageable safety profile in advanced NSCLC (Sehgal, ASCO 2025). Based on these results, SV plus pembrolizumab is being investigated in the phase 3 SigVie-003 study. Methods: SigVie-003 (NCT06758401) is an open-label, randomized, controlled study evaluating the efficacy of SV plus pembrolizumab vs pembrolizumab monotherapy as first-line treatment in adults with locally advanced, unresectable, or metastatic NSCLC with high PD-L1 expression (tumor proportion score ≥50%). Patients (pts) with nonsquamous histology must have negative documentation for EGFR , ALK , and ROS1 mutations and no known actionable genomic alterations with approved first-line treatments per local standard of care. Pts must have an ECOG PS of 0 or 1 and have adequate organ function. Pts with stable, definitively treated, or inactive brain metastases <0.5 cm are eligible. Approximately 714 pts will be randomized at a 1:1 ratio to receive either SV 1.8 mg/kg AiBW (adjusted ideal body weight) intravenously on days 1, 15, and 29 plus pembrolizumab 400 mg intravenously on day 1 of a 42-day cycle (Q6W) or pembrolizumab 400 mg monotherapy Q6W. Randomization will be stratified by histology (nonsquamous vs squamous), ECOG PS (0 vs 1), region (East Asia vs rest of world), and presence or absence of brain metastases. Dual primary endpoints are overall survival and progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1. Secondary endpoints include PFS by investigator per RECIST 1.1, confirmed objective response rate and duration of response by both BICR and investigator per RECIST 1.1, safety, and pharmacokinetics and immunogenicity of SV when combined with pembrolizumab. Enrollment began Jul 23, 2025. A genAI tool (2/27/25; Pfizer; GPT-4o) developed the 1st draft; authors assume content responsibility. Frontline sigvotatug vedotin plus pembrolizumab vs pembrolizumab for non-small cell lung cancer with PD-L1 tumor proportion score ≥50%: phase III study design, Reck M, et al., Future Oncol , Dec 13, 2025, Taylor & Francis, reprinted by permission of the publisher Informa UK Limited trading as Taylor & Francis Ltd. Clinical trial information: NCT06758401 .
Effect of time to treatment initiation in MCL: A SEER analysis from 2000-2022.
e23069 Background: Mantle Cell Lymphoma (MCL) is a rare subtype of Non-Hodgkin Lymphoma (NHL) with a heterogeneous clinical course that can present as aggressive or indolent. The impact of delayed time to treatment initiation (TTI) remains understudied in MCL patients. Prior analysis from Canadian data found that patients who deferred treatment for greater than 3 months from diagnosis had a similar overall survival (OS) compared to patients treated immediately. Here, we expand on that data with the Surveillance, Epidemiology and End Results (SEER) database to determine if delayed TTI impacts OS. Methods: We conducted a retrospective study using the SEER database. Only patients with a single primary malignancy were included. OS was determined using Kaplan–Meier survival curves with logrank tests to determine significance. Further analysis was performed with multivariate Cox proportional hazards regression model testing. Hazard ratios were calculated for each parameter with p-values to assess significance. Covariates included age, sex, race, and stage. Results: We identified a total of 15,892 MCL patients diagnosed between 2000 to 2022 in SEER. In our survival analysis, we found one-year OS of 80.2% and five-year OS of 51.6%. Female patients had improved OS with a median OS of 67 months compared to male patients with a median OS of 58 months (p<0.003). After multivariate Cox regression model analysis, female patients continued to have a superior OS with HR of 0.8872 (95% CI 0.8226-0.9562; p<0.0017). Age was categorized as patients < 65 years old and > 65 years old. Patients < 65 years old had superior OS after controlling for sex, stage, and race (HR of 0.4272, 95% CI 0.3969-0.4596; p<0.0001). Next, we performed analysis of TTI in days from date of diagnosis. Patients without treatment date information were excluded from this analysis. First, we analyzed TTI by year of diagnosis and found increasing TTI over time: 15 (2005-2009) to 21 (2010-2014) to 27 (2015-2019) to 32 (2020-2022). Median TTI did not significantly vary between male and female patients. Delayed TTI was associated with improved OS. In comparison to TTI < 30 days, TTI of 30 – 89 days (HR of 0.7674, 95% CI 0.7102-0.8288; p<0.0001) and TTI of > 90 days (HR of 0.7202, 95% CI 0.6119-0.8424; p<0.0001) showed statistically significantly improved survival. Conclusions: In our large national cohort of patients, we found that female MCL patients maintain superior survival outcomes. This supports prior analysis from the National Cancer Database that also reported superior survival outcomes in female MCL patients. We also found that delayed TTI was paradoxically associated with improved survival outcomes concordant with prior data. These findings suggest that the aggressive disease biology may be driving the poor survival outcomes of early treatment initiation patients. Future studies should incorporate real-world data to further define aggressive disease biology in MCL patients.