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Quality of life among caregivers of patients with breast cancer in Mexico: A multicenter cross-sectional survey using the Caregiver Quality of Life Index–Cancer (CQOLI-C).
11103 Background: Family caregivers of patients with breast cancer (BC) often experience emotional, physical, social, and financial strain that can compromise their quality of life (QoL). The Caregiver Quality of Life Index–Cancer (CQOLI-C) is a validated cancer-specific instrument, however data on factors associated with caregiver QoL across healthcare settings in Mexico remain limited. Methods: We conducted a multicenter, cross-sectional survey of primary caregivers of patients with BC in Mexico. Consecutive eligible caregivers were recruited across public and private care settings (Sep 2025 – Jan 2026) and completed an online questionnaire. QoL was measured using the CQOLI-C (35 items scored 0–4; total score range 0–140; higher scores = greater caregiver burden (CB)); positively worded items were reverse-coded and summed to generate the total score. We summarized caregiver/patient characteristics and CQOLI-C scores with descriptive statistics and compared them across key groups (metastatic status, caregiving hours/week, additional helpers, self-reported unsustainable caregiving (yes/no), and care setting (public vs private)). We evaluated associations between CQOLI-C total score and prespecified predictors using multivariable OLS linear regression with robust standard errors (two-sided p < 0.05). Results: Seventy-three caregivers completed the survey (mean age 46.9±15.5 years; 54.8% male). Caregivers were most commonly partners (43.8%) or adult children (32.9%). 53.4% of patients received care in the private sector; 26% had metastatic disease. The most common numbers of additional caregivers were 2 (27.4%) and 0 (21.9%). Over half of caregivers (52.1%) reported providing 0–10 hours/week of care, while 16.4% reported > 50 hours/week. Median caregiver burden measured by CQOLI-C was 45 (IQR 29.5–62). 41% reported caregiving became too difficult to sustain. High burden items most frequently endorsed (score 3–4) included fear of patient death (54.8%), concern about treatment adverse effects (42.5%), and anger to see loved one deteriorating (41.1%). In adjusted regression (n = 73), compared with no helpers, reporting two helpers (β = 16.5; p = 0.020) and five helpers (β = 24.4; p = 0.016) was associated with higher scores, while six or more helpers was associated with substantially lower scores (β = -42.0; p = 0.002). Metastatic disease (β = 16.7; p = 0.043) and public vs private sector (β = 24.2; p = 0.009) were associated with worse scores; caregiving hours showed no consistent independent association. Conclusions: Caregiver burden was substantial and clustered around unsustainable caregiving demands, metastatic disease, and public care settings. These factors can help identify caregivers most in need of support and should guide systematic caregiver screening and targeted supportive-care interventions in Mexico.
Healthcare provider use of a community-based narrative resource to support psychosocial care in AYA oncology.
e13570 Background: Adolescents and young adults (AYAs) with cancer experience heightened psychosocial distress, including social isolation and loneliness, which are associated with reduced engagement in care and poorer health outcomes. Social connectedness and peer support are critical protective factors for this population; however, healthcare providers (HCPs) often report challenges in connecting AYAs with effective, age-appropriate resources for connection. Limited awareness of available tools and lack of confidence in referral practices contribute to these gaps. A national nonprofit serving AYA patients, survivors, and caregivers produces the only free, quarterly magazine featuring first-person narratives written by and for the AYA cancer community. The current study examined HCP use and dissemination of the magazine and HCP perceptions of how the magazine impacts their AYA patients. Methods: An anonymous, online survey was distributed to 212 healthcare providers who received quarterly magazines in bulk to assess dissemination practices, perceived value, and impact on clinical practice and AYA psychosocial support. A total of 47 HCPs completed the survey, representing diverse roles including social workers, nurses, program managers, patient navigators, and child life specialists. Descriptive analyses summarized provider characteristics, patterns of magazine use, and perceived benefits for AYAs. Results: Most respondents worked in hospital-based settings (80%), primarily at academic medical centers (52%), and reported engaged with AYAs daily (66%). The magazine was frequently shared with patients, with 78% reporting they often or always distributed it to patients. Providers rated the magazine as very helpful for AYAs (83%) and reported it addressed a critical gap in existing psychosocial resources (98%). The most valued content included first-person narratives (85%), resource listings (78%), and coping strategies (78%). Reported key functions included validating patient experiences (94%), connecting AYAs to additional resources (91%), and reducing isolation (89%). Most providers (91%) indicated that the magazine informed their clinical practice by strengthening understanding of the AYA perspective, enhancing rapport, initiating supportive conversations, and guiding psychosocial care strategies. Conclusions: This community-based narrative resource may function as a scalable psychosocial support tool that promotes social connectedness among AYAs while also strengthening provider capacity to deliver developmentally appropriate supportive care. Findings underscore the potential role of narrative-driven, community-informed resources in strengthening social connectedness, supporting provider practice, and addressing unmet psychosocial needs in AYA oncology care.
Diabetes-related mortality among cancer survivors: A population-based cohort study.
e23068 Background: As cancer survival improves, noncancer causes of death have taken the attention. Diabetes mellitus is common among cancer survivors. So long-term diabetes management becomes essential, as underestimation of diabetes risk may contribute to excess mortality during survivorship. Methods: Using the U.S. SEER-17 database, representing about 26.5% of the U.S. population. Patients diagnosed with invasive cancers between 2000 and 2022 were included. Diabetes mellitus was defined as the cause of death based on death certificates. Standardized mortality ratios (SMRs) with 95% confidence intervals (CIs) were calculated by comparing observed diabetes-specific deaths among cancer patients with expected deaths in the general population, matched for age, sex, race, calendar year, and latency. Results: Among 8,103,974 cancer patients. 3,704,416 (45.7%) died during the follow-up, including 46,075 (0.56%) from diabetes. During the first 2-11 months after diagnosis, diabetes-specific mortality was significantly raised (SMR 1.27, 95% CI 1.24-1.30, P <0.05), then declined toward unity overall with longer follow-up (SMR 0.99, 95% CI 0.98–1.00, P <0.05). Marked heterogeneity was observed by cancer site. The highest excess mortality was found for liver (SMR 2.57), gallbladder (SMR 2.24), pancreatic (SMR 1.89), and stomach (SMR 1.52) cancers, which remained elevated SMRs throughout follow-up. Colorectal cancer showed a consistently moderate increase. While breast cancer and melanoma were consistently associated with reduced diabetes-related mortality. Conclusions: Diabetes-specific mortality among cancer patients varies by cancer site and time since diagnosis. Mortality was highest during the first year, with subsequent attenuation over time. Persistently elevated mortality in liver, pancreatic, gallbladder, and stomach cancers reflects strong metabolic and organ-specific interactions. These findings highlight the importance of survivorship care and endocrinology involvement in cancer management. Overall SMRs (95% CI) for diabetes-specific mortality according to cancer site. Cancer site SMR (95% CI) Liver 2.57* (2.35–2.81) Gallbladder 2.24* (1.82–2.72) Pancreas 1.89* (1.70–2.09) Stomach 1.52* (1.40–1.65) Small intestine 1.34* (1.17–1.53) Colon & Rectum 1.24* (1.21–1.27) Breast 0.83* (0.81–0.85) Skin melanoma 0.71* (0.69-0.74) *Statistically significant at P < 0.05.
Who gets access? National discrepancies in clinical trial enrollment among patients with brain metastases.
1655 Background: Patients with brain metastases (BM) have historically been underrepresented in clinical trials. Contemporary national data describing clinical trial enrollment (CTE) patterns and sociodemographic predictors in this population remain limited. Methods: Using the National Cancer Database, adults (≥18 years) diagnosed with BM (2010-2021) from the five most common primary sites (lung, breast, melanoma, colorectal, and renal cell carcinoma) were included. The key outcome was CTE (yes/no). Multivariable logistic regression was used to evaluate associations between enrollment and primary tumor site, age, sex, race/ethnicity, facility type, geographic region, residence, insurance status, area-level education and income, comorbidity burden (Charlson-Deyo score), and time epoch (2010-2013, 2014-2017, 2018-2021). Results: The analytic cohort included 238,129 patients with BM (lung n=206,813; melanoma n=10,394; breast n=9,915; renal n=7,409; colorectal n=3,598). Overall, <1% of patients (n=385) had CTE. In adjusted analyses, compared with patients aged 18-39 years, those aged 40-64 years (aOR: 0.15) and ≥65 years (aOR: 0.12) had significantly lower odds of enrollment (P<0.001). Female sex was associated with higher enrollment (aOR: 1.30, P=0.013), while Hispanic ethnicity was associated with lower enrollment compared with non-Hispanic White patients (aOR: 0.39, P=0.014). Higher comorbidity burden (Charlson–Deyo score: 2-3) was associated with lower enrollment (aOR: 0.68, P=0.04). Treatment at an academic/research facility had the highest odds of CTE compared with community facilities (aOR: 4.83, P<0.001), as well as care within an integrated network (aOR: 1.87, P=0.001). CTE increased over time (2014-2017, aOR 1.58, P=0.002; 2018-2021, aOR 1.63, P=0.001, vs 2010-2013). Conclusions: CTE among patients with BM was low across primary tumor sites. Enrollment was higher at academic facilities and among younger patients, while Hispanic patients had lower odds of enrollment. These findings indicate persistent disparities in clinical trial access and support more inclusive enrollment strategies for patients with BM. Key predictors of CTE. Variable Strata aOR (95% CI) P Sex Male (Ref) - - Female 1.30 (1.06–1.60) 0.013* Race/ethnicity NH-White (Ref) - - NH-Black 0.83 (0.57–1.16) 0.292 Hispanic 0.39 (0.16–0.77) 0.014* Asian/Other 0.87 (0.54–1.32) 0.526 Facility type Community (Ref) - - Academic/Research 4.83 (3.69–6.39) <0.001* Integrated Network 1.87 (1.31–2.67) 0.001* *Geographic region, residence, and insurance status were insignificant.
Incretin-based therapies and all-cause mortality and progression to multiple myeloma in patients with MGUS and type 2 diabetes: A real-world cohort study.
7572 Background: Monoclonal gammopathy of undetermined significance (MGUS) progresses to multiple myeloma (MM) at an estimated rate of approximately 1–2% per year. Emerging evidence suggests metabolic dysfunction, including type 2 diabetes mellitus (T2DM) may influence the trajectory of progression to MM.Incretin based therapies have immunomodulatory and metabolic effects that could modify outcomes in patients with plasma cell dyscrasias. We conducted this study to evaluate the association between incretin-based therapies and the risk of progression to MM and all-cause mortality among patients with MGUS and T2DM. Methods: A multicenter, retrospective cohort study was conducted using the TriNetX Global Collaborative Network, a federated electronic health record database, from January 1, 2015, to December 31, 2025. Adult patients with T2DM and MGUS who had at least one year of treatment exposure to incretin-based therapies both before and after MGUS diagnosis were included. Patients were categorized into six exposure cohorts. Outcomes among glucagon-like peptide-1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 inhibitor (DPP-4i) users were compared with matched cohorts receiving sulfonylureas (SU), sodium–glucose cotransporter-2 inhibitors (SGLT2i), and thiazolidinediones (TZDs). Individuals with a prior cancer diagnosis were excluded. A 1:1 propensity score matching (PSM) approach was applied to balance demographics, comorbidities, laboratory parameters, and concurrent medication use. The primary outcome was all-cause mortality, and the secondary outcome was progression to MM. All statistical analyses were performed within the TriNetX platform. Results: After 1:1 PSM, GLP-1RA use was associated with lower all-cause mortality compared with SU (n = 393 per group; RR 0.35, 95% CI 0.25–0.49). No significant differences were observed in all-cause mortality or progression to MM when GLP-1RAs were compared with SGLT2i or TZDs. In contrast, DPP-4i use was associated with significantly higher all-cause mortality compared with SGLT2i (n = 315 per group; RR 2.53, 95% CI 1.77–3.62) and TZDs (n = 120 per group; RR 2.37, 95% CI 1.27–4.44). DPP-4i exposure was not significantly associated with progression to MM across any comparator group. Conclusions: Among patients with T2DM and MGUS, GLP-1RA use was associated with significantly lower all-cause mortality compared with SU, whereas DPP-4i use was associated with increased mortality compared with SGLT2i and TZDs, with no significant effect on progression to MM. These findings suggest a clinically meaningful survival differences across antihyperglycemic therapies and should be validated in future prospective studies.
Addressing geographic disparities in cancer care: An examination of the contributions of international medical graduates (IMGs).
1516 Background: IMGs comprise 38% of the US hematology and medical oncology workforce according to the Association of American Medical Colleges. We examined the geographic distribution of oncologists by IMG status to quantify and contextualize the role of IMGs in providing cancer care across the United States, particularly in rural and underserved areas. Methods: We used Medicare Care Compare to identify and locate physicians practicing in the U.S. as hematology and medical oncology specialists. IMG status, defined as graduation from a medical school outside of the US, Puerto Rico, and Canada, was assigned from Care Compare where information was available (51%), then from AMA Masterfile data (43%). For the 6% missing IMG data, Google Gemini was used for imputation. We cross-tabulated oncologist IMG status with whether they practiced in a rural county, a county with high cancer incidence (in top 25% of counties for age-adjusted cancer incidence from the National Cancer Institute), and a primary care Health Provider Shortage Area (HPSA). Across counties, we assessed the distribution of new cancer cases by oncologist availability according to IMG status. Proportions and odds ratios with 95% confidence intervals are reported to demonstrate associations. Results: There were 14,946 oncologists practicing in the US as of March 2025, of which 5,840 (39%) were IMGs. IMG status was associated with locations that are rural, have high cancer incidence, and have provider shortages (Table). In county-level analysis, among 1,395 counties with oncologists, 1,105 (80%) had IMG oncologist presence. In 662 (47%), IMGs comprised ≥50% of the oncology workforce, corresponding to areas where 32% of patients with newly diagnosed cancer live (549K/1.72M). In 250 counties (18%), only IMG oncologists provided care; 191 (76%) of those were rural and/or had high cancer incidence. Conclusions: IMG oncologists play a pivotal role in the geographic availability of cancer care in the United States. They are more likely to practice in rural areas and in areas with increased cancer burden and provider shortages. Any reductions in the IMG oncologist workforce could impede patient access to cancer care on a broad scale and further aggravate shortages in rural and underserved areas. Oncologist practice site characteristics by IMG status. Site Characteristic All Oncologists,N (%) IMG Oncologists,n (%) Non-IMG Oncologists,n (%) Odds Ratio for IMG vs. Non-IMG(95% CI) Overall 14,946 5,840 9,106 Rural 1.34(1.20, 1.50) Yes 1,488 (10) 677 (12) 811 (9) No 13,458 (90) 5,163 (88) 8,295 (91) High Cancer Incidence* 1.54(1.41, 1.68) Yes 2,346 (16) 1,116 (20) 1230 (14) No 12,264 (82) 4,554 (80) 7710 (86) HPSA 1.38(1.29, 1.49) Yes 3,923 (26) 1,760 (30) 2,163 (24) No 11,023 (74) 4,080 (70) 6,943 (76) *County incidence data unavailable for 336 (2%) oncologists.
Systemic therapy–associated differences in intracranial disease in metastatic prostate cancer: A real-world study.
e17080 Background: Brain or leptomeningeal involvement in prostate cancer has historically been rare. As systemic therapies with distinct biological targets have expanded, it remains unclear whether patterns of intracranial metastases or related disease phenotypes, such as neuroendocrine transformation, have changed over time. Real-world evidence is limited. Methods: A retrospective, multicenter analysis was conducted using the TriNetX federated electronic health record network. Adult males (≥18 years) with metastatic prostate cancer (ICD-10 C61, C77-79) were stratified by treatment era (2015-2017 vs 2021-2023) and by exposure to conventional systemic therapies. Brain (C79.31) and meningeal (C79.32) metastases were primary endpoints, and neuroendocrine transformation (C7A, C7B) was the secondary endpoint. Cohorts were compared after 1:1 propensity score matching for age at index event, race, ethnicity, surgeries of the prostate, radiation, PSA, TNM staging, Olaparib/Rucaparib use. Regimens of interest were androgen receptor signaling inhibitors (ARSI), Docetaxel, Cabazitaxel and 177Lu-PSMA-617. Treatment exposure was limited to on or before 12/31/2024, and those reaching endpoints before exposure were excluded.Intracranial (IC) disease did not include base of skull involvement. Results: Across time periods, patients diagnosed in 2021–2023 demonstrated a significantly lower incidence of IC metastases when compared with 2015–2017 at both 1-year (p = 0.0006) and 3-year follow ups (p < 0.0001). In contrast, the incidence of neuroendocrine disease was significantly higher in the 2021–2023 cohort at 1-year (p = 0.007) and 3-years (p = 0.0005). In treatment-based analyses, patients receiving ARSI had a lower 1-year incidence of IC metastases than the docetaxel group (p < 0.0001), with no significant difference in neuroendocrine disease (p = 0.4). Among ARSI-treated patients, abiraterone was associated with a lower 1-year incidence of IC metastases compared with enzalutamide (p = 0.0478), while neuroendocrine incidence remained similar (p = 0.39). In late line comparisons, 177Lu-PSMA-617 was associated with a lower 1-year IC incidence than cabazitaxel(p = 0.0159); neuroendocrine events were too few to analyze. Upon stratification by therapy combinations and treatment line, no increase in neuroendocrine disease was observed. Conclusions: Modern treatments for metastatic prostate cancer appear to have influenced patterns of intracranial involvement, with some therapies potentially reflecting improved disease control. In contrast, increasing neuroendocrine involvement remains unexplained and may be due to underlying selective pressure on androgen signaling, new pathways for progression with evolving disease biology, or survival-related selection rather than treatment-driven induction, highlighting the need for mechanistic and prospective studies.
Integrated clinical and molecular characterization of WNT pathway alterations in metastatic castration-resistant prostate cancer (mCRPC) liver metastases (mets).
5048 Background: mCRPC patients (pts) with liver mets (LM) have an aggressive clinical course and poor response to established treatments. LM frequently exhibit low PSMA expression, limiting the utility of PSMA-targeted therapies. The mechanisms driving hepatic organotropism and therapy resistance in advanced disease are poorly understood. Methods: We analyzed metastatic biopsies with matched transcriptional and genomic profiling from 4 independent mCRPC cohorts from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) West Coast Dream Team, SU2C/PCF East Coast Dream Team, University of Washington rapid autopsy program, and Weill Cornell Medicine. Tumors were classified by FOLH1 gene expression tertile and by androgen receptor (AR) and neuroendocrine (NE) gene signature expression. Individual cohorts were assessed for differential gene expression and validated between cohorts. Cohorts were pooled for genomic and survival analyses. Multivariable Cox proportional hazard models were used to assess outcomes. Results: 595 mCRPC biopsies were analyzed, comprising 88 (15%) liver, 130 (22%) non-liver visceral, 166 (28%) bone, and 211 (35%) lymph node mets. 54% of pts had prior androgen receptor pathway inhibitor (ARPI) exposure and 29% had prior taxane chemotherapy. LM had lower FOLH1 expression (log2FC = -1.5, q < 0.001) than non-LM. Amongst FOLH1 -low LM, 32% had elevated NE gene expression, with high histological concordance (80% NE prostate cancer [NEPC], 9% adenocarcinoma with NE features). WNT pathway mutations in APC or CTNNB1 were enriched in LM compared to non-LM (20% vs. 10%, p = 0.01) and FOLH1- low compared to FOLH1 -high mets (16% vs. 6%, p = 0.006). Notably, in FOLH1 -low LM, APC mutations were exclusively found in tumors with low NE gene expression (28% vs. 0%, p = 0.02). In contrast, NE LM were enriched for alterations in RB1 (71% vs. 15%, p < 0.001) and homologous recombination repair genes (41% vs. 15%, p = 0.04). Compared to NE LM, non-NE FOLH1 -low LM demonstrated persistence of AR signaling, enrichment for inferred ß-catenin transcription factor activity, and upregulation of adaptive metabolic pathways including HIF-1α mediated hypoxia signaling and unfolded protein response. ß-catenin downstream targets including CCND1, MYC, MSX2, AXIN2, and LEF1 were transcriptionally upregulated, while AR targets STEAP1 and KLK2 remained highly expressed. In the overall cohort, WNT pathway mutations were associated with shorter treatment duration on first-line ARPI (HR 2.2, 95% CI 1.04-4.8, p = 0.03) and inferior overall survival from start of first-line ARPI (HR 1.7, 95% CI 1.04-2.7, p = 0.03). Conclusions: WNT pathway alterations are enriched in a clinically aggressive PSMA-low subset of non-NE mCRPC that maintains luminal markers, suggesting distinct clonal evolution from NEPC and clinical actionability with emerging therapies.
Reassessing neutropenic vs liberalized diets in post-chemotherapy and hematopoietic stem cell transplantation patients: An updated meta-analysis.
e18571 Background: Neutropenia following high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies heightens infection risk. While recent guidelines de-emphasize neutropenic diets (ND), this meta-analysis reevaluates their role across pediatric and adult populations with different types of hematologic malignancies, consolidating all available evidence on infection and nutritional outcomes of ND versus liberalized diets (LD). Methods: A total of 489 articles were retrieved from ScienceDirect, PubMed, Embase, Cochrane Library, and Scopus; 14 studies were included that compared ND vs LD in patients with hematologic malignancies. Data were pooled in R (v4.5.2) using random-effects models to calculate risk ratios (RR) with 95% confidence intervals (CI), including subgroup analyses by study design (RCTs vs non-RCTs), age group (adults vs pediatric), HSCT status (HSCT vs non-HSCT), cancer types (non-Hodgkin lymphoma (NHL), multiple myeloma, Hodgkin lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia(ALL)) and geographic region (USA vs other). The primary outcomes were neutropenic infection and all-cause mortality. Results: A total of 3,469 patients received ND (n=1,777) and LD (n=1,692). ND showed no significant association with neutropenic infection (RR = 1.06, 95% CI 0.99–1.14, I² = 14%) and all-cause mortality (RR = 0.95, 95% CI 0.67–1.34, I² = 0%) compared to LD. Subgroup analyses by geographic region, HSCT status, age group, cancer type, and study design yielded similar results across most categories, except for pediatric patients, NHL, and ALL, where ND was significantly associated with higher neutropenic infections and all-cause mortality compared to LD. For secondary outcomes, ND increased the risk of graft-versus-host disease (RR = 1.86, P = 0.03), while fever and diarrhea showed no significant differences. Microbiologically confirmed infections were similar between diets overall (RR = 1.14, P = 0.27); however, ND conferred a higher risk in the non-HSCT subgroup (RR = 1.29, 95% CI 1.09–1.52). Specific bloodstream infections (Streptococcus, Staphylococcus, Pseudomonas, Klebsiella, Enterococcus, E. coli, and Clostridium difficile) showed no differences between the two groups, with dietary adherence and meal intake compliance also being comparable. No evidence of publication bias was detected, with consistently low heterogeneity across analyses. Conclusions: ND offers no overall benefit against neutropenic infections or mortality compared to LD. Exceptions include increased risks with ND in pediatric patients, NHL and ALL subgroups along with greater microbiologically confirmed infections among non-HSCT patients. LDs align with current guidelines, supporting food safety education over restrictions given comparable adherence and low heterogeneity.
Trust, ethics, and patient engagement in clinical research: Findings from the LACOG 1123 ASTRAL survey in Brazil.
e23171 Background: Trust, ethical understanding, and engagement are critical determinants of successful and equitable clinical research. However, limited data describe how individuals with cancer perceive ethical safeguards, voluntariness, and their potential role in the design of clinical trials, particularly in middle-income countries. This analysis explored ethical perceptions, trust, and attitudes toward patient engagement in clinical research among Brazilian patients with breast cancer. Methods: ASTRAL (LACOG 1123) is a prospective, observational survey conducted among adults with breast cancer (stages I-IV) treated in public and private oncology centers in Brazil. Participants completed a structured electronic questionnaire assessing perceptions of research ethics, trust in institutions, understanding of voluntariness and data protection, and attitudes toward patient and community involvement in clinical trial design. Descriptive analyses and exploratory associations with educational level and healthcare setting were performed. Results: Among 350 respondents, most demonstrated positive perceptions of clinical research ethics despite knowledge gaps. While 66.1% were aware that clinical trials require approval by ethics committees, understanding of regulatory structures varied by educational level (p < 0.001). The majority agreed that participation in research is voluntary (77.1%) and that refusal would not compromise quality of care (74.5%). Trust in academic research information was higher than trust in pharmaceutical industry sources (58.3% vs 26.2%), while nearly half of respondents reported uncertainty regarding government protection against unethical research practices. Importantly, 66.0% supported active involvement of patients and community representatives in clinical trial design, prioritizing improved patient information (25.7%), facilitation of participation (18.0%), and contributing patient perspectives to study planning (34.5%). Concerns regarding privacy and data use focused primarily on understanding the purpose of data collection (64.5%) and who has access to personal information (30.8%), while the majority (81.5%) don’t known or don’t think that all clinical research results are all made publicly available. Conclusions: Brazilian patients with breast cancer report high trust in the ethical foundations of clinical research and strong support for patient and community engagement, despite incomplete understanding of regulatory frameworks and distrust regarding the clarity of available data, especially when the research is funded by industry or the government. These findings highlight an opportunity to strengthen participant-centered research by improving transparency, ethical education, and meaningful patient involvement in trial design, rather than focusing solely on recruitment strategies.
Proteomic profiling of circulating tumor cells (CTCs) in metastatic urothelial cancer (mUC) as associated with upregulation of EGFR, HER2, and B7-H3 in patients (pts) progressing on enfortumab vedotin (EV) plus pembrolizumab.
4580 Background: Pts with mUC have poor prognosis, and while EV/pembro have improved outcomes, therapeutic targets arising after EV-pembro treatment are elusive. Proteomic profiling of circulating tumor cells (CTCs) offer a minimally invasive approach to capture tumor biology changes in real-time. We evaluated CTC burden and proteomic changes in relation to treatment response in mUC. Methods: Pts with mUC were prospectively enrolled at UT Southwestern Medical Center. Peripheral blood samples were collected at baseline, 4 weeks, and 12 weeks of treatment, as well as progression of disease. CTCs were isolated using a dendrimer-based microfluidic chip assay functionalized with antibodies against EpCAM, Trop-2, Nectin-4, and FGFR3, identifying nucleated CTCs (DAPI+/CK+, CD45-). After CTCs were selected within regions of interest, spatial proteomic profiling was performed via the Nanostring GeoMx Immuno-Oncology Proteome Atlas panel. CTC variation and surface proteomics after treatment were primary objectives. CTC changes were considered concordant if they decreased >10% in pts with complete or partial response (CR or PR), remained stable (within 10% of baseline) in pts with stable disease (SD), or increased >10% in pts with progressive disease (PD), as defined by RECIST 1.1. One pt underwent post-treatment biopsy with IHC analysis. Results: Thirty pts with mUC were enrolled, with a median age of 71.5 years, predominantly male (26/30, 87%) and Caucasian (24/30, 80%). Most received EV/pembro (26/30, 86.7%), while the rest were treated with chemotherapy (3/30, 10%) or SG (1/30, 3%). Median CTC counts (cells/ml) were assessed at baseline (30.3, IQR 18.5–62.9), at week 4 (22.3, IQR 6.0–37.0), and at week 12 (29.5, IQR 15.2–44.5). Twenty-two pts had sufficient radiographic and clinical follow up. CTC changes were concordant with treatment responses in 77% (17/22) of pts, including 12/22 pts with CR/PR, 3/22 with SD, and 7/22 with PD. Proteomic profiling of serial CTCs from 9 pts treated with EV/pembro revealed dynamic proteomic changes from baseline to week 12 and at disease progression. Together, these pts demonstrated upregulation of activated EGFR (phospho-Y1068), HER2 (phospho-Y877), STAT5, FAK, and vimentin. Pts with primary PD (n=3) showed B7-H3 upregulation on CTCs, whereas pts with secondary PD(n=2) showed higher expression of vimentin, c-MET, and MHC class I on CTCs. IHC of a post-EV/pembro progression bone metastasis confirmed increased HER2 expression (2+). Conclusions: CTCs with proteomic profiling can serve as a dynamic, noninvasive biomarker in mUC, identifying distinct therapeutic targets for pts progressing on EV/pembro. The emergence of actionable pathways, including EGFR, HER2, c-MET, and B7-H3, suggests opportunities for rational, biomarker-driven therapeutic strategies.
Long-term survival update of TRUCE-01: A phase 2 study of preoperative tislelizumab combined with low-dose nab-paclitaxel for muscle-invasive bladder cancer (MIBC).
4585 Background: The TRUCE-01 study (NCT04730219) previously met its primary endpoint, demonstrating that preoperative tislelizumab combined with low-dose nab-paclitaxel achieved a high clinical complete response (cCR) rate of 52% and a favorable safety profile in patients with muscle-invasive bladder cancer (MIBC). Here, we report the long-term survival outcomes after 4 years of study follow-up. Methods: Eligible patients with cT2-4aN0M0 MIBC received three cycles of tislelizumab (200 mg, day 1) plus low-dose nab-paclitaxel (200 mg, day 2) every 3 weeks, followed by radical cystectomy (RC) or maximal transurethral resection of bladder tumor (mTURBT) based on response assessment. The primary endpoint was cCR. Secondary endpoints included event-free survival (EFS), overall survival (OS), disease-specific survival (DSS), and metastasis-free survival (MFS). Results: At the clinical data cutoff of October 2025, the median follow-up was 47.4 months (IQR 24.8–53.3). Among the intention-to-treat population (n = 62), 25 patients experienced clinical events, including 15 recurrences and 20 deaths (13 due to disease progression, 7 due to non-disease-related causes). Notably, among the 24 patients who elected for bladder preservation, a bladder preservation rate of 75% was achieved(4 due to recurrence requiring salvage radical cystectomy, 2 due to disease progression). The 4-year EFS and OS rates were 59.7% and 67.8%, respectively. Survival analysis stratified by response showed that patients achieving a cCR had significantly superior long-term outcomes compared to non-cCR patients. The cCR group demonstrated a robust and significant benefit in OS (HR 0.28, 95% CI 0.09–0.83, p = 0.0212), DSS (HR 0.10, 95% CI 0.02–0.46, p = 0.0029), and MFS (HR 0.19, 95% CI 0.06–0.63, p = 0.0068). No new safety signals or late-onset immune-related adverse events were observed with extended follow-up. Conclusions: With approximately 4 years of median follow-up, preoperative tislelizumab combined with low-dose nab-paclitaxel continues to demonstrate robust and durable survival benefits for patients with MIBC. Clinical trial information: NCT04730219 .
Spatial Solvation Regulation by a Swollen Polymer Interphase Enables Ultrastable Sodium Metal Batteries
ABSTRACT Sodium (Na) metal batteries are considered promising candidates for next‐generation electrochemical energy storage because of their low costs and high energy densities. However, their development is hindered by a fundamental trade‐off in electrolyte design: strong Na + solvation enhances conductivity but aggravates undesirable anode degradation. Herein, we construct a swellable artificial polymer interphase rich in F─(Si─O─) n on the anode via a competitive coordination reaction involving fluoroethylene carbonate (FEC), ethyl trifluoroacetate, and (3‐aminopropyl)triethoxysilane. Employing in situ atomic force microscopy, in situ attenuated total reflection infrared spectroscopy and X‐ray absorption near‐edge structure spectra, we demonstrate that the interphase selectively attracts weakly solvating solvents while effectively excluding the highly polar tris(ethyl) phosphate (TEP) from the anode surface. This results in a gradient transition from a strong solvation configuration in the bulk electrolyte to a weak one at the interface, thereby enhancing the overall ionic conductivity, reducing the Na + desolvation energy barrier, and improving interfacial stability. Consequently, Na||Na 3 V 2 (PO 4 ) 3 cells deliver stable long‐term cycling, remarkable fast‐charging performance, and operate over a wide temperature range. The practical applicability of this strategy is further validated by pouch‐cell tests. This work paves the way for rational design of high‐performance and safe sodium metal batteries through advanced interfacial chemistry.
Suppressing Charge Screening via Z‐Scheme With Polarization Field for In Situ H <sub>2</sub> O <sub>2</sub> Generation and Utilization
ABSTRACT Piezoelectric polarization in n‐type semiconductors provides a sustainable pathway for hydrogen peroxide (H 2 O 2 ) production. However, its efficiency is fundamentally constrained by the piezoelectric screening effect, whereby accumulated free carriers rapidly neutralize polarization‐induced charges, leading to short‐lived internal fields and suppressed redox activity. Herein, ZnO nanoparticles are electrostatically integrated with a Zr‐based metal–organic layer to construct a ZnO/Zr‐MOL Z‐scheme heterojunction that intrinsically mitigates this screening limitation. Interfacial coupling enables polarization‐regulated band bending, spatially separating piezo‐generated electrons and holes, and preventing their premature compensation by mobile carriers. The Z‐scheme configuration preserves strong redox potentials while suppressing bulk and interfacial recombination, and the polarization‐driven charge redistribution and dynamic realignment of the conduction and valence bands sustain the piezoelectric potential and markedly enhance carrier mobility and lifetime. Consequently, the optimized ZnO/Zr‐MOL catalyst achieves an H 2 O 2 production rate of 13.21 m m g −1 h −1 in pure water under ambient air conditions. When incorporated into an autonomous tidal‐driven reactor, the heterostructure demonstrates strong environmental adaptability, achieving 74.5% degradation of Rhodamine B in 5 L of wastewater within 180 min. This study provides a fundamental strategy to overcome piezoelectric screening and establishes a mechanistic framework for polarization‐assisted charge transfer in heterostructure systems.
Research on the development and application of bundled care protocols for radiation dermatitis in nasopharyngeal cancer patients.
e18123 Background: To develop a bundled care protocol for radiation dermatitis in patients with nasopharyngeal carcinoma (NPC) receiving concurrent chemoradiotherapy (CCRT), and to preliminarily evaluate its clinical efficacy and impact on quality of life (QoL). Methods: Seventy patients with locally advanced NPC undergoing CCRT were enrolled from the Department of Head and Neck Oncology, Affiliated Cancer Hospital of Guizhou Medical University between October 2020 and July 2022. Patients were randomly assigned to an intervention group or a control group. The intervention group received a bundled care protocol in addition to routine nursing care, while the control group received routine care alone throughout CCRT. QoL was assessed using the EORTC QLQ-C30 at three time points: before CCRT, after 15–20 radiotherapy sessions, and at the end of CCRT. The incidence and severity of acute radiation dermatitis and QoL scores were compared between groups. Chi-square test and rank-sum test were used for statistical analysis. Results: The incidence of Grade II acute radiation dermatitis was significantly lower in the intervention group than in the control group (28.57% vs. 51.43%, P < 0.05). No significant differences were observed in Grade I or Grade III dermatitis, and no Grade IV dermatitis occurred in either group. After 15–20 radiotherapy sessions, the intervention group showed significantly higher emotional functioning scores than the control group (P < 0.05). At the completion of CCRT, global QoL, physical functioning, and emotional functioning scores were significantly higher in the intervention group (all P < 0.05). Although fatigue increased in both groups during treatment, fatigue scores were significantly lower in the intervention group at the end of CCRT (P < 0.05). Insomnia scores were also significantly improved in the intervention group compared with the control group (P < 0.05). Conclusions: The bundled care protocol effectively reduced the incidence of acute radiation dermatitis in NPC patients undergoing CCRT and was associated with improved fatigue, sleep quality, physical and emotional functioning, leading to a significant improvement in overall quality of life during treatment.
Cancer-associated sepsis hospitalizations: Outcomes, inequities, and palliative care—National Inpatient Sample analysis (2016–2022).
e23097 Background: Among patients with cancer, sepsis is a leading cause of hospitalization and mortality. Data on clinical outcomes, resource use, and palliative care utilization (PC) across hematologic (HM) and solid malignancies (SM) in sepsis-associated hospitalizations needs to be elucidated. We aimed to characterize these patterns in a nationally representative cohort. Methods: We analyzed adult cancer-associated sepsis hospitalizations from the National Inpatient Sample (2016–2022). HM, SM, metastatic malignancies (MM), and PC use were identified via ICD-10 codes. Outcomes included in-hospital mortality (IHM), length of stay (LOS), and total hospital charges (THC). Survey-weighted logistic and linear regression models evaluated factors associated with IHM. Adjusted odds ratios (aOR) reflect comparisons to cohort mean after multivariable adjustment. Results: Among 82,471 cancer-associated sepsis hospitalizations, 72.4% were SM and 27.6% HM. HM hospitalizations had lower mean age (64.7 vs 67.4 years), longer LOS (12.1 vs 9.2 days), higher THC ($194,507 vs $131,622), and lower PC use (21.6% vs 27.9%, aOR 0.72). MM hospitalizations accounted for 43.6%; patients were younger (66.2 vs 67.1 years) and more often female (46.2% vs 41.5%). Multivariable regression adjusted for demographics, organ dysfunction and septic severity (Table1) revealed older age (aOR 1.01), Black race and lower ZIP income quartile were independent predictors for higher IHM. Teaching hospital status and PC predicted lower IHM. Among HM, leukemia had highest IHM (aOR 1.22), myeloma had prolonged LOS (aOR 1.55), and lymphoma had greater sepsis severity (SS) (aOR 1.48). Among SM, thoracic (1.18) and CNS (1.14) tumors had highest IHM; CNS tumors had greater SS (1.28) and prolonged LOS (1.34), followed by sarcoma/bone tumors (SS 1.22; LOS 1.29). Acute kidney injury (aOR 1.51), acute respiratory failure (3.00) and septic shock (2.88) were independently associated with increased IHM across all cancers. PC was associated with shorter LOS in both HM and SM (−1.37 and −2.68 days, respectively) and lower THC (adjusted difference −$6,682) overall. All p < 0.001. Conclusions: Cancer-associated sepsis outcomes differ by malignancy type and socio-demographic factors. Persistent inequities by race and socioeconomic status highlight the need for equitable resource allocation, expanded access to academic centers, and comprehensive palliative care integration. In-hospital mortality regression analysis. Predictor : aOR (95% CI) HM SM MM p-value Black race vs White 1.36 (1.21–1.52) 1.42 (1.28–1.56) 1.38 (1.25–1.51) <0.001 ZIP income quartile (Q1 vs Q4) 1.08 (1.04–1.12) 1.12 (1.07–1.18) 1.10 (1.05–1.15) <0.001 Teaching hospital 0.91 (0.85–0.97) 0.94 (0.89–0.99) 0.92 (0.87–0.98) ≤0.015 PC 0.63 (0.57–0.70) 0.68 (0.62–0.74) 0.70 (0.65–0.76) <0.001
Overall survival in veterans with metastatic hormone sensitive prostate cancer by initial therapy and STRATOS-P somatic tumor classification.
5105 Background: The STRATOS-P somatic tumor classification stratifies patients with metastatic hormone-sensitive prostate cancer (mHSPC) into favorable, intermediate, or unfavorable risk groups based on tumor comprehensive genomic profiling (CGP). Currently, no studies have compared the mortality benefits or overall survival (OS) differences between mHSPC treatments in these risk categories. Methods: Veterans within the Veterans Health Administration with mHSPC diagnosed between December 2018 and September 2024 were included if tumor CGP was completed within 6 months of diagnosis. Patients were grouped based on STRATOS-P genomic classification (favorable vs. intermediate/unfavorable). With each group, OS was analyzed by initial therapy: androgen deprivation therapy (ADT) alone, ADT+androgen receptor pathway inhibitor (ARPI), ADT+docetaxel, or triple therapy with ADT+ARPI+docetaxel. Survival was analyzed using Kaplan-Meier and Cox proportional hazards models, adjusting for baseline differences in age, PSA, Charlson comorbidity index, race, and metastatic volume. Results: Of 2,820 veterans with mHSPC, 1,109 (39.3%) had risk classified as favorable per STRATOS-P and 1,711 (60.7%) as intermediate/unfavorable. Initial therapy distribution differed moderately between groups (p=0.046). The favorable group had more patients receiving ADT monotherapy (55.5% vs. 52.0%) and fewer receiving ADT+docetaxel or triple therapy (3.0% vs. 4.7%, 4.4% vs. 5.4%, respectively). The intermediate/unfavorable group had a higher max PSA (median 37.7 vs 23.7, p<0.001) lower percentage of African American patients (27.5% vs 36.0%, p<0.001), and a higher percentage of patients with high volume of disease (28.9% vs. 19.7% p=0.002). In the favorable group, OS did not significantly differ by treatment; however, in a pairwise comparison, ADT+ARPI showed a modest decrease in mortality risk versus ADT alone (aHR [95% CI]: 0.745 [0.561 – 0.989]). In the intermediate/unfavorable group, median OS differed by therapy (ADT monotherapy: 30.7 months, ADT+ARPI: 36.8 months, ADT+docetaxel: 27.9 months, Triple Therapy: 37.6 months; p<0.001). Further, ADT+ARPI and triple therapy were associated with a decreased risk of mortality compared to ADT alone (aHR [95% CI]: 0.638 [0.541 – 0.753], 0.542 [0.360 – 0.817], respectively). Conclusions: In patients with intermediate/unfavorable STRATOS-P genomic risk, choice of initial therapy can lead to differences in OS, with ADT+ARPI and triple therapy associated with decreased mortality compared to ADT alone. In favorable risk, choice of initial therapy had smaller effect on OS, and only ADT+ARPI was associated with a modest decrease in mortality. These findings highlight the role of early genomic testing in mHSPC and that high risk tumors may benefit more from combination therapy than those with favorable risk.
Final results and correlative analysis of entinostat (E) plus pembrolizumab (P) in patients (Pts) with metastatic melanoma (MM) previously treated with anti–PD-(L)1 therapy (Tx).
9522 Background: PD(L)1 inhibitors have transformed MM tx, yet several pts experience resistance. Preclinical data suggest that epigenetic modifications may overcome this. Here, we present the results of an expansion MM cohort treated with E+P following prior anti-PD(L)1 tx. Methods: Pts with unresectable stage III/IV melanoma, progression to anti-PD(L)1 and BRAF-targeted tx (if BRAF -mutant) were eligible. Pts were treated with E, 5 mg PO qwk, and P, 200 mg IV q3wks. The primary endpoint was to determine the objective response rate (ORR) per the irRECIST criteria. Secondary endpoints included assessment of the safety of E+P tx, progression-free (PFS), and overall survival (OS). Correlative analyses were performed on baseline and on-tx tissues. Results: 53 pts were treated (median [mdn] age, 61 years; 60% male; 55% with ECOG performance status of 0; 64% with visceral metastases; 23% with BRAFV600 mutation), including 43% with primary resistance to anti-PD(L)1 inhibitors, respectively. The mdn number of prior systemic tx was 3 (range 1-8), and 70% of pts had previous tx with CTLA4 inhibitors. 49% pts developed ≥ grade 3/4 toxicity, and 19% pts discontinued at least one drug due to adverse events. 10 pts had a partial (n=9) or complete (n=1) response, for an ORR of 19%. The mdn follow-up was 11.5 months (mon), and the mdn response duration was 23.7 mon (range 2.6-45.6+ mon); 9 pts had stable disease > 6 mon. The mdn PFS and OS were 4.0 and 11.5 mon, respectively. Blood analysis showed that the tx significantly decreased Ki67-PD1+ T cells and T regs and significantly increased Ki67-HLA-DR+ and ICOS+ T cells. Analysis of baseline (n=30) and on-tx (n=10) tumor biopsies using NanoString and/or bulk RNAseq showed increased immune infiltration with tx and increased expression of key genes in antigen presentation ( ß2M ), chemoattraction ( CXCL11 & 13 ), and IFNγ. Hallmark gene set enrichment analysis suggests that pts bearing inflamed, non-proliferating baseline tumors had a more durable clinical benefit to tx (i.e., no disease progression for > 6 mon). Exploratory analysis using quantitative multiplex immunohistochemistry showed that pts with more durable clinical benefit had baseline tumors with a higher lymphoid-to-myeloid (L/M) ratio, and higher numbers of tumor-infiltrating (TI) CD4+ and CD8+ cells, particularly CD8+PD1+ cells. With tx, pt tumors with clinical benefit maintained a higher L/M ratio, had lower TI CD8+PD1+ cells, and increased density of TI CD20+ cells. TI CD8+PD1+ cells increased in pt tumors without clinical benefit. Conclusions: E+P tx in anti-PD(L)1-resistant MM was associated with durable clinical benefit in a pt subset and was well tolerated. Correlative analysis revealed that tx increased inflammation across most analyzed pt tumors; the most significant benefit, however, was observed in pts with pre-existing inflamed tumors. Clinical trial information: NCT02437136 .
Impact of para-cervical boost with volumetric modulated arc therapy on local control in locally advanced cervical cancer: A single-arm study.
e17516 Background: Concurrent chemoradiation is the standard treatment for locally advanced cervical cancer (LACC). Treatments such as interstitial brachytherapy, immune checkpoint inhibitors, or systemic chemotherapy are often added in combination to reduce tumor burden; however, these are often inaccessible to patients in low- and middle-income countries, elderly patients, or those with high-risk factors for hematologic toxicity. This study investigates whether a precise paracervical boost delivered via simultaneous integrated boost (SIB) can improve oncologic outcomes without increasing toxicity. Methods: Patients with FIGO 2018 stage IIB-IV LACC and an ECOG performance status of 0–1 were retrospectively included. All received definitive concurrent chemoradiotherapy. The paracervical boost was delivered via SIB to 60 Gy, combined with conventional pelvic radiotherapy (50.4 Gy in 28 fractions of 1.8 Gy) using volumetric modulated arc therapy (VMAT), followed by high-dose-rate brachytherapy. Dose-volume parameters for targets (CTV parametrium) and organs at risk (bladder, rectum, bowel) were evaluated. The primary endpoint was 6-month disease-free survival (DFS). Secondary endpoints included treatment response and late toxicity (graded by CTCAE v5.0). Results: Until January 10, 2026, 41 patients were enrolled, with a median age of 60.5 years (IQR 49–67). Stage distribution was: IIB in 5 (12.20%), IIIA in 1 (2.44%), IIIB in 3 (7.32%), IIIC1r in 21 (51.22%), IIIC2r in 7 (17.07%), and IV in 4 (9.76%). Histology was squamous carcinoma in 97.56% and adenocarcinoma in 2.44%. All patients received CCRT, with 20 (48.78%) receiving ipsilateral SIB and 21 (51.22%) receiving bilateral SIB. Among 37 patients who completed radiotherapy, imaging evaluation at 1 month showed complete remission in 35 (94.59%) and partial remission in 2 (5.41%). After a median follow-up of 6 months, 3 patients had relapsed (2 with lung metastasis, 1 with multiple muscle metastases). Nineteen patients had follow-up >6 months, with a 6-month DFS rate of 94.73%. Grade II radiation proctitis occurred in 3 patients (7.32%); no grade III/IV adverse events were observed. Conclusions: A tailored paracervical boost using SIB represents a promising treatment option for patients with locally advanced cervical cancer. These results warrant further validation with longer follow-up and a larger sample size.
The CO.33/BATTMAN trial: A phase 3 randomized study of botensilimab + balstilimab versus best supportive care in chemorefractory unresectable colorectal adenocarcinoma that is not dMMR/MSI-H.
TPS3676 Background: Despite significant progress and newly approved agents, metastatic colorectal cancer (mCRC) has limited prognosis after progressing on standard cytotoxic chemotherapies. Many patients remain well enough for treatment at the time when their cancer is refractory to all available therapy, creating a significant unmet need. Once refractory, patient management with best supportive care (BSC) results in a median overall survival (OS) of 4–6 months. To date, immune checkpoint inhibitors (ICIs) have shown limited activity in mCRC that is not mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H). Prior data from the CCTG CO.26 randomized phase 2 trial demonstrated doublet ICI with durvalumab + tremelimumab improved OS in refractory mCRC; however, a phase 3 trial was not undertaken. Botensilimab (BOT) is an Fc-enhanced multifunctional anti–CTLA-4 antibody designed to increase efficacy in poorly immunogenic cancers. The combination of BOT with the anti–PD-1 antibody balstilimab (BAL) has shown impressive objective response rates (ORRs), durations of response (DOR), and survival in heavily treated non–MSI-H/dMMR mCRC across phase 1 and 2 studies. The CO.33/BATTMAN trial will evaluate BOT + BAL + BSC versus BSC alone in patients with refractory mCRC that is not MSI-H/dMMR. Methods: BATTMAN (NCT07152821) is an international multi-centre, open-label randomized phase 3 trial that will be conducted in Canada (CCTG), Australia/New Zealand (AGITG) and France (Unicancer). Eligible patients will be ≥18 years old, have received and progressed on or been intolerant of all available therapies, have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1, have RECIST 1.1 measurable/evaluable disease, have a life expectancy of ≥12 weeks, and have adequate end organ function without concurrent illness contraindicating ICI. Exclusion criteria include: prior organ transplant or primary immunodeficiency, ongoing use of non-physiologic corticosteroid dosing, autoimmune disorders requiring ongoing management, and prior ICI exposure. The trial’s statistical plan will ascertain efficacy of BOT and BAL in all comers, as well as key subgroups based on the presence or absence of liver metastases. A planned 834 patients will be randomized 1:1 to BOT (75 mg IV every 6 weeks up to 4 doses) + BAL (450 mg IV every 3 weeks until progression) + BSC or BSC alone, with stratification for region of recruitment, ECOG PS, and presence of liver metastases. The primary endpoint is OS, with secondary endpoints including progression-free survival, ORR, clinical benefit rate, quality of life, safety, and toxicity, with correlative studies and economic evaluations planned. Support for this study is provided by: The Canadian Cancer Society and Agenus Inc. Clinical trial information: NCT07152821 .