Browse Articles

Comparative pharmacovigilance analysis of adverse events associated with zanidatamab versus trastuzumab using the FDA Adverse Event Reporting System.

e23383 Background: Zanidatamab, a bispecific antiHER2 antibody, has demonstrated promising activity in HER2 expressing malignancies including breast cancer, but its postmarketing safety profile relative to trastuzumab is not well defined. Spontaneous reporting systems such as the FDA Adverse Event Reporting System (FAERS) enable hypothesis generating comparisons of adverse event (AE) disproportionality between agents targeting the same pathway. Methods: We conducted a retrospective disproportionality analysis of FAERS reports listing zanidatamab or trastuzumab as suspect drugs. We identified 182 zanidatamab reports (2022–2026) and 80,579 trastuzumab reports (1998–2026). Adverse events were grouped using MedDRA and for predefined AEs of clinical and mechanistic interest, 2×2 contingency tables were constructed, reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated, and two-sided Fisher’s exact tests assessed statistical significance. Results: Compared with trastuzumab, zanidatamab showed higher disproportional reporting of gastrointestinal, renal, and cardiovascular events, with strong enrichment for diarrhea (ROR 4.16, 95% CI 3.01–5.74; p < 0.001) and infusion-related reactions (ROR 9.85, 95% CI 6.23–15.59; p < 0.001). Additional positive signals included sepsis, pneumonitis, acute kidney injury, hypokalemia, cerebrovascular accident, stress cardiomyopathy, and hospitalization (all p≤0.006). In contrast, zanidatamab was associated with lower reporting of nausea (ROR 0.41, 95% CI 0.18–0.93; p = 0.024), death (ROR 0.32, 95% CI 0.12–0.86; p = 0.015), and neutropenia (ROR 0.17, 95% CI 0.02–1.18; p = 0.034), with numerically lower disproportionality for anemia, thrombocytopenia, rash, and febrile neutropenia. Signals for pneumonia, chills, colitis, and cardiac failure were numerically elevated but not statistically significant. Conclusions: In our study, zanidatamab demonstrated a distinct AE profile compared with trastuzumab, with higher reporting of diarrhea, infusion related reactions, sepsis, pneumonitis, acute kidney injury, and select cardiovascular and cerebrovascular events, alongside lower disproportional reporting of nausea, death, and some hematologic toxicities. This analysis is subject to the inherent limitations of spontaneous reporting, unknown exposure denominators and the relatively small number of zanidatamab reports reflecting its recent regulatory approval and shorter duration of real-world exposure. Prospective pharmacovigilance studies are needed to validate these signals and refine zanidatamab’s risk-benefit profile.

Liposomal irinotecan combined with 5-FU/LV and bevacizumab as second-line therapy for metastatic colorectal cancer: A multicenter, single-arm phase II study (IRIS).

e15569 Background: For patients with metastatic colorectal cancer (mCRC) who progress after first-line oxaliplatin-based therapy, irinotecan-based regimens represent a standard second-line option. Liposomal irinotecan, designed to exploit the enhanced permeability and retention (EPR) effect, may improve tumor targeting while reducing systemic toxicity. This study evaluated the efficacy and safety of liposomal irinotecan combined with 5-FU/LV and bevacizumab as second-line treatment for mCRC. Methods: This was a multicenter, single-arm phase II study conducted across multiple institutions in China. Eligible patients were aged 18-75 years with histologically confirmed unresectable mCRC, progressive disease after first-line oxaliplatin-based therapy. Patients received liposomal irinotecan (70 mg/m²) + 5-FU (2400 mg/m²) + LV (400 mg/m²) + bevacizumab (5 mg/kg) on Day 1, every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between December 2023 and September 2025, 172 patients were enrolled and included in the full analysis set. At data cutoff, 60 patients remained on treatment and 112 had completed treatment. Median age was 60 years (range: 18-75), 57.6% were male, and 39.0% had rectal primary tumors. Among 111 efficacy-evaluable patients, the ORR was 18.0% (95% CI: 11.4–26.4%) and the DCR was 82.9% (95% CI: 74.6–89.4%). After a median follow-up of 4.7 months (range: 0.03-19.0), the median PFS was 7.8 months (95% CI: 5.54-9.96), and median OS was not reached. Subgroup analyses revealed longer PFS in patients with baseline CEA < 5 ng/L (9.3 vs. 6.5 months, p = 0.037) and in those who had not received bevacizumab in the first-line setting (9.6 vs. 6.1 months, p = 0.015). Treatment-related adverse events (TRAEs) occurred in 90.1% of patients, with grade ≥3 TRAEs in 43.6%. The most common grade ≥3 TRAEs were neutropenia (21.5%), leukopenia (13.4%), and diarrhea (8.7%). Serious adverse events (SAEs) occurred in 6.4% of patients, with no new safety signals identified. Conclusions: Liposomal irinotecan combined with 5-FU/LV and bevacizumab showed promising antitumor activity and a manageable safety profile as second-line therapy for mCRC. These results support this regimen as a valuable therapeutic option for patients progressing after oxaliplatin-based first-line treatment. Clinical trial information: NCT06184698 .

Biocatalytic Access to Natural Mosquito Repellent <i>p</i> ‐Menthane‐3,8‐diol via Direct Asymmetric Prins Cyclohydration

ABSTRACT Vector‐borne diseases pose a rising global health challenge, necessitating the development of safe and effective pest protection agents. Here, we report a highly selective biocatalytic direct Prins cyclohydration for the synthesis of (1 R )‐ cis ‐ p ‐menthane‐3,8‐diol (PMD), a natural insect repellent with high efficacy. By strategically engineering squalene‐hopene cyclases (SHCs), we achieved &gt;96% diastereomeric excess, surpassing previous synthetic methods. Structural and mechanistic analyses suggest direct Prins cyclohydration and a precisely positioned water molecule within the enzyme's active pocket adjacent to the final carbocation that drives hydration and catalytic efficiency. Fine‐tuning the biocatalytic setup enabled preparative scale production, without losing much product selectivity. Moreover, we demonstrate access to the other naturally occurring PMD isomers from ( R )‐ and ( S )‐citronellal, as well as a one‐pot cascade starting from E / Z ‐citral. This study paves the way for highly selective access to stereodefined terpene‐derived repellents and establishes engineered squalene‐hopene cyclases as a tool for direct asymmetric Prins cyclohydration.

Zn-MOF Derived Zn-N-C as anode material for lithium/sodium ion batteries: Experiments and density functional theory calculations

A phase 2 clinical study of nimotuzumab plus S-1 and concurrent radiotherapy in 75 years and older patients with esophageal squamous cell carcinoma.

4027 Background: Concurrent chemoradiotherapy is the standard treatment method for inoperable and locally advanced esophageal cancer. Nevertheless, due to decreased physical function and the presence of multiple complications, older patients often have reduced tolerance to radiotherapy and chemotherapy. Methods: We conducted this prospective, single-center, phase II study to evaluate the efficacy and safety of nimotuzumab (an epidermal growth factor receptor antibody) plus concurrent radiotherapy and S-1 in 75 years and older patients with stage II-IVB esophageal squamous cell carcinoma (ESCC). The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, nutritional indicators, and quality of life (QOL). Most nutritional indicators remained stable after treatment. Results: As of June 2024, a total of 56 patients were enrolled in this study. The median follow-up was 24.1 months (95% CI: 8.8, 34.1). 11 patients had complete response, 39 patients had partial response, 5 patients had stable disease, and 1 patient had progressive disease. The ORR was 89.2%, and the DCR was 98.1%. The 1- and 3-year PFS rates were 67.8% (95% CI: 55.5%, 80.1%) and 35.8% (95% CI: 17.6%, 54.0%), with the median PFS was 25.3 months (95% CI: 16.5, 34.1). The 1- and 3-year OS rates were 79.6% (95% CI: 68.8%, 90.4%) and 40.1% (95% CI: 21.1%, 59.1%), with the median OS was 28.2 months (95% CI: 24.1, 32.3). Most adverse events were grade 1-2 (85.7%). Among survivors, 45.5% patients reported high satisfaction with their QOL, and 84.8% patients did not experience weight loss. Conclusions: Our treatment combination of nimotuzumab plus S-1 and concurrent radiotherapy indicated favorable efficacy and safety profile. This might be an underlying treatment choice for older patients with ESCC. Clinical trial information: NCT06048913 .

Cardiac safety of aldoxorubicin compared to doxorubicin: Integrated results from two randomized studies in advanced soft tissue sarcoma.

11565 Background: Doxorubicin clinical benefit is limited by cumulative, irreversible cardiotoxicity that restricts dosing. Aldoxorubicin is an albumin-binding prodrug of doxorubicin designed to enhance tumor delivery while reducing systemic exposure to cardiotoxic metabolites such as doxorubicinol. Prior reports suggest improved cardiac tolerability of aldoxorubicin, but no integrated analysis across randomized studies has been presented. Methods: Cardiac safety data were analyzed from two randomized studies, INNO-206-STS-P2-01 (NCT01514188) and ALDOXORUBICIN-P3-STS-01 (NCT02049905), comparing aldoxorubicin with doxorubicin in advanced soft tissue sarcoma. Left ventricular ejection fraction (LVEF) was assessed at baseline and prespecified intervals during and after treatment. Outcomes included mean and change-from-baseline LVEF, proportion of patients with LVEF &lt;45%, treatment-emergent heart-failure and cardiovascular adverse events (AEs), and composite endpoints integrating LVEF decline and cardiac AEs. Cumulative doxorubicin-equivalent dose was calculated using a 0.74 conversion factor. Results: Across both studies (N≈383), baseline demographics and cardiac risk factors were balanced. Aldoxorubicin was administered at approximately 3.5-fold higher doxorubicin-equivalent cumulative doses than doxorubicin. Despite higher exposure, aldoxorubicin was associated with smaller mean LVEF declines (pooled lowest on-treatment change −3.17% vs −5.77%; nominal p&lt;0.05). Approximately three-fold more doxorubicin-treated patients reached LVEF &lt;45% (1.1% vs 3.8%). Composite endpoints favored aldoxorubicin, including HF-AE plus LVEF &lt;45% (0.7% vs 3.4%), HF-AE plus ≥10-point decline (2.0% vs 4.6%), prespecified cardiovascular AE plus LVEF &lt;45% (0.3% vs 1.1%), and prespecified cardiovascular AE plus ≥10-point decline (1.4% vs 4.6%). Treatment-emergent prespecified heart-failure events occurred less frequently with aldoxorubicin (3.0% vs 6.9%). LVEF–exposure plots showed higher LVEF with aldoxorubicin despite substantially higher cumulative exposure. In Phase 1 aldoxorubicin pharmacokinetic data, the doxorubicinol-to-doxorubicin exposure ratio was ~5–6%, compared with ~40–60% reported for conventional doxorubicin, consistent with lower systemic doxorubicinol burden and supporting the observed cardiac safety findings. Conclusions: Across two randomized studies, aldoxorubicin demonstrated a consistently more favorable cardiac safety profile than doxorubicin despite higher cumulative exposure, with smaller LVEF declines and fewer heart-failure–related events. These findings support aldoxorubicin as a potentially safer anthracycline option for patients requiring sustained exposure.

NRG-HN015: A phase II randomized trial of neoadjuvant chemotherapy or chemo-immunotherapy in patients with recurrent/persistent PD-L1–positive squamous cell carcinoma of the head and neck undergoing salvage surgery.

TPS6128 Background: Treatment for locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN) remains a challenge. 30-40% of patients treated with definitive-intent therapy will recur, the majority locoregionally (Ang 2010, Galloway 2016, Tan 2010). Despite improvements in the effectiveness of palliative systemic therapy over the last decade (Vermorken 2008), salvage surgery (SS) remains the modality of choice to achieve cure in patients with locally recurrent disease particularly in patients who have previously received radiation. Thus, there is a pressing need to improve the therapeutic ratio by increasing the benefit of SS and improving oncologic outcomes. One promising means would be early introduction of systemic therapy with or without immune checkpoint inhibition for patients who are candidates for SS. NRG-HN015 proposes to investigate the effect on event-free survival (EFS) of pre-operative chemotherapy or chemo-immunotherapy in comparison to the standard SS approach. Methods: NRG-HN015 (NEOPOLIS) is a randomized, multicenter, controlled, 3-arm, superiority phase II study of neoadjuvant chemotherapy or chemo-immunotherapy in patients with recurrent/persistent PD-L1 enriched SCCHN who have planned SS. The primary objective is to compare investigator-assessed EFS of patients treated with neoadjuvant chemotherapy or chemo-immunotherapy prior to SS versus SS alone. The primary hypothesis is that neoadjuvant chemotherapy or chemo-immunotherapy added to SS will improve EFS. Enrolled patients will be randomized 1:1:1 to receive SS (Arm 1 - control), chemotherapy + SS (Arm 2), or chemo-immunotherapy + SS (Arm 3). Prior to randomization, patients will be stratified by primary tumor site (Oropharynx or oral cavity vs. larynx or hypopharynx, stage (rT4a or rN3a vs. other), and prior use of iPD1/PDL1 inhibitors in the definitive setting. Patients must have locally recurrent or persistent SCCHN arising within the oral cavity, oropharynx, larynx, or hypopharynx and are deemed candidates for salvage surgery. P16-positive oropharynx patients with T2, T3, T4, N0, N1, N2 and all other patients with T2, T3, T4a, N0, N1, N2a, N2b, N2c, N3a are eligible. Patients must have PDL1-positive and measurable disease, with no major vascular involvement (&gt;180° involvement of the common carotid or internal carotid artery), jugular foramen involvement, or prevertebral, paraspinous muscle involvement precluding a curative resection. Patients who are candidates for salvage laryngectomy to treat recurrent laryngeal cancer and who are having SS for curative intent are eligible. The trial is opened to enrollment. Clinical trial information: NCT071953734 .

MATCHES-NOVEL: A randomized controlled trial in progress of hospital-at-home (HaH) versus inpatient hospitalization for post tarlatamab monitoring.

TPS1683 Background: Tarlatamab is a bispecific T-cell engager (BiTE) therapy approved for the treatment of extensive-stage small cell lung cancer (ES-SCLC) and is the first BiTE therapy approved for a solid tumor. Due to the risk of cytokine release syndrome, patients are routinely hospitalized for ≥24 hours following each of the first two doses. These hospitalizations can pose substantial logistical, financial, and psychosocial challenges, particularly for patients in rural communities or with caregiver or employment constraints. HaH is an emerging care delivery model that provides hospital-level care in patients’ homes and has been associated with reduced readmission rates, improved patient experience, and lower cost in other populations. Whether HaH can safely and efficiently replace inpatient hospitalization for post-tarlatamab monitoring is unknown. The MAking Telehealth Delivery of Cancer Care at Home Effective and Safe (MATCHES)-Novel trial evaluates a HaH model compared with standard inpatient hospitalization following tarlatamab administration. Methods: MATCHES-Novel is an active, single-center, prospective randomized controlled trial comparing HaH with standard inpatient hospitalization for post-administration monitoring of tarlatamab in patients with ES-SCLC. Eligible patients have an ECOG performance status of 0-2, are initiating tarlatamab for an FDA-approved indication, reside within a 60-minute response catchment area, and have an available in-home caregiver. Participants are randomized 1:1 to HaH or standard inpatient monitoring following drug administration, with monitoring duration and discharge criteria aligned with institutional standards. The HaH intervention includes scheduled in-home community paramedic assessments on the day of and the day after infusion, home phlebotomy, telehealth physician oversight, patient and caregiver education, and 24/7 care escalation pathways. The primary objective is to compare efficiency, measured by the number of inpatient hospital days during the two 7-day periods after each infusion. Assuming a mean number of 4 inpatient hospital days in the control arm, enrollment of 70 patients provides ≥80% power to detect a statistically significant difference if the mean inpatient days per patient in the HaH arm is ≤2.8. Secondary objectives include safety outcomes (transfers from home to inpatient care, clinician adjudicated toxicity events) and patient, caregiver and physician reported experiences and preferences, assessed through prespecified surveys and interviews. These findings may inform future care-delivery models for administering innovative cancer therapies outside the inpatient setting, potentially improving access. The trial opened to accrual in April 2025, and 16 of the planned 70 patients have been enrolled. Clinical trial information: NCI-2025-03406 .

Role of CAR-T cell therapy in prostate cancer: A systematic review and meta-analysis.

e17075 Background: Chimeric antigen receptor (CAR) T-cell therapies targeting prostate-associated antigens, such as prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), and six-transmembrane epithelial antigen of the prostate 1 (STEAP1), have demonstrated preliminary antitumor activity in heavily pretreated prostate cancer patients. However, their overall safety and efficacy in prostate cancer remain uncertain. We conducted a systematic review and meta-analysis to evaluate clinical outcomes of CAR-T cell therapy in this setting. Methods: Following PRISMA guidelines, we searched PubMed, Cochrane Library, and Embase from inception to November 21, 2025, using MeSH terms and keywords including “CAR-T,” “chimeric antigen receptor,” and “prostate cancer.” Eligible studies were prospective early-phase open-label, dose-escalation clinical trials reporting safety or efficacy outcomes. Pooled estimates for cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), objective response rate (ORR), and PSA50 response (≥50% PSA decline) were generated using random-effects models with restricted maximum likelihood estimation. Freeman–Tukey transformation and Knapp–Hartung adjustment were applied as appropriate. Heterogeneity was assessed via I² and τ² statistics. Analyses were performed in R version 4.5.2. Results: Seven studies encompassing 69 patients were included. All patients had metastatic castration-resistant prostate cancer (mCRPC) and were heavily pretreated (median prior lines 2–8), with frequent exposure to androgen deprivation therapy, androgen receptor signaling inhibitors, and taxane-based chemotherapy (docetaxel exposure 46%-86% where reported). Median age ranged from 61 to 70 years when reported; baseline performance status (ECOG 0-1) was documented in only one study. Efficacy outcomes (from subset reporting) showed a pooled ORR of 39.0% (95% CI, 24.2%- 54.7%, I 2 = 0.0%) and a PSA50 response rate of 47.8% (95% CI, 15.0%-81.6%, I 2 = 33.9%). The pooled CRS rate was 45.0% (95% CI, 10.9%-81.5%, I 2 = 82.1) for any grade and 9.2% (95% CI, 0.1%-25.4%, I 2 = 42.3%) for grade ≥3. ICANS occurred in 13.2% (95% CI, 4.8%-23.8%, I 2 = 0.0%) for any grade and 4.4% (95% CI, 0.0%-16.8%, I 2 = 9.2%) for grade ≥3. Conclusions: CAR-T cell therapy demonstrates early antitumor activity in mCRPC, with meaningful biochemical (PSA50) responses and a manageable safety profile across various targets and CAR constructs. CRS and ICANS rates are notable but predominantly low-grade. Larger phase II/III trials are essential to confirm efficacy, optimize antigen selection, mitigate toxicities, and evaluate combination strategies to enhance durability in this refractory population.

Oral cavity and oropharyngeal cancer incidence: 5-year survival vs. air pollution levels across New York State.

e18111 Background: Smoking prevalence in the US has decreased but incidence of oral cavity and oropharyngeal cancers (OCC/OP) is increasing, particularly in never-smokers. Patterns of new diagnoses have been shown to vary geographically, but the relationship with air pollution has been inconsistent across studies. We examined the dispersion of OCC/OP cases in New York State (NYS) and created models to quantify associations between county-level ozone and PM2.5 with incident and 5-year survival rates of these diseases. Methods: Incidence and 5-year survival data were from NYS Cancer Registry; air pollution levels were from the CDC and SES characteristics were from the American Community Survey. Getis-Ord Gi was calculated to assess for hot/cold spots in incidence and 5-year survival. County levels of PM 2.5 and ozone were compared to county-level OCC/OP incidence and 5-year survival rates while controlling for SES county characteristics and percentage of adult smokers using negative binomial and fractional logit models respectively. Spatial autocorrelation was assessed with Moran’s I and when present, spatial lag models were used to test for spatial autocorrelation interference. PM 2.5 and ozone were tested individually. Results: A seven-county hot spot of OCC/OP incidence in western NYS was identified; with a corresponding cold spot comprised of New York City and two neighboring counties (p&lt;.05). In upstate NYS, a two-county cold spot of 5-year survival rates was located (p&lt;.05). Counties with higher levels of ozone had statistically significantly higher incidence of OCC/OP (IRR= 1.04; 95% confidence interval, 1.01 -1.07). Moran’s I showed no evidence of spatial autocorrelation in this model. PM2.5 was not statistically significantly correlated with OCC/OP incidence (IRR=.99; 95% confidence interval, .93 - 1.06). Negative binomial results are reported because while Moran’s I detected spatial autocorrelation, the spatial lag model showed no evidence of interference from this. Neither pollutant was statistically significantly associated with OCC/OP 5-year survival; however higher levels of PM 2.5 non-statistically significantly trended toward lower 5-year survival rates (.89; 95% confidence interval, .27 - 3.01). Conclusions: OCC/OP incidence and 5-year survival rates exhibited spatial clustering in NYS and incident rates were higher in counties with higher ozone levels. Neither of the pollutants was statistically significant with 5-year survival but higher levels of PM 2.5 trended toward lower 5-year survival rates. Results from this hypothesis generating analysis suggest that ozone might play a role in the development of oral and oropharyngeal cancers. Incidence Model Coefficient 95% Confidence Interval P-Value PM 2.5 .99 .93 to 1.06 .81 Ozone 1.04 1.01 to 1.07 &lt;.01 5-Year Survival PM 2.5 .89 .27 to 3.01 .84 Ozone 1.02 .54 to 1.92 .95

Impact of clinical and treatment characteristics on fear of cancer recurrence and quality of life in survivors of early-stage breast cancer.

e12684 Background: Fear of cancer recurrence (FCR) is one of the most frequent concerns among breast cancer survivors and can significantly affect health-related quality of life (HRQoL). However, it remains insufficiently explored in routine clinical practice. Objective: To describe the prevalence of FCR and HRQoL in patients with early breast cancer and to analyze their association with clinical and sociodemographic characteristics. Methods: An ambispective observational study was conducted in two public centers. A total of 301 women with stage I–III breast cancer, disease-free and at least 12 months post-treatment, were included. FCR was assessed using the Cancer Worry Scale, and HRQoL using the PROMIS Global-10 instrument. Results: High FCR was observed in 34.9% of participants, and moderate FCR in 20.9%. FCR was significantly associated with ≤5 years since diagnosis, age &lt;50 years, education level, chemotherapy, and endocrine therapy. No associations were found with tumor stage, breast surgery type, axillary surgery, or radiotherapy. Nearly half of the patients had not discussed FCR with their medical team, mainly because they did not consider it a serious issue or were unaware that it could be addressed during consultations. PROMIS scores showed median values of 37.4 for physical health and 43.5 for mental health. HRQoL did not vary according to clinical characteristics or treatments but was associated with age and education. Patients with higher FCR consistently showed poorer HRQoL across all domains (p &lt; 0.001). Conclusions: FCR is highly prevalent and strongly associated with poorer HRQoL, independently of clinical variables. Its identification and management should be systematically integrated into survivorship care for women with breast cancer.

Where climate hits hardest: Geographic patterns in climate education across 266 U.S. oncology fellowship programs.

e23155 Background: Climate change disproportionately affects cancer patients through care disruptions and treatment delays with 65% of US cancer patients living in climate-vulnerable counties and documenting worse survival following disasters. Oncology trainees will practice for decades in a climate-altered reality, yet it remains unknown whether US training programs are positioned to prepare fellows for climate-resilient care. We mapped fellowship programs against climate hazard and social vulnerability indices to identify where climate curricula are most urgently needed. Methods: We identified all ACGME-accredited hematology-oncology and radiation oncology programs (January 2025), linking locations to the CDC Social Vulnerability Index (SVI) and FEMA National Risk Index for heat, flooding, wildfire, and hurricane hazards. High vulnerability was defined as top-quartile scores. Double vulnerability was defined as high SVI plus high climate risk. We performed chi-square tests and Random Forest predictive modeling. Results: We identified 266 programs (188 hematology-oncology, 78 radiation oncology) across 46 states. 72 programs (27.1%) were in high-SVI states and 158 (59.4%) in high climate-risk states. 50 programs (18.8%) faced double vulnerability with marked geographic clustering (coefficient = 0.70, p &lt; 0.001), located in seven states (AZ, CA, FL, LA, NM, OK, SC) that collectively diagnose over 438,000 new cancer cases annually. Regional variation was highly significant (χ² = 120.09, p &lt; 0.0001). Predictive modeling achieved near-perfect discrimination (ROC-AUC≥0.998, Table 1). SVI correlated strongly with wildfire risk (r = 0.73, p &lt; 0.0001) but not hurricane risk (r = 0.10, p = 0.11). Conclusions: Nearly 1 in 5 US oncology programs (18.8%) face both high social vulnerability and climate hazards, serving populations where disaster exposure is associated with worse cancer survival. Despite the critical need, only 1 of 9 existing climate education initiatives is located in a hotspot region, leaving most programs without targeted curricula. We propose targeted implementation of our proposed HEAT-ONC model (Hazards, Effects, Adaptation, Teaching) with regional customization. This evidence-based approach addresses a critical training gap where vulnerability is highest. Regional analysis of double vulnerability: climate risk, social vulnerability, and predictive modeling. Region Programs (n) High SVI n (%) Climate risk n (%) Double Vulnerability n (%) Test Statistic P-value West 39 5 (12.8) 35 (89.7) 30 (76.9) Clustering coef=0.70 &lt;0.001 South 86 8 (9.3) 41 (47.7) 20 (23.3) χ²=16.44 0.0009 Northeast 78 0 (0.0) 77 (98.7) 0 (0.0) χ²=4.64 0.031 Midwest 63 0 (0.0) 5 (7.9) 0 (0.0) χ²=120.09 &lt;0.0001 Overall 266 13 (4.9) 158 (59.4) 50 (18.8) Predictive model: SVI (28.7%),Wildfire(21.3%),Region (13.2%)ROC-AUC≥0.998

Paclitaxel, carboplatin, and durvalumab in extensive stage small-cell lung cancer (ES-SCLC; IFCT-2203 TAXIO phase II trial): Can we improve the chemotherapy (CT) immunotherapy combination in SCLC?

8091 Background: Etoposide+platinum-based CT and anti-PD-L1 is the backbone of ES-SCLC treatment. We hypothesize a deleterious action of etoposide on lymphocyte activation. A “proof-of-concept”, multicenter and single arm phase II trial was designed to assess the efficacy and safety of an etoposide-free chemotherapy combining durvalumab (Durva) to paclitaxel and carboplatin (Pac-Carbo) CT in ES-SCLC. Methods: Patients (pts) with ES-SCLC, PS 0-1 were enrolled and received 4 induction cycles of Durva 1500 mg + paclitaxel 200 mg/m² + carboplatin AUC6 (PCD), every 3 weeks followed by single-agent Durva every 4 weeks until progression or unacceptable toxicity. The primary endpoint was overall survival at 12 months (OS@12m), secondary endpoints were overall response rate (ORR), overall survival (OS), OS at 24 and 36 months, progression-free survival (PFS), duration of response, safety (CTC v5.0) and quality of life (EORTC QLQ-C30 LC13). PFS and ORR were also assessed by independent reviewer committee. To reject the null hypothesis and achieve a 12-month survival rate of at least 34 patients (55.7%), 61 patients were required. Safety was assessed in all patients who received at least one dose of their study treatment. Results: 68 pts were enrolled between Nov 2023 and Feb 2025. Pts characteristics at baseline were: median age 66.6 years; 51.5% female, 67.6% PS1, 19.1% brain metastasis and 51.5% liver metastasis. The median number of cycles was 4 for chemotherapy and 6 for Durva injections. With a median follow-up of 17.1 months, the primary objective was reached. The OS@12m of the first 61 enrolled pts was 57.4% [IC95%: 44.1-70.0]. Median OS was 14.5 months [IC95%: 9.9-17.6]. ORR was 82.4% [IC95%: 73.3-91.4]. Median PFS was 4.6 months [IC95%: 4.4-4.7]. Treatment-related adverse events (TRAE) of grade 3-5 occurred in 48.5% of pts. TRAE leading to death occurred in 2 pts (sepsis). Conclusions: In the IFCT-2203 TAXIO phase 2 trial, the PCD regimen showed a signal of improved OS@12m and reached its statistical objective. Safety findings were consistent with the known safety profiles of all drugs received with no new safety signal for this population. PCD regimen is an active, easy to administer one-day regimen in ES-SCLC and should be integrated in future trials of new IO agents. Pac-Carbo is an alternative to etoposide platinum with potentially better synergy with durvalumab. Clinical trial information: 2023-504670-38-00.

Organ preservation and local excision for rectal cancer: Long-term oncologic outcomes.

3655 Background: Organ preservation is a desired outcome for rectal cancer patients after neoadjuvant chemoradiotherapy. In patients where a complete response is in question, endoscopically assisted full-thickness local excision offers a great option. Long-term data with this approach is limited. We report our experience with transanal endoscopic microsurgery (TEM) status post chemotherapy. Methods: Between January 2005 and October 2019, from a prospectively maintained rectal cancer database, we identified all patients who underwent TEM for adenocarcinoma after neoadjuvant CRT. Demographic data as well as follow-up interval and oncologic outcomes were reviewed and analyzed. Results: Ninety-two patients who underwent TEM for rectal cancer were included. The mean age was 67 years (32–94), 66% were male, and the mean BMI was 29.3 kg/m² (19.1–43). ASA classifications were II in 38%, III in 51%, and IV in 5% of patients. The mean tumor size was 3.1 cm (1–6) and mean estimated blood loss (EBL) was 29 mL (0–500). Postoperative 30-day morbidity occurred in 6.5% of patients, with no mortalities. The mean follow-up was 57.5 months (0.4-194.5), during which 7.6% of patients developed local recurrence and 6.5% developed systemic metastases. Based on final pathology, 48 patients with a complete pathologic response (ypT0) had local recurrence and distant metastasis rates of 4% and 2%, respectively. In patients with stage I disease (n=35), local recurrence occurred in 11% and distant metastasis occurred in 9%. Stage II patients (n=7) experienced a 14% rate of local recurrence with no distant metastases. Among stage III patients (n=2), both local and distant failure occurred in 50% of cases. Conclusions: TEM after neoadjuvant CRT was associated with excellent oncologic outcomes in patients achieving complete pathologic response. Selected patients with favorable residual disease experienced acceptable recurrence rates, supporting TEM as a potential organ-preserving strategy in this subgroup. In contrast, higher pathologic stage was associated with substantially increased local and distant failure, highlighting the need for strict selection, pathology-driven decision-making, and close surveillance.

Trends in cancer incidence and mortality of children, adolescents, and young adults in Hong Kong, 2003-2023: Comparison with East Asia, US, UK, and Australia.

e22614 Background: Although survival of cancers in childhood, adolescence and young adulthood (CAYA) has improved globally, incidence and mortality data remain limited in Hong Kong. This study aims to compare long-term trends of CAYA cancer in Hong Kong with East Asian and high-income Western countries to inform regional cancer burden and survivorship strategies. Methods: All cancers except non-melanoma skin cancer were analyzed among individuals aged 0–39 years. Cancer incidence and mortality in Hong Kong (2003-2023) were obtained from the population-based Hong Kong Cancer Registry. Incidences for mainland China, Japan, Korea, the US, UK and Australia were extracted from GLOBOCAN 2022 and CI5 plus (2003-2017), while mortality data were derived from the Global Burden of Disease Study (2003-2023). Age-standardized incidence rates (ASIRs, per 100,000) and mortality rates (ASMRs, per 100,000) were calculated using Segi’s world standard population. Temporal trends were assessed by average annual percentage changes (AAPCs) using Joinpoint regression. Results: In 2022, ASIR of CAYA cancer in Hong Kong (34.43) was lower than Australia (49.1), US (44.5), Korea (41.7), UK (38.2) and mainland China (34.8), but higher than Japan (31.6). Hong Kong had the lowest ASMR (4.12) among mainland China (8.38), Korea (5.16), US (5.0), Japan (4.68), UK (4.4) and Australia (4.4). From 2003 to 2023, the average annual increase of ASIRs in Hong Kong (AAPC = 0.99%, 95% CI: 0.73–1.26) was comparable to Australia (0.51%, 0.03–1.01) and US (0.57%, 0.37–0.82), but slower than UK (1.80%, 1.48–2.13), Japan (2.95%, 2.36–3.54), Korea (3.89%, 2.86–4.66) and mainland China (4.37%, 4.02–4.71). ASMRs declined in Hong Kong (AAPC = -2.08%, 95% CI: -2.51– -1.65) and Korea (-2.53%, -2.89– -2.18), showing a smaller decrease than mainland China (-3.30%, -3.58– -3.01), but larger than US (-0.86%, -1.06– -0.68), UK (-1.20%, -1.50– -0.92), Japan (-1.40%, -1.64– -1.16) and Australia (-1.67%, -1.88– -1.49). Among males in Hong Kong, leading cancer types included leukemia (ASIR = 4.75), nasopharyngeal cancer (ASIR = 3.19) and testicular cancer (ASIR = 2.57) over the past two decades. Female incidence patterns were more stable, dominated by breast cancer (ASIR = 7.56), thyroid cancer (ASIR = 5.38) and leukemia (ASIR = 3.62). Notably, nasopharyngeal cancer incidence in Hong Kong (male ASIR: 3.19; female: 1.08) was more than 10-fold higher than in other regions for both sexes, likely due to endemic EB virus exposure, genetic susceptibility, and region-specific environmental factors. Conclusions: CAYA cancer burden in Hong Kong remains comparatively low versus neighboring East Asian and Western countries, with declining mortality but rising incidence in recent years. High incidence of selected cancer highlights the need for ongoing surveillance, tarted prevention, and strengthened survivorship care.

Plasma exchange in myeloma-associated acute kidney injury: A multicenter propensity-matched cohort study.

7575 Background: Acute kidney injury (AKI) in newly diagnosed multiple myeloma (MM) is frequently driven by light chain cast nephropathy and associated with dialysis dependence and early mortality. Plasmapheresis or plasma exchange (either one referred to here as PLEX) have been used to accelerate free light chain (FLC) removal, despite inconsistent evidence of clinical benefit. Whether PLEX improves renal or survival outcomes in the modern treatment era remains uncertain. Methods: A retrospective multicenter cohort study using the TriNetX Research Network identified newly diagnosed MM pts from 2014-2024 presenting with AKI (an ICD-10 code for acute renal failure or Cr &gt; / = 3.0 mg/dL and a 6 mo prior Cr &lt; 1.5) and laboratory evidence of light chain cast nephropathy (defined as a free light chain concentration &gt; 1,500 mg/L). Pts were included if they received PLEX within 7d of diagnosis, and were compared to those who did not receive PLEX. Pts were excluded if they had pre-existing end stage renal disease. Propensity score matching included demographics, comorbidities, myeloma therapies and laboratory values (Cr, calcium, albumin, hgb). Results: Among 5,454 eligible pts, 251 (4.6%) received PLEX (81% were plasma exchange and 19% were plasmapheresis). After propensity score matching, 248 pts were included in each group with well-balanced baseline characteristics (ex: ave Cr 4.1 and 4.2 in the PLEX vs no PLEX groups, respectively; 38% received PIs in each group). PLEX was not associated with reduced dialysis dependence at 90 days (16.1% vs 18.1%; odds ratio [OR] 0.87, 95% confidence interval [CI] 0.54–1.39) or 180 days (18.5% vs 20.2%; OR 0.90, 95% CI 0.58–1.41). Mortality at 90 (17.7% vs 15%) and 180 days (23.4% vs 23.9%) and ICU admission rates (20% vs 21%) were similar between groups. Dialysis-free survival over 180 days did not differ. Findings were consistent across all prespecified sensitivity analyses, including pts receiving early PI-based therapy and those with extreme free light chain burden (FLC &gt; 5000mg/L, 28% of total cases), with no differences in dialysis dependence or survival. Patients treated with PLEX were numerically more likely to achieve creatinine &lt; 2.0 mg/dL at both 90 days (83.9% vs 77.4%; OR 1.81, 95% CI 0.97–2.38; p = 0.07) and 180 days (86.3% vs 79.8%; OR 1.59, 95% CI 0.98–2.56; p = 0.06), but these differences did not reach statistical significance, except for those with FLC &gt; 5000 (at 90d: 77% vs 63%, p = 0.02; and at 180d: 83% vs 66%, p = 0.006). Conclusions: In this large, contemporary, real-world retrospective cohort, PLEX was not associated with significantly improved renal recovery, dialysis-free survival, or mortality among patients with newly diagnosed myeloma-associated AKI due to light chain nephropathy. These results support current guidelines emphasizing rapid initiation of effective anti-myeloma therapy rather than routine extracorporeal light chain removal.

Trends in mortality related to anal carcinoma in the United States, 1999–2023: A population-based analysis using CDC WONDER.

e15500 Background: Anal carcinoma is an uncommon but increasingly recognized malignancy with established associations to human papillomavirus infection, immunosuppression, and health inequities. While incidence trends have been reported, contemporary national patterns in anal cancer–related mortality over the past two decades remain insufficiently characterized. This study evaluates long-term mortality trends and demographic disparities related to anal carcinoma in the United States from 1999 to 2023. Methods: Mortality data were obtained from the CDC WONDER Multiple Cause of Death database for decedents with anal carcinoma identified using ICD-10 code C21. Age-adjusted mortality rates (AAMRs) and crude rates (CRs) per 1000,000 population were calculated using the 2000 U.S. standard population. Temporal trends were assessed using Joinpoint regression to estimate Annual Percent Change (APC) and Average Annual Percent Change (AAPC) with 95% confidence intervals. Results: Between 1999 and 2023, 27,223 deaths were attributed to anal carcinoma, corresponding to an overall AAMR of 3.00 per 1000,000 population. Mortality rose gradually between 1999–2018 (APC = 3.14, p &lt; 0.000001) and more rapidly from 2018–2021 (APC = 10.07, p = 0.0187), followed by a slight decline between 2021–2023 (APC = −1.94, p= 0.577), resulting in an overall AAPC of 3.54 (p &lt; 0.000001). Females had higher mortality (AAMR = 3.33) compared to males (AAMR = 2.59). Across ten-year age groups, crude mortality rates increased with advancing age, with the highest rates observed in the 75–84 years (CR = 15.095) and ≥85 years (CR = 24.073) age groups. Black or African American individuals (AAMR = 3.109) and White individuals (AAMR = 3.111) had comparable mortality rates. Regional variation in AAMR was observed (Northeast: 2.77; Midwest: 2.91; South: 3.11; West: 3.14). Residents of Urban areas showed greater AAMR (2.80) than those of rural areas (2.71). Oklahoma had the highest state-level mortality rate (5.09). Conclusions: Anal carcinoma–related mortality in the United States has risen significantly over the past 25 years, with accelerated increases in recent decades and a disproportionate burden among older adults and females. These findings highlight the urgent need for strengthened HPV-related prevention strategies, timely diagnosis, equitable access to oncologic care, and targeted public health interventions to curb rising mortality from this preventable malignancy.

Burden of coronary heart disease and hepatocellular carcinoma mortality among U.S. adults: A 25-year analysis.

e16492 Background: Coronary heart disease (CHD) and hepatocellular carcinoma (HCC) are leading causes of morbidity and mortality worldwide. Metabolic dysfunction and shared risk factors link these conditions, yet temporal trends and disparities in mortality among adults with both diseases remain poorly understood. Methods: We conducted a population-based analysis using CDC WONDER Multiple Cause of Death (MCOD) data from 1999–2023 in adults aged ≥45 years with CHD (ICD-10: I20–I25) and HCC (ICD-10: C22.0) listed as underlying or contributing causes of death. Age-adjusted (AAMR) and crude mortality rates (CMR) per 100,000 were calculated. Trends were analyzed by age, sex, region, urbanization, and place of death. Annual percent changes (APCs) with 95% confidence intervals (CI) were estimated using Joinpoint regression. Results: Among 11,767 decedents, 3,746 deaths occurred in inpatient settings. Overall AAMR rose steadily from 2013-2023 (APC: +4.88*,95%CI: 4.08,5.68,p &lt; 0.05). Middle-aged adults (45-64 years) experienced a sharp early increase (1999-2007; APC: +15.55, 95% CI: -7.02 to -24.78; p &lt; 0.05), while AAMR declined in this group from 2015-2023 (APC: -5.24, 95% CI: -9.43 to -0.85; p &lt; 0.05). Females showed a significant rise from 2012-2023 (APC: +6.51, 95% CI: 4.28 to 8.79; p &lt; 0.05). Regionally, the Midwest demonstrated increasing mortality (2015-2023; APC: +6.53, 95% CI: 3.89–9.21; p &lt; 0.05). Both metropolitan (2011-2020; APC: +4.37, 95% CI: 2.65-6.12; p &lt; 0.05) and non-metropolitan areas (2016-2020; APC: +10.22, 95% CI: 1.66 to 19.50; p &lt; 0.05) experienced rising AAMRs. The highest CMR in 2023 was among adults ≥65 years (1.29; 95% CI: 1.20 to 1.39). Conclusions: Mortality from CHD and HCC continues to rise, particularly among females, older adults, and residents of the Midwest and both metropolitan and rural areas. These trends underscore the urgent need for integrated national screening programs, targeted public health interventions, and research to address underlying disparities.

Extrachromosomal DNA as a shaper of aggressive transcriptional states in multiple myeloma.

7555 Background: Extrachromosomal DNA (ecDNA) is increasingly recognized as a key driver of oncogene amplification, intratumoral heterogeneity, and poor clinical outcomes across solid tumors. However, its significance in multiple myeloma remains largely unexplored. Multiple myeloma is characterized by marked genomic instability including hyperdiploidy or IgH translocations, and widespread structural rearrangements that underlie biological heterogeneity and therapy resistance. Defining whether ecDNA contributes an additional layer of genomic complexity in this disease therefore represents an important unmet need. Methods: Whole-genome sequencing (WGS) BAM files of primary myeloma cells from the Multiple Myeloma Research Foundation (MMRF) CoMMpass study were analyzed using the AmpliconSuite pipeline to identify circularized DNA amplicons indicative of ecDNA. Matched transcriptome (RNA-seq) data and clinical metadata from the same cohort were integrated to evaluate the prognostic impact of gene expression associated with ecDNA-harboring loci. Gene Set Enrichment Analysis (GSEA) was performed using the clusterProfiler R package to assess pathway-level biological signatures linked to ecDNA-positive tumors. Results: We identified ecDNA in 28 of 904 patients (3.1%) from the MMRF CoMMpass dataset. Despite the low prevalence, ecDNA-positive myeloma patients exhibited significantly inferior survival compared with patients without ecDNA. Frequently amplified ecDNA loci contained oncogenes such as MYC, TNFRSF17 (BCMA), and SNX29, as well as pro-tumoral lncRNAs including CASC11 and PVT1. GSEA revealed strong enrichment of MYC and E2F targets, oxidative phosphorylation, and PI3K–AKT–mTOR and mTORC1 signaling in ecDNA-positive tumors, highlighting transcriptional addiction and metabolic activation. These pathways align with known mechanisms of proliferation, metabolic rewiring, and treatment resistance in multiple myeloma. Conclusions: ecDNA-positive myeloma represents a biologically aggressive subset characterized by oncogene-enriched circular amplicons and hyperactivated proliferative and metabolic programs. Myeloma patients with ecDNA showed significantly worse survival, supporting ecDNA as a previously underrecognized high-risk feature. These findings highlight ecDNA as potential therapeutic vulnerabilities in myeloma and warrants further investigation.

Final results of a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin, and pazopanib: 2ND-STEP study, JCOG1802.

11508 Background: The optimal second-line treatment for advanced soft tissue sarcomas (STS) after doxorubicin therapy remains unclear. This trial aimed to identify the most promising agent among trabectedin, eribulin, and pazopanib for subsequent phase III comparison against gemcitabine plus docetaxel (GD), which has traditionally been considered a standard treatment. We previously reported the results of the primary analysis at 6 months after accrual completion. Here, we present the final analysis results with an additional year of follow-up. Methods: This multicenter, randomized, phase II selection design trial enrolled patients with unresectable or metastatic STS who were refractory to doxorubicin-based chemotherapy. Participants were randomized to receive trabectedin, eribulin, or pazopanib. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), disease control rate (DCR), objective response rate (ORR), and safety. Results: From December 2019 to March 2023, 120 patients with advanced STS were enrolled (31 leiomyosarcomas, 26 liposarcomas, 18 translocation-related sarcomas, and 45 other types). The median PFS was 2.9 months (95% CI, 1.3-5.3) for trabectedin, 2.2 months (1.5-3.8) for eribulin, and 3.8 months (2.3-5.2) for pazopanib. The hazard ratios for eribulin and pazopanib compared to trabectedin were 1.22 (0.77-1.94) and 0.99 (0.63-1.56), respectively. When examining the PFS curves for each treatment arm, the three arms appeared to exhibit nearly identical curves; however, the PFS hazard ratio indicated that pazopanib showed the best result. The median OS was 14.7 months (10.8-18.5) for trabectedin, 13.3 months (7.6-20.1) for eribulin, and 15.7 months (9.7-18.0) for pazopanib. The DCR was 50.0% (32.4-67.6) for trabectedin, 37.1% (21.5-55.1) for eribulin, and 64.9% (47.5-79.8) for pazopanib. The ORR was 17.6% (6.8-34.5) for trabectedin, 5.7% (0.7-19.1) for eribulin, and 8.1% (1.7-21.9) for pazopanib. A histological subtype–specific subgroup analysis, demonstrated that the PFS/OS for each arm in liposarcoma were as follows: trabectedin, 3.1 months (95% CI, 1.1–7.2) / 12.9 months (3.7–36.5); eribulin, 3.8 months (1.1–6.8) / 13.3 months (4.3–20.1); and pazopanib, 5.2 months (2.0–10.2) / 18.0 months (4.1–NE). No previously unrecognized adverse events related to the investigational drugs were observed, and no treatment-related deaths occurred. Conclusions: Consistent with the primary analysis, pazopanib generally showed favorable PFS, OS, and DCR among the three agents. Based on these results, pazopanib was identified as the most appropriate candidate to be compared with GD in a phase III trial, which is currently being planned. Clinical trial information: jRCTs031190152.