Browse Articles

Concordance of liquid biopsy and tissue CGP for identification of guideline-recommended actionable variants.

e15061 Background: Comprehensive genomic profiling (CGP) is essential for managing patients (pts) with advanced solid tumors. Liquid biopsy (LBx) and tissue CGP are known to provide complementary information; however, concordance may be influenced by factors such as test intervals, tumor shedding and heterogeneity, and differences in genomic regions covered by each assay. We evaluated two assays performed within short intervals to determine concordance, LBx or tissue only detection, and factors impacting detection. Methods: Actionable, NCCN-guideline variants were assessed in 99 advanced cancer pts tested by similar CGP platforms, PanTracer LBx and PanTracer Tissue, within a 90-day interval. Results: Among the 99 pts, 68% had lung, 19% colorectal, and 13% breast cancer; 58% were females. LBx and tissue testing was performed within 30 days in 66 pts (median 9 days; range 0–28) and 32–90 days in the remaining 33 pts (median 47 days). Median result turnaround time (TAT) was 8 days for LBx (range 5–46) and 28 days for tissue (range 10–125). Guideline-recommended actionable alterations (N = 48) were identified in 41 pts (42%) with detection rates of 36% in lung (24/67) and 54% in colorectal (10/19) and breast cancer (7/13). Of these, 54% (26/48) were detected by both assays in 23/41pts (56%). Concordance rate varied by tumor type: 50% for lung (12/24), 60% for colorectal (6/10) and 71.5% for breast cancer (5/7). Three variants (6%) were detected only by LBx; two ESR1 variants in a breast cancer pt (with a third concordant ESR1 variant) and an ALK fusion in a lung cancer pt with no further variants. The remaining 19 variants (40%) were detected only in tissue in 17 pts (41.5%), none of whom had concordant or LBx-only variants. Importantly, median ctDNA-estimated tumor fraction (TF) was higher in pts with concordant (7.85%; range 0.11–67%) and LBx-only variants (9.41%; range 0.31–18.5%) compared to tissue-only variants (0.21%; range 0.07–0.86%). Median LBx-tissue testing interval in pts with concordant or tissue-only variants was 21 days. Conclusions: LBx identified 60% of actionable variants (29/48; concordant and LBx-only) in 24/41 pts (59%) underscoring its clinical value for faster, urgent treatment decisions due to improved TAT. Tissue testing in low-shedding tumors can mitigate LBx false negatives and expand access to targeted therapies. Analyses evaluating LBx detection and other actionable/informative alterations (e.g. resistance mechanisms, clinical trial access) will be presented.

Inpatient chemotherapy in small cell lung cancer as a high-risk care-delivery phenotype: National Inpatient Sample analysis.

e23193 Background: Small cell lung cancer (SCLC) is typically treated with outpatient systemic therapy; inpatient chemotherapy during acute hospitalization represents a high-risk care-delivery phenotype driven by delayed diagnosis, access barriers, or acute clinical decompensation rather than tumor biology alone. National data describing this care pathway and its inpatient outcomes remain limited. Methods: The U.S. National Inpatient Sample (2016–2023) was analyzed using survey weights. Adult hospitalizations meeting an ICD-10–based proxy definition for small cell lung cancer, defined by lung cancer diagnoses combined with neuroendocrine malignancy codes and excluding palliative care admissions, were identified. Inpatient chemotherapy was defined using ICD-10-PCS administration codes with prespecified sensitivity definitions. Outcomes included in-hospital mortality (primary), ICU-level care, sepsis, acute kidney injury, length of stay, hospitalization costs, and routine discharge. Multivariable survey-weighted logistic regression adjusted for patient demographics, payer, admission characteristics, and hospital factors. Results: The analytic cohort included 2,507 unweighted hospitalizations, representing 12,535 nationally weighted admissions. In multivariable analyses adjusting for demographics, payer, admission characteristics, and hospital factors, inpatient chemotherapy was independently associated with higher in-hospital mortality (adjusted odds ratio [aOR] 2.31, 95% CI 1.48–3.60) and greater ICU-level care (aOR 2.80, 95% CI 1.86–4.23). These associations were consistent across prespecified sensitivity analyses. In unadjusted analyses, inpatient chemotherapy occurred in 12.3%–19.3% of admissions annually from 2016–2023 and was associated with higher mortality (8.7% vs 5.2%), greater ICU-level care (11.8% vs 4.9%), longer length of stay (11.6 vs 7.0 days), higher costs ($38,446 vs $23,746), and lower routine discharge rates (42.8% vs 48.4%). Among 400 admissions with procedure-day data, chemotherapy was administered a mean of 3–5 days after admission. Late inpatient chemotherapy (day ≥2) was associated with higher mortality (10.6% vs 5.6%), greater ICU-level care (14.8% vs 9.2%), longer hospitalization (14.1 vs 8.0 days), and higher costs ($46,203 vs $28,025) compared with early chemotherapy (day 0–1), supporting inpatient chemotherapy as a marker of late care escalation rather than planned inpatient treatment. Conclusions: Inpatient chemotherapy identifies a high-risk care-delivery phenotype in hospitalized small cell lung cancer, with higher mortality, greater ICU-level care, and increased resource use, supporting its role as a marker of late care escalation or system-level barriers and a scalable quality indicator.

The effect of glucagon-like peptide-1 (GLP-1) receptor agonists on outcomes in metastatic non-small cell lung cancer (mNSCLC) patients treated with tyrosine kinase inhibitors (TKIs): Real-world retrospective analysis.

8636 Background: The therapeutic landscape of mNSCLC has rapidly evolved, with multiple oncogenic alterations now targetable by approved TKIs used in first-line settings, leading to substantial survival gains. However, several TKIs are associated with metabolic toxicities, including weight gain and hyperlipidemia, particularly with ALK inhibitors (e.g., lorlatinib) and selective RET inhibitors. As use of GLP-1 has increased among patients with cancer, their impact on outcomes in oncogene-driven mNSCLC treated with TKIs remains unknown. We evaluated the association between GLP-1 use and survival outcomes in TKI-treated mNSCLC using real-world data. Methods: We conducted a retrospective analysis using TriNetX, a Global Collaborative electronic health record with > 190 million patients and > 170 healthcare organizations, from 2010-2025. Adults (≥18 years) with mNSCLC, metabolic comorbidities (T2DM, obesity, or hyperlipidemia), and treatment with first line-approved TKIs (EGFR, ALK, ROS1, RET, NTRK, BRAF, MET) were included. Patients were stratified by concomitant GLP-1 use and matched 1:1 using propensity scores based on demographics, ECOG performance status, cardiometabolic comorbidities, tobacco and alcohol use, and outpatient healthcare utilization. 5 year overall survival (OS) was assessed. Results: A total of 25,008 patients met inclusion criteria, including 24,459 (97.8%) non-GLP1 users and 549 (2.2%) in GLP-1 users. After 1:1 propensity score matching (PSM), 546 patients were included per group. Amongst both cohorts average age was 64, 61% were female, 60% were White, 13% were Asian. In the overall mNSCLC TKI-treated patients, GLP-1 use was associated with significantly improved 5-year OS compared with non-use (63% vs 40%; HR 0.45, 95% CI 0.36-0.57; p < 0.001). In subgroup analyses, patients treated with ALK TKIs (lorlatinib or alectinib; n = 128/group) demonstrated improved 5 year OS with GLP-1 use 85% vs 48% in non-users (HR, 0.18; 95% CI, 0.09 - 0.36; p < 0.0001). Furthermore, GLP-1 use was also associated with improved 5-year OS among EGFR TKI-treated patients (54% vs 44%; HR 0.60, 95% CI 0.44-0.82; p = 0.001) and BRAF TKI-treated patients (41% vs 35%; HR 0.52, 95% CI 0.30-0.91; p = 0.02). Other TKI groups comprised relatively small numbers of patients and therefore were not analyzed separately. Conclusions: In this large real-world analysis, GLP-1 use was associated with significantly improved survival in patients with oncogene-driven mNSCLC treated with TKIs, with consistent benefit across ALK, EGFR, and BRAF-driven mNSCLC. To our knowledge, this is the first study to link the impact of the GLP-1 agonists on the outcomes of TKI treated mNSCLC. Further prospective studies are needed to validate these findings and to identify underlying mechanisms.

Zongertinib combination therapy in HER2-positive metastatic breast cancer (mBC): First results from a phase Ib/II trial.

1044 Background: Zongertinib, an irreversible TKI, selectively inhibits HER2 while sparing wild-type EGFR, thereby minimizing associated toxicities. Beamion BCGC-1 (NCT06324357) is an ongoing Ph Ib/II multicohort trial investigating zongertinib as monotherapy or in combination with other agents in HER2-positive mBC, metastatic colorectal cancer, and metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma. Here, we report the first data from 4 Ph Ib cohorts evaluating zongertinib plus antibody-drug conjugates (ADCs) or trastuzumab-based therapy in patients (pts) with HER2-positive mBC, focusing on ADC combinations, as well as supporting preclinical data. Methods: Preclinical activity of zongertinib combinations was assessed in xenograft mouse models. Beamion BCGC-1 includes pts with confirmed, unresectable HER2-positive mBC who progressed following HER2-directed therapy. Pts received escalating doses of zongertinib plus fixed doses of T-DM1 (Cohort A; 3.6 mg/kg), T-DXd (Cohort B; 5.4 mg/kg), trastuzumab (Cohort K; 8 mg/kg loading dose followed by 6 mg/kg) or capecitabine (1000 mg/m 2 ) plus trastuzumab (Cohort G; 8 mg/kg loading dose followed by 6 mg/kg). The primary endpoint is the occurrence of DLTs during the MTD evaluation period. Secondary endpoints included further safety assessments and objective response (investigator-assessed; RECIST v1.1). Results: In xenograft mouse models, the addition of zongertinib to T-DM1 or T-DXd led to increased antitumor activity. As of November 4, 2025, 12 pts had been enrolled to Cohort A (median age: 58 years), 16 to Cohort B (median age: 58 years), 4 to Cohort G (median age: 48 years) and 7 to Cohort K (median age: 58 years). Most pts were heavily pretreated, with prior exposure to T-DXd, T-DM1 and/or TKIs. In Cohort A, treatment emergent adverse events (TEAEs) and zongertinib-related AEs (any grade [G]/G3) were reported in 12/5 (100%/42%) and 11/5 (92%/42%) pts, respectively. Three (25%) pts had AEs leading to zongertinib dose reduction. No pts had an AE leading to zongertinib discontinuation. The most common TEAEs (any G/G3) were increased AST (7/1 [58%/8%] pts), decreased platelet count (5/2 [42%/17%] pts) and increased ALT (5/1 [42%/8%] pts). In Cohort B, TEAEs and zongertinib-related AEs (any G/G3) were reported in 14/7 (88%/44%) and 14/5 (88%/31%) pts, respectively. Three (19%) pts had AEs leading to zongertinib dose reduction and 3 (19%) had AEs leading to zongertinib discontinuation. The most common TEAEs (any G/G3) were anemia (8/2 [50%/13%] pts), diarrhea (8/2 [50%/13%] pts) and nausea (8/1 [50%/6%] pts). No grade 4 or 5 TEAEs occurred in Cohorts A and B. Efficacy analyses are ongoing and will be presented. Conclusions: No new safety signals were observed with zongertinib plus T-DXd or T-DM1. Dose escalation was ongoing in Cohorts A and B at data cutoff. Clinical trial information: NCT06324357 .

Graphite-based nanocomposite for advancement of wastewater treatment: A comprehensive review

Self‐Adaptive Solar‐Thermal System With Moss‐Like Surface for Efficient Energy Utilization

ABSTRACT In order to achieve high‐efficiency solar utilization, inspired by the “black carpet effect” of moss population in cold regions, a self‐adaptive Janus solar–thermal system with the solar–thermal conversion‐conduction‐storage‐loss control ability is designed. The solar–thermal system features a composite phase change material (CPCM) thermal storage base and a moss‐like switchable solar–thermal surface. This surface is constructed from graphene skeletons containing graphene/polydopamine/MXene heterostructures and MXene secondary nano‐porous structures. High‐efficiency solar–thermal conversion (98.1%) is realized in this surface, due to the interlayer carrier interaction at the heterostructure, as proved by femtosecond transient absorption spectroscopy (fs‐TAS), Raman and photoluminescence (PL) spectroscopies, and multiscale calculations, along with the multiple reflections and absorption in porous structures. The converted thermal energy is then rapidly conducted (26.5 W/(m·K)) and stored (236.7 J/g) in the CPCM base. At night, the moss‐like surface with ultralow thermal conductivity of 0.03 W/(m·K) and emissivity of 0.2 greatly restrains the thermal loss to the external environment, thereby achieving long‐term thermal management (13.3 times longer than that without the system). This study utilized a systematic bioinspired design strategy for preparing the high‐performance solar–thermal system, which possesses broad potential for long‐term solar utilization.

The Resolution–Throughput Conflict In Material Extrusion Additive Manufacturing

ABSTRACT Material extrusion additive manufacturing enables a wide range of technologies, from microscale functional devices to meter‐scale structural components, yet its broader adoption as a manufacturing platform and, increasingly, as a materials discovery tool remains constrained by a persistent coupling between resolution and throughput. Across materials, architectures, and length scales, improvements in geometric resolution are systematically accompanied by disproportionate reductions in deposition rate and printable volume. Consequently, progress has largely relied on optimizing isolated subsystems, yielding only incremental improvements or introducing constraints elsewhere in the system. This perspective argues that overcoming the resolution–throughput tradeoff requires a unified, system‐level approach that explicitly accounts for the coupled interactions among materials physics, flow dynamics, and machine architecture. Strategies are organized into three mechanistic domains according to how they intervene in deposition: software and control, deposition hardware and architecture, and hybrid processes. Examined within this structure, existing and emerging approaches reveal shared limitations, unrealized complementarities, and fundamental incompatibilities. Together, these insights outline pathways toward material extrusion systems in which resolution and throughput can be adjusted with greater independence, enabling reliable manufacturing across diverse materials, scales, and application domains.

Life-course epidemiology of body size and risk of early and advanced breast cancer.

e22627 Background: There has been limited studies of the life-course epidemiology of body sizes and the risk of early and advanced breast cancer (BC) in women, particularly from low- and middle-income countries (LMIC). To overcome the challenge of nonavailability of data, we used somatotypic classification of overall body shape to evaluate critical/sensitive period, cumulative exposure, trajectory and change, and saturated models of association between body sizes at different life stages and BC risk. Methods: We analyzed 960 BC cases from the African Female Breast Cancer Epidemiology (AFBRECANE) study. We categorized self-reported somatotypes as ‘Not large’ or ‘Large’ at multiple life stages and derived trends. The outcomes were early (≤5 cm without chest wall or skin involvement) and advanced ( > 5 cm or any tumor with direct extension to chest wall or skin) stages of breast cancer. We performed multivariable logistic regression, adjusting for factors that were found to be significant during age-adjusted analysis. Results: In adjusted analyses, higher BMI was associated with lower odds of advanced BC stage (OR = 0.94, 95% CI [0.89-0.98], = < 0.01), while older age at menarche was associated with higher odds of advanced BC stage at diagnosis (OR = 1.35, 95% CI [1.14-1.61], p < 0.01). Large body size one year prior to diagnosis was also associated with increased odds of advanced BC stage (OR = 2.88, 95% CI [1.21-6.88], p = 0.02). Body size during early age and at ages 7-10, and somatotype trends across life stages were not independently associated with BC stage in the final adjusted model. Conclusions: Our findings suggest that recent adult body size, BMI, and age at menarche are independently associated with BC tumor stage at diagnosis. While large body size one year prior to diagnosis was associated with increased odds of advanced stage tumor, higher BMI was associated with lower odds. These findings highlight how body size throughout adulthood can influence tumor biology, supporting risk stratification and prevention. Further large, diverse longitudinal studies are warranted.

Prognostic and predictive value of baseline derived neutrophil-to-lymphocyte ratio (dNLR) in <i>RAS</i> wild-type (WT) metastatic colorectal cancer (mCRC) receiving 5-fluorouracil and folinic acid (FU/FA) with or without panitumumab (Pmab) maintenance: A post-hoc analysis of the PANAMA/AIO KRK 0212) trial.

e15552 Background: The derived neutrophil-to-lymphocyte ratio (dNLR) is an established prognostic marker in solid tumors including metastatic colorectal cancer (mCRC), but its predictive value remains unclear. The dNLR was evaluated as a prognostic biomarker and as a potential predictor of treatment outcome during fluorouracil/folinic acid (FU/FA) ± panitumumab (pmab) maintenance therapy in patients with RAS wild-type mCRC enrolled in the PANAMA trial (NCT01991873). Methods: Patients with available baseline blood counts prior to induction therapy were grouped according to dNLR using a predefined cut-off of 2.2. Progression-free survival (PFS) and overall survival (OS) from initiation of maintenance therapy, as well as PFS of reinduction therapy, were estimated using the Kaplan–Meier method and compared by log-rank testing and Cox proportional hazards regression. Multivariable Cox models adjusted for confounders were used to assess independent prognostic effects. Predictive effects were evaluated using interaction tests within Cox proportional hazards models for maintenance and reinduction. Results: Of 241 patients included into the full analysis set with available data, n = 140 had baseline dNLR ≤2.2 and n = 101 dNLR &gt; 2.2. While median PFS during maintenance therapy did not differ according to baseline dNLR (dNLR ≤2.2 vs. &gt; 2.2: 10.1 vs. 9.7 months; log-rank p = 0.25), OS was significantly longer in patients with dNLR ≤2.2 (30.8 vs 22.7 months; log-rank p &lt; 0.001). Baseline dNLR remained independently associated with OS in multivariable Cox regression (HR 1.56, 95% CI 1.15–2.12; p = 0.004). Despite numerical prolongation of PFS and OS during maintenance therapy by the addition of pmab to FU/FA, no significant interaction between baseline dNLR and maintenance treatment arms was observed (PFS (maintenance): dNLR ≤2.2 = 8.8 vs 5.6 months; dNLR &gt; 2.2 = 9.7 vs 5.8 months; interaction p = 0.72; OS: dNLR ≤2.2 = 33.7 vs 28.2 months; dNLR &gt; 2.2 = 26.1 vs 20.1 months; interaction p = 0.294). By contrast, PFS after treatment reinduction was significantly shorter after FU/FA + pmab compared with FU/FA maintenance in patients with dNLR ≤2.2, whereas no difference according to prior maintenance treatment was observed in patients with dNLR &gt; 2.2 (dNLR ≤2.2 = 2.6 vs 7.4 months; dNLR &gt; 2.2 = 5.8 vs 6.2 months; interaction p = 0.036). Conclusions: Baseline dNLR is an independent prognostic biomarker for OS in patients with RAS WT mCRC treated within the PANAMA trial. Potential information might be derived for the optimal choice of maintenance and reinduction strategies.

Reproducible modulation of tissue Ki-67 across lung and prostate cancer interception trials.

10574 Background: The clinical utility of cancer interception is limited by the lack of validated surrogate endpoints that capture early biological response before histopathologic progression. While morphologic changes often require prolonged follow-up, Ki-67, a nuclear marker of cellular proliferation, provides a dynamic, tissue-based measure of epithelial proliferative activity. However, its reproducibility across high-risk tissue contexts remains debated. We evaluated the consistency of tissue Ki-67 modulation across two independent randomized trials in high-risk lung and prostate epithelia. Methods: We analyzed data from two prospective, randomized, placebo-controlled phase II cancer interception trials that prespecified tissue Ki-67 as an endpoint. In the lung cohort (NCT03232138; n=98), high-risk smokers with bronchial dysplasia were randomized to oral sulforaphane (200 μmol/day) or placebo for 6 months. In the prostate cohort (CAPFISH-3; n=58), patients with low-grade prostate cancer on active surveillance were randomized to long-chain omega-3 fatty acids (3 g/day) or placebo for 12 months. Paired tissue biopsies were obtained at baseline and study completion. Ki-67 expression was quantified by immunohistochemistry with central pathology review. Results: Baseline Ki-67 indices were comparable between intervention and placebo arms in both cohorts. Following the intervention, a statistically significant divergence in tissue proliferative activity was observed. In the lung cohort, sulforaphane treatment was associated with a 20% reduction in bronchial epithelial Ki-67, whereas the placebo arm demonstrated a 65% increase (P=0.014). In the prostate cohort, omega-3 supplementation resulted in a 15% reduction in intratumoral Ki-67, compared with a 24% increase in the control arm (P=0.043). Sub-analysis by staining intensity demonstrated preferential suppression among high-intensity (3+) Ki-67–positive cells, including a 44% reduction in the lung intervention arm. Ki-67 modulation correlated with baseline proliferative activity but not with baseline histopathologic features. No significant changes in histopathologic grade or dysplasia scores were observed. Conclusions: Tissue Ki-67 demonstrates consistent, reproducible modulation across randomized lung and prostate interception trials, preceding detectable morphologic change. These findings support Ki-67 as a practical early biologic endpoint for phase II cancer interception studies. Tissue Ki-67 modulation across randomized cancer interception trials. Cohort (n) Intervention Ki-67 change (Tx) Ki-67 change (Pbo) P value Lung (98) Sulforaphane −20% +65% 0.014 Prostate (58) Omega-3 −15% +24% 0.043 Abbreviations: Tx, treatment; Pbo, placebo.

Tumor load change as a functional biomarker for prognosis and treatment modulation in metastatic colorectal cancer (mCRC): Individual patient data (IPD) analysis of 12 randomized trials.

3561 Background: The use of overall response rate (ORR) and progression-free survival (PFS) as surrogacy of overall survival (OS) has limitations in mCRC. Change in tumor load (ΔTL; tumor burden at progressive disease [PD] vs baseline) at treatment failure may reflect tumor aggressiveness and resistance biology. We evaluated the prognostic value of ΔTL in mCRC using IPD from twelve randomized first-line trials. Methods: IPD from ATEZOTRIBE, FIRE3, FIRE4, FIRE4.5, MACBETH, ML22011, MOMA, PANAMA, TRIBE, TRIBE2, TRIPLETE, and VALENTINO were pooled. ΔTL was defined as the ratio of the sum of longest target lesion diameters at PD vs baseline, per RECIST. Primary endpoint was OS; secondary endpoints included post-progression survival (PPS). Estimated marginal means were controlled for treatment type. Associations between ΔTL and outcomes were assessed using Cox models adjusted for prespecified baseline tumor burden and clinical covariates (ECOG, age, sex, sidedness, RAS/BRAF status, metastatic patterns, previous therapies). Incremental prognostic value beyond early tumor shrinkage (ETS) and depth of response (DpR) was assessed using likelihood ratio testing. Effect modification by treatment regimen was evaluated using ΔTL × treatment interaction terms for EGFR- vs VEGF-based therapy and for triplet vs doublet-chemotherapy across trials. Results: A total of 4852 patients evaluable for ΔTL were included. Mean ΔTL was 0.63 (SD 0.45) and significantly lower in patients receiving EGFR- vs VEGF-based therapy (0.58 vs 0.66, p&lt;0.001) and triplet vs doublet chemotherapy (0.57 vs 0.67, p&lt;0.001). Lower ΔTL (lower tumor load at PD vs baseline) was associated with better OS (HR 0.58 [95% CI 0.55–0.61], p&lt;0.001) and PPS (HR 0.65 [0.61–0.69], p&lt;0.001) after adjustment for baseline tumor burden and clinical covariates. For OS, ΔTL added prognostic information beyond ETS (likelihood ratio χ² = 282.13, p&lt;0.001) and DpR (likelihood ratio χ² = 121.91, p&lt;0.001). Lower ΔTL was associated with improved OS in patients receiving EGFR- (n = 1609; HR 0.62 [0.58–0.67], p&lt;0.001) and VEGF-based therapy (n = 1916; HR 0.39 [0.35–0.43], p&lt;0.001); doublet (n = 2177; HR 0.61 [0.57–0.65], p&lt;0.001) and triplet (n = 1348; HR 0.34 [0.30–0.38], p&lt;0.001) chemotherapy, with significant ΔTL × treatment interaction (VEGF vs EGFR: HR 0.50 [0.46–0.54], p&lt;0.001; triplet vs doublet: HR 0.60 [0.54–0.66], p&lt;0.001) after adjustment for treatment regimen, RAS/BRAF status and other clinical covariates. Conclusions: TL appears to be a strong, independent prognostic marker for OS and PPS in mCRC. ΔTL seems to vary by biologic and chemotherapy intensity, indicating it captures differential treatment effect/resistance not captured by ORR or PFS. Prospective validation as an early, treatment-sensitive prognostic endpoint is warranted.

Second primary malignancies in patients with chronic lymphocytic leukemia: A SEER analysis, 2000–2022.

e18587 Background: Survivors of chronic lymphocytic leukemia (CLL) face an increased risk of second primary malignancies (SPMs) due to intrinsic immune dysregulation and prolonged survival from novel therapies. Contemporary data quantifying this risk across age, race, and diagnosis era are limited. Methods: Using SEER 17 registries (2000–2022), we identified 83,930 adult patients with CLL as a first primary malignancy. Patients with latency &lt;2 months were excluded. Standardized incidence ratios (SIRs), absolute excess risks (AERs per 10,000 person-years), and 95% confidence intervals (CIs) were calculated, comparing observed SPMs to expected rates in the general population. Analyses were stratified by age, race, and calendar year. Results: Over 546,737 person-years (mean follow-up 6.5 years), 13,570 SPMs occurred (SIR 1.32, 95% CI 1.29–1.34; AER 59.5). Solid tumors (n=10,309) showed a modest but significant excess (SIR 1.17, 95% CI 1.15–1.19; AER 27.6). The highest site-specific risks (SIR; AER) were for: skin excluding basal/squamous (2.16; 13.3), melanoma (1.97; 10.1), lung/bronchus (1.33; 8.8), kidney (1.52; 3.1), salivary gland (2.78; 1.0), and thyroid (1.84; 1.7). Younger patients exhibited the highest relative risk (SIR 11.4 for ages 15–19), while risk increased in recent diagnosis years (peak SIR 1.69 in 2021). Non-White patients, particularly Asian/Pacific Islanders, experienced higher SPM risk (SIR 1.87). Conclusions: CLL survivors face a persistently elevated risk of SPMs, particularly at immune-related sites, with increased risk in younger and non-White populations and in more recent diagnosis years. These findings support enhanced, tailored cancer screening and ongoing monitoring in this growing survivor population.

Histology and stage-specific incidence trends in appendiceal adenocarcinoma in the United States, 2000–2022: A SEER analysis.

e15701 Background: Appendiceal adenocarcinoma is rare, but recent population-based studies suggest a rising incidence. We examined whether this increase occurred and, if so, whether it was driven by specific histologies, stage migration, or early-onset disease. Methods: We conducted a population-based trend analysis using SEER 17 registries (Nov 2024 submission), 2000–2022. Microscopically confirmed malignant appendiceal adenocarcinomas were identified and grouped as mucinous (ICD-O-3 8480/3, 8481/3), signet ring (8490/3), and non-mucinous adenocarcinoma (selected adenocarcinoma histologies excluding mucinous/signet). Annual age-adjusted incidence rates (per 100,000; 2000 U.S. standard) were calculated. Temporal trends were summarized using log-linear average annual percent change (AAPC) with 95% CIs. Stage-specific patterns were evaluated using the Combined Summary Stage (2004+) and summarized as both distribution and stage-specific incidence trends. Sensitivity analyses excluded 2022. Results: Overall incidence increased from 2000–2022 (AAPC 3.15%, 95% CI 2.58–3.72) with a sharp uprise in the year 2022. Rising incidence was observed for mucinous (AAPC 3.51%, 95% CI 2.71–4.32) and non-mucinous histologies (AAPC 3.21%, 95% CI 2.46–3.97), while signet ring showed no significant increase (AAPC −0.05%, 95% CI −2.24 to 2.19). From 2004–2022, stage-specific incidence increased across localized, regional, and distant disease, indicating that the rise is not solely attributable to stage migration. In sensitivity analyses excluding 2022, trends were similar (overall AAPC 2.95%, 95% CI 2.38–3.51), suggesting a true rise in disease burden. Crude incidence increased in both &lt; 50 and ≥50 age groups, with higher absolute rates in ≥50. Conclusions: Appendiceal adenocarcinoma incidence rose steadily in SEER from 2000–2022, driven primarily by mucinous and non-mucinous histologies, with increases observed across all stages. A sharp rise in the incidence in 2022 motivated evaluation with a sensitivity analysis excluding 2022. However, the findings remained similar suggesting a true rise in disease burden.

LITESPARK-033: Phase 3 study of belzutifan plus zanzalintinib versus cabozantinib for recurrent clear cell renal cell carcinoma during or after adjuvant anti–PD-(L)1 therapy.

TPS4633 Background: Adjuvant pembrolizumab is standard of care for patients with renal cell carcinoma (RCC) at increased risk for recurrence after nephrectomy. However, treatment options are needed following adjuvant anti–PD-(L)1 therapy because none of the currently available treatments for advanced RCC were evaluated in this setting. Belzutifan, a potent and selective hypoxia-inducible factor 2α inhibitor, is approved for advanced RCC following a PD-(L)1 inhibitor and vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Zanzalintinib is a multitargeted kinase inhibitor of VEGF receptors, MET, and the TAM family of kinases (TYRO3, AXL, and MER). VEGF-TKIs, such as cabozantinib, are approved as first-line treatment for advanced RCC and in patients who have received subsequent lines of therapy. Promising antitumor activity has been observed in phase 2 studies when combining a VEGF-TKI with belzutifan for advanced clear cell RCC. The randomized, multicenter, open-label phase 3 LITESPARK-033 study (NCT07227402) is designed to evaluate the efficacy and safety of belzutifan plus zanzalintinib versus cabozantinib in participants with advanced clear cell RCC who experienced recurrence during or after anti–PD-(L)1 adjuvant therapy. Methods: Eligible participants are aged ≥18 years with histologically confirmed, unresectable, advanced (stage IV) RCC with a clear cell component; have measurable disease per RECIST v1.1 as assessed by investigator; received adjuvant anti–PD-(L)1 therapy after nephrectomy; and experienced recurrence during or up to 24 months from the last dose of adjuvant therapy. Approximately 904 participants will be randomly assigned 1:1 to receive belzutifan 120 mg orally once daily plus zanzalintinib 60 mg orally once daily or cabozantinib 60 mg orally once daily. Treatment will continue until unacceptable toxicity or disease progression. Randomization will be stratified according to time of recurrence after adjuvant anti–PD-(L)1 therapy (≤6 months vs &gt;6 months after the last dose), International Metastatic RCC Database Consortium risk (favorable vs intermediate vs poor), and presence of sarcomatoid features (yes vs no). Primary end points are progression-free survival per RECIST v1.1 as assessed by blinded independent central review (BICR) and overall survival. Secondary end points are objective response rate and duration of response per RECIST v1.1 as assessed by BICR, and safety. The study is open and currently enrolling as of November 26, 2025. Clinical trial information: NCT07227402 .

Designing a solid tumor oncology curriculum for medical residents: A single-institution needs assessment.

e21011 Background: Patients with solid tumor malignancies comprise a large portion of inpatient medicine admissions at many academic institutions; however, structured solid tumor oncology education for internal medicine (IM) residents is variable. At our institution, IM residents do not rotate through inpatient solid tumor oncology services, limiting formal exposure to cancer-specific management principles. We conducted a needs assessment to assess resident exposure to hospitalized solid tumor patients, oncology-specific teaching, and comfort managing common inpatient oncology conditions. Methods: We developed an anonymous survey to assess IM resident experiences in the University of Pennsylvania Health System (UPHS) caring for hospitalized patients with solid tumor malignancies, then distributed the survey via email from November 12, 2025 to January 23, 2026. Survey domains included demographic data, perceived frequency of formal teaching, clinical setting and frequency of inpatient solid oncology care, and comfort managing solid oncology topics. Comfort was assessed using a 5-point Likert scale (1, “very uncomfortable” to 5, “very comfortable”). Open-ended questions captured qualitative feedback. Results: A total of 18 categorical IM residents at UPHS completed the survey (response rate = 21%) including PGY-1 (n = 2), PGY-2 (n = 6), and PGY-3 (n = 10) respondents. All reported caring for hospitalized patients with solid tumors. Most residents (n = 15; 83%) reported providing care on four or more inpatient services including general medicine, medical ICU, pulmonology, and gastroenterology rotations. However, most residents (n = 16; 89%) reported “never” or “infrequently” receiving solid oncology teaching. Residents reported lowest comfort managing oncologic emergencies, namely "superior vena cava syndrome” (mean comfort score 2.33) and “cord compression” (mean 3.11), as well as “cancer-treatment toxicity” (mean 3.11). Greater clinical exposure generally correlated with higher reported comfort, though persistent gaps remained for “cord compression” and “malignant bowel obstruction”. In qualitative responses, residents expressed strong interest in formal education on initial diagnosis and inpatient work-up of new malignancy (n = 6), including treatment intent and inpatient diagnostic testing. Residents preferred online mobile-friendly resources (n = 16; 89%) over printable materials (n = 6; 33%) and video content (n = 6; 33%). Conclusions: Internal medicine residents frequently provide inpatient care to patients with solid tumors across non-oncology rotations, yet most report limited formal oncology teaching and low comfort managing oncologic emergencies and treatment complications. These findings will inform the development of targeted, mobile-friendly educational resources to improve resident preparedness in caring for hospitalized oncology patients.

Testing, treatment, and teamwork: Differential learning curves and translational barriers in EGFR-mutated NSCLC care.

e23216 Background: Advances in EGFR-targeted therapies have transformed the management of non–small cell lung cancer (NSCLC), expanding options while increasing clinical complexity. Translating rapidly evolving evidence into real-world practice requires timely biomarker testing, appropriate treatment selection, and effective multidisciplinary coordination. As care for EGFR-mutated NSCLC becomes more complex, understanding how clinicians acquire and apply these competencies may help identify translational barriers, particularly in community practice. Methods: We evaluated outcomes from nine accredited continuing medical education/professional development (CME/PD) activities focused on EGFR-mutated NSCLC conducted between January 2023 and February 2025. More than 5,500 learners participated, including medical and radiation oncologists, pulmonologists, thoracic surgeons, pathologists, and nurse practitioners/physician assistants. Learning objectives were grouped into three domains central to evidence translation: biomarker testing, treatment selection and management, and multidisciplinary teamwork. Pre- and post-activity assessments measured changes in knowledge and applied clinical decision-making. Outcomes were stratified by specialty, practice setting (academic vs community), and EGFR TKI prescribing experience. Results: Performance improved across all domains; however, the magnitude and trajectory of gains varied. Biomarker testing showed the lowest baseline performance among non-oncology specialties (≈25%–50%) but the largest absolute improvements post-education, particularly among pulmonologists and pathologists, with post-test performance increasing to approximately 85%–90%. Treatment selection and management also demonstrated substantial gains, with community-based clinicians achieving post-test performance comparable to academic peers. In contrast, improvements in multidisciplinary teamwork were more modest and variable. Although surgeons and pathologists demonstrated marked gains (absolute increases of ~30–50 percentage points), teamwork remained the lowest-performing domain post-education for several roles, particularly among prescribers with lower EGFR TKI experience. Conclusions: Educational initiatives addressing EGFR-mutated NSCLC reveal differential learning curves across competencies required to translate scientific advances into practice. While biomarker testing and treatment selection are highly responsive to education, multidisciplinary teamwork appears constrained by system-level and workflow factors beyond knowledge alone. Improving real-world adoption of EGFR-targeted therapies will likely require educational strategies complemented by structural approaches that support coordinated, team-based care, particularly in community oncology settings.

Racial differences in clinical, genomic, and survival outcomes in colorectal cancer.

10593 Background: Racial differences influence colorectal cancer incidence, biology, and survival, but the clinical and genomic drivers remain unclear. This study evaluates race-based variation in clinical features, metastatic patterns, and key mutations in a large real-world cohort to improve risk stratification and promote equitable treatment. Methods: Clinical and genomic data were obtained from MSK-CHORD via cBioPortal, including patients identified as Asian, White, or Black. Variables were analysed in RStudio. Group differences were assessed using chi-square, Fisher’s exact tests, or Kruskal–Wallis. Survival was analysed with Kaplan–Meier and Cox models. Significance was set at p &lt; 0.05. Results: Among 5,168 colorectal cancer patients (White 83.9%, Asian 8.8%, Black 7.4%), several clinical and genomic features varied. Age differed significantly (p &lt; 0.001), with Asians and Blacks diagnosed younger (median 58 y vs. 61 y) than Whites. Gender distribution was similar (p = 0.303). MSI-instability varied (p = 0.0321), lowest in Asians (7.7%) and Blacks (8.3%), and highest in Whites (11.9%). Right-sided tumours differed (p &lt; 0.001), being least common in Asians (23.7%) and most common in Blacks (40.8%). Stage at diagnosis was similar (p = 0.0961). TMB differed modestly (p = 0.042): 5.87 in Asians vs. 6.05 in Black and White patients. FGA showed similarly small variation (p = 0.046): 0.17 in Asians, 0.16 in Blacks, and 0.15 in Whites. Liver metastases varied by race (p &lt; 0.001): Asians 52%, Blacks 66%, Whites 56%. Reproductive organ involvement differed (p = 0.012): Asians 25%, Blacks 27%, Whites 20%; all other metastatic sites showed no differences (p &gt; 0.05). Overall survival varied significantly (p &lt; 0.001), highest in Asians (71.6 months) and Whites (54.3 months) and lowest in Blacks (32.3 months); Asians had similar mortality risk to Whites (HR 0.94), whereas Blacks had higher risk (HR 1.44). Genomic variation was notable: KRAS (p = 1.6×10⁻⁷) was highest in Blacks (56.8%), TP53 (p &lt; 0.001) was highest in Asians (81.5%), and BRAF (p = 0.0046) was lowest in Blacks (7.1%), with no other genes differing. Conclusions: Racial differences were evident across outcomes. Black patients had the highest KRAS mutations and worst survival; Asians had the highest TP53 rates and best survival; Whites had the most MSI-H tumours. Other clinical features were similar. These patterns suggest biologic differences relevant to risk and treatment.

Exploration of tumor-informed ctDNA detection and dynamics in a real-world cohort of colorectal cancer patients from the MD Anderson Cancer Center.

e15658 Background: Circulating tumor DNA (ctDNA) is a promising tool for the treatment of patients with cancer. In the colorectal cancer (CRC) setting, various MRD assays are gradually being adopted into routine care, to assist with risk stratification and recurrence monitoring. In real-world usage, this type of test offers a timely assessment of treatment response and monitoring, which is otherwise mostly dependent on imaging. This study aims to characterize the association between ctDNA status and clinical data, during treatment and disease monitoring in a curative intent setting, and explore reproducibility. Methods: Here we retrospectively applied the tumor informed RaDaR ST assay to plasma samples from an initial group of 83 patients with stage II-IV resectable colon or rectal cancer. Participants had plasma collected at up to 4 timepoints, over the course of 6 months from enrollment. Collection coincided with real-world clinical care, with no pre-defined collection schedule relative to treatment. ctDNA detection and quantity (estimated variant allele fraction, eVAF) are compared against matching clinical data, as it becomes available, as well as orthogonal results for a subset. Results: After excluding 5 samples that failed QC checks, 107 plasma samples from 80 patients were analyzed by RaDaR ST, with ctDNA detected in 29 (27%) at levels ranging from 0.00056% (5.6 parts per million) to 3.4% eVAF. ctDNA detection was compared against clinical data, revealing a correlation with treatment response and disease recurrence status in the initial 46 cases with available clinical records. Use cases included post-surgery, pre- and post-systemic therapy, and on therapy monitoring. Further associations between ctDNA detection and patient outcomes will be explored in the wider cohort. To determine the generalizability of these findings to alternative ctDNA testing approaches, results were compared against matching data generated using two alternative tumor-informed assays, for a subset of samples (n = 71 and 65). In both cases this demonstrated &gt; 95% concordance in detection, and good correlation between ctDNA measurements in positive samples ( R &gt; 0.96, P &lt; 0.001) . Conclusions: This is an ongoing effort to define ctDNA dynamics and explore the benefits of various approaches, in the setting of stage II-IV CRC treated with curative intent. These preliminary findings add to growing data supporting the potential of ctDNA to be routinely utilized in the management of patients treated for CRC, particular in a clinical setting outside of an interventional clinical trial. The detection of ctDNA at levels as low as 5.6 parts per million, and orthogonal confirmations, shows the importance of using highly sensitive assays to accurately detect and quantify disease. Whilst promising, further data are needed to confirm how best to exploit ctDNA to guide patient care in this setting.

AcTION: Phase 1 study of [ ²²⁵ Ac]Ac-PSMA-617 ( ²²⁵ Ac-PSMA-617) in men with metastatic castration-resistant prostate cancer (mCRPC) with or without prior [ ¹⁷⁷ Lu]Lu-PSMA ( ¹⁷⁷ Lu-PSMA) radioligand therapy (RLT).

5010 Background: AcTION is the first prospective dosage escalation study of 225 Ac-PSMA-617, an alpha-emitting, PSMA-targeted RLT in patients (pts) with mCRPC (NCT04597411). Methods: This study enrolled pts with progressive, PSMA-positive mCRPC in 3 groups (Gps). Gp A: prior chemotherapy (ChT) and an androgen receptor pathway inhibitor (ARPI) but no prior 177 Lu-PSMA RLT; Gp B: no prior ChT, ARPI, or 177 Lu-PSMA RLT (ChT/ARPI-naive); Gp C: prior 177 Lu-PSMA RLT. Dosage escalation of 225 Ac-PSMA-617 used a Bayesian logistic regression model with administered activities of 4, 6, 8 or 10 MBq given intravenously for ≤6 cycles every 8 weeks. Primary objective was to identify the recommended phase 2 dosage (RP2D), based on dosage-limiting toxicities (DLTs) within the first 6 weeks of 225 Ac-PSMA-617 administration. This analysis includes all 101 treated pts per 13 Nov 2025. Results: Gp A pts had a median of 3 prior systemic therapies and median baseline [BL] PSA 73.4 (range 1-3320) ng/mL. At a median follow-up [FU] of 7.46 months (mos), PSA50 response rate (PSA50) was 20/34 (58.8%; 95% CI 40.7, 75.4) and PSA90 was 15/34 (44.1%; 95% CI 27.2, 62.1). Gp B pts had BL PSA 223.4 (5-12308) ng/mL. At a FU of 13.24 mos, PSA50 was 23/27 (85.2%; 95% CI 66.3, 95.8) and PSA90 was 22/27 (81.5%; 95% CI 61.9, 93.7). Gp C pts had 5 prior systemic therapies and BL PSA 85.5 (5-1760) ng/mL. At a FU of 8.57 mos, PSA50 was 21/40 (52.5%; 95% CI 36.1, 68.5) and PSA90 was 7/40 (17.5%; 95% CI 7.3, 32.8). Across all 3 Gps, there were no DLTs and a maximum tolerated dosage was not reached. No Grade [G] 4/5 TRAEs occurred. No dosage-dependent safety signals were observed. Dry mouth (G1/2 only) was the most common treatment-related (TR) adverse event (AE), observed in &gt; 90% of pts across all Gps and mostly reported as not resolved at data cut off. Two TRAEs led to treatment discontinuation (G2 dry mouth at 8 MBq, and G3 anemia at 10 MBq; both occurring in Gp C). The RP2D for all 3 Gps was 10 MBq. Additional efficacy data will be presented. Conclusions: 225 Ac-PSMA-617 demonstrated an acceptable safety profile and promising anti-tumor activity up to 10 MBq in pts with mCRPC regardless of prior 177 Lu-PSMA RLT. Two phase 3 trials, AcTFirst (NCT06855277) and PSMAcTION (NCT06780670), are currently recruiting. Clinical trial information: NCT04597411 . Overall pts A: Prior ChT + ARPI; N=34 B: ChT/ARPI-naive; N=27 C: Prior 177 Lu-PSMA RLT; N=40 Selected AEs regardless of study dose, n (%): All Gs / G ≥3 Dry mouth 33 (97.1) / 0 26 (96.3) / 0 36 (90.0) / 0 Fatigue 18 (52.9) / 0 4 (14.8) / 0 27 (67.5) / 0 Anemia 9 (26.5) / 6 (17.6) 4 (14.8) / 4 (14.8) 16 (40.0) / 6 (15.0) Thrombocytopenia 2 (5.9) / 0 2 (7.4) / 1 (3.7) 5 (12.5) / 0 Renal impairment 1 (2.9) / 1 (2.9) 0 / 0 3 (7.5) / 1 (2.5) Anti-tumor activity, n (%) [95% CI] PSA50 20 ( 58.8% ) [40.7, 75.4] 23 ( 85.2% ) [66.3, 95.8] 21 ( 52.5% ) [36.1, 68.5] PSA90 15 ( 44.1% ) [27.2, 62.1] 22 ( 81.5% ) [61.9, 93.7] 7 ( 17.5% ) [7.3, 32.8]

Body composition and quality of life (QOL) with lenvatinib + everolimus (len + eve) versus cabozantinib (cabo) in metastatic clear cell renal cell carcinoma (ccRCC) after PD-1 inhibitor progression: Results from the randomized phase II LenCabo trial.

4538 Background: The LenCabo trial (NCT05012371) was the first randomized head-to-head comparison of contemporary second-line or later treatments after progression on PD-1 based immune checkpoint inhibition (ICI). Len + eve significantly improved progression-free survival (PFS). There were numerical, but not statistically significant, differences in treatment discontinuation and ≥ grade 3 adverse events. Although cabo and len share many kinase targets, lenvatinib also blocks FGFR, and its combination with the mTOR inhibitor everolimus may affect body composition through metabolic effects. We sought to investigate how patient QOL and body composition changed after treatment with len + eve and cabo. Methods: LenCabo was a multicenter, phase II trial that randomized pts with metastatic ccRCC to len 18 mg/d plus eve 5 mg/d vs cabo 60 mg/d after 1-2 prior lines of treatment, including a PD-1 ICI. Pre-planned, health-related QOL was measured by FKSI DRS at baseline and after 60 days. Post-hoc, body composition was measured using an AI segmentation tool (Voronoi DAFS) at the L3 vertebra from baseline CT scans and after 4 months. Outcomes were compared using proportional odds models adjusting for baseline values and including nonlinear terms as restricted cubic splines. Pre-specified, body composition models additionally adjusted for prior VEGF-targeted therapy, age, IMDC risk category, and sex. Results: 86 pts received at least 1 dose of assigned len + eve (n=40) or cabo (n=46). 38 pts completed baseline and day 60 FKSI DRS (len + eve = 20, cabo = 18). The QOL comparison by FKSI DRS at day 60 was inconclusive (OR = 0.51 in favor of cabozantinib, 95% CI 0.16-1.64, p=0.26). 67 pts had body composition measured at baseline and 4 months (len + eve = 30, cabo = 37). After 4 months of treatment, len + eve was associated with a significantly lower odds of having a higher body mass index (BMI), skeletal muscle mass (SMMi), and subcutaneous adiposity (SATi, Table). Conclusions: In patients with metastatic ccRCC progressing on PD-1 ICI, len + eve was associated with significantly greater reductions in BMI, skeletal muscle mass, and subcutaneous adiposity compared with cabo at 4 months. The study did not contradict the supposition that the two treatment arms yield the same QOL at day 60. These results suggest that the superior PFS efficacy of len + eve in this setting is accompanied by a more pronounced catabolic effect. Clinical trial information: NCT05012371 . Body composition measures at 4 months by treatment. Adjusted mean of len + eve vs. cabo Odds ratio for higher measure(95% CI) P value BMI 28.5 vs. 29.4 0.36(0.15 – 0.88) 0.03 SMMi 47.5 vs. 49.7 0.30(0.11 – 0.79) 0.01 SATi 65.7 vs. 73.4 0.21(0.08 – 0.55) 0.002 Abbreviations: BMI, body mass index; SMMi, skeletal muscle mass index; SATi, subcutaneous adipose tissue index.